Pathoma Chapter 2

Front 1

tissue necrosis is always followed by?

Back 1

Acute Inflammation (↑ in Neutrophils)

Front 2

Goal of acute inflammation?

Back 2

Eliminate pathogen

or

Clear Necrotic Debris

Front 3

How do Macrophages recognize G- bacteria?

Back 3

Recognize LPS on G- bacteria w/ CD14 receptor

Front 4

Describe pathway of TLR's

Back 4

1) PAMPs activate TLR's on macrophages/lymphocytes

2) Causes upregulation of NF-kB (transcription factor)

3) NF-kB -> production of multiple immune mediators

Front 5

TLR on B-cells importance

Back 5

TLR activation/signaling helps with IgM response (Tcell Indipendent)

Front 6

Arachidonic Acid Metabolites

Back 6

Arachidonic Acid released from cell membrane by Phospholipase A2

Acted upon by:

COX => prostoglandins, prostocyclines, thromboxanes

5-lipoxygenase=> leukotrienes

Front 7

Factors that mediate Vasodilation and Increases Vascular Permeability

Back 7

PGD2, PGE2, PGI2 =

DEI= "God"

vasodilation & increased vascular permeabiity are

"prosto Gods (DEI)" of inflammation

Front 8

mediates pain and fever

Back 8

PGE2 - fEver and pain

Front 9

Neutrophil chemoattractants

Back 9

LTB4

IL-8

C5a

Neutrophil says, "I come only if I, "C 5 B4 I 8" - See 5 (o'clock) before I ate"

Front 10

Vasoconstriction, Bronchospasm, & Increased Vascular Permeability mediate by:

Back 10

* LTC4
* LTD4
* LTE4

Leukotrienes cause smooth muscle contraction -- bronchial muscles (Bronchospasm), smooth muscle in vessels (Vasoconstrict) and pericytes(edema)

"To constrict, you have to TRY C, D, E, be4 giving up."

Front 11

Vasodilation occurs at the...

Back 11

arteriole ->slows down flow so that leukocytes can attach to wall

Front 12

increased vascular permeability occurs at...

Back 12

venule - once attached to wall leukocytes can extravasate, and swelling creates room for entering leukocytes

Front 13

Mast cells activated by

Back 13

1) tissue trauma,

2) C3a, C5a

3) cross linking by IgE on Fc receptors

Front 14

Mast cell immediate response

Back 14

Release Histamine -> vasodilation and increase permeability

Front 15

Mast cell delayed response

Back 15

Release Leukotrienes (LTC4, LTD4, LTE4)=> contract smooth muscle ->

1. vasoconstriction
2. bronchospasm
3. increase vascular permeability

Front 16

Complement System

Back 16

Classical Pathway -> C1 binds IgG or IgM that's bound to antigen

Alternative pathway -> microbial products directly activate complement

Mannose binding lectin pathway -> MBL binds to mannose on microorganisms and activates complement

Front 17

Review Complement pathway

Back 17

Front 18

DIC Pathophysiology

Back 18

Tissue Factor (TF=Normally foundsuendothelially) release into circulation due to either

1) Damage

2) IL-1/TNF (normally endothelial cells do not express, only in response to these)

3) Endotoxin->

TF binds activated factor VIIa->Activates Extrinsic Pathway

Front 19

Cardinal Signs of inflammation

Back 19

1) Redness (rubor) = caused by Histamine mediated vasodilation

2) Warmth (calor) = also caused by Histamine mediated vasodilation

3) Swelling (tumor) = caused by Histamine mediated increase in vascular permeability

4) Pain (dolor) mediated by Bradykinin & PGE2 which sensitize nerve endings

5) Fever due to IL-1 & TNF -> ↑ cyclooxygenase activity in perivascular cells of the hypothalamus -> increases local PGE2 synthesis -> raises temperature setpoint

Front 20

Leukocyte margination occurs through?

Back 20

postcapillary venules!

Cells marginate from center flow to the periphery due to turbulence caused by slow down of blood flow from arteriolar vasodilation

Front 21

Leukocyte ROLLING occurs via?

Back 21

Selectin speed bumps

(upregulated in endothelial cells)

Histamine -> release of P-selectin from Weibel-Palade bodies in endothelial cells

TNF and IL-1 -> release of E-selectins

Interaction of Sialyl Lewis X on Leukocytes w/ P-selectin and E-selectin causes leukocytes to roll along vessel wall

Front 22

What does selectin on endothelial cells bind on leukocytes (Neutrophils, Macrophages, etc)

Back 22

Sialyl Lewis X

Front 23

Leukocyte ADHESION to endothelial cells occur via?

