Pbl Exam 9 Case 1

Front 1

1. How are the leukocytes and thrombocytes classified?

Back 1

The leukocytes can be classified either as polymorphonuclear leukocytes (granulocytes) or mononuclear leukocytes, depending on the morphology of the nucleus in these cells.

The mononuclear leukocyte has a rounded nucleus, whereas the polymorphonuclear leukocytes have a multilobed nucleus.

Front 2

2. What are granulocytes?

Back 2

Named b/c of the presence of secretory granules visible on staining.

Include:
1. Neutrophils
2. Eosinophils
3. Basophils

Are activated in response to chemical stimuli and release their granule contents (degranulation)

Front 3

3. Staining color of neutrophils, eosinophils, and basophils?

Back 3

Neutrophils: pink

Eosinophils: red

Basophils: blue

Front 4

4. What is the role of neutrophils?

Back 4

Phagocytic cells that migrate rapidly to areas of infection or tissue damage. As part of the response to acute infection, neutrophils engulf foreign bodies and destroy them, in part, by initiating the respiratory burst.

The respiratory burst creates oxygen radicals that rapidly destroy the foreign material found at the site of infection.

Front 5

5. What is the role of eosinophils?

Back 5

Destroy parasites such as worm.

The eosinophilc granules are lysosomes containing hydrolytic enzymes and cationic proteins, which are toxic to parasitic worm.

Eosinophils have also been implicated in asthma and allergic response, although their exact role in the development of these disorders is still unknown.

Front 6

6. What is the role of basophils?

What is stored in the granules of basophils?

Back 6

Basophils are the least abundant of the leukocytes. They participate in hypersensitivity reactions, such as allergic responses.

Histamine, produced by the decarboxylation of histidine, is stored in the secretory granules of basophils.

Release of histamine during basophil activation stimulates smooth muscle cell contraction and increases vascular permeability.

Th granules also contain enzymes such as proteases, β-glucoronidase, and lysophospholipase. These enzymes degrade microbial structures and assist in the remodeling of damaged tissue.

Front 7

7. What are mononuclear leukocytes?

Back 7

Consist of various classes of lymphocytes and the monocytes.

Front 8

8. What are the three major types of lymphocytes?

Back 8

1. T-cells
2. B-cells
3. NK-cells

Front 9

9. What are the roles of macrophages in the spleen?

Back 9

Play an important role in maintaining the oxygen-delivering capabilities of the blood by removing damaged red blood cells that have a reduced oxygen carrying capacity.

Front 10

10. What are platelets?

Back 10

Platelets are heavily granulated disc-like cells that aid in intravascular clotting.

Like the erythrocyte, platelets lack a nucleus.

They arise by budding of the cytoplasm of megakaryocytes, multinucleated cells that reside in the bone marrow.

Front 11

11. What is anemia?

Back 11

The major function of erythrocytes is to deliver oxygen to the tissues. To do this, a sufficient concentration of hemoglobin is necessary for efficient oxygen delivery to occur.

When the Hb concentration falls below normal values, the patient is classified as anemic.

Front 12

12. What are the functional deficits and causes of microcytic, hypochromic anemias?

Back 12

Functional deficit: Impaired hemoglobin synthesis

Possible causes:
1. Iron deficiency
2. Thalassemia mutation
3. Lead poisoning

Front 13

13. What are the functional deficits and causes of macrocytic, normochromic anemias?

Back 13

Functional deficit: Impaired DNA synthesis

Possible causes:
1. Vitamin B12 or folic acid deficiency
2. Erythroleukemia

Front 14

14. What are the functional deficits and causes of normocytic, normochromic anemias?

Back 14

Functional deficit: Red cell loss

Possible causes:
1. Acute bleeding
2. Sickle cell disease
3. Red cell metabolic defects
4. Red cell membrane defects

Front 15

15. What is MCV?

Back 15

Mean corpuscular volume

This is the average volume of the red blood cell, expressed in femtoliters.

Normal MCV values range from 80-100 fL

A value of < 80 fL indicates microcytic cells

Front 16

16. What is MCHC?

Back 16

Mean corpuscular hemoglobin concentration

This is the average concentration of hemoglobin in each individual erythrocyte, expressed in grams per liter.

The normal range is 32-37 g/L

A value of < 32 g/L indicates hypochromic cells

Front 17

17. What are four unique aspects of erythrocytes?

Back 17

1. No nucleus
-no DNA, RNA or protein synthesis

2. No mitochondria
-no TCA cycle, oxidative phosphorylation, electron transport chain to generate ATP

3. Must survive oxidative environment
-passage thru lungs

4. Larger than capillaries
-must deform to pass thru

Front 18

18. Do RBCs have mitochrondria?

Back 18

No mitrochrondria, no ATP from TCA cycle

***Use glycolysis to produce ATP

Provide substrates for Hexose monophosphate shunt and Rapaport-Luberin Shunt, NADH, and NADPH for other reactions.

Front 19

19. What is the Rapaport-Luberin Shunt?

Back 19

Erythrocyte glycolysis uses this shunt to generate 2,3-BPG

Front 20

20. In order for hemoglobin to bind oxygen, what is necessary?

Back 20

The iron of Hb must by in the ferrous (+2) state.

However, reactive oxygen species can oxidize the iron to the ferric (+3) state, producing methemoglobin.

Front 21

21. What does the NADH produced by glycolysis accomplish?

Back 21

The NADH is used to regenerate hemoglobin from methemoglobin by the NADH-cytochrome b5 methemoglobin reductase system.

Cytochrome b5 reduces the ferric form of iron (+3) of methemoglobin.

The oxidized cytochrome b5 is then reduced by a flavin-containing enzyme, cytochrome b5 reductase, using NADH as the reducing agent.

Front 22

22. How is NADPH generated by RBCs?

What is the role of NADPH?

Back 22

Approx 5 - 10% of the glucose metabolized by RBCs is used to generate NADPH by way of the *hexose monophosphate shunt.*

The NADPH is then used to maintain glutathione in the reduced state.

The glutathione cycle is the RBC's chief defense against damage to proteins and lipids by reactive oxygen species.

Front 23

23. What enzyme catalyzes the first step of the hexose monophosphate shunt?

Back 23

G6PD (Glucose 6-phosphate dehydrogenase)

The lifetime of the RBC correlates with G6PD activity.

Lacking ribosomes, the RBC cannot synthesize new G6PD protein.

Consequently, as the G6PD activity decreases, oxidative damage accumulates.

Front 24

24. What are five important roles of the hexose monophosphate shunt?

Back 24

1. Present in many cell types

2. Produces 5-carbon sugars (i.e. ribose)

3. Returns carbons to glycolysis in RBC's

4. Produces NADPH, which reduces glutathione for antioxidant effect

5. Protects cell

Front 25

25. What is cytochrome b5, and why is it important?

Back 25

Hb can become methemoglobin by a change in oxidation state of iron in heme

This form will not carry oxygen to tissues - about 3% normally

NADH reduces cytochrome b5 which reduces iron

Front 26

26. What is the structure of the heme molecule?

Back 26

Heme consists of a porphyrin ring coordinated w/an atom of iron.

Four pyrrole rings are joined by methenyl bridges to form the porphyrin ring.

Eight side chains serve as substituents on the porphyrin ring, two on each pyrrole.

In heme, the order of these groups is characteristic of the porphyrins of the type III series, the most abundant in nature.

Front 27

27. How is heme synthesized?

Back 27

Heme is synthesized from glycine and succinyl CoA which participate in a series of reactions to generate heme.

Two produce one molecule of heme:
1. 8 molecules each of glycine and succinyl CoA are required.
2. A series of porphyrinogens is generated in sequence
3. Finally, iron is added to produce heme.

Front 28

28. How is heme synthesis regulated?

Back 28

Heme regulates its own production by repressing the synthesis of δ-aminolevulinic acid (δ-ALA) and by directly inhibiting the activity of this enzyme (allosteric modifier)

Thus, heme is synthesized when heme levels fall; as they rise, the rate of synthesis decreases.

Front 29

29. What else does heme regulate?

Back 29

Heme also regulates the synthesis of hemoglobin by stimulating synthesis of the protein globin. Heme maintains the ribosomal initiation complex for globin synthesis in an active state.

Front 30

30. What is δ-ALA dehydratase?

Back 30

Contains zinc and ferrochelatase, which are inactivated by lead.

Thus, in lead poisoning, δ-ALA and protoporphyrin 9 accumulate, and the production of heme is decreased.

Anemia results from a lack of Hb, and energy production decreases b/c of the lack of cytochromes for the electron transport chain.

Front 31

31. What are six facts to know about iron for heme?

In which form is iron stored in the liver?

Back 31

1. Iron from diet must reach organs
2. Transferrin is major serum carrier
3. Ceruloplasmin changes oxidation state
4. Stored in liver as ferritin
5. Serum ferritin levels rise w/excess iron
6. Hemosiderin is storage form, and is not mobilized easily.

*Also, vitamin C increases the uptake of nonheme iron from the GI tract.

Front 32

32. Because free iron is toxic, how does the body handle it?

Back 32

It is usally found in the body bound to proteins.

Iron is carried in the blood as Fe 3+ by the protein apotransferrin, with which it forms a complex known as transferrin.

Front 33

33. What is ferritin?

Back 33

Storage of iron occurs in most cells but esp those of the liver, spleen and bone marrow.

In these cells, the storage protein, apoferritin, forms a complex with iron (Fe 3+) known as ferritin.

Normally, little ferritin is present in the blood. This amount increase, however, as iron stores increase.

***Therefore, the amt of ferritin in the blood is the most sensitive indicator of the amt of iron in the body's stores.

Front 34

34. Excess iron goes to where?

Back 34

When excess iron is absorbed from the diet, it is stored as hemosiderin, a form of ferritin complexed w/additional iron that cannot be readily mobilized.

Front 35

35. How is heme degraded?

Back 35

Heme is degraded to form bilirubin, which is then conjugated w/glucoronic acid and excreted in the bile.

Although heme from cytochromes and myoglobin also undergoes conversion to bilirubin, the major source of this bile pigment is Hb.

Front 36

36. What are the 4 steps in the degradation of heme?

Back 36

1. After RBCs die, the globin is cleaved to its constituent AAs, and iron is returned to the body's iron stores.

2. Heme is then oxidized and cleaved to produce carbon monoxide and biliverdin.

3. Biliverdin is reduced to bilirubin, which is transported to the liver complexed w/serum albumin.

4. In the liver, bilirubin is converted to a more water soluble compound by reacting with UDP-glucuronate to form bilirubin monoglucuronide, which is converted to the diglucuronide. This conjugated form of bilirubin is excreted into the bile.

Front 37

37. What happens to the bilirubin diglucuronide in the intestine?

Back 37

Bacteria deconjugate bilirubin diglucuronide and convert the bilirubin to urobilinogens.

Some urobilinogen is absorbed into the blood and excreted in the urine.

However, most of the urobilinogen is oxidized to urobilins, i.e. stercobilin, and excreted in the feces.

These pigments give feces their brown color.

Front 38

38. What is the importance of the red cell membrane?

Back 38

To survive in the circulation, the red cell must be highly deformable. Damaged red cells that are no longer deformable become trapped in the passages in the spleen, where they are destroyed by macrophages.

The reason for this deformability lies in its shape and in the organization of the proteins that make up the red blood cell membrane.

Front 39

39. What are the red cell membrane proteins?

Back 39

1. Membrane proteins can have a variety of functions. Major proteins are:
a. spectrin
b. actin
c. band 4.1
d. band 4.2
e. ankyrin

2. Glycophorin provides large negative change, and prevents aggregation

3. Band 3 is a chloride-bicarbonate exchange transporter

4. Multiple spectrins can bind to each actin filament, resulting in a branched membrane cytoskeleton

Front 40

40. What is spectrin?

Back 40

Spectrin is the major protein in the cell membrane; multiple spectrins can bind to each actin filament, resulting in a branched membrane cytoskeleton

Front 41

41. What is ankyrin?

Back 41

Ankyrin is the first membrane-cytoskeleton anchor.

The spectrin cytoskeleton is connected to the membrane lipid bilayer by ankyrin, which interacts with beta-spectrin and the integral membrane protein, band 3. Band 4.2 helps to stabilize this connection.

Front 42

42. What is band 4.1?

Back 42

Band 4.1 is the other membrane-cytoskeleton anchor.

Membrane proteins associate with ankyrin and band 4.1 proteins.

Band 4.1 anchors the spectrin skeleton with the membrane by binding the integral membrane protein glycophorin C and the actin complex.

Front 43

43. What happens when the RBC is subjected to mechanical stress?

Back 43

The spectrin network rearranges.

Some spectrin molecules become uncoiled and extended; others become compressed, thereby changing the shape of the cell, but not its surface area.

Front 44

44. What three agents affect oxygen binding?

Back 44

1. Hydrogen ions
2. 2,3-BPG
3. Covalent binding of CO2

Front 45

45. What is 2,3-BPG?

Back 45

Formed in RBCs from the glycolytic intermediate 1,3-BPG.

2,3-BPG binds to Hb in the central cavity formed by the four subunits, increasing the energy required for the conformational changes that facilitate the binding of oxygen.

Thus, 2,3-BPG lowers the affinity of Hb for oxygen.

Therefore, oxygen is less readily bound (i.e. more readily released from tissues) when Hb contains 2,3-BPG.

Front 46

46. What is the Bohr effect?

Back 46

The binding of protons by Hb lowers it affinity for oxygen, contributing to a phenomenon known as the Bohr effect.

