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231 Cards in this Set

  • Front
  • Back
How long is the lag phase for Primary Response for particulate antigens?
3 - 4 days
Primary Response:

When are peak plasma-cell levels attained for particulate antigens (SRBC)?
4 -5 days
Primary Response:

When are peak serum Ab levels attained for particulate antigens (SRBC)?
5 - 7 days
How long is the lag phase for Primary Response for protein antigens?
week - 10 days
Primary Response:

When are peak plasma-cell levels attained for protein antigens?
9 - 10 days
What are the antibody isotypes involved in Primary Response?
-The first isotype produced is IgM.

-Toward the end of the primary response IgG is produced and specific IgM drops off due to antigen competition.
How long does the primary response last from lag period to the decline of specific IgG?
-depends on the nature of the antigen

-Antigens using an adjuvant take a lot longer to clear

-(primary response lasts longer between the lag period and the decline of specific IgG)
What are the two most evident differences between primary and secondary response?
1. The lag period is much shorter
-may be only a few hours

2. The level of specific Ab produced is much greater
Why is the lag time reduced in secondary response?
-due to the fact there is now a much higher [specific B cells]

-secondary response benefits from the expansion of reacting B cells from the primary response
What role do memory B cells play in secondary response?
-they are some of the progeny of the expanding B cell pop, therefore greater [memory B cell]

-leads to higher density of responding B cells in secondary response
Why are Ab levels increased in secondary response?
-mainly due to increased levels of IgG (and IgA)

-also due to increased density of specific B cells
Why is the level of IgM production almost identical between primary and secondary response?
-due to class switching that occurred late in the primary respnse adn early in the secondary response
Why does the serum antibody in secondary have a higher affinity?
-due to cumulative effects of somatic mutation and selection
What is affinity maturation?
-it is when the antibody pool becomes more avid during secondary response as those clones which weakly bind antigen are eliminated
What is complement?
-a group of proteins found in the serum and body fluids which react in sequence and results in damage to infectious agents

-if not properly regulated can damage human tissue

***every step in the pathways result in an amplification of the response
What are the two pathways of complement activation?
1. Classical pathway
-discovered first

2. Alternative Pathway
-in daily life, this pathway is probably more important
What is the majority of proteins of complement?
-enzymes that are normally not reactive or only weakly so

-once activated the component possesses its full enzymatic activity
C1 component
-composed of 3 subunits q, r, s

-C1q subunit binds to two closely spaced antibody Fc regions causing a conformational change in the C1 molecule
What results from the conformational change of the C1 molecule?
-C1s subunit is activated

-C1s is now enzymatically active

-substrates of C1s are C4 and C2
What happens when C1s splits C2 and C4?
-split into 'a' and 'b' fragments

-'a' fragments diffuse away
-'b' fragments attach to the cell
C3 convertase
-complex that results from the fact that C4b and C2b come together to form C4bC2b

-purpose to activate C3
-split into C3b and C3a

-C3a diffuses away
-C3b attaches to the cell and then activates C5, splitting it into a and b fragments
-this fragment attaches to the cell and binds C6 and C7 forming a C5b67 complex
C5b67 complex
activates the final two components of complement C8 and C9
what happens when C8 and C9 are activated?
-they insert themselves into the cell's plasma membrane forming a channel through which passe the cells macromolecules

***this type of killing is referred to as osmotic lysis
Reaction Sequence of the Complement System Classical Pathway
1.) C1q,r,s + C4 + C2 --> C4b2b + C4a & C2a

2.) C4b2b + C3 --> C4b2b3b + C3a

3.) C4b2b3b + C5,C6,C7,C8,C9 -->
C5b,6,7,8,9 + C5a
The alternative pathway is a different method of activating what?
-C3 is present in large quantities in the serum

-also very unstable, will spontaneously split into it's a and b fragments
-normally is very unstable

-unless it binds to a membrane it will rapidly become inactive, unless it comes into contact with something with a stabilizing influence
Substances that help stabilize C3b
-cobra venom

-IgA aggregates

-cell walls of yeasts and bacteria
What happens when C3b lands on one of your own cell walls?
-rapidly inactivated by the normal components of mammalian cell membrane

-bacteria do not have these components and if C3b binds to a bacterial cell it will remain
What is Factor B
-a component of complement which when bound by membrane-bound C3b is activated by Factor D
What happens when C3b attaches to a bacterial cell surface?
-binds factor B and Factor B is in turn activated by Factor D

-Factor B split into a and b fragments

-Factor Bb helps to stabilize C3b
-aka factor P

-binds to BbC3b complex and further stabilizes it
BbC3b complex
-activates more C3 and c5

-purpose of C3 activation is to amplify the response

-newly activated C3b will stick to the surface and bind more Factor B, etc.
What is the purpose of activating C5?
-to form the membrane attack complex (MAC) C6789
Outline of the Alternative Pathway
1.) C3 + lipopolysacch + Factor B --->