Back 23

Adhesion molecules: ICAM and VCAM upregulated by TNF & IL-1

ICAM & VCAM bind to Integrins on leukocytes

TNF & IL-1 :

1) Rolling (Release E-selectins on Endothelial cells)

2) Adhesion (ICAM/VCAM expression on Endothelial cells)

3) Tissue Factor release from Endothelial cells

4) Fever: b/c ↑COX activity in Perivascular cells of Hypothalamus->↑PGE2

Front 24

What causes upregulation of adhesion molecules?

Back 24

IL-1 & TNF

Front 25

What causes upregulation of selectins on Endothelial cells?

Back 25

Histamine causes release of P-selectin from Weibel Palade bodies

TNF & IL-1 for E-selectin

Selectins bind to Sialyl Lewis X on Leukocytes (Neutrophils, Macroph)

Front 26

What causes upregulation of integrins on leukocytes?

Back 26

C5a & LTB4, the chemotactic factors! (this is how they achieve Neutrophil chemotaxis)

Front 27

MCC of leukocyte adhesion deficiency?

What is the clinical presentation?

Back 27

Lack of leukocyte extravasation from blood into tissues due to Defective CD18 (Integrin component)

NOTABLE CLINICAL SIGNS:

1) Failure of umbilical cord to detach

2) INCREASED circulating neutrophils because they can't be stored by attaching to vascular walls (marginated pool)

3) Recurrent bacterial infections that LACK pus formation

*pus=dead neutrophils sitting in fluid

Front 28

Opsonins...?

Back 28

IgG and C3b

Front 29

Chediak-Higashi syndrome

Back 29

Impaired phagolysosome formation

Pathophys: Microtubule polymerization disorder: "tracks" to get around the cell are broken->transport of phagosomes is deficient

Front 30

Giant granules in leukocytes and defective primary hemostasis, albinism

Back 30

Chediak-Higashi syndrome = Abnormal dense granules in Golgi apparatus->impaired primary hemostasis

Gant granules (in leukocytes) arise from fusion of granules in Golgi since they are NOT able to move

Front 31

Generation of bleach

Back 31

O2 -NADPH Oxidase (oxidative burst)->

O2- radical -Superoxide Dismutase->

H2O2 -MPO->

HOCl

Front 32

NTB dye

Back 32

O2-->O2 radical

If NADPH oxidase works, will stain blue

Front 33

Chronic Granulomatous Disease

What organisms are you susceptible to?

Back 33

Poor O2 dependent killing due to NADPH oxidase defect

Vulnerable to Catalase + organisms:

Reaction of catalase in the decomposition of hydrogen peroxide in living tissue:

2 H2O2 → 2 H2O + O2

Staph aureus

Pseudomonas capacia

Serratia marcescens

Nocardia

Aspergillus

Front 34

MPO Deficiency

Back 34

Defective conversion of

H2O2 -> HOCl

↑ risk for Candida infections

Front 35

Leukocyte O2 independent killing

What does it bind to?

Back 35

Reliant on lysozyme and major basic protein

Bind heparin sulfate proteoglycans

Front 36

Anti-inflammatory cytokines produced by macrophages? Pro-inflammatory cytokines produced by macrophages?

Back 36

Anti-inflammatory: IL-10 & TGF-ß

Pro-inflammatory: IL-8

Front 37

Macrophage management of Acute Inflammation

Back 37

Resolve with IL-10 & TGF-ß

Continue inflammation with Neutrophil recruitment using IL-8

Abscess Chronic inflammation via CD4 lymphocytes

Front 38

Histological description of plasma cells

Back 38

Plasma cells have eccentric nucleus with slight pale pallor next to nucleus

Not multilobulated like neutrophils.

Front 39

T cells have what receptors

Back 39

TCR and CD3 on all T cells.

Front 40

CD4+ TH-cell activation

Back 40

APC presents antigen on MHC II binds TCR

B7 on APC binds T-cell CD28 receptor

Front 41

Th1 cytokines

Back 41

IL-2 (T-cell growth factor and CD8+ activator)

IFN-γ

IL-6 (pyrogen, stimulates acute phase proteins)

Front 42

Th2 cytokines

Back 42

IL-4 (facilitates B-cell class switch to IgE & IgG)

IL-5 (eosinophil chemotaxis and activation, B cell maturation to plasma cells and class switch to IgA)

IL-10 (inhibits Th1 phenotype)

Front 43

CD8+ Cytotoxic T-cell activation how does it initiate apoptosis?