As the pH decreases, the affinity of Hb for oxygen decreases, shifting the curve to the right.

Front 47

47. How does CO2 levels affect oxygen binding?

Back 47

Although most of the CO2 produced by metabolism in the tissues is carried to the lungs as bicarbonate, some of the CO2 is covalently bound to Hb.

In the tissues, CO2 reacts with the amino groups of the deoxyhemoglobin and stabilizes the deoxy conformation.

Front 48

48. What are the 6 steps in erythropoiesis?

Back 48

1. Start as hematopoietic stem cells

2. These form pluripotent stem cells

3. Stem cells form mixed myeloid progenitor cells (GFU-GEMM)

4. GFU-GEMM form burst forming unit - erythroids (BFU-E)

5. BFU-E forms colony forming unit - erythroids (CFU-E)

6. CFU-E forms the first recognizable red cell precursor, the normoblast.

Front 49

49. What are the four final steps in RBC differentiation?

Back 49

1. Normoblasts are committed progenitors

2. They divide 4 times after which Hb synthesis begins

3. Nucleus becomes inactive, and then extruded

4. Released in circulation as reticulocyte; later matures in 1-2 days.

Front 50

50. What regulates erythropoiesis?

Back 50

Regulated by the demands of oxygen delivery to the tissues.

In response to reduced tissue oxygenation, the kidney releases the hormone erythropoietin, which stimulates the multiplication and maturation of erythroid progenitors

Front 51

51. What are the 3 major problems in nutritional anemias?

Back 51

1. Vitamin deficiencies
-Folate and vitamin B12 needed for nucleotide synthesis

2. Deficiency slows mitosis of progenitors

3. Cells divide too few times

Front 52

52. What occurs in anemia due to iron deficiency?

Back 52

These cells are microcytic and hypochromic. The lack of iron results in decreased heme synthesis, which in turn affects globin synthesis.

Iron deficient RBCs continue dividing past their normal stopping point, resulting in small red cells. They are also pale, because of the lack of Hb, compared with normal cells.

Front 53

53. What occurs in anemia due to folate or vitamin B12 deficiencies?

Back 53

Can cause megalobastic anemia, in which the cells are macrocytic.

Folate and B12 are required for DNA nucleotide synthesis, and when these are deficient, DNA replication and nuclear division do not keep pace w/ the maturation of the cytoplasm.

Consequently, the nucleus is extruded before the requisite number of cell divisions has taken place, and the cell volume is greater than it should be, and fewer blood cells are produced.

Front 54

54. What are thalassemias?

Back 54

For optimum function, the Hb α- and β- globin chains must have the proper structure and be synthesized in a 1:1 ratio.

A large excess of one subunit over the other results in thalassemia.

These anemias are clinically very heterogeneous, and they provide resistance to malaria in the heterozygous state.

Front 55

55. Causes of thalessemias?

α-thalessemias and β-thalessemias?

Back 55

1. Hemoglobin single AA replacement mutations that give rise to a globin subunit of decreased stability

2. More common are mutations that result in decreased synthesis of one subunit:

***α-thalessemias usually result from complete gene deletions***

***β-thalessemias can result from deletions, promoter mutations and splice-junction mutations***

Front 56

56. What is α-thalessemia?

Back 56

Two copies of the α-globin gene are found on each chromosome 16, for a total of 4 α-globin genes per precursor cell.

If one copy of the gene is deleted, the size and Hb concentration of the individual RBCs is minimally reduced.

The more copies that are deleted, the more the RBCs will become microcytic and hypochromic

Absence of 3 α-globin genes causes moderately severe microcytic hypochromic anemia with splenomegaly

Absence of all four α-globin chains is usually fatal in utero (hydrops fetalis)

Front 57

57. What is β-thalessemia?

Back 57

Many different variations; can be asymptomatic all the way to severe anemia. β°β° homozygotes are the most severely affected.

In general, disease of β-chain deficiency are more severe than disease of α-chain deficiency.

Front 58

58. Why are diseases of β-chain deficiency are more severe than diseases of α-chain deficiency?

Back 58

Excess β-chains form a homotetramer, HbH, which is useless for delivering oxygen to the tissues b/c of its high oxygen affinity. As RBCs age, HbH precipitates in the cells, forming inclusion bodies.

RBCs with inclusion bodies have shortened lifespans, b/c they are more likely to be trapped and destroyed in the spleen.

Excess α-chains are unable to form a stable tetramer. *However, excess α-chains precipitate in erythrocytes at every developmental stage. The α-chain precipitating results in their widespread destruction. They also damage RBC membranes, particularly band 4.1.

Front 59

59. What is hereditary persistence of fetal hemoglobin?

Back 59

HbF, the predominant Hb of the fetal period, consists of two α-chains and two γ-chains, whereas adult Hb consists of two α- and two β-chains.

The process that regulates the conversion of HbF to HbA is called hemoglobin switching.

Hb switching is not 100%; most individuals continue to produce a small amt of HbF in place of HbA.

Front 60

60. What is the relationship between patients with sickle cell anemia or β-thalassemia and HbF levels?

Back 60

Those patients with hemoglobinopathies frequently have less severe illnesses if their levels of HbF are elevated.

Front 61

61. What are two causes of hereditary persistence of fetal hemoglobin (HPFH)?

Back 61

These individuals express HbF past birth

Caused by:
1. Point mutations in the Aγ and Gγ promoters; these mutations can have ameliorating effects on sickle cell or β-thalassemia, b/c of increased production of the γ-chain

2. Both the entire δ- and β-genes have been deleted from one copy of chromosome 11 and only HbF can be produced.

Front 62

62. What is the difference between individuals w/ δ°β°-thalassemia and those with deletion HPFH (who are clinincally normal)?

Back 62

Difference between the two outcomes is believed to be the site at which the deletions end within the β-globin gene cluster.

In deletion HPFH, power enhancer sequences 3' of the β-globin gene are re-situated b/c of the deletion so that they activate the γ-promoters of HbF

In individuals w/ δ°β°-thalassemia, the enhancer sequences have not been relocated so that they can interact w/ the γ-promoters. Thus, they do not produce enough fetal hemoglobin to compensate for the deletion.

Front 63

63. What are the nondeletion forms of HPFH?

Back 63

The nondeletion forms of HPFH are those that derive from point mutations in the Aγ and G =γ promoters.

When these mutations are found w/sickle cell or β-thalassemia mutations, they have an ameliorating effect on the disease, b/c of the increased production of γ-chains.

Front 64

64. What is Hb switching?

Back 64

1. Globin genes are in two complex loci
2. Several genes in each, in order of appearance during development
3. Embryonic and fetal forms are present
4. Fetus not affected by many mutations; premature newborns convert from HbF to HbA on schedule w/their gestational ages.

Front 65

65. What is spherocytosis?

Back 65

In spherocytosis, the red blood cells are deficient in spectrin. This deficiency impairs the ability of the erythrocytes to maintain the redundant surface area necessary to maintain deformability.

Mechanical stresses in the circulation cause progressive loss of pieces of membrane. As membrane components are lost, the RBCs become spherical and unable to deform.

Splenomegaly occurs b/c of the large numbers of RBCs that have become trapped within it.

This hemolytic process results in anemia.

Front 66

66. What causes hereditary spherocytosis?

Back 66

Mutations in the genes for ankyrin, β-spectrin, or band 3 account for 3/4ths of the cases of hereditary spherocytosis.

Mutations in the genes for α-spectrin or band 4.2 account for the remainder.

Results in improper formation of the membrane cytoskeleton.

Splenectomy is often recommended as the spleen is the major source of RBC destruction that causes anemia.

Front 67

67. Without a spleen, what bacterial agents would the person be susceptible to?

Back 67

1. Pneumococcus
2. Meningococcus
3. H. influenzae type B

Front 68

68. What happens with an inherited deficiency in pyruvate kinase?

Back 68

Leads to hemolytic anemia.

B/c the amt of ATP formed from glycolysis is decreased by half, RBC ion transporters cannot function effectively.

The RBCs tend to gain calcium and lose potassium and water.

The water loss increases the intracellular Hb concentration, the internal viscosity of the cell is increased to the point that the cell becomes rigid, and, therefore more susceptible to damage by shear forces in the circulation.

However, the effects of the anemia are freq moderated by the 2-3x elevation in 2,3-BPG concentration that results form the blockage of the conversion of phoenolpyruvate to pyruvate. B/c 2,3-BPG binding to Hb decreases the affinity of Hb for oxygen, the RBCs that remain in circulation are highly efficient in releasing their bound oxygen to the tissues.

Front 69

69. What is congenital methemoglobinemia?

Back 69

The presence of excess methemoglobin

Found in people w/an enzymatic deficiency in cytochrome b5 reductase or in people who have inherited hemoglobin M.

Methemoglobinemia Can be acquired by ingestion of certain oxidants such as nitrites, quinone, aniline, and sulfonamides.

Can be treated by the administration of reducing agents, such as methylene blue or ascorbic acid.

Front 70

70. What is Hemoglobin M?

Back 70

A single AA substitution in the heme-binding pocket stabilizes the ferric Fe 3+ oxygen.

Front 71

71. What is G6PD deficiency?

Back 71

The most common enzyme defiency in humans, probably, in part, b/c individuals w/ this are resistant to malaria.

The resistance to malaria counterbalances the deleterious effects of the deficiency.

G6PD-deficient red cells have a shorter life span and are more likely to lyse under conditions of oxidative stress.

Front 72

72. What is the G6PD deficiency gene and variants?

Back 72

Gene is found on the X chromosome.

All known G6PD variant genes contain small in frame deletions or missense mutations.

The corresponding proteins, therefore, have decreased stability or lowered activity, leading to a reduced half-life or life span of the red cell.

Front 73

73. Pyridoxine (vitamin B6) deficiencies are often associated w/microcytic, hypochromic anemia.

Why?

Back 73

In a B6 deficiency, the rate of heme production is slow b/c the first reaction in heme synthesis requires pyridoxal phosphate.

Thus, less heme is synthesized, causing red blood cells to be small and pale. Iron stores are usually elevated.

Front 74

74. What are porphyrias?

Back 74

A group of rare inherited disorders resulting from deficiencies of enzymes in the pathway for heme biosynthesis.

Intermediates of the pathway accumulate and may have toxic effects on the nervous system that cause neuropsychiatric symptoms.

When prophyrinogens accumulate, they may be converted by light to porphyrins, which react w/molecular oxygen to form oxygen radicals, which may cause severe damage to the skin.

Related to werewolf legends due to increased scarring and facial hair seen in some porphyrias.

Front 75

75. How does phenobarbital affect cytochrome p450?

Back 75

Induce enzymes of the drug metabolizing systems of the ER that contain cytochrome p450.

*B/c heme is used for synthesis of cytochrome p450, free heme levels fall and δ-ALA synthase is induced to increase the rate of heme synthesis.

Front 76

76. In an iron deficiency, what characteristics will blood exhibit?

Back 76

Results in a microcytic, hypochromic anemia.

Front 77

77. What is X-linked severe combined immunodeficiency disease (SCID)?

Back 77

In the most common form of SCID, circulating T lymphocytes are not formed, and B lymphocytes are not active.

The affected gene encodes the γ-chain of the IL2 receptor.

Mutant receptors are unable to activate JAK3, and the cells are unresponsive to the cytokines that stimulate growth and differentiation.

Recall also that ADA deficiency, which is not X-linked, also leads to a form of SCID, but for different reasons.

Front 78

78. What are the effects of a mutant erythropoietin (epo) receptor?

Back 78

The receptor is unable to bind SHP-1, a tyrosine phosphatase necessary for proper development of myeloid and lymphoid lineages.

*Individuals w/the mutant epo receptor have a higher than normal percentage of RBCs in the circulation, b/c the mutant epo receptor cannot be deactivated by SHP-1.

Front 79

79. Perturbed JAK/STAT signaling is associated with the development of what 3 things...?

Back 79

1. Lymphoid and myeloid leukemias

2. Severe congenital neutropenia

3. Fanconi anemia, which is characterized by bone marrow failure and increased susceptibility to malignancy.

Front 80

80. A sickle cell crisis can lead to ...?

Back 80

Increased formation of gallstones.

A sickle cell crisis accompanied by the intravascular destruction of RBCs increases the amt of unconjugated bilirubin that is transported to the liver.

If the concentration of this unconjugated bilirubin exceeds the capacity fo the hepatocytes to conjugate it to the more soluble diglucuronide thru interaction w/hepatic UDP glucuronate, both the total and the unconjugated bilirubin levels in the blood increase.

This results in precipitation within the gallbladder lumen, leading to the formation of pigmented gallstones.

Front 81

81. What are the characteristics of HbS/HbC individuals?

Back 81

HbS/HbC individuals have significantly more hematopathology than individuals w/ sickle cell trait (HbA/HbS)

Polymerization of deoxygenated HbS is dependent on the HbS concentration within the cell. The presence of HbC in the compound heterozygote increases the HbS concentration by stimulating potassium and water efflux from the cell.

B/c the HbC globin is produced more slowly than HbA or HbS, the proportion of HbS tends to be higher in HbS/Hbc cells than in the cells of individuals with sickle cell trait (HbS/HbA).

Front 82

82. Does HbF have a lower or higher affinity for 2,3-BPG compared to adult Hb?

Back 82

HbF has a lower affinity for 2,3-BPG than adult hemoglobin (HbA)

Therefore, the oxygen released from the mother's hemoglobin is readily bound by HbF in the fetus.