2.) C3bB + Factor D --> C3bBb + Properdin

3.) C3bBb + C3 --> C3bBbC3b + C3a

4.) C3bBbC3b + C5,C6,C7,C8,C9-->
C5b,6,7,8,9 (MAC) + C5a
What can complement components result in?
-anaphylaxis, chemotaxis, opsonization, target cell lysis, C3, C5 convertase stabilization, or virus neutralization
-substances that may cause increases in vascular permeability and SM contraction and can result in shock

-C3a, C5a, and C4a
Why are moderate increases in vascular permeability beneficial?
-because it facilitates the entry of phagocytic cells and T cells
occurs when cells migrate into an increasing gradient of complement components and thus are directed to the site of infected tissue

-C3a, C5a, and C5b67 are chemotactic
process by which complement components or Abs coat particles resulting in enhanced binding and ingestion by phagocytic cells

-C3b is an opsonin
Various activities of complement component - Anaphylatoxin
C3a, C4a, C5a
Various activities of complement component - Chemotaxis
C3a, C5a, C5b67
Various activities of complement component - Opsonization
-C3b, C3d, c4b
Various activities of complement component - Target cell lysis
Various activities of complement component - C3, C5, Convertase stabilization
Various activities of complement component - Virus Neutralization
C3b, C4b
What do regulatory factors do in complement?
-they not only prevent premature activation of the complement cascade, but also help to limit and contain the response
What is the major difference between the two complement pathways?
-The classical pathway requires the presence of antibody

***this means it is your second exposure to the bacterium
How do you survive the first infection, if the classical pathway of complement requires antibody?
-the alternative pathway because it does not require the presence of antibody

-it is active when you first encounter a strange bacterium
Why does the complement system not necessarily work in vacuo?
-bc phagocytes are usually summoned by the chemotactic factors (C3a, C5a)

-they are let in by the vasodilation due to the anaphylotoxins (C3a, C4a, C5a)
What do phagocytes have on their surface?
-receptors for C3b

-they will ingest the invaders using their C3b receptors even though the complement system is perfectly capable of destroying the bacteria
How can the complement cascade be used to measure the presence of specific antibodies?
-the gist of the procedure is a competition between anti-RBC antibody and RBCs on one hand and the test antigen and test antibody on the other

-both reactions are competing for a limited amount of complement
Step by step method of this test
1. all of the endogenous C in the antiserum is inactivated by gentle heating

2. premeasured amount of guinea pig C is added at the begging of the procedure

3. The test antiserum and antigen are added to a rxn chamber
What will happen if antibody against the test antigen is present?
Complement will be activated

-once activated is unstable, and will decay in a few minutes

-after this incubation is completed the anti-RBC antiserum and RBCs are added
What does a negative test mean?
-the complement is still intact, and SRBCs will lyse

-the first rxn could not have occurred
What does it mean if the SRBCs remain intact?
-the first reaction did occur

-all of the available complement was fixed and thus the rxn is positive
Function of mucosa in immunity
much more complex than the skin and therefore certain areas of the musosa have specialized functions (gas exchange, absorption of nutrients, storage of wastes

-most is relatively thin and must selectively allow passage of certain substances
How effective are mucus membranes in preventing microbial invasion when compared to the intact skin?
-only 80% as effective

-difference in efficacy is responsible for the fact that most infections occur across a membrane
Why is mucosa of GI tract used as an example for talking about mucosal immunity?
-much more is known about the GI tract mucosa than the oral mucosa

-most of the cells and functions of those cells are the same regardelss of the mucous membrane, only their distribution and density changes
What happens if an antigen is encountered across a mucus membrane?
-All mucous membranes become immune to that antigen, at least to a certain extent

-ex: an antigen encountered in the gut will cause IgA to be released in the saliva against that antigen
What are the cells of the mucosal immune system?
-lymphocytes, macrophages, dendritic cells

-some lymphocytes are called Intraepithelial Lymphocytes (IELs)
Intraepithelial Lymphocytes (IELs)
-differ from other lymphocytes, exclusively T cells, expressing CD3 (CD3+)

-85 - 95% are CD8+ (cytotoxic/suppressor)
What is much higher among the IEL population when compared with the peripheral lympocyte population?
the proportion of cells bearing the Ύ/ϧ TCR

-in intestines btwn 13 - 37% of the IELs bear the Ύ/ϧ TCR compared to 1-5% of the T cells in the lamina propria that bear the Ύ/ϧ TCR
Lamina propria
-layer immediately beneath a mucous membrane

-relatively thin layer of CT that helps anchor the epi to the underlying tissue
Immune cells found in the lamina propria
-B cells, mainly memory and plasma cells

-T cells

-macrophages, eosinophils, neutrophils, and mast cells
Lamina propria and IgA
-location where most of the secretory IgA (SIgA) is produced

-in mice 40% of lympocytes here produce immunoglobins, mainly IgA

-another 25% of the lymphocytes are CD4+ T cells
What else do epithelial cells of mucous membranes do?
-express class II MHC molecules

-may participate in antigen presentation
-the process in which the same epithelial cells are the ones that participate in the secretion of IgA into the lumen
-diffuse mucosa associated lymphoid tissue

-the immune cells scattered within the epi layers as well as the lamina propria constitute this
-organized mucosa associated lymphoid tissue