Back 43

Intracellular antigen presented on MHC I

IL-2 from TH1(CD4+) Tcell: confirmatory

CD8 induces apoptosis via perforin and granzyme GRENADES or Expression of FasL which binds to Fas receptor on cells inducing apoptosis

Front 44

B-Cell activation

Back 44

Ag binding by surface IgM or IgD->maturation to IgM or IgD secreting plasma cells

No second signal needed if enough Ag present to activate & cross link Ig's or Ag activates TLR

Alternate Pathway: B-cell presents Ag to TH2 T-cell via MHC II -- CD40 receptor on B cell binds CD40L on TH2 as 2nd signal -- Th2 secretes IL-4 and IL-5 to mediate isotype switching, hypermutation and plasma cell maturation

Front 45

A granuloma is characteristically defined by

Back 45

epithelioid histiocytes (Macrophages with abundant pink cytoplasm) usually surrounded by lymphoctes/giant cells

Front 46

Characteristic of non-caseating granuloma. Common causes?

Back 46

Lacks central necrosis

Usually caused by: 1)Sarcoidosis

2) Reaction to foreign material

3) beryllium exposure

4) Crohn's disease

5) Cat scratch disease(Bartonella hensellae)

Front 47

Characteristic of Caseating granulomas

Back 47

central necrosis characteristic of tuberculosis and fungal infections

Front 48

Steps for Granuloma formation

Back 48

1) Macrophage Processes Ag

2) MHC II on Macrophage presents Ag on MHC II to CD4+ cell

3) Macrophage secretes IL-12 differentiating CD4+ to TH1

4.) TH1 secretes IFN-γ converting macrophages to Epithelioid histiocytes and Giant cells

Front 49

DiGeorge Syndrome

Back 49

Failure of 3rd and 4th pouch development due to 22q11 microdeletion->

1) T-cell deficiency (lack of thymus)

2) Hypocalcemia (lack of parathyroids)

3) Abnormalities of Heart, great vessels, & face

Front 50

lack of thymus, hypocalcemia and abnormalities in heart and great vessels

Back 50

DiGeorge Syndrome (22q11 microdeletion) ->

1) Lack of thymus ->T-cell deficency (recurrent infections)

2) Lack parathyroids ->hypoparathyroidism (low PTF) causing hypocalcemia

Front 51

Bruton's Agammaglobulinemia or X-linked Agammaglobulinemia

Back 51

Complete lack of Ig due to disordered B-cell maturation->

Naive B cells can NOT mature into plasma cells ->No Ig secreted (Due to mutation in a tyrosine Kinase)

Front 52

Recurrent bacterial, enterovirus (polio, coxsackie), and giardia lamblia

after 6 months of life

Back 52

Bruton's agammaglobulinemia

Presents >6 months b/c Mother's Ig's present first 6 months.

Enterovirus infection due to lack of IgA

Front 53

Severe Combined Immunodeficiency

Back 53

Combined humoral and cell-mediated defect, so usually involves TH cells b/c they mediate both

Can be due to multiple causes

1) Due to Cytokine receptor defect, leads to failure to development and differentiation of T and B cells (specifically IL-2R which promotes Tcell activation) - b/c IL-2Receptor located on X chromosome = called X-linked SCID

ADA (adenosine deaminase deficiency=Adenosine ) & MHC Class II deficiency ADA involved in breakdown of purines. Lack of ADA causes accumulation of dATP. This metabolite will inhibit the activity of ribonucleotide reductase, the enzyme that reduces ribonucleotides to generate deoxyribonucleotides. Without functional ribonucleotide reductase, lymphocyte proliferation is inhibited and the immune system is compromised.

MHC class II NECESSARY for CD4 to do anything

Front 54

most common selective Ig deficiency? a/w?

Back 54

IgA defficiency -> celiac disease and viral gastroenteritis

All upper respiratory diseases

this is why many people get anaphylactic rxns. w/ blood transfusions

Front 55

Hyper-IgM Syndrome etiology?