Differences due to the structural changes caused by the different composition of hemoglobin subunits

Front 83

83. What is the importance of the F-cell-producing locus on the short arm of the X chromosome?

Back 83

Is thought not to be susceptible to X inactivation.

Both normal individuals and individuals w/hemoglobinopathies vary in the amount of HbF they produce.

The FCP locus is responsible for a substantial amt of the variation in hemogloin F seen among sickle cell patients.

Front 84

84. What is the physiologic function of the immune system?

Back 84

To prevent infections and to eradicate established infections

Front 85

85. What are the host defense mechanisms?

Back 85

They consists of (1) innate immunity, which mediates the initial protection against infections, and (2) adaptive immunity, which develops more slowly and mediates the later, even more effective, defense against infections.

Front 86

86. What is the first line of defense in innate immunity?

Back 86

The epithelial barriers and by specialized cells and natural antibiotics present in the epithelia, all of which function to block the entry of microbes.

Front 87

87. What are the major components of innate immunity?

Back 87

Epithelial barriers, phagocytic cells (mainly neutrophils and macrophages), natural killer (NK) cells, and several plasma proteins, including the proteins of the complement system.

Front 88

88. What are the two types of adaptive immunity?

Back 88

1. Humoral immunity
-mediated by proteins called antibodies produced by B lymphocytes
-defends against extracellular microbes

2. Cell-mediated immunity
-mediated by T lymphocytes
-defends against intracellular microbes

Front 89

89. What is one of the most important functions of antibodies?

Back 89

To stop microbes that are present at mucosal surfaces and in the blood from gaining access to and colonizing host cells and connective tissues.

Front 90

90. Important difference between B and T lymphocytes?

Back 90

Most T cells recognize only protein antigens, whereas antibodies are able to recognize many different types of molecules, including proteins, carbs, and lipids.

Front 91

91. What do phagocytes recognize?

Back 91

Phagocytes recognize microbes by several membrane receptors.

These include receptors for mannose residues and N-formyl methionine containing peptides, which are produced by microbes but not by host cells, and a family of receptors that are homologous to a Drosophila protein called Toll.

Front 92

92. What are toll-like receptors (TLRs)?

Back 92

Different Toll-like receptors (TLRs) are involved in responses to different microbial products.

Upon recognition of the relevant microbial structure, the TLRs signal by a common pathway that leads to the activation of transcription factors, notably NF-κB (nuclear factor κB).

Phagocytes internalize microbes into vesicles, where the microbes are destroyed by reactive oxygen and nitrogen intermediates and hydrolytic enzymes.

Front 93

93. What is NF-κB?

Back 93

NF-κB stimulates production of cytokines and several proteins that are responsible for the microbicidal activities of the phagocytes.

Front 94

94. How is the complement system activated in adaptive vs. innate immune systems?

Back 94

In innate immunity, the complement system is activated by binding to microbes using the alternative and lectin pathways.

In adaptive immunity, the complement system is activated by binding to antibodies using the classical pathway.

Front 95

95. What are other circulation proteins of innate immunity?

Back 95

Other circulating proteins of innate immunity are mannose binding lectin and C-reactive protein, both of which coat microbes for phagocytosis and complement activation. Lung surfactant is also a component of innate immunity, providing protection against inhaled microbes.

Front 96

96. The adaptive immune system consists of...?

Back 96

The adaptive immune system consists of lymphocytes and their products, including antibodies. The receptors of lymphocytes are much more diverse than those of the innate immune system, but lymphocytes are not inherently specific for microbes and they are capable of recognizing a vast array of foreign substances.

Front 97

97. What are the two main types of adaptive immunity, and what mediates each?

Back 97

There are two main types of adaptive immunity-cell-mediated (or cellular) immunity, which is responsible for defense against intracellular microbes, and humoral immunity, which protects against extracellular microbes and their toxins.

Cellular immunity is mediated by T (thymus derived) lymphocytes, and humoral immunity is mediated by B (bone marrow-derived) lymphocytes and their secreted products, antibodies.

All these mechanisms of adaptive immunity are capable of causing injury to the host and subsequent disease.

Front 98

98. Where are T lymphocytes generated and stored?

Back 98

T lymphocytes are generated from immature precursors in the thymus. Mature, naive T cells are found in the blood, where they constitute 60-70% of lymphocytes, and in T-cell zones of peripheral lymphoid organs, such as the paracortical areas of lymph nodes and periarteriolar sheaths of the spleen.

Front 99

99. The segregation of naive T cells to these anatomic sites is because...?

Back 99

The segregation of naive T cells to these anatomic sites is because the cells express receptors for chemoattractant cytokines (chemokines) that are produced only in these regions of lymphoid organs.

Each T cell is genetically programmed to recognize a specific cell-bound antigen by means of an antigen specific T cell receptor (TCR).

Front 100

100. What is the structure of the T-cell receptor?

Back 100

In approximately 95% of T cells, the TCR consists of a disulfide-linked heterodimer made up of an α and a β polypeptide chain, each having a variable (antigen-binding) and a constant region.

The αβ TCR recognizes peptide antigens that are displayed by major histocompatibility complex (MHC) molecules on the surfaces of antigen presenting cells.

T-cell receptors are capable of recognizing a very large number of peptides; each T cell expresses TCR molecules of one structure and specificity.

Front 101

101. What is required for activation of T cells?

Back 101

T cells (in contrast to B cells), cannot be activated by soluble antigens; therefore, presentation of processed, membrane-bound antigens by APCs is required for induction of cell-mediated immunity.

Front 102

102. What are most TCRs linked to?

What do these chains do?

Back 102

Each TCR is noncovalently linked to a cluster of five polypeptide chains, three of which form the CD3 molecular complex and two are a dimer of the ζ chain. The CD3 and ζ proteins are invariant.

They do not bind antigen but are involved in the transduction of signals into the T cell after the TCR has bound the antigen.

Front 103

103. How is TCR diversity generated?

Back 103

TCR diversity is generated by somatic rearrangement of the genes that encode the TCR chains. Every somatic cell has TCR genes from the germ line.

Rearrangements of these genes occur only in T cells during their development in the thymus; hence the presence of TCR gene rearrangements demonstrated by molecular analysis is a marker of T lineage cells.

Front 104

104. What is the importance of TCRs composed of γ and δ polypeptide chains?

Where are they located?

Back 104

A minority of mature T cells express another type of TCR composed of γ and δ polypeptide chains. The γδ TCR recognizes peptides, lipids, and small molecules, WITHOUT a requirement for display by MHC proteins.

γδ T cells tend to aggregate at epithelial surfaces, such as the mucosa of the respiratory and GI tracts, suggesting that these cells are sentinels that protect against microbes that try to enter through these epithelia.

Front 105

105. What are NK-T cells?

What do they recognize?

Back 105

Another small subset of T cells expresses markers that are found on natural killer (NK) cells; these cells are called NK-T cells.

NK-T cells express a very limited diversity of TCRs, and they recognize glycolipids that are displayed by the MHC-like molecule CD1.

Front 106

106. In addition to CD3 and ζ proteins, what else do T cells express?

Back 106

T cells express a number of nonpolymorphic, function-associated molecules, also called accessory molecules, including CD4, CD8, CD2, integrins, and CD28.

CD4 and CD8 are expressed on two mutually exclusive subsets of αβ T cells.

Front 107

107. What is CD4 and where is it found?

What does it recognize?

Back 107

CD4 is expressed on approximately 60% of mature CD3+ T cells.

During antigen presentation, CD4 molecules bind to the nonpolymorphic portions of class II MHC molecules expressed on antigen-presenting cells.

CD4+ helper T cells can recognize and respond to antigen only in the context of class II MHC molecules.

Front 108

108. What is CD8 and where is it found?

What does it recognize?

Back 108

CD8 is expressed on about 30% of T cells.

CD8 molecules bind to class I MHC molecules.

CD8+ cytotoxic T cells recognize cell-bound antigens only in association with class I MHC molecules

Front 109

109. It is now established that T cells need two signals for activation. Signal 1 is provided when...?

Back 109

Signal 1 is provided when the TCR is engaged by the appropriate MHC-bound antigen, and the coreceptors CD4 and CD8 bind to MHC molecules.

Front 110

110. Signal 2 is provided when...?

Back 110

Signal 2 is delivered by the interaction of the CD28 molecule on T cells with the costimulatory molecules B7-1 (CD80) and B7-2 (CD86) expressed on antigen-presenting cells.

Front 111

111. What happens when T cells are activated by antigen and costimulators?

What causes T cells to proliferate?

Back 111

They secrete locally acting cytokines.

Under the influence of IL-2, the T cells proliferate, thus generating large numbers of antigen-specific lymphocytes. Some of these cells differentiate into effector cells, which perform the function of eliminating the antigen that started the response.

Other activated cells differentiate into memory cells.

Front 112

112. What is the role of the CD4+ T cell?

Back 112

The CD4+ T cell can be viewed as a master regulator, AKA - the mafia boss.

By secreting cytokines, CD4+ T cells influence the function of virtually all other cells of the immune system, including other T cells, B cells, macrophages, and NK cells.

Front 113

113. What are the two functionally distinct populations of CD4+ helper cells, and what doe they produce?

Back 113

1. The T-helper-1 (TH1) subset synthesizes and secretes IL-2 and interferon-γ (IFN-γ).
- the TH1 subset is involved in facilitating delayed hypersensitivity, macrophage activation, and synthesis of opsonizing and complement-fixing antibodies, such as IgG2a in mice, all of which are actions of IFN-γ.

2. TH2 cells produce IL-4, IL-5 and IL-13.
- the TH2 subset aids in the synthesis of other classes of antibodies, notably IgE (mediated by IL-4 and IL-13) and in the activation of eosinophils (mediated by IL-5).

Front 114

114. What are CD8+ T cells?

Back 114

They function mainly as cytotoxic cells to kill other cells but, similar to CD4+ T cells, they can secrete cytokines, primarily of the TH1 type.

Front 115

115. How do B cells develop?

Back 115

B lymphocytes develop from immature precursors in the bone marrow.

Mature B cells constitute 10-20% of the circulating peripheral lymphocyte population and are also present in peripheral lymphoid tissues such as lymph nodes, spleen, or tonsils, and extralymphatic organs such as the GI tract.

Front 116

116. Where are B cells found in the spleen and in lymph nodes?

Back 116

In lymph nodes, they are found in the superficial cortex. In the spleen, they are found in the white pulp.

At both sites, they are aggregated in the form of lymphoid follicles, which on activation develop pale-staining germinal centers

B cells are located in follicles, the B-cell zones of lymphoid organs, because the cells express receptors for a chemokine that is produced in follicles.

Front 117

117. How do B cells recognize antigen?

Back 117

Via the B-cell antigen receptor complex.

IgM and IgD, present on the surface of all naive B cells, constitute the antigen-binding component of the B-cell receptor complex.

Front 118

118. The presence of what in a lymphoid cell is used as a molecular marker of B-lineage cells?

Back 118

Rearranged immunoglobulin genes.

As with T cells, each B-cell receptor has unique antigen specificity, derived in part from somatic rearrangements of immunoglobulin genes.

Front 119

119. What happens after B cells are activated via antigenic stimulation?

Back 119

After antigenic stimulation, B cells form plasma cells that secrete immunoglobulins, which are the mediators of humoral immunity.

Antibody-secreting cells reside in lymphoid organs and mucosal tissues, and some plasma cells may migrate to the bone marrow and live for many years in this tissue.

Secreted antibodies enter mucosal secretions and the blood and are able to find, neutralize, and eliminate antigens.

Front 120

120. In addition to membrane Ig, what are B-cell antigen receptors composed of?

Back 120

In addition to membrane immunoglobulin, the B-cell antigen receptor complex contains a heterodimer of nonpolymorphic transmembrane proteins Igα and Igβ.

Similar to the CD3 proteins of the TCR, Igα and Igβ do not bind antigen but are essential for signal transduction through the antigen receptor.

Front 121

121. What else do B cells express?

Where does the Epstein-Barr virus infect?

Back 121

B cells also express several other nonpolymorphic molecules that are essential for B-cell function. These include complement receptors, Fc receptors, and CD40.

*The complement receptor-2 (CD21) is also the receptor for the Epstein-Barr virus (EBV), and thus EBV readily infects B cells.

Front 122

122. B lymphocytes may be activated by...?

Back 122

Protein and nonprotein antigens. The end result is their differentiation in to antibody secreting cells, called plasma cells. Plasma cells reside in lymphoid organs and mucosal tissues, and some plasma cells may migrate to the bone marrow and live for many years in this tissue.

Front 123

123. B-cell responses to antigens require help from...?

How?

What is this necessary for?

Back 123

B-cell responses to protein antigens require help from CD4+ T cells.

Helper T cells activate B cells by engaging CD40, a member of the tumor necrosis factor (TNF)-receptor family, and by secreting cytokines. Activated helper T cells express CD40 ligand, which specifically binds to CD40 expressed on B cells.

This interaction is essential for B-cell maturation and secretion of IgG, IgA, and IgE antibodies.

Front 124

124. Patients with mutations in the CD40 ligand have...?

Back 124

Patients with mutations in the CD40 ligand have an immunodeficiency disease called X-linked hyper-IgM syndrome.

Front 125

125. What are 3 important roles of macrophages?

Back 125

1. Macrophages that have phagocytosed microbes and protein antigens process the antigens and present peptide fragments to T cells. Thus, macrophages are involved in the induction of cell-mediated
immune responses.