-the central feature is a lymphoid follicle with a germinal center, doe not have any type of capsule
What does the follicle consist of?
-a germinal center, the follicle proper, a parafollicular region and a dome
What is the dome region or corona?
the area between the follicle proper and the epithelium
What is the parafollicular region?
-lateral to the follicle

-most B cells here (and corona) express IgM surface immunoglobulin
In the germinal center, most of the B cells have been switched to what?
IgA isotype
Comparison of CD4+ and CD8+ T Cells in the regions of the follicle
-CD4+ are found in the corona

-CD*+ are more abundant in the parafollicular region
What is the epithelium overlying the follicle?
-called Follicle-associated-epithelium or FAE

-within the FAE there are special cells called M cells
What is the appearance of M cells?
-they are M like

-no dense brush border, have rather diffuse small folds, hence their name M(icrofold) cells
What is in the invagination on the basal side of the M cell?
-dendritic cells, macrophages, and perhaps a T cell
What is the purpose of the M cell
-to transport Ags from the lumen to the APCs on the basal surface

-APCs then take up the Ag, process it and present it to the T-H cells in the corona of the follicle
What does the M cell do with the Ag?
-does not process it, but merely transports it

-however M cell does express class II MHC molecules on its surface
Cells in the FAE?
-10% of the FAE are M cells

-remaining cells are epithelial cells and IELs

-goblet cells are rare in the FAE
O - MALT is often given an unique name depending on its location
-GALT - gut-associated-lymphoid tissue

-BALT - bronchus-associated lymphoid tissue

-NALT - nasal-associated lymphoid tissue in the upper respiratory tract
-term has been applied to the lymphoid tissue surrounding the minor salivary glands
How is Ag endocytosed?
-M cells or by FAE

-then transported through the cell by a process similar to transcytosis
What do dendritic cells or macrophages do with the antigen?
-endocytose it and this time the antigen is processed and displayed in the context of MHC molecules

-Ag primed macros and dentritic cells migrate to the mantle zone or the extrafollicular zone, presenting Ag fragments
What happens when T(H) cells react with antigenic fragments?
-they release cytokines which stimulate the development of the immune response
Peyer's Patches
-contain few plasma cells

-lymphocytes are activated by antigen here, and in case of B cells induced to switch to IgA production
***signal to switch, NOT a signal to secrete IgA
What happens to B cells after the induction to switch to IgA production in Peyer's patches?
-they leave and migrate to the mesenteric lymph nodes, where they proliferate
What happens to B cells after they proliferate in the mesenteric lymph nodes?
-leave and enter the systemic circulation

-most of cells migrate bact to their orginating mucosa (gut in this case)

-selectively leave the vascualture in post cap venules of intestine and reside in the lamina propria
What happens to B cells after they enter the lamina propria?
-may become either IgA memory cells or IgA secreting plasma cells

-most of B cells here are committed to IgA production
Where else do some of the migrating B cells settle?
-other mucous membranes

-a few of the migrating B cells settle out in lymph nodes and other non-mucosa associated lymphoid organs
-major Ab present in secretions

-monomeric, consisting of 2 heavy chains and 2 light chains

-structure similar to IgG

-major form in blood, and is secreted by B cells or plasma cells in bone marrow
What is pIgA?
-polymeric IgA, usually a dimer

-in dimeric form consists of 4 heavy chains, 4 light chains, and a J chain
How does the dimeric arrangement of pIgA result?
-arrangement results from 2 monomers of IgA being linked by their Fc regions through the J chain
Where does the polymerization of IgA occur?
-in the producing cell
***extracellular polymerization of IgA NEVER occurs

-if it is secreted by the plasma cell as a monomer, it will remain a monomer
Secretion of pIgA
-minor species in blood of humans

-secreted by B cells or plasma cells in the lamina propria

-most is secreted into the lumen by epithelial cells, some does end up in the blood
***if it is in the blood it is not thought to be cleared by the liver or bile ducts
What is SIgA?
-secretory IgA

-most often a dimer, 4 heavy chains, 4 light chains, a J chain, and the secretory component
What is the secretory component?
-it binds to the J chain and is the remnants of the polyimmunoglobulin (pIg) receptor which is expressed on the basal side of the epithelial cell
What happens during transcytosis?
-the receptor is cleaved, leaving the secretory component with the pIgA molecule

-the secretory component retards degradation by proteases
How is pIgA bound to basal surfaces of epithelial cells?
-by a specific receptor which recognizes the J chain

-the receptor-pIgA complex is endocytosed by the cell
What happens to the receptor-pIgA complex once it is inside the cell?
-it is transported to the luminal side of the cell and the secretory component is added during secretion

-secretory component confers some protection against proteolytic enzymes
Where are most IgA producing plasma cells located?
-in or near the mucus membranes

-more IgA is produced daily than any other antibody isotypes combined

-in body btwn 3,600 and 9,100 mg
What is the primary function of SIgA?
-to interfere with microbial adhesion

-said to facilitate microbial killing by activating lysozyme
***really an INDIRECT EFFECT
What is mucin?
-component of mucous and saliva

-both SIgA and lysozyme bind to mucin

-if SIgA binds to a bacterium, it will be more susceptible to lysozyme because it is also bound to mucin
Why is SIgA called the silent defender?
-because it does not cause cellular rxns, the immune system is not activated