Back 55

Elevated IgM Mutated CD40L (T-cells) or CD40(B-cells) - as such second signal cannot be delivered for required class switching

Front 56

thrombocytopenia, eczema, recurrent infections

Back 56

defective humoral and cellular immunity due to WASP gene. This is X-linked. Called Wiskott-Aldrich Syndrome Small platelets that do not function properly are removed by the spleen causing the thrombocytopenia

WASp activates actin polymerization by binding Arp2/3 complex necessary for immunological synapse

In T-cells, WASp is important because it is known to be activated via T-cell receptor (TCR) signaling pathways to induce formation of immunological synapse

Immune deficiency caused by decreased Ab production & inability of T cells to form synapse (combined immunodeficiency)

Front 57

C5-C9 deficiencies

Back 57

increased risk for Neisseria infection

Front 58

hereditary angioedema, edema of the skin, periorbital edema and mucosal surface

Back 58

C1 inhibitor deficiency C1 inhibitor is a serine protease inhibitor that is the most important inhibitor of kallikrein in the body. decreased C1 inhibitor --> increased kallikrein --> increased bradykinin --> increased permeability

Front 59

What's a method of T-cell inactivation that occurs after mature T-cells leave thymus?

Back 59

Anergy - stimulation without second signal deactivates them

Front 60

Systemic Lupus Erythematosus is what type of hypersensitivity?

Back 60

TypeII & III hypersensitivity, Antibodies against host damage multiple tissues, and depositing immune complexes cause further damage

Front 61

Classic symptom of SLE

Back 61

Renal damage -- diffuse proliferative glomerulonephritis

Front 62

Small sterile deposits on both sides of heart valve

Back 62

Libman-sacks endocarditis secondary to SLE Caused by non-infectious inflammatory response to Ag-Ab caused by Lupus

Front 63

Lupus lab test findings

Back 63

ANA positive, anti-dsDNA (highly specific)

Front 64

anti-histone antibody Common associations?

Back 64

drug induced lupus, reversible common drugs, hydralazine, procainamide, isoniazid

Front 65

increased PTT time but hypercoaguable?

Back 65

think lupus anticoagulant or anticardiolipin(cardiolipin is present on mitochondrial membrane)

Front 66

recurrent pregnancy loss in female with fever and weight loss

Back 66

Anti-cardiolipin Ab or Lupus anti-coagulant cause frequent thrombosis in arteries and veins

ARTERIES AND VEINS causing DVT's

hepatic vein thrombosis (Budd-Chiari)

placental thrombosis(recurrent pregnancies)

stroke

Front 67

Unilateral enlargement of the parotid gland

Back 67

B-cell lymphoma in marginal zone secondary to Sjogren's

Front 68

CREST Scleroderma

Back 68

C - Calcinosis/anti-Centromere antibodies

R - Raynaud's

E - Esophageal Dysmotility

S - Sclerodactyly

T - Telangiectasias

Front 69

Lots of dental carries and corneal abrasions. What do you test for?

Back 69

ANA and anti-ribonucleoprotein (anti-SS-A/Ro and anti-SS-B/La)

Front 70

Sjogren's associated with?

Back 70

Auto-immune attack of salivary & lacrimal glands -> development of xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes) ->lymphocytic infiltration of the glands

Iinflammatory process eventually severely damages or destroys the glands

If both parotid glands swell

If 1 parotid gets worse, think: B-cell lymphoma in the MARGINAL zone

Front 71

Anti-U1 Ribonucleoprotein (Anti-U1RNP)

Back 71

mixed connective tissue disease features from SLE, systemic sclerosis and polymyositis

Front 72

Stem cells of lung...

Back 72

Type II Pneumocyte

Front 73

Stem cell of GI tract

Back 73

Mucosal Crypts

Front 74

Stem cell of bone marrow are positive for what molecule?

Back 74

CD34+ = HSC

Front 75

What type of collagen present in keloids?

Back 75

Type III collagen (that is why so soft) Also present in blood vessels and embryonic tissue and early wound healing

Front 76

Collagen in early wound healing

Back 76

Type III collagen

Front 77

What cofactor does collagenase require?

Back 77

Zinc

Front 78

TGF-α

Back 78

Epithelial & Fibroblast

growth factor

Front 79

TGF-β

Back 79

1) Important fibroblast growth factor

2) Inhibits inflammation

Front 80

Platelet Derived Growth Factor (PDGF)

Back 80

Growth Factor for:

1) Endothelium

2) Smooth muscle

3) Fibroblasts

Front 81

Fibroblast Growth Factor (FGF)

Back 81

1) IMPORTANT FOR ANGIOGENESIS

2) mediates skeletal development

Front 82

what kind of signaling is wound healing mediated by?