2. Macrophages are important effector cells in certain forms of cell-mediated immunity, such as the delayed hypersensitivity reaction. As mentioned earlier, macrophages are activated by cytokines, notably IFN-γ produced by the TH1 subset of CD4+ cells. Such activation enhances the microbicidal properties of macrophages and augments their ability to kill tumor cells.

3. Macrophages are also important in the effector phase of humoral immunity. They phagocytose microbes that are opsonized (coated) by IgG or C3b.

Front 126

126. What are the two types of dendritic cells?

Back 126

1. Interdigitating dendritic cells
2. Follicular dendritic cells

Front 127

127. What are interdigitating dendritic cells?

Back 127

AKA dendritic cells

These cells are the most important antigen-presenting cells for initiating primary immune responses against protein antigens. They are located at the right place to capture antigens - under epithelia, and in the interstitia of all tissues, where antigens may be produced.

Front 128

128. What are four reasons for why dendritic cells have a key role in antigen presentation?

Back 128

1. These cells are located at the right place to capture antigens - under epithelia, and in the interstitia of all tissues.
2. Dendritic cells express many receptors for capturing and responding to microbes, including TLRs and mannose receptors.
3. In response to microbes, dendritic cells express the same chemokine receptor as do naive T cells and are thus recruited to the T-cell zones of lymphoid organs.
4. Dendritic cells express high levels of MHC class II molecules as well as the costimulatory molecules B7-1 and B7-2. Thus, they possess all the machinery needed for presenting antigens to an activating CD4+ T cells.

Front 129

129. What are Langerhans cells?

Back 129

Immature denddritic cells within the epidermis are called Langerhans cells.

Front 130

130. What are follicular dendritic cells?

Back 130

These cells are present in the germinal centers of lymphoid follicles in the spleen and lymph nodes.

These cells bear Fc receptors for IgG and receptors for C3b and can trap antigen bound to antibodies or complement proteins. Such cells play a role in ongoing immune responses by presenting antigens to B cells and selecting the B cells that have the highest affinity for the antigen, thus improving the quality of the humoral immune response.

These cells also have a role in the pathogenesis of AIDS.

Front 131

131. What are NK cells?

What two cell surface molecules are used to identify NK cells?

Back 131

NK cells make up approximately 10% to 15% of the peripheral blood lymphocytes and do not bear T-cell receptors or cell surface immunoglobulins.

NK cells are endowed with an innate ability to kill a variety of tumor cells, virally infected cells, and some normal cells, without previous sensitization. NK cells do not rearrange T-cell receptor genes and are CD3 negative.

***Two cell surface molecules, CD16 and CD56, are widely used to identify NK cells.

Front 132

132. What is the importance of CD16 in NK cells?

Back 132

CD16 is the Fc receptor for IgG and it endows NK cells with another function, the ability to lyse IgG-coated target cells.

This phenomenon is known as antibody-dependent cell-mediated cytotoxicity.

Front 133

133. How is the functional activity fo NK cells regulated?

Back 133

The functional activity of NK cells is regulated by a balance between signals from activating and inhibitory receptors.

The activating receptors stimulate NK cell killing by recognizing ill-defined molecules on target cells, some of which may be viral products; the inhibitory receptors inhibit the activation of NK cells by recognition of self-class I MHC molecules.

Front 134

134. What are killer inhibitor receptors?

Back 134

The class I MHC-recognizing inhibitory receptors on NK cells are called killer inhibitory receptors.

They are biochemically distinct from T-cell receptors. It is believed that NK cells are inhibited from killing normal cells because all nucleated normal cells express self-class I MHC molecules.

If virus infection or neoplastic transformation perturbs or reduces the expression of class I MHC molecules, inhibitory signals delivered to NK cells are interrupted, and lysis occurs.

Front 135

135. What activates NK cells?

Back 135

Several types of activating receptors have been discovered, including members of the NKG2D family and some Iglike receptors.

The NKG2D receptors recognize stress-induced proteins that are normally expressed by only a few cells in the gut epithelium but whose expression increases on many cells following viral infection or neoplastic transformation.

Other activating receptors recognize viral proteins that are structurally similar to class I MHC molecules.

Thus, NK cells are activated by contact with virus-infected and tumor cells, both of which often express reduced levels of class I MHC molecules and therefore do not engage inhibitory receptors.

Front 136

136. What do NK cells secrete?

What regulates their activity?

Back 136

NK cells also secrete cytokines, such as IFN-γ, TNF, and granulocyte macrophage colony-stimulating factor (GM-CSF).

The activity of NK cells is regulated by many cytokines, including IL-2, IL-15, and IL-12.

IL-2 and IL-15 stimulate proliferation of NK cells, whereas IL-12 activates killing and secretion of IFN-γ.

Front 137

137. Which cytokines mediate innate immunity?

Back 137

Cytokines that mediate innate immunity include IL-1, TNF (tumor necrosis factor, also called TNF-α), type 1 interferons, and IL-6.

Some cytokines, such as IL-12 and IFN-γ, are involved in both innate and adaptive immunity against intracellular microbes. Certain of these cytokines (e.g., the interferons) protect against viral infections, whereas others (e.g., IL-1 and TNF) promote leukocyte recruitment and acute inflammatory responses.

Front 138

138. Which cytokines regulate lymphocyte growth, activation, and differentiation?

Back 138

Within this category are IL-2, IL-4, IL-12, IL-15, and transforming growth factor-β (TGF-β).

IL-2 is an important growth factor for T-cells, IL-4 stimulates differentiation to the TH2 pathway and acts on B cells as well, IL-12 stimulates differentiation to the TH1 pathway, and IL-15 stimulates the growth and activity of NK cells.

Other cytokines in this group, such as IL-10 and TGF-β, down-regulate immune responses.

Front 139

139. Which cytokines activate inflammatory cells?

Back 139

IFN-γ, which activates macrophages;

IL-5, which activates eosinophils;

TNF and lymphotoxin (also called TNF-β), which induce acute inflammation by acting on neutrophils and endothelial cells.

Front 140

140. Which cytokines affect leukocyte movement?

Back 140

AKA chemokines.

Most fall into two structurally distinct subfamilies, referred to as C-C and C-X-C chemokines, on the basis of the position of cysteine (c) residues.

The C-X-C chemokines are produced mainly by activated macrophages and tissue cells (e.g., endothelium), whereas the C-C chemokines are produced largely by T cells.

Front 141

141. Which cytokines stimulate hematopoiesis?

Back 141

Many cytokines derived from lymphocytes or stromal cells stimulate the growth and production of new blood cells by acting on hematopoietic progenitor cells.

Some members of this group (e.g., GM-CSF and G-CSF) act on committed progenitor cells, whereas others, exemplified by stem cell factor (c-kit ligand), act on pluripotent stem cells.

Front 142

142. How are the actions of cytokines pleotropic?

Back 142

Means that any one cytokine may act on many cell types and mediate many effects.

For example, IL-2, initially discovered as a T-cell growth factor, is known to affect the growth and differentiation of B cells and NK cells as well. Cytokines are also often redundant, meaning that different cytokines may stimulate the same or overlapping biologic responses.

Front 143

143. In what three ways do cytokines induce their effects?

Back 143

1. Autocrine, such as when IL-2 produced by antigen-stimulated T cells stimulates the growth of the same cells.

2. Paracrine, as when IL-7 produced by bone marrow or thymic stromal cells promotes the maturation of B-cell progenitors in the marrow or T-cell precursors in the thymus, respectively.

3. Endocrine, such as IL-1 and TNF, which produce the systemic acute-phase response during inflammation.

Front 144

144. How do cytokines mediate their effects?

Back 144

They bind to specific high-affinity receptors on their target cells.

For example, IL-2 activates T cells by binding to high-affinity IL-2 receptors (IL-2R). Blockade of the IL- 2R by specific antireceptor monoclonal antibodies prevents T-cell activation.

Front 145

145. What is the main function of the cell surface MHC molecules?

What genes encode these molecules?

Back 145

The principal physiologic function of the cell surface histocompatibility molecules is to bind peptide fragments of foreign proteins for presentation to antigen-specific T cells.

In humans, the genes encoding the most important histocompatibility molecules are clustered on a small segment of chromosome 6, the major histocompatibility complex, or the human leukocyte antigen (HLA) complex in humans

Front 146

146. What are the roles of MHC class I, II, and III?

Back 146

Class I and class II genes encode cell surface glycoproteins involved in antigen presentation.

Class III genes encode components of the complement system.

Front 147

147. Antigen binding cleft differences between Class I and II MHC molecules?

Back 147

Class I: The extracellular region of the heavy chain is divided into three domains: α1, α2, and α3 . Crystal structure of class I molecules has revealed that the α1 and α2 domains form a cleft, or groove, where peptides bind to the MHC molecule.

Class II: The extracellular portions of the α and β chains have two domains each: α1, α2 and β1, β2. Crystal structure of class II molecules has revealed that, similar to class I molecules, they have an antigen-binding cleft facing outward.

In contrast to class I molecules, however, the antigen-binding cleft is formed by an interaction of the α1 and β1 domains of both chains, and it is in this portion that most class II alleles differ.

Front 148

148. What do class II molecules present?

Back 148

In general, class II molecules present exogenous antigens (e.g., extracellular microbes, soluble proteins) that are first internalized and processed in the endosomes or lysosomes.

Front 149

149. What do class I molecules present?

Back 149

In general, class I MHC molecules bind and display peptides that are derived from proteins, such as viral antigens, synthesized within the cell.

Front 150

150. In what two ways do MHC molecules play a key role in regulating T-cell mediated immune response?

Back 150

1. B/ different antigenic peptides bind to different class II gene products, a person will mount an immune response against an antigen only if he or she inherits the gene(s) for those class II molecule(s) that can bind the antigen and present it to helper T cells.

2. Second, during their maturation in the thymus, only T cells that can recognize self-MHC molecules are selected for export to the periphery. Thus, the type of MHC molecules that T cells encounter during their development influences the reactivity of mature peripheral T cells.

Front 151

151. What are the three main classes of diseases that show association with the HLA locus?

Back 151

1. inflammatory diseases, including ankylosing spondylitis and several postinfectious arthropathies, all associated with HLA-B27.

2. Inherited errors of metabolism, such as 21-hydroxylase deficiency (HLA-BW47) and hereditary hemochromatosis (HLA-A)

3. Autoimmune diseases, including autoimmune endocrinopathies, associated mainly with alleles at the DR locus.

Front 152

152. What are type I hypersensitivity reactions?

Back 152

Immediate hypersenitivity, or type I, is a type of pathologic reaction that is caused by the release of mediators from mast cells. This reaction most commonly is triggered by the production of IgE antibody against environmental antigens and the binding of IgE to mast cells in various tissues.

Front 153

153. What are type II hypersensitivity reactions?

Back 153

Antibodies other than IgE may cause diseases in two ways:

Antibodies directed against cell or tissue antigens can damage these cells or tissues or impair their function. These diseases are said to be antibody mediated and represent type II hypersensitivity.

Front 154

154. What are type III hypersensitivity reactions?

Back 154

Sometimes, antibodies against soluble antigens may form complexes w/the antigens, and the immune complexes may deposit in blood vessels in various tissues, causing inflammation and tissue injury.

Such diseases are called type III hypersensitivity reactions.

Front 155

155. What are type IV hypersensitivity reactions?

Back 155

Some diseases result from the reactions of T lymphocytes, often against self antigens in tissues.

These T cell-mediated diseases represent type IV hypersensitivity.

Front 156

156. What is a type I hypersensitivity reaction?

What is it mediated by?

Back 156

Type I hypersensitivity is a rapidly developing immunologic reaction occurring within minutes after the combination of an antigen w/antibody bound to mast cells in individuals previously sensitized to the antigen.

Immediate hypersensitivity is mediated by IgE antibodies directed against specific antigens (allergens).

Synthesis of IgE antibody requires the induction of CD4+ helper T cells of the TH2 type; these TH2 cells produce multiple cytokines that contribute to various aspects of this response.

Front 157

157. What cytokine is essential for IgE synthesis?

What is the first step in IgE synthesis?

Back 157

IL-4, produced by TH2 cells, is essential for IgE synthesis.

The first step in the synthesis of IgE is the presentation of the antigen to naive CD4+ helper T cells by dendritic cells that capture the antigen from its site of entry.

Front 158

158. What cytokines are responsible for promoting production and survival of eosinophils - important effector cells in type I hypersensitivity reactions?

Back 158

IL-5, IL-3, and granulocyte-macrophage colony stimulating factor (GM-CSF) promote production and survival of eosinophils.

Front 159

159. What occurs in the initial phase of a type I hypersensitivity reaction?

Four things are released...

Back 159

Primary mast cell mediators that include the initial rapid response include:
1. Biogenic amines (e.g. histamine) which cause bronchial smooth muscle contraction, increased vascular permeability and dilation, and increased mucous gland secretions.
2. Chemotactic mediators (e.g. eosinophil chemotactic factors and neutrophil chemotactic factors)
3. Enzymes contained in granule matrix (e..g chymase, tryptase) that generate kinins and activated complement by acting on their precursor proteins.
4. Proteoglycans (e.g. heparin)

Front 160

160. What are the characteristics of the initial response?

Back 160

The initial response is characterized by vasodilation, vascular leakage, and depending on the location, smooth muscle spasm or glandular secretions.