-does NOT lead to C activation, phagocytosis, or cellular degranulation
Why is SIgA therefore sufficient in protecting the host in many circumstances?
-SIgA interferes with binding, and therefore is good at neutralizing toxins and viruses
What are the two isotypes of IgA in humans?
-IgA 1

-IgA 2
-predominant in most secretions
*in the oral cavity the ratios are nearly equal
How do pathogenic bacteria affect IgA1 and IgA2?
-S. pneumoniae, and H. influenzae are able to secrete a protease that destroys SIgA1

***SIgA2 is not affected by this protease
-Ags that produce allergic reactions in the body
-an overreaction to a substance which is not normally immunogenic or only mildly so
What is Type I or Anaphylactic (Immediate) Hypersensitivity (AH)?
-IgE is present on mast cells and basophils

-IgE is bound by its Fc region to receptors on the cell surface

-when IgE encounters its specific Ag degranulation of mast and basophils occur
What do the granules contain?
-histamine and the leukatrienes LTC4, LTD4, and LTE4

-formerly known as the Slow Reacting Substance of Anaphylaxis or SRS-A
What do the SRS-A do?
-can cause smooth muscle constriction

-other products of the granules cause vasodilation and increased vascular permeability
How fast do Immediate Hypersensitivity Reactions occur?
-within 30 minutes of exposure to the sensitizing Ag

-can be localized: hay fever, hives, or asthma
-Type I if it is systemic and not localized

-substances known to cause fatal anaphylaxis include drugs, bee venom, nuts, peanuts, eggs, and milk
How is the responsible IgE Ab demonstrated?
-by the ability of the pt's serum to passively sensitize the skin of normal, nonsensitive people (Prausnitz-Kustner test)
What is treatment for Type I hypersensitivity?
-avoidance of the allergen, use of immunosuppressive drugs, and by desensitization procedures that are based on blocking IgE activity, the development of tolerance, or by induction of T(s) cells
What releases histamine and where does it bind?
-released by Mast cells and basophils

-binds to two receptors H1 and H2
What does Histamine do when it is bound to H1 receptors?
-when bound to H1 receptor on bronchial SM, histamine causes constriction
What does Histamine do when it is bound to H2 receptors?
-when bound to H2 receptors on endothelial cells histamine causes the cells to change shape resulting in vascular permeability
What signs is Histamine responsible for?
-major signs of systemic anaphylaxis

-difficulty in breathing (asthma) due to SM constriction in the bronchi

-a drop of BP due to the extravasation of fluid into the tissue spaces resulting from increased vascular permeability
-block the H1 receptor

-ineffective in controlling the constriction of SM because of the fact that SRS-A causes prolonged smooth muscle contraction
What substance present in mast cells has an effect similar to that of histamine?
What are 3 life-threatening reactions of systemic anaphylaxis in humans?
1. asphyxiation from laryngeal edema

2. suffocation from bronchiolar constriction

3. loss of adequate BP from overwhelming peripheral edema

***symptoms can be alleviated by the rapid administration of epinephrine
What is hyposensitization?
-the injection of small amounts of antigen over a long period
What is the three fold purpose of hyposensitization?
1. increase the level of IgG specific for the allergen
*IgG competes with the IgE, blocking some of the degranulation of mast cells

2. Induction of tolerance

3. The generation of T(s) cells
How are protective effects of type I hypersensitivity seen?
-in clearance of parasites from the body

-here local anaphylaxic reaction occurs allowing for a local increase in vascular permeabiliity
How does a local increase in vascular permeability help clear parasites from the body in Type I?
-allows eosinophils to rapidly enter the area where the worms are

-they then deposit basic protein on the worms which leads to their expulsion or death
When does Type II or cytotoxic hypersensitivity (CH) occur?
-when Ab is directed against cell surface Ags
What does Ag-Ab binding result in, in terms of Type II hypersensitivity?
-phagocytosis of the tissue cells through Fc or C3b adherence by:

1. C-mediated cytotoxicity
2. Ab Dependent Cell-mediated Cytoxicity (ADCC)
Ab Dependent Cell-mediated Cytoxicity (ADCC)
-occurs when the cells bearing Fc receptors bind to an Ab coated cell and release mediators which kill the cell

-distinct process and is not to be confused with C-mediated lysis
When do blood transfusion incompatibilities occur?
-when mismatched erythrocytes are coated by Abs initiating lysis of erythrocytes and subsequent vascular reactions
Blood transfusion reactions are an example of Type II hypersensitivity
-in serum of most ppl are Abs against nonself blood group Ags

-if pt receives transfusion with an incompatible blood group, Abs in pt blood will lyse the transfused RBCs via the classical C pathway
Why does pathology arise in blood transfusion reactions?
-due to the toxicity of the free hemoglobin from the lysed RBCs received in the transfusion
Why are anti-blood group Abs present even if you have never had a transfusion?
-result of your exposure to normal gut flora

***some bacterial surface Ags are chemically similar to the blood group Ags and hence Abs are produced against the bacteria will cross-react with nonself blood groups
What is the majority of Ab formed in a transfusion reaction?