Back 82

paracrine macrophages secrete growth factors that target fibroblasts

Front 83

Necessary factors for wound healing

Back 83

1) Zinc

2) Copper

3) Vitamin C

Front 84

What role does Vit C play in wound healing

Back 84

Hydroxylates proline residues so that they can cross link each other and form collagen

Front 85

What role does Copper play in wound healing?

Back 85

Cofactor for lysyl oxidase which cross-links lysine and hydroxylysine to form stable collagen (Hydrogen Bonding)

Front 86

What role does Zinc play in wound healing?

Back 86

Zinc is a cofactor for collagenase, which replaces type III collagen of granulation tissue with the stronger type I collagen

Front 87

African-American recently got an ear piercing

What should you be afraid of?

Back 87

Keloid formation. Characterized by type III collagen overproduction

Front 88

What collagen is a hypertrophic scar made out of?

Back 88

Type I Collagen

Front 89

Compare hypertrophic scar with keloid

Back 89

keloid = overgrowth of granulation tissue (type III collagen) at the site of a healed skin injury that grows far beyond the boundaries of the original wound (slowly replaced w/ Type 1 Collagen, but is HUGE!)

hypertrophic scar = excessive amounts of Type 1 Collagen which gives rise to a raised scar - but is limited to site of wound (due to excessive TGF-β)

Front 90

Treat antiphospholipid syndrome with?

Back 90

lifelong anti-coagulants

Front 91

Defects in Inteferon Signaling predispose to what kind of infection?

Back 91

Mycobacterium tuberculosis, b/c Macrophage will produce IL-12 upon phagocytosis of M. tuberculosis, and TH1 in turn, wil produce IFN-Gamama. IGN Gamma that induces Mphage to engage in phagocytic killing

Additionally IFN_Gamam induces upregulation of MHC. These pts will therefore need liefelong anti-mycobacterial antibiotics

Front 92

Thymus Cortex and Medulla: Tcell Maturation

Back 92

Cortex:Positive Selection

Medulla: Negative Selection

Front 93

Low C1 esterase inhibitor is diagnostic for:

Back 93

Angioedema

Front 94

Angioedema

Back 94

Inherited Autosomal Dominant condtion painless, non-pitting, well circumscribed edema

Face neck lips, and tongue most often affected, but internal organs can swell as well

If affects tracheobronchial tree, can cause respiratory obstruction & is potentially fatal

Front 95

Types of Organ Rejection

Back 95

Host vs. Graft

Graft vs. Host

Front 96

Types of Host vs. Graft Rejection

Back 96

Hyperacute - Happens almost immediately. It is due to preformed Anti-ABO Ab's. The inflammation is so severe that it leads to acute thrombosis of vascular supply->infarct. Screening for ABO blood grp. incompatability has eliminated Hyperacture rejection.

Acute Rejection - Happens 1-4 wks following transplant. Host Tcells get sensitized to graft MHC Ag.

Chronic

Front 97

Prevention and Tx of Acute Graft Rejection.

Back 97

Precention - calcineurin Inhibitors: cyclosporine & tacrolimus

Calcineurin: When APC interacts with Tcell->Increase in Cytoplasmic Ca2+->Activating Calcienurin->Incr IL-2->IL-2 activates TH cells

Amount of IL-2 produced by TH cells significantly influences extent of immune response

Tx. Add corticosteroids to Calcineurin Inhibitors

Front 98

IL-5

Back 98

Made by TH2 cells

Promotes Production/Activation of Eosinophils

Promotes Bcell synthsis of IgA production

Front 99

IL-4

Back 99

Promotes IgE Ab production by Bcells

Front 100

IL-2

Back 100

Stimulates TH1 cell proliferation

Front 101

IFN-Gamma

Back 101

Stimulates Macrophage Activation

Front 102

IL-10

Back 102

Downregulates Immune responses. Produced by Macrophages if they enter after Acute Inflammation (Neutrophils) and that pathogen/necrosis is cleared

Front 103

IL-3

Back 103

Supports growth/differentiation of BM stem cells

Front 104

IL-1

Back 104

Produced by Macrophages (after CD4+ THcell TCR binds to MHC Class2 on Macrophage) and induces TH cells to proliferates/secrete lymphokines