These changes usually become evident within 5-30 minutes after exposure to an allergen and tend to subside in 60 minutes.

Front 161

161. What occurs in the second, delayed phase of a type I hypersensitivity reaction?

What drives this phase?

Back 161

This stage is characterized by an intense inflammatory cell infiltration with associated tissue damage. This late secondary phase is driven by lipid mediators and cytokines produced by the activated mast cells.

Front 162

162. What are mast cells?

Back 162

Mast cells are bone marrow-derived cells that are widely distributed in the tissues. They are found predominantly near blood vessels and nerves and in subepithelial sites, where local immediate hypersensitivity reactions tend to occur.

Front 163

163. How are mast cells activated?

Back 163

Mast cells (and basophils) are activated by the cross-linking of high-affinity IgE Fc receptors; in addition mast cells may also be triggered by several other stimuli, such as complement components C5a and C3a, both of which act by binding to their receptors on the mast cell membrane.

Front 164

164. What are basophils?

Back 164

Basophils are similar to mast cells in many respects, including the presence of cell-surface IgE Fc receptors as well as cytoplasmic granules. In contrast to mast cells, however, basophils are not normally present in tissues but rather circulate in the blood in extremely small numbers.

Front 165

165. Most immediate hypersensitivity reactions are mediated by...?

Back 165

IgE antibodies.IgE-secreting B cells differentiate from naive B cells, and this process is dependent on the activity of CD4+ helper T cells of the TH2 type.

*Hence, TH2 cells are pivotal in the pathogenesis of type I hypersensitivity.

Front 166

166. What six allergens can trigger mast cell and basophil degranulation?

Back 166

1. Complement fragments (C3a and C5a (anaphylatoxins)
2. Certain drugs i.e. codeine, morphine, adenosine
3. Mellitin (bee venom)
4. Sunlight
5. Trauma
6. Heat/cold

Front 167

167. Where are IgE antibodies synthesized in response to prior exposure to allergens are normally bound to where?

Back 167

Mast cells and basophils via specific surface Fc receptors.

On re-exposure, allergen bind to and cross-links the IgE on mast cells and results in:
1. Degranulation of vesicles containing primary mediators
2. De novo synthesis and release of secondary mediators

Front 168

168. What are the four lipid mediators produced by the mast cells in the delayed phase?

What is the role of each lipid mediator?

Back 168

1. Leukotriene B4 is highly chemcotactic for neutrophils, monocytes, and eosinophils
2. Leukotrienes C4, D4, and E4 are 1000x more potent than histamine in increasing vascular permeability and causing bronchial smooth muscle contraction. These also cause marked mucous gland secretion
3. Prostaglandin D2 causes intense bronchospasm, vasodilation, and mucous secretion
4. Platelet-activating factor causes platelet aggregation, histamine release, bronchoconstriction, vasodilation, and increased vascular permeability. It also has proinflammatory effects, such as chemoattraction and degranulation of neutrophils.

Front 169

169. In sum, what do the lipid mediators lead to?

Back 169

The lipid mediators are generated by sequential reactions in the mast-cell membranes that lead to activation of phospholipase A2, an enzyme that acts on the membrane phospholipids to yield arachidonic acid.

This is the parent compound from which leukotrienes and prostaglandins are derived by the 5-lipoxygenase and cyclooxygenase pathways.

Front 170

170. What are the important cytokine mediators in type I hypersensitivity reactions?

Back 170

The cytokines include TNF, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF, as well as chemokines, such as macrophage inflammatory protein (MIP)-1α and (MIP)-1β.

Mast cell derived TNF and chemokines are important mediators of the inflammatory response seen at the site of allergic inflammation. Inflammatory cells that accumulate at the sites of type I hypersensitivity reactions are additional sources of cytokines and of histamine-releasing factors that cause further mast-cell degranulation.

Front 171

171. What cytokines can epithelial cells produce?

Back 171

IL-6, IL-8 and GM-CSF

Front 172

172. The development of immediate hypersensitivity reactions is dependent on...?

Back 172

The development of immediate hypersensitivity reactions is dependent on the coordinated actions of a variety of chemotactic, vasoactive, and spasmogenic compounds.

Front 173

173. What is the role of TNF-α in type I hypersensitivity reactions?

Back 173

TNF-α in particular is a powerful proinflammatory cytokine that recruits and activates many additional inflammatory cells.

Recruited inflammatory cells also release cytokines, and TNF-α-activated epithelial cells secrete chemokines (e.g. eotaxin and RANTES) that recruit eosinophils.

Front 174

174. What is the role of eosinophils in type I hypersensitivity reactions?

Back 174

Eosinophils are particularly important in late-phase responses; they cause tissue damage by releasing major basic protein and eosinophil cationic protein.

Front 175

175. What does atopy mean?

Back 175

Atopy refers to a predisposition to develop localized immediate hypersensitivity reactions to a variety of inhaled and ingested allergens.

Atopic individuals seem to have a higher serum IgE level, and more IL-4 producing TH2 cells, compared w/the general population.

Front 176

176. What are the genetic components of immediate hypersensitivity?

Back 176

A positive family history of allergy is found in 50% of atopic individuals.

Candidate genes have been mapped to 5q31 for asthma, where genes for the cytokines IL-3, 4, 5, 9, 13, and GM-CSF are located, consistent with the idea that these cytokines are involved in the reactions.

Linkage has also been noted to 6p, close to the HLA complex, suggesting that the inheritance of certain HLA alleles permits reactivity to certain allergens.

Another asthma associated locus is on chromosome 11q13, the location of the gene encoding the β chain of the high-affinity IgE receptor.

Front 177

177. What is the summary of type I hypersensitivity?

Back 177

Type I hypersensitivity is a complex disorder resulting from an IgE mediated triggering of mast cells and subsequent accumulation of inflammatory cells at sites of antigen deposition. These events are regulated in large part by the induction of TH2 type helper T cells that promote synthesis of IgE and accumulation of inflammatory cells, particularly eosinophils. The clinical features result form release of mast-cell mediators as well as the accumulation of an eosinophil-rich inflammatory exudate.

Front 178

178. What is systemic anaphylaxis?

Back 178

Systemic anaphylaxis typically follows parenteral or oral administration of an allergen. The severity reflects the level of sensitization, and even minuscule doses may induce anaphylactic shock in an appropriate host.

Pruritus, urticaria, and erythema occur minutes after exposure, followed by bronchoconstriction and laryngeal edema; this can escalate into laryngeal obstruction, hypotensive shock, and death within minutes to hours.

Front 179

179. What are local immediate hypersensitivity reactions?

Back 179

These reactions are exemplified by atopic allergies. There is a hereditary predisposition affecting 10% of the population (mapping to 5q31, where many of the TH2 type cytokines are located).

Affected individuals tend to develop local type I responses to common inhaled or ingested allergens.

Symptoms include urticaria, angioedema, rhinitis, and asthma.

Front 180

180. What is antibody-mediated (type II) hypersensitivity?

Back 180

Type II hypersensitivity is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix.

The antigenic determinants may be intrinsic to the cell membrane or matrix, or they may take the form of an exogenous antigen such as a drug metabolite that is adsorbed on a cell surface or matrix.

In either case, the hypersensitivity reaction results from the binding of antibodies to normal or altered cell surface antigens. Most of these reactions involve the effector mechanisms that are used by antibodies, namely the complement system and phagocytes.

Front 181

181. What are the three major pathways in type II hypersensitivity reactions?

Back 181

1. Opsonization and complement- and Fc receptor-mediated phagocytosis

2. Complement- and Fc receptor-mediated inflammation

3. Antibody-mediated cellular dysfunction

Front 182

182. Opsonization and complement- and Fc receptor-mediated phagocytosis

Back 182

Cells can be directed lysed via the C5-C9 complement membrane attack complex (MAC) or they can be opsonized (enhanced phagocytosis) as a result of fixation of antibody or C3b fragments.

Low concentrations of bound antibody (IgG or IgE) can also cause cell lysis (w/o phagocytosis) by nonsensitized cells bearing Fc receptors (e.g. NK cells, so called antibody-dependent cell mediated cytotoxicity (ADCC).

Front 183

183. What is antibody-dependent cell mediated cytotoxicity (ADCC)?

Back 183

This form of antibody mediated cell injury does not involve fixation of complement but instead requires the cooperation of leukocytes.

Cells that are coated with low concentrations of IgG antibody are killed by a variety of effector cells, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis.

Front 184

184. What mediates ADCC?

Back 184

ADCC may be mediated by monocytes, neutrophils, eosinophils, and NK cells.

Although, in most instances, IgG antibodies are involved in ADCC, in certain cases, e.g. eosinophil-mediated cytotoxicity against parasites), IgE antibodies are used.

Front 185

185. In what four situations does antibody-mediated cell destruction and phagocytosis occur?

Back 185

1. Transfusion reactions, in which cells from an incompatible donor react w/and are opsonized by preformed antibody in the host.
2. Erythroblastosis fetalis, in which there is an antigenic difference between the mother and the fetus, and antibodies (of the IgG class) from the mother cross the placenta and cause destruction of fetal red cells.
3. Autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are then destroyed.
4. Certain drug reactions, in which antibodies are produced that react w/the drug, which may be attached to the surface of erythrocytes or other cells.

Front 186

186. What is complement- and Fc receptor-mediated inflammation?

Back 186

The deposition of antibodies w/subsequent complement activation, e.g. C5a, in the extracellular matrix leads to the recruitment and activation of nonspecific inflammatory cells (neutrophils and macrophages).

These activated cells can release injurious proteases and reactive oxygen species that lead to tissue pathology.

Ex: glomerulonephritis, vascular rejection in organ grafts.

Front 187

187. Antibody-mediated cellular destruction

What are some diseases that exemplify this mechanism?

Back 187

In some cases, antibodies directed against cell surface receptors impair or dysregulate function without causing cell injury or inflammation.

For example, in myasthenia gravis, antibodies reactive w/ACh receptors in the motor end-plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

In pemphigus vulgaris, antibodies against desmosomes disrupt intercellular junctions in epidermis, leading to the formation of skin vesicles.

The converse (i.e. antibody-mediated stimulation of cell function) is noted in Graves disease. In this disorder, antibodies against the TSH receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.

Front 188

188. What is immune complex-mediated (type III) hypersensitivity?

Back 188

Antigen-antibody complexes produce tissue damage mainly by eliciting inflammation at the sites of deposition.

The toxic reaction is initiated when antigen combines w/antibody within the circulation and these are deposited, typically in vessel walls, or the complexes are formed at extravascular sites where antigen may have been deposited previously (in situ immune complexes).

Front 189

189. What are the two general types of antigens that cause cell mediated injury?

Back 189

1. The antigen may be exogenous, such as a foreign protein, a bacterium, or a virus
2. Under some circumstances, the individual can produce antibody against self-components -endogenous antigens.

The latter can be circulating antigens present in the blood or, more commonly, antigenic components of one's own cells and tissues.

Front 190

190. What is systemic immune complex disease?

Back 190

Systemic immune complex disease is characterized by circulating immune complexes that are systemically deposited.

Acute serum sickness is the prototypical systemic immune complex disease. it is caused by administration of large amts of a foreign protein; after inoculation, newly synthesized antibodies complex w/the foreign antigen to form circulating immune complexes

Front 191

191. Do larger or smaller immune complexes circulate for longer periods of time?

Back 191

Smaller immune complexes circulate for longer periods of time b/c they bind w/low avidity to mononuclear phagocytes and are ineffectively cleared; these complexes are prone to deposit within a capillary or arteriolar walls, causing vasculitis.

With continued antibody production, large immune complexes eventually form; these are cleared by phagocytes, ending the disease process.

Front 192

192. What other factors enhance immune complex deposition?

Back 192

Immune complex deposition is enhanced by increased vascular permeability resulting from inflammatory cell activation by immune complex binding to Fc or C3b receptors.

The activated inflammatory cells release vasoactive mediators, including cytokines.

Front 193

193. Deposition of immune complexes causes...?

Back 193

Deposition of immune complexes activates the complement cascade and subsequent tissue injury derives largely from complement-mediated inflammation and cells bearing Fc receptors.

Front 194

194. C3b does...?

C5a does...?

Back 194

C3b enhances opsonization

C5a (chemotactic factor) release promotes neutrophil and monoctyte recruitment w/subsequent protease and reactive oxygen species elaboration.

Front 195

195. C3a and C5a do...?

Back 195

C3a and C5a release increases vascular permeability and causes smooth muscle contraction

Front 196

196. What is the relationship between immune complexes and platelet aggregation?

Back 196

Immune complexes also aggregate platelets (w/subsequent degranulation) and activate factor XII (Hageman factor).

Both of these reactions augment the inflammatory process and initiate the formation of microthrombi. The resultant inflammatory lesion is termed vasculitis if it occurs in blood vessels, glomerulonephritis if it occurs in renal glomeruli, arthritis if it occurs in the joints, and so on.

The coagulation cascade and kinin systems are thus involved as well.

Front 197

197. What is the pathogenesis of immune complex disorders?

Back 197

Complement-fixing antibodies (IgG and IgM) and antibodies that bind to leukocyte Fc receptors (some subclasses of IgG) induce pathologic lesions of immune complex disorders.

B/c IgA can activate complement by the alternative pathway, IgA-containing complexes may also induce tissue injury. The important role of complement in the pathogenesis of the tissue injury is supported by the observations that during the active phase of the disease, consumption of complement decreases the serum levels, and experimental depletion of complement greatly reduces the severity of the lesions.