-explains the agglutination reaction observed between incompatible blood groups
Individuals with blood group O and pregnancy
-a substantial fraction of the anti-A and anti-B is the IgG isotype

-problems with blood group O women carrying a fetus with blood A or B have been reported, but rarely

-most problems are minor and do not require medical treatmen
Erythroblastosis fetalis
-occurs when mothers with Rh- blood type carry a baby with Rh+ erythrocytes

-during birth cord blood mixes and the mother is sensitized to Rh+ erythrocytes from the baby

***mother produces anti-Rh+ IgG
What happens during the second pregnancy if the fetus is also Rh+?
-the anti-Rh+ IgG can cross the placenta and lyses the erythrocytes of the fetus creating a life threatening condition for the fetus
What is Rho-gam?
-trade name for an anti-Rh+ IgG, and is used to treat the condition

-given following every pregnancy involving a Rh+ fetus
How does Rho-gam work?
-it clears the fetal erythrocytes without generating an active immune response to the fetal erythrocytes

-as a result, during second preg there are no anti-Rh+ IgG memory cells--> No antifetal response
What type of pregnancies can sensitize the mother to fetal antigens?

-includes abortions, miscarriages, and stillbirths
How can organ grafts be rejected?
-when Ab is produced in recipients because of incompatibilities with the graft

-usually a strong CMI component as well
What do myasthenia gravis and Grave's disease have in common with Type II hypersensitivity?
-these are autoimmune diseases

-the pathology of autoimmune diseases follow the same course as seen in Type II hypersensitivity
What is Type III hypersensitivity (Immune Complex-mediated hypersensitivity)?
-characterized by the formation of soluble Ag-Ab complexes which result in an acute inflammatory reaction in blood vessels

-due to tendency of immune complexes to "settle out" in cap beds
What are Ag-Ab complex formation dependent on?
1. the amounts of Ag and Ab present which will determine the intensity of the rxn

2. The relative proportions of Ag and Ab, which govern the nature of the complexes

3. Their distribution within the body
What role does Complement play in Type III hypersensitivity?
-C is activated and anaphylatoxins (C3a or C5a) are released causing mediators to be released from platelets that affect vascular permeability
What role do Neutrophils play in Type III hypersensitivity?
-they phagocytose the Ag - Ab complexes

-results in extracellular release of proteolytic enzymes into the vascular area
What is Arthus type hypersensitivity?
-due to Ab excess which produces complexes that are rapidly precipitated and tend to be localized in the site of Ag introduction

-at site of deposition, C is fixed causing local tissue damage
What is Farmer's Lung?
-an example of Arthus type hypersensitivity

-farmer inhales too many bacterial spores, usually in spring when cleaning out what’s left in silo, saturated in spores and endospores

***causes large amount of edema and vascular damage in lungs (often fatal)
Serum Sickness
-can result when a pt is given an antitoxin or antivenom
Antitoxin or antivenom
-Abs directed against the harmful components of the venom or toxin

-antiserum is generated by immunizing a large animal (horse, cow) with the venom
*good bc the animals are big and domestic so you can get a lot out of them
Why do problems arise when using the antitoxin or antivenom?
-bc foreign serum proteins are present and are antigenic

-if pt forms Ab against these components a Type III hypersensitivity rxn may result
If a Type III hypersensitivity reaction occurs from the administration of antivenom what happens?
-Immune complexes deposited into the joints, kidneys, and skin producing local reactions

-Symptoms include fever, vasculitis, arthritis, glomeronephritis (some), rashes, weakness

-Symptoms take 8-12 days to develop
Why can serum sickness occur the first time a pt receives an antivenom?
-this is bc the half-life of IgG (dominant isotype of antivenom) is so long

-the antibody remaining after neutralizing the toxin will remain in circulation for about 23 days
Why does the pt mount an immune response?
-antivenom is an antiserum, there will be unreacted Abs directed against the Ags the horse or cow was exposed to most recently

-pt will perceive these unreacted Abs as foreign --> immune response
Why is the species of animal more important than the venom (snake)?
-so in the future you get bit again, you need to use a different animal because of the fact that you still will likely have circulatory Ab against whatever was in the serum from that animal that you got the initial serum from

-immediate immune response, bad

-two anti-venoms may come from the same species
Rheumatoid arthritis
-example of an autoimmune disease caused at least in part by immune complexes

-rheumatoid factor is an IgM which binds to an abnormal IgG produced in the synovium

-C is fixed -->local inflamation results
What is Type IV (Delayed cellular hypersensitivity) [DTH]?
has the same mechanism of action and kinetics as CMI except it is directed at an allergen

***only one that is strictly cellular sensitivity
T lymphocyte-mediated response is characterized by?
-an infiltration of predominantly macrophages with interstitial deposition of fibrin, with some eosinophils

-patho changes range from cellular infiltration to severe necrosis with fibrinoid vascular lesions
How can DTH be transferred from a sensitized person to a nonsensitized person?
-by sensitized T lymphocytes or by a factor from extracts of T lymphocytes called transfer factor (TF) which turns on a precommited, Ag-sensitive, T lymphocytes
Why is migration inhibition factor (MIF) important?
-the production of MIF by exudate cells from sensitzed people, following incubation with Ag, is widely acceped as an in vitro correlate of DTH
What are many of the effector functions of DTH (and CMI) performed by?