Front 198

198. What is the morphology of immune complex injury?

Back 198

The morphologic consequences of immune complex injury are dominated by acute necrotizing vasculitis, with necrosis of the vessel wall and intense neutrophilic infiltration. The necrotic tissue and deposits of immune complexes, complement, and plasma protein produce a smudgy eosinophilic deposit that obscures the underlying cellular detain *an appearance termed fibrinoid necrosis.

When complexes are deposited in kidney glomeruli, the affected glomeruli are hypercellular b/c of swelling and proliferation of endothelial and mesangial cells, accompanied b neutrophilic and monocytic infiltration. The complexes can be seen on immunofluorescence microscopy as granular lumpy deposits of immunoglobulin and complement and on electron microscopy as electron-dense deposits along the glomerular basement membrane.

Front 199

199. Disease progression in immune complex injury

Back 199

With time and clearance of the inciting antigen and immune complex, the lesions resolve.

In chronic serum sickness, resulting from recurrent or prolonged antigen exposures and ongoing immune complex deposition (e.g. systemic lupus erthematosus, SLE), there is intimal thickening and vascular and/or parenchymal scarring.

Front 200

200. What is the local immune complex disease (Arthus reaction)?

Back 200

The Arthus reaction is a localized are of tissue necrosis resutling from acute immune complex vasculitis, usually elicited in the skin. The reaction can be produced experimentally by intracutaneous injection of antigen in an immune animal having circulating antibodies against the antigen. As the antigen diffuses into the vascular wall, it binds the preformed antibody, and large immune complexes are formed locally which precipitate in the vessel walls and trigger and inflammatory reaction.

In contrast to IgE mediated type I reactions, which appear immediately, the Arthus lesion develops over a few hours and reaches a peak 4-10 hours after injection.

Front 201

201. What is the morphology of local immune complex disease?

Back 201

It can be seen as an area of visible edema w/severe hemorrhage followed occasionally by ulceration.

Immunofluorescent stain reveal complement, immunoglobulins, and fibrinogen deposited in the vessel walls, usually the venules, and histologically the vessels show fibrinoid necrosis and inflammation. Thrombi are formed in the vessels, resulting in local ischemic injury.

Front 202

202. What is cell mediated (type IV) hypersensitivity?

Back 202

Cell mediated hypersensitivity is initiated by specifically sensitized T lymphocytes and includes delayed-type hypersensitivity mediated by CD4+ T cells, and T-cell mediated cytotoxicity, mediated by CD8+ T cells.

It is the principal pattern of immunologic response not only to a variety of intracellular microbiologic agents, such as Mycobacterium tuberculosis, but also to many viruses, fungi, protozoa, and parasites.

Front 203

203. What is delayed type hypersensitivity?

What drives it?

Back 203

This resposne is largely mediated by CD4+ TH1 cells that secrete specific cytokines after encounter w/processed antigen expressed by APCs.

The TH1 response is driven by IL-12 secreted by activated macrophages.

Front 204

204. What is the morphology of delayed type hypersensitivity?

1/2

Back 204

Morphologically, delayed type hypersensitivity is characterized by the accumulation of mononuclear cells around small veins and venules, producing a perivascular "cuffing".

There is an associated increased microvascular permeability caused by mechanisms similar to those in other forms of inflammation. Not unexpectedly, plasma proteins escape, giving rise to dermal edema and deposition of fibrin in the interstitium.

Front 205

205. What is the morphology of delayed type hypersensitivity?

2/2

Back 205

A classic example is the tuberculin reaction, which is produced by the intracutaneous injection of tuberculin, a protein LPS component of the tubercle bacillus.

With certain persistent or nondegradable antigens, such as tubercle bacilli colonizing the lungs or other tissues, the initial perivascular lymphatic infiltrate is replaced by macrophages over 2-3 weeks.

The accumulated macrophages often undergo a morphologic transformation into epithelium-like cells and are then referred to as eptheliod cells. A microscopic aggregation of epithleiod cells, usually surrounded by a collar of lymphocytes, is referred to as a granuloma. This pattern of inflammation is called granulomatous inflammation.

Front 206

206. What are the TH1 cytokines?

Back 206

TH1 cytokines include IFN-γ, IL-2, and TNF-α; these cytokines mediate injury by recruiting and activating antigen-nonspecific monocytes and macrophages.

Front 207

207. What is the importance of IL-12?

Back 207

IL-12, a cytokine produced by macrophages and dendritic cells, is critical for the induction of the TH1 response and hence delayed hypersensitivity. On initial encounter w/a microbe, the macrophages and dendritic cells that are presenting microbial antigens secrete IL-12, which drives the differentiation of naive CD4+ helper cells to TH1 cells.

These, in turn, produce other cytokines. IL-12 is also a potent inducer of IFN-γ secretion by T cells and NK cells. IFN-γ further augments the differentiation of TH1 cells.

Front 208

208. What is the importance of IFN-γ?

Back 208

IFN-γ has many effects and is the key mediator of delayed type hypersensitivity. Most importantly, it is a powerful activator of macrophages.

Activated macrophages are altered in several ways: their ability to phagocytose and kill microorganisms is markedly augmented; they express more class II molecules on the surface, thus facilitating further antigen presentation; they secrete several polypeptide growth factors, such as PDGF, which stimulate fibroblast proliferation and augment collagen synthesis; they secrete TNF, IL-1, and chemokines, which promote inflammation, and they produce more IL-12, thereby amplifying the TH1 response.

Front 209

209. What does IL-2 do?

Back 209

IL-2 causes autocrine and paracrine proliferation of T cells, which accumulates at sites of delayed hypersensitivity; included in this infiltrate are some antigen specific CD4+ TH1 cells and many more bystander T ells that are recruited to the site.

Front 210

210. What three things do TNF and lymphotoxin do to endothelial cells?

Back 210

1. Increased secretion of prostacyclin, which, in turn, favors increased blood flow causing local vasodilation
2. Increased expression of P-E selectins, adhesion molecules that promote attachment of the passing lymphocytes and monocytes
3. Induction and secretion of chemokines such as IL-8

Together, all these changes in the endothelium facilitate the extravasation of lymphocytes and monocytes at the site of the delayed hypersensitivity reaction.

Front 211

211. What is T cell-mediated cytotoxicity?

Back 211

Generation of cytotoxic T lymphocytes is the principal pattern of response to many viral infection and to tumor cells.

CTLs also contribute to allograft rejection. CTL-induced injury is mediated by perforin-granzyme and Fas-FasL pathways that ultimately induce apoptosis.

Front 212

212. What is perforin?

Back 212

Perforin can perforate the plasma membranes of the target cells that are under attack by CD8+ lymphocytes. At first, CD8+ T cells come in close contact w/the target cells; this is followed by polymerization of the released perforin molecules and their insertion into the target cell membranes, thus drilling holes into the membranes.

In addition, the perforin pores allow water to enter the cells, thus causing osmotic lysis.

Front 213

213. What are granzymes?

Back 213

The CTL granules contain proteases called granzymes, which are delivered into the target cells via the perforin-induced pores.

Once within the cells, granzymes activate caspases, which induce apoptosis of the target cells.

Front 214

214. What are the global health problems associated with inadequate nutrition in third world countries and in industrialized societies?

Back 214

In third world countries, under-nutrition or protein-energy malnutrition continues to be common.

In industrialized societies, the most frequent diseases (atherosclerosis, cancer, diabetes, and hypertension) have all been linked to some form of dietary impropriety.

Front 215

215. An adequate diet should provide what three things?

Back 215

1. Energy, in the form of carbs, fats, and proteins
2. Essentials (as well as non-essential) AAs and FAs to be used as building blocks for synthesis of structural and functional proteins and lipids
3. Vitamins and minerals, which function as coenzymes or hormones in vital metabolic pathways or, as in the case of calcium and phosphate, as important structural components

Front 216

216. What is primary malnutrition?

Secondary or conditional malnutrition?

Back 216

Primary malnutrition is when one or all of these components of the diet are missing.

By contrast, in secondary or conditional malnutrition, the supply of nutrients is adequate, but malnutrition may result from nutrient malabsorption, impaired nutrient use or storage, excess nutrient losses, or increased need for nutrients.

Front 217

217. What are the common causes of undernutrition in alcoholism?

Back 217

Alcoholics may sometimes suffer from protein energy malnutrition, but are more freq deficient in several vitamins, especially thiamine, pyridoxine, folate, and vit A, owing ot oa cobo of dietary deficiency, defective GI absorption, abnormal nutrient use and storage, increased metabolic needs, and an increased rate of loss.

Front 218

218. What is PEM?

Back 218

PEM refers to a range of clinical syndromes characterized by an inadequate dietary intake of protein and calories to meet the body's needs.

Front 219

219. What are the two functional protein compartments in the body?

Which is more affected in a caloric vs. a protein deficiency?

Back 219

1. Somatic protein compartment, represented by skeletal muscles
2. Visceral protein compartment, represented by protein stores in the visceral organs, primary the liver.

*These two compartments are regulated differently; the somatic compartment is affected more severely in marasmus (calorie deficiency), while the visceral compartment is depleted more severely in kwashiorkor.

Front 220

2220. How is a diagnosis of PEM made?

Back 220

The Dx of PEM is usually made by comparing the body weight for a given height with a standard table, although eval of fat stores, muscle mass, and serum proteins can also be helpful.

If the somatic protein compartment is catabolized, the resultant reduction in muscle mass is reflected by reduced circumference of the midarm.

Measurement of serum proteins (albumin, transferrin, and others) provides a measure of the adequacy of the visceral protein compartment.

Front 221

221. Who are the most common victims of PEM worldwide?

Back 221

Children. A child whose weight falls to less than 80% of normal is considered malnourished.

Front 222

222. What is Marasmus?

Back 222

Marasmus refers to malnutrition caused by reduction in caloric intake. It results in greater than 60% reduction in body weight adjusted for height and sex. A child w/marasmus suffers growth retardation and loss of muscle.

Interestingly, the visceral protein compartment is depleted only marginally, and hence serum albumin levels are either normal or only slightly reduced.

With such losses of muscle and subcutaneous fat, the extremities are emaciated; by comparison, the head appears too large for the body. Anemia and manifestations of multivitamin deficiencies are present, and there is evidence of immune deficiency, particularly of T cell mediated immunity.

Front 223

223. What is Kwashiorkor?

Back 223

Kwashiorkor occurs when protein deprivation is relatively greater than the reduction in total calires. This is the msot common form seen in African children who have been weaned (often too early) and are subsequently fed an exclusive diet on carbs.

*Kwashiorkor is a more severe form of malnutrition than marasmus. Unlike marasmus, marked protein deprivation is associated w/severe loss of the visceral protein compartment, and the resultant hypoalbuminemia gives rise to generalized, or dependent, edema. The weight of children w/severe kwashiorkor is typically 60-80% of normal. The true loss of weight is masked by the increased edema. Also, there is relative sparing of the subcutaneous fat and muscle mass.

Front 224

224. What are some other symptoms that differentiate kwashiorkor from marasmus?

Back 224

Children w/kwashiorkor have characteristic skin lesions, w/alternating zones of hyperpigmentations, areas of desquamations, and hypopigmentations, giving a "flaky paint" appearance. Hair changes include overall loss of color or alternating bands of pale and darker hair, straightening, line texture, and loss of firm attachment of the scalp.

Other features include an enlarged, fatty liver, and a tendency to develop early apathy, listlessness, and loss of appetite.

As in marasmus, other vitamin deficiencies are likely to be present as are defects in immunity and secondary infections.

Front 225

225. What is secondary PEM?

What are 3 signs of PEM in hospital pts?

Back 225

Secondary PEM is a common complication in advanced cancer pts and in pts w/AIDS. The malnutrition in these settings is sometimes called cachexia. Individuals w/chronic GI disease and elderly pts who are weak and bedridden may show signs of PEM:

1. Depletion of subcutaneous fat in the arms, chest wall, shoulders, or metacarpal regions
2. Wasting of the quadriceps femoris and deltoid muscles
3. Ankle or sacral edema

Front 226

226. What are the biochemical mechanisms responsible for secondary PEM?

Back 226

Pats w/cachexia show a loss of fat as well as muscle mass, which may occur before a decrease in appetite.

Cachectic pts show increased expenditure of resting energy. Cytokines produced by the host during sepsis, for example, or by tumors have been postulated to be involved in cachexia; TNF, IL-1, IL-6, and IFN-y.

Front 227

227. What are the 3 central anatomic changes in PEM?

Back 227

1. Growth failure
2. Peripheral edema in kwashiorkor
3. Loss of body fat and atrophy of muscle, more marked in marasmus

Front 228

228. What is the morphology of the liver and small bowel in PEM?

Back 228

The liver in kwashiorkor, but not in marasmus, is enlarged and fatty; superimposed cirrhosis is rare.

In kwashiorkor (rarely in marasmus), the small bowel shows a decrease in the mitotic index in the crypts of the glands, associated w/mucosal atrophy and loss of villi and microvilli. In such cases, concurrent loss of small intestinal enzymes occurs, most often manifested as disaccharidase deficiency. Hence, infants w/kwash may not initially respond well to a full-strength, milk-based diet.

Front 229

229. What is the morphology of the bone marrow in PEM?

Back 229

The bone marrow in both kwash and marasmus may be hypoplastic, mainly b/c of decreased numbers of red cell precursors. How much of this derangement is due to a deficiency of protein and folates or to reduced synthesis of transferring an ceruloplasmin is uncertain. Thus, anemia is usually present, most often hypochromic microcytic anemia, but a concurrent deficiency of folates may lead to a mixed microcytic-macrocytic anemia.

Front 230

230. What is the morphology of the brain in PEM?

Back 230

The brain in infants who are born to malnourished mothers and who suffer from PEM during the first 1-2 years of life has been reported by some observers to show cerebral atrophy, a reduced number of neurons, and impaired myelinization of the white matter.

Front 231

231. What are three other changes that may be present in PEM?

Back 231

1. Thymic and lymphoid atrophy (more marked in kwash than in marasmus)
2. Anatomic alterations induced by intercurrent infections, particularly w/all manner of endemic worms and other parasites
3. Deficiencies of other required nutrients, such as iodine and vitamins

Front 232

232. What is anorexia nervosa?

What is bulimia?

Back 232

Anorexia nervosa is a self induced starvation, resulting in marked weight loss. Bulimia is a condition in which the pt binges on food and then induces vomiting.

Front 233

233. What are the clinical findings in anorexia?

Back 233

The clinical findings in anorexia nervosa are generally similar to those in severe PEM. In addition, amenorrhea, (resulting from decreased secretion of Gn-RH and subsequent decreased secretion of LH and FSH) is so common that its presence is a Dx feature for the disorder.

Other common findings, related to decreased thyroid hormone release including cold intolerance, bradycardia, constipation, and changes in the skin and hair. Body hair may be increased but is usually fine and pale (lanugo). Bone density is decreased.

As expected w/severe PEM, anemia, lymphopenia, and hypoalbuminemia may be present.

*A major complication of anorexia nervosa is an increased susceptibility to cardiac arrhythmia and sudden death, resulting in all likelihood from hypokalemia.

Front 234

234. What are clinical findings in bulimia?

Back 234

In bulimia, although menstrual irregularities are common, amenorrhea occurs in less than 50% of bulimic pts, probably b/c weight and Gn levels are maintained near normal.

The major medical complications are related to continued induced vomiting and include:
1. Electrolyte imbalances (hypokalemia - leads to cardiac arrhythmias)
2. Pulmonary aspiration of gastric contents
3. Esophageal and cardiac rupture

Front 235

235. What is vitamin A?

Back 235

Vit A is actually a group of related chemicals w/hormone-like function. Retinol is the transport and also the storage form of vit A.

Carotenoids, found in yellow and leafy green vegetables, are metabolized to active vitamin A. About 90% of the body's vitamin A reserve is found in the perisinusoidal stellate (Ito) cells in the liver).

Front 236

236. What happens when a dietary intake of vitamin A is inadequate?

Back 236

The retinol esters in the liver are mobilized, and released retinol is then bound to a specific retinol-binding protein, synthesized in teh liver. The uptake of retinol by the various cells of the body is dependent on surface receptors specific for retinol binding protein, rather than receptors specific for the retinol. Retinol is transported across the cell membrane, where it binds to a cellular retinol binding protein, and the retinol binding protein is release back in the blood.

Front 237

237. What are the 4 best defined functions of vitamin A?

Back 237

1. Maintaining normal vision in reduced light
2. Potentiating the differentiation of specialized epithelial cells, mainly mucus secreting cells
3. Enhancing immunity to infections, particularly in children
4. In addition, the retinoids, beta-carotene, and some related carotenoids have been shown to function as photoprotective and antioxidant agents

Front 238

238. How does vitamin A help vision?

Back 238

The synthesis of rhodopsin from retinol involves oxidation to all-trans-retinal; isomerization to 11-ciis-retinal; and interaction w/the rod protein opsin to form rhodopsin.

When a photon impinges on the retina, rhodopsin undergoes changes to an all-trans-retinal and opsin. During dark adaptation, some of the all-trans-retinal is reconverted to 11-cis-retinal but most is reduced to retinol and lost to the retina, dictating the need for continuous input of retinol.

Front 239

239. How does vit A help differentiate mucus secreting epithelium?

Back 239

When a deficiency in vit A exist, the epithelium undergoes squamous metaplasia and differentiation to a keratinizing epithelium. Apparently, retinoic acid regulates the expression of genes encoding a number of cell receptors and secreted proteins, including receptors for growth factors.

Front 240

240. How does vit A play a role in host resistance to infection?

Back 240

This beneficial effect seems to derive from its ability to stimulate the immune system, possible through the formation of a metabolite called 14-hydroxyretinol.

In addition, it appears that during infections, the bioavailability of vit A is reduced. The acute phase response that accompanies many infections reduces the formation of retinol-binding protein in the liver, resulting in depression of circulating retinol levels, which in turn leads to reduced tissue availability of vitamin A. *Thus giving vit A during the course of infections can improve the outcome.

Front 241

241. What are the four main manifestations of vit A deficiency?

Back 241

1. Impaired vision and night blindness
2. Xerophthalmia (dry eye), Bitot spots, and keratomalacia, and total blindness
3. The epithelium lining the upper respiratory passages and urinary tract is replaced by keratinizing squamous cells (squamous metaplasia). Loss of the mucociliary epithelium of the airways predisposes to secondary pulmonary infections, and desquamation of keratin debris in the urinary tract predisposes to renal and urinary bladder stones.
4. Immune deficiency leading to higher mortality rates from measles, pneumonia, and infectious diarrhea

Front 242

242. What about vit A toxicity?

Back 242

Can cause:

1. Acute toxic manifestations include headache, vomiting, stupor, and papilledema
2. Chronic toxicity is associate with weight loss, nausea, and vomiting, lip dryness, and bone and joint pain, hepatomegaly with parenchymal damage and fibrosis.

Front 243

243. What is the major function of vitamin D?

Back 243

The major function of vitamin D is the maintenance of normal plasma levels of calcium and phosphorus. In this capacity, it is required for the prevention of bone disease and of hypocalcemic tetany.

Front 244

244. What is the metabolism of vitamin D?

Back 244

1. Absorption of vitamin D in the gut or synthesis from precursors in the skin
2. Binding to a plasma α₁-globulin and transport to the liver
3. Conversion to 25-hydroxyvitamin D, 25(OH)D by 25-hydroxylase in the liver
4. Conversion of 25(OH)D to 1,25(OH)₂D by α₁-hydroxylase in the kidney (***This is the biologically active form of vitamin D)

Front 245

245. What are the 3 mechanisms by which the kidney regulates vitamin D production?

Back 245

1. In a feedback loop, increased levels of 1,25(OH)₂D down-regulate synthesis of this metabolite by inhibiting the action of α₁-hydroxylase, and decreased levels have the opposite effect.

2. Hypocalcemia stimulates secretion of PTH, which in turn augments the conversion of 25(OH)D to 1,25(OH)₂D by activating α₁-hydroxylase

3. Hypophosphatemia directly activates α₁-hydroxylase and thus increases formation of 1,25(OH)₂D

Front 246

246. What are the three main functions of vitamin D in its active form?

Back 246

1. Stimulates intestinal abosprtion of calcium and phosphorus
2. Collaborates w/PTH in the mobilization of calcium from bone
3. Stimulates the PTH dependent reabsorption of calcium in the distal renal tubules.

Front 247

247. How does vitamin D help bone mineralization?

Back 247

It is likely that vitamin D favors differentiation of osteoclasts from their precursors (monocytes).

Front 248

248. What are the effects of vit D deficiency?

Back 248

Vitamin D deficiency causes both rickets in growing children and osteomalacia in adults. Both forms of skeletal disease result from altered vitamin D absorption or metabolism or, less commonly, from disorders that affect the function of vitamin D or disturb calcium or phosphorus homeostasis.

Front 249

249. When hypocalcemia occurs, PTH production is increased, which does what four things?

Back 249

1. Activates renal α₁-hydroxylase, thus increasing the amt of active vitamin D and calcium absorption
2. Mobilizes calcium from bone
3. Decreases renal calcium excretion
4. Increases renal excretion of phosphate.

Front 250

250. What are 5 predisposing conditions for Rickets or Osteomalacia?

Back 250

1. Inadequate synthesis or dietary deficiency of vitamin D (sunlight deprivation)
2. Decreased absorption of fat soluble vitamin D (celiac sprus, liver disease)
3. Derangements in vitamin D metabolism - inherited deficiency of renal α₁-hydroxylase (*vitamin D-dependent Rickets type I)
4. End-organ resistance to 1,25(OH)₂D (*vitamin D-dependent Rickets type II)
5. Phosphate depletion (ex: X-linked hypophosphatemic rickets)

Front 251

251. What is the basic derangement in both rickets and osteomalacia?

Back 251

The basic derangement in both rickets and osteomalacia is an excess of unmineralized matrix.

The changes that occur in the growing bones of children w/rickets, however, are complicated by inadequate provisional calcification of epiphyseal cartilage deranging endochrondral bone growth.

Front 252

252. What are the 6 steps in the formation of rickets?

Back 252

1. Overgrowth of epiphyseal cartilage due to inadequate provisional calcification and failure of the cartilage cells to mature and disintegrate
2. Persistence of distorted, irregular masses of cartilages, many of which project into the marrow cavity
3. Deposition of osteoid matrix on inadequately mineralized cartilaginous remnants
4. Disruption of the orderly replacement of cartilage by osteoid matrix, w/enlargement and lateral expansion of the osteochondral junction
5. Abnormal overgrowth of capillaries and fibroblasts in the disorganized zone b/c of microfractures and stresses on the inadequately mineralized, weak, poorly formed bone
6. Deformation of the skeleton due to the loss of structural rigidity of the developing bones

Front 253

253. How do the changes of the skeleton depend on the stresses to which individual bones are subjected?

Back 253

During the nonambulatory stage of infancy, the head and chest sustain the greatest stresses. The softened occipital bones may become flattened, and the parietal bones can be buckled inward by pressure; with the release of the pressure, elastic recoil snaps the bones back into their original positions (craniotabes).

***An excess of osteoid produces frontal bossing and a squared appearance to the head.

Front 254

254. What about the chest deformities?

Back 254

Deformation of the chest results from overgrowth of cartilage or osteoid tissue at the costochondral junction, producing the "rachitic rosary".

The weakened metaphyseal areas of the ribs are subject to anterior protrusion of the sternum, creating a pigeon breast deformity.

The inward pull at the margin of the diaphragm creates Harrison's groove, girdling the thoracic cavity at the lower margin of the rib cage.

Front 255

255. What are the other deformities associated with vit D deficiency in children?

Back 255

The pelvis may become deformed. When an ambulating child develops rickets, deformities are likely to affect the spine, pelvis, and long bones (e.g. tibia), causing, most notably *lumbar lordosis and bowing of the legs.

Front 256

256. What is the morphology of osteomalacia?

Back 256

The newly formed osteoid matrix laid down by osteoblasts is inadequately mineralized, thus producing the excess of persistent osteoid characteristic of osteomalacia.

Although the contours of the bone are not affected, the bone is weak and vulnerable to gross fractures or microfractures, which are most likely to affect vertebral bodies and femoral necks.

Front 257

257. What are the histological characteristics of osteomalacia?

Back 257

The unmineralized osteoid can be visualized as a thickened layer of matrix (which stain pink in H & E), arranged about the more basophilic, normally mineralized trabeculae.

Front 258

258. What is osteopenia?

Back 258

Persistent failure of mineralization in adults leads eventually to loss of skeletal mass, referred to as osteopenia. It is then difficult to differentiate osteomalacia from other osteopenias such as osteoporosis.

Osteoporos, unlike osteomalacia, results from reduced production of osteoid, the protein matrix of the bone.

Front 259

259. What is vitamin E?

Back 259

Vitamin E comprises a group of eight closely related fat-soluble compounds abundant in most foods; α-tocopherol is the most active and widely available.

The absorption of the tocopherols, similar to other fat-soluble vitamins, requires normal biliary and pancreatic function. After absorption, vitamin E is transported in the blood by chylomicrons, and accumulates throughout the body, mostly in fat depots.

Front 260

260. What are three main functions of vitamin E?

Back 260

1. It acts as a scavenger of free radicals formed in redox reactions throughout the body
2. It may inhibit atheroma formation in atherosclerosis by reducing LDL oxidation
3. In the context of cancer, the antioxidant effect may reduce mutagenesis

Front 261

261. Hypovitaminosis E resulting from deficient diet is uncommon but occurs almost exclusively in association with what four conditions?

Back 261

1. Fat malabsorption that accompanies cholestasis, CF, and primary small intestinal disease
2. Infant low birth weight w/immature liver and GI tract
3. Abetalipoproteinemia, a rare autosomal recessive disorder in which transport of vitamin E is abnormal b/c the apoprotein B component of chylomicrons, LDLs, and vLDLs is not synthesized
4. Rare autosomal recessive syndrome of impaired vitamin E metabolism

Front 262

262. What are the morphologic changes associated with vit E deficiency and the CNS?

Back 262

***Most consistent is degeneration of the axons in the posterior columns of the spinal cord, w/focal accumulation of lipopigment and loss of nerve cells in the dorsal root ganglia, attributed to a dying-back type of axonopathy.***

Degeneration in sensory axons of peripheral nerves may also be present and in more marked cases, degenerative changes in the spinocerebellar tracts may occur as well.

Front 263

263. What about RBCs and vit E?

Back 263

Vitamin E-deficient RBCs are more susceptible to oxidative stress and have a shorter half life in the circulating blood.