-they can become activated by T cells by Interferon gamma

-activated-->extremely metabolically active

-efficient killers
What are some common causes of DTH?
-soaps, metals, plants, rubber
Macros present Ag to TH1 cells and release:
1. Chemokines-->Macro recruitment

2. Cytokines--> IFN-Y activates macros and increase inflame
-IL-3, GM-CSF -->monocyte production in bone marrow

3. Cytotoxins-->TNF alpha and beta local tissue destruction
Example of DTH: Mantoux Reaction
-performed by the injection of tuberculin into the skin of a person who was previously infected with M. tuberculosis and who had previously developed CMI to tuberculin

-rxn include erythema and induration of the injection site reaching a max of 24-48 hours
CMI (DTH) is involved in?
-organ allograft rejection, parasite clearance, some autoimmune phenomena
-Reaction against self-tissues

-exact cause is unknown

-some correlate with the presence of certain HLA’s.

-some correlate with certain infections
a.) some viruses
b.) bacteria (mycoplasmas without cell walls)
People who carry the HLA-DR5 allele have a threefold greater chance of contracting?
Hashimoto’s thyroiditis
People who have MS are 5x more likely to have what allele?
HLA-DR2 Allele
People with HLA-B27 87 times more likely to have?
ankylosing spondylitis
Autoimmune Hemolytic Anemia
-Ab against own RBCs

-against surface molecules
-destroyed by C’ or phagogcytosis

2 types:
1. Warm Autoanitbodies
2. Cold Agglutinations
Warm autoantibody type of Autoimmune Hemolytic Anemia
-IgG against Rh on RBC surface

-detect by adding Coombs

-react at normal body temperature

-reason for Ab formation is unknown
Cold agglutinins type of Autoimmune Hemolytic Anemia
-fine if body temp is 37 C

-if temp drops, severe hemolysis


-IgM against glycophorin a major protein of erythrocytes

-may be due to viruses or Mycoplasma pneumonia
Myasthenia Gravis
-Autoantibody against Ach receptor at NMJ

-muscle weakness

-Flaccid paralysis

-Binding of acetylcholine is prevented, death occurs by respiratory arrest.
Grave’s Disease
-Autoantibody against Thyroid Stimulating Hormone (TSH) receptor

-when bound stimulates thyroid just as TSH would

-Hyperthyroidism--> there is no feedback inhibition to stop the production of T3 and T4

***Unusual because it is overstimulation rather than destruction of a system
Systemic Lupus erythematosus (SLE)
-Autoantibiodies against components of cell nucleus
-against DNA
-against Histones
-against other nuclear proteins

-Immune complexes form
-Autoantibody + DNA
-tend to settle out in capillary beds
-symptoms determined by location of capillary bed, therapy is constantly changing because the location is constantly changing, where the capillary bed being destroyed
Systemic Lupus erythematosus (SLE) mechanism is similar to what hypersensitivity?
-Similar mechanism to Type III hypersensitivity
In Hashimoto’s Thyroiditis Ab are developed against?
-Several Ag, implicated

1. Against Thyroglbulin, Thyroglobulin--> (stored as colloid***very important to remember, it is not seen by immune system)

2. Against Thyroid epithelium itself
What is the result of Hashimoto’s Thyroiditis?
-Thyroid tissue is destroyed

-hypertrophy of gland, wants to replicate new tissue

-hypothyroidism is the final result
What type of immunity is involved in Hashimoto’s Thyroiditis?
Both cellular and humoral immunity involved
-Type II and Type IV
How does Hashimoto’s and Grave’s relate?
-Same gland--> but two vastly different clinical manifestations

-Different Ag
-Different Diseases
-Different clinical manifestations
MS - Multiple Sclerosis
-Demyelinating disease
-paralysis, No AP
-Probable Autoimmune Disease
-Clinicians waver

-Myelin basic protein is found on the oligodendrocytes

-T helper releases Tumor Necrosis Factor, telling macrophage to destroy the oligodendrocyte

-Lesions similar to that seen in Experimentally induced Allergic Encephalomyelitis (EAE) in animal models
Experimentally induced Allergic Encephalomyelitis (EAE)
-produced in rats by injecting Myelin Basic Protein

-Transient paralysis – low doses
-Fatal – high doses

-thought to be a good model for human MS

***demyelination is a Type IV mechanism
Complement deficiencies: 80% who lack C1, C4 or C2 will develop?

-C3b cannot be produced in adequate amounts, and thus immune complexes stemming from infectious disease, cannot be cleared from the circulation in a normal manner.

-Immune complexes fix C3b on their surfaces and allow cells of the reticuloendothelial system to phagocytose the complexes.