Front 264

264. What are the neurologic manifestations of vitamin E deficiency?

Back 264

Neurologic symptoms include depressed, or more often, absent tendon reflexes; ataxia; dysarthria; loss of position and vibratio sense; and loss of pain sensation. Muscle weakness is also common.

In addition, there may be impaired vision and disorders of eye movement, sometimes progressing to ophthalmoplegia.

Front 265

265. What is the importance of vitamin K?

Back 265

Vitamin K is a required cofactor for a liver enzyme that carboxylates specific glutamate residues found in a variety of proteins. Clotting factors 7, 9, 10 and prothrombin all requires carboxylation of glutamate residues for functional activity.

Carboxylation provides calcium-binding sites and thus allows a calcium dependent interaction of these clotting factors with a phospholipid surface involved in the generation of thrombin. in addition, activation of anticoagulant proteins C and S also requires glutamate carboxylation.

Front 266

266. What about vitamin K and bones?

Back 266

Vitamin K serves to facilitate carboxylation of glutamyl residues in osteocalcin, a noncollagenous protein secreted by osteoblasts.

Thus, it appears that vitamin K may favor calcification of bone proteins. Studies also reveal that vit K can inhibit bone resorption by reducing the expression fo the osteoclast differentiation factor, RANK-ligand.

Front 267

267. Vitamin K deficiency usually occurs in what four situations?

Back 267

1. Fat malabsorption syndromes, particularly w/biliary tract disease, as with the other fat-soluble vitamins
2. After destruction of the endogenous vitamin K-synthesizing flora, particular with ingestion of broad spectrum antibiotics
3. In the neonatal period, when liver reserves are small, the bacterial flora is not yet developed, and the level of vitamin K in breast milk is low
4. In diffuse liver disease, even in the presence of normal vitamin K stores, b/c hepatocyte dysfunction interferes with synthesis of the vitamin K dependent coag factors.

Front 268

268. What is the major consequence of vitamin K deficiency?

Back 268

The development of a bleeding diathesis. In neonates, it causes hemorrhagic disease of the newborn. Its most serious manifestation is intracranial hemorrhage but bleeding may occur at any site.

In adults, it may present via hematomas, hematuria, melena, ecchymoses, and bleeding from the gums.

Front 269

269. What is thiamine?

Back 269

Thiamine is widely available in the diet, although refined foods have little. During absorption from the gut, thiamine undergoes phosphorylation to produce thiamine pyrophosphate, the functionally active coenzyme form of the vitamin.

Front 270

270. What are three functions of thiamine pyrophosphate?

Back 270

1. It regulates oxidative decarboxylation of α-keto acids, leading to the synthesis of ATP
2. It acts as a cofactor for transketolase in the pentose phosphate pathway
3. It maintains neural membranes and normal nerve conduction *chiefly of peripheral nerves

Front 271

271. When do thiamine deficiencies occur?

Back 271

In underdeveloped countries where a large part of the scant diet consists of polished rise, as occurs in Southeast Asia.

In developed countries, clinically evident thiamine deficiency affects as many as 25% of chronic alcoholics admitted to general hospitals.

A thiamine deficiency state may also result from the pernicious vomiting of pregnancy or from debilitating illnesses that impair the appetite, predispose to vomiting, or cause protracted diarrhea.

Front 272

272. What are the major targets of thiamine deficiency, and what three syndromes does it give rise to?

Back 272

The major targets are the peripheral nerves, teh heart, and the brain. It gives rise to 3 syndromes:
1. A polyneuropathy (dry beriberi)
2. A cardiovascular syndrome (wet beriberi)
3. Wernicke-Korsakoff syndrome

Front 273

273. What is dry beriberi?

Back 273

The polyneuropathy is usually symmetric and takes the form of a nonspecific peripheral neuropathy w/myelin degeneration and disruption of axons involving motor, sensory, and reflex arcs.

It usually first appears in the legs but it may also extend to the arms, so classically these pts present with toe drop, foot drop, and wrist drop. The progressive sensory loss is accompanied by muscle weakness and hyporeflexia or areflexia

Front 274

274. What is wet beriberi?

Back 274

Beriberi heart disease is associated w/peripheral vasodilation, leading to more rapid arteriovenous shunting of blood, high-output cardiac failure, and eventually peripheral edema. The heart may be normal, have subtle changes, or be markedly enlarged and globular (owing to 4 chamber dilation), with pale, flabby myocardium. The dilation things the ventricular walls. Mural thrombi are often present, particularly in the dilated atria.

Front 275

275. What is Wernicke-Korsakoff syndrome?

Back 275

Wernicke-Korsakoff syndrome is seen in protracted severe deficiency states, typically in chronic alcoholics. Wernicke encephalopathy is marked by ophthalmoplegia, nystagmus, ataxia of gait and stance, and derangement of mental function, typically confusion.

Korsakoff psychosis consists of impairment of remote recall, confabulation, and inability to acquire new information.

Front 276

276. Where are the CNS lesions in Wernicke-Korsakoff syndrome?

Back 276

Hemorrhages in:

1. Mamillary bodies
2. Periventricular regions of the thalamus
3. The floor of the fourth ventricle
4. The anterior region of the cerebellum

Front 277

277. What is riboflavin?

Back 277

Riboflavin is a critical component of the coenzymes flavin mononucleotide and flavin adenine dinucleotide, which participate in a wide range of redox reactions. In addition, flavin in covalent linkage is incorporated into succinic dehydrogenase and MOA as well as into other mitochondrial enzymes.

It is widely distributed in meat, dairy products, and vegetables as free riboflavin or riboflavin phosphate and is absorbed in the upper GI tract.

Front 278

278. When does ariboflavinosis occur?

Back 278

Ariboflavinosis still occurs as a primary deficiency state among persons in economically deprived and developing countries. In developed nations, it is found in alcoholics and in individuals with debilitating disease, such as cancer.

Front 279

279. What are the symptoms of ariboflavinosis?

Back 279

1. Changes at the angles of the mouth (known as cheilosis or cheilitis)
2. Glossitis
3. Ocular and skin changes

Front 280

280. What is cheilosis?

What is glossitis?

Back 280

Cheilosis is usually the first and most characteristic sign of ariboflavinosis. It begins as areas of pallor at the angles of the mouth. Later, cracks or fissures may appear, radiating from the corners of the mouth which tend to become secondarily infected.

Glossitis is when the tongue becomes atrophic, taking on a magenta hue strongly resembling the red-blue coloration of cyanosis

Front 281

281. What are the ocular changes in ariboflavinosis?

Back 281

The eye change is a superficial interstitial keratitis. In the earlier stages, the superficial layers of the cornea are invaded by capillaries. Interstitial inflammatory infiltration and exudation follow, producing opacities and sometimes ulcerations of the corneal surface.

Front 282

282. What are the skin changes in ariboflavinosis?

Back 282

A greasy, scaling dermatitis over the nasolabial folds may extend into a butterfly distribution to involve the cheeks and skin about the ears.

Scrotal and vulvar lesions are common.

Erythroid hypoplasia in the bone marrow is typically present but is usually not marked.

Front 283

283. What is niacin?

Back 283

Niacin is the generic designation for nicotinic acid, an essential component of NAD and NADP. NAD is a coenzyme for multiple dehydrogenases involved in the metabolism of fat, carbs, and AAs. NADP participates in similar reactions, notably in the hexose monophosphate shunt of glucose metabolism.

Niacin can be derived from the dietary grains or may be synthesized endogenously from tryptophan. Thus, pellagra may result from either a niacin or a trytophan deficiency.

Front 284

284. When is pellagra encountered?

Back 284

May result form either a niacin or a tryptophan deficiency. In industrialized countries, pellagra is encountered sporadically, principally among alcoholics and persons suffering from chronic debilitating illnesses, including HIV infection. It may also occur w/protracted diarrheal states, w/diets that are grossly deficient in protein, and with long term admin of drugs such as INH and 6-MP.

Front 285

285. What are the three Ds of pellagra?

Back 285

1. Dermatitis
2. Diarrhea
3. Dementia

Front 286

286. What is the morphology of dermatitis in pellagra?

Back 286

Dermatitis is usually bilaterally symmetric and is found mainly on exposed areas of the body. The changes at first comprise redness, thickening, and roughening of the skin, which may be followed by extensive scaling and desquamation, producing fissures and chronic inflammation. similar lesions may occur in the mucous membranes of the mouth and vagina.

Front 287

287. What is the morphology of diarrhea and dementia in pellagra?

Back 287

Diarrhea is caused by atrophy of the columnar epithelium of the GI tract mucosa, followed by submucosal inflammation. Atrophy may be followed by ulceration.

Dementia results from degeneration of the neurons in the brain, accompanied by degeneration of the corresponding tracts in the spinal cord. The spinal cord lesions bear a close resemblance to the posterior column alterations observed in pernicious anemia.

Front 288

288. What is pyridoxine (vitamin B6)?

Back 288

Pyridoxine comprises a group of naturally occurring substances that participate as cofactors for enzymes involved in the metabolism fo lipids and AAs. Vitamin B6 is present in most foods; however, food processing may destroy it and in the past was responsible for severe deficiency in infants fed dried milk preparations.

Front 289

289. What drugs/conditions can cause secondary hypovitaminosis B6?

Back 289

This is most often produced by long term use of any drugs that act as pyridoxine antagonists. These include isoniazid, estrogens, and penicillamine.

Alcoholics are susceptible b/c acetaldehyde enhances pyridoxine degradation.

Pregnancy is associated with increased demand.

Front 290

290. What are the clinical findings in B6 deficiency?

Back 290

Clinical findings include seborrheic dermatitis, cheilosis, glossitis, peripheral neuropathy, and sometimes convulsions.

A deficiency is also associated with high levels of plasma homocysteine which is a risk factor for atherosclerosis.

Front 291

291. What are the two main functions of vitamin C?

Back 291

Functions include:
1. Activating prolyl and lysyl hydroxylases, providing for hydroxylation of procollagen
2. Scaenging free radicals and acting indirectly by regenerating the antioxidant form of vitamin E. The synergistic antioxidant properties of both of these vitamins may retard atherosclerosis by reducing the oxidation of LDL

Front 292

292. A vitamin C deficiency can lead to...?

Back 292

Leads to the development of scurvy, characterized principally by bone disease in growing children and hemorrhages and healing defects in both children and adults.

Also, anemia is common, resulting from bleeding and from a secondary decrease in iron absorption.

Front 293

293. What is the morphology of the hemorrhages in scurvy?

Back 293

Hemorrhages are one of the most striking features. B/c the defect in collagen syntehsis results in inadequate support of the walls of capillaries and venules, purpura and ecchymoses often appear in the skin and in the gingival mucosa.

*Furthermore, the loose attachment of the periosteum to bone, together with the vascular wall defects, leads to extensive subperiosteal hematomas and bleeding into joint spaces after minimal trauma.*

Retrobulbar, subarachnoid, and intracerebral hemorrhages may prove fatal.

Front 294

294. What is the morphology of the skeletal changes in scurvy?

Back 294

The primary disturbance is in the formation of osteoid matrix, rather than in mineralization or calcification, such as occurs in rickets.

There is cartilaginous overgrowth, with long spicules and plates projecting into the metaphyseal region of the marrow cavity, and sometimes widening of the epiphysis. The bone changes include bowing of the long bones of the lower legs and abnormal depression of the sternum with outward projection of the ends of the ribs.

Front 295

295. What are the other clinical features of scurvy?

Back 295

Gingival swelling, hemorrhages, and secondary bacterial periodontal infection are common.

A distinctive perifollicular, hyperkeratotic, papular rash that may be ringed by hemorrhage often appears.

Wound healing and localization of focal infections are impaired b/c of derangement in collagen synthesis.

Front 296

296. What is folate?

Back 296

Folates are essential cofactors in the transfer and use of single-carbon units in DNA synthesis. They are found in whole-wheat flour, beans, nuts, and leafy green vegetables. Folate is heat labile and depleted in cooked and processed foods.

In the US, it is estimated that 15-20% of adults have low serum folate. Even in those people with adequate diets, oral contraceptives, anticonvulsants, ethanol, and cigarettes interfere with folate absorption and metabolism.

Front 297

297. What are the symptoms of folate deficiency?

Back 297

Folate deficiency is associated with megaloblastic anemia and neural tube defects in the developing fetus.

Combined folate and vitamin B12 deficiency has been postulated to contribute to the development of colon cancer.

Front 298

298. By what 3 mechanisms does combined folate and vitamin B12 deficiency lead to colon cancer?

Back 298

1. Altered DNA methylation
2. Accumulation of cells in S phase with increased susceptibility in induction of DNA damage
3. Perturbations of nucleotide pools that impair DNA synthesis and repair

Front 299

299. What five minerals have been associated with well-characterized deficiency states?

Back 299

1. Iron
2. Zinc
3. Copper
4. Selenium
5. Iodine

Front 300

300. What are the 9 features of zinc deficiency?

Back 300

1. A distinctive rash, most often around the eyes, nose, mouth, anus, and distal parts, called acrodermatitis enteropathica
2. Anorexia
3. Growth retardation in children
4. Impaired wound healing
5. Hypogonadism w/diminished reproductive capacity
6. Altered immune function
7. Impaired night vision related to altered vitamin A metabolism
8. Depressed mental function
9. An increased incidence of congenital malformations in infants of zinc deficient mothers

Front 301

301. What are the features of selenium deficiency?

Back 301

Selenium deficiency is well known in China as Keshan disease, which presents as a congestive cardiomyopathy, mainly in children and young women.