-Remember role of C' in clearing immune complexes. Lack of C5-C9 (MAC) means trouble clearing bacteria
Comment on Autoimmunity
Some autoimmune conditions can be caused by a combination of HLA and infection
Reiters Syn
Chlamydida trachomatis HLA-B27
Chronic arthritis, lyme disease
-Borrelia burgdorferi HLA-DR2, DR4

-sometimes you can get the disease if you are bitten by the tick, but you may not have all of the clinical manifestations of the chronic lyme disease unless you have these markers
How can injury cause an autoimmune disease?
For example if there is injury to the cornea (immonologically privileged site) and corneal proteins enter systemic circulation, you can get autoimmune response to corneal proteins which may affect the uninjured eye

-trauma to one eye release sequest Ags
-Ag presented Act T cells
-T cells find Ag destroy 2 eyes
When should one suspect an autoimmunodeficiency?
-Chronic infections
-Frequent, Recurrent Infections
-Infections involving normal, opportunistic flora
Primary immunodeficiencies
-Affect process before the introduction of Ag
-Ontogency of T and B Cells
-Production of complement
-Phagocytic processes

-Often Congenital
Frequency of Primary immunodeficiencies
-Frequency 1 in 10,000
-Antibody deficiencies 50%
-Combined deficiencies 20%
-Phagocytic disorders 18%
-Defects in CMI 10%
-Complement deficiencies 2%
Immunodeficiencies of Humoral immunity:

X-linked infantile hypogammaglobulinemia
-A.K.A Bruton’s Disease

-Affects > 6 month males (internal antibodies, cant diagnose before)

-high level of IgM means some sort of infection at birth

-At about 6 months, mom’s IgG starts to decrease greatly, the baby should be making own IgG at this point

-can’t tell which is moms which is kids until > 6 months

-Recurrent Infections
-B cell precursors are absent or arrested
How are blood lymphocyte levels in X-linked infantile hypogammaglobulinemia?
-Blood lymphocyte levels are normal – Predominately T-Cells

-Low levels of circulating Abs of all classes

-Lack of humoral immunity (trouble responding to vaccines, its not going to take)

-Incomplete development of lymph nodes

-Rarely reach puberty

-May be failure of VDJ rearangement
Immunodeficiencies of Humoral immunity:

Common variable (acquired) hypogammaglobulinemia
-Varying degree s of deficit

-Can effect either sex

-occur at any age

-Block in development of plasma

-some reports of overactive Ts

-other people report low level of TH

-->both are theoretical possibilities
Immunodeficiencies of Humoral immunity:

IgA deficiency (dysgammaglobulinemia)
-most common (1/500)

-absence of both serum and SIgA

-develop recurrent infections at mucosal surfaces

-Lack of IgA producing precursors

-Lack of TH for IgA product

-Overactive IgA specific TS

-can strike at any age
-->secretory IgM, the concentration
Should you treat IgA deficiency (dysgammaglobulinemia) with gammaglobulin?
-DO NOT treat with gammaglobulin

-going to become hyperimmune to IgA in serum
-gammaglobulin is usually a great thing to give for immunodefiency pts for almost any other deficiency except for this one
40% of pts with ataxia-telagiectasia have what deficiency?
IgA deficiency
Hyper IgM syndrome
-increased [IgM]
-decreased [IgA] and [IgG]

-marked susceptibility to pyogenic infections, otitis media, pneumonia, and septicemia

-***no germinal centers in lymph nodes of pts
Hyper- IgE syndrome
-recurrent pyogenic infections

-deficiency of Ts

-increased [IgE] (usually well under 1% found in serum)


-Other serum Abs normal
Cellular Immunodeficiencies:

DiGeorges’s Syndrome
-Thymic aplasia
-Hypocalcemic tetany (is the first thing diagnosed)

-Severe hypoparathyroidism (tissue of origin is the 3rd and 4th pharyngeal pouches)

-Impaired T cell function, especially TH -->very little immune response

-Low levels of blood lymphocytes (b/c most are T cells)
-Low serum Ab levels
-what’s there is very functional (IgM)

-Ability to mount humoral response to most Ags is absent
How do pt with DiGeorges’s Syndrome die?
-Pt dies of overwhelming infections

****NO IMMUNIZATIONS AT ALL-->they won’t respond

-some success with fetal thymus transplant
--> Not great bc of scarcity and need exact match for at least one HLA antigens

-if pts has some T cells, thymic hormone treatment may help
Cellular Immunodeficiencies

Chronic mucocutaneous candidiasis (CMC)
-infection of normal fungus candida albicans

-“Umbrella” category

-Poorly defined collection

-Either sex, mainly children

-There is some indication the condition may be inherited
What are Combined immunodeficiencies?
-are both humoral and cellular deficiencies
Combined immunodeficiencies:

Reticular dysgenesis
-defect in fetal stem cells
-no WBC, lympho nor leukocytes
-->life expectancy is obviously not long
Combined immunodeficiencies:

Hematopoietic hypoplasia
-severe immunodeficiency of both humoral and cellular responses

-failure to differentiate beyond stem cell stage

***problem with hematopiesis, life expectancy very short
Combined immunodeficiencies:

-Nezelof’s syndrome
-6 mo old fail to thrive

-Chronic diarrhea

-then they die (“shrivel up and die”)

-T cells are low and non-functional

-variable levels of B cells and Abs
Combined immunodeficiency disease (CID)
-Variable presentations

-complete absence of T and B cell function

-or mild abnormalities

-Phagocytic function typically is normal, helping quite a bit

-severity of symptoms is correlated to degree of lymphocyte dysfunction
-->looks like some sort of an enzyme issue, accounts for variation
What are two groups of Combined immunodeficiency disease (CID)
1. without known enzyme defect
2. Known enzyme defect

-Enzyme defects – 15% but thought to eventually count for all or most
****Most common
1. Adensosine deaminase deficiency (ADA)-->nucleotide metabolism

2. Nucleoside phosphrylase deficiencies-->nucleotide metabolism

***Both of these have been approved for gene replacement therapy
Wiskott-Aldrich Syndrome
-X-linked syndrome, Die young
-Allergy related eczema
-recurrent infections
-T cell dysfunction
-elevated levels of [IgE] and [IgA]
-depressed [IgM]
-Overall normal Ab levels (basically IgG is normal)
Ataxia Telangiectasia (AT)
-succumb to chronic infections at young age
-ataxia refers to uncoordinated movement
-Multisystem defect
-Vascular, endocrine, nervous, immune
-Develop progressive cerebellar ataxia and failure of muscular coordination
-Progeric changes (premature aging)
-decreased levels of serum [IgA], [IgE], [SIgA]
-rarely survive past puberty
Intrinsic Phagocyte disorders

Chronic granulomatous disease
-Dysfunction of the enzymes of the respiratory burst (not using O2 for metabolism)
-Cytochrome b
-glucose 6 phosphate DH
-NADPH oxidase
Chronic granulomatous disease and Respiratory Burst
-Respiratory burst-->generating H2O2 and O2-(superoxide radical), OH., oxidized halogens
***we do have enzymes that can neutralize these compounds
-need the O2 and the reducing power

-Respiratory burst is used to kill certain bacteria and fungi following phagocytosis
When is Chronic granulomatous disease diagnosed?
-Diagnosed before age 2

-Susceptibility to infection by organisms of low disease causing ability – multiple abscess formation

-long term survival depends on early diagnosis and aggressive treatment of infections
Intrinsic Phagocytic disorders

Chedick-Higashi Syndrome
-due to fragile lysosomal membranes

-do not degranulate properly

-delayed killing times of bacteria

-burst--> local damage of tissues

-prognosis poor bc of increasing susceptibility to infection and progrssive neruological deterioration
Leukocyte Adhesion deficiencies (LAD)

Deficient expression of CAM’s (cell adhesion molecules)
-defects in cell adhesion molecules

-Interfere with leukocyte adhesion

-abnormal migration

-hypoplasia of lymph nodes, especially t cells, monocytes.

-diminished cytotoxicity

-Early treatment helps
Complement deficiencies
-Defects in all components except factor B

-early components (everything above C5 on both complement pathways)
-C1, C2, C3, C4

-Increase in Immune complex disease--> clinically indistinguishable from SLE

-C3 deficiency is most severe
Why is a C3 defect the most severe in C' deficiencies?
-If C1, C2 or C4 is missing you can still activate complement through alternative pathway

-but if C3 is defective it will knock out both pathways
MAC defect (C5-C9)
-recurrent Neisseria infections and immune complex syndromes like rheumatoid arthritis
Congenital deficiencies of complement regulatory proteins include?
- hereditary angioedema due to C1 inhibitor deficiency
Secondary immunodeficiencies
-defect occurs after antigen challenge.

-many of these are acquired, you don’t inherit them.

-causes include alcoholism, drug abuse, malnutrition, burns, cancer therapy, uncontrolled diabetes, cancer itself, organ transplantation, and infections diseases including viruses (measles, cytomegalovirus, Megabegleyvirus, rubella, HIV are all immunosuppressive).
-Virus targets CD4+ T-cells and macrophages

-(roseola also seeks cd4 positive t cells).

-Macrophages often serve as reservoir for the virus, which can reinfect T cells, virus only grows in activated T-cells, which is one of the reasons why it has such a long latent period between infection an clinical consequence.
Growth of HIV
-grows slowly at first, typically another virus comes along that up-regulates expression of HIV, and T cells start to die off.

-These viruses are common, like herpes, hepatitis b-->HIV grows rapidly and kills the cell.
What happens if too many progeny are produced by HIV?
-when it’s growing slowly will not kill the cell it’s growing on. But if it produces too many progeny it will bud faster than the plasma membrane can repair, and the cell will lyse.
Does HIV try to kill the human cell?
-The virus does not kill the host, what happens is it causes very profound immunosuppression, such that normal stuff you can fight off you can’t fight any more.
What are the causes of death for pts with HIV?
pneumocystis pneumoniae, candidiasis cryptococcal toxoplasmosis, TB, herpes simplex infection. chickenpox, cytomegalovirus

-spread by body fluids, time course 10 years
What is the best way to diagnose HIV?
-Diagnosed with ELISA and confirmed by Western Blot
What are attempts to fight HIV?
-Potential drugs include reverse transcriptase inhibitors, protease inhibitors

-virus when it buds is not infectious, capsid is not well formed, if you can interfere with it’s maturation, the virus will not be infective, this is what protease inhibitors do.