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Pathoma > Chapter 2 > Flashcards

Chapter 2 Flashcards

1
Q

What characterizes acute inflammation ?

A

The presence of Edema and neutrophils

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2
Q

Acute inflammation is the process which follows which two events

A

Infection
tissue necrosis

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3
Q

Acute Inflammation is an example of what type of immunity ?

A

Innate

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4
Q

What are the mediators of acute inflammation?

A

Toll-like receptors (TLRs)
Arachidonic Acid metabolites
Mast Cells

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5
Q

What are Toll-like receptors, and how do they work ?

A

these are receptors present cells of innate immunity (dendritic cells and macrophage)
They are activated by Pathogen associated molecular patterns (PAMPs) that are commonly shared by microbes
This activativation results in upregulation of NF-kB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators.
TLRs are also present on cells of adaptive immunity and therefore, also play an important role in mediating chronic inflammation

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6
Q

How do Arachadonic acid metabolites work

A

AA is released from the phospholipid plasma membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase

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7
Q

what happens when arachadonic acid is acted upon by cyclooxygenase compared to 5-lipoxygenase

A

cycloxygenase produces prostaglandins
PGI2, PGD2, and PGE2 mediate vasodilation and increased vascular permeability
PGE2 also mediates pain and fever

5-lipoxygenase produces leukotrienes
LTB4 attracts and activates neutrophils
LTC4 LTD4 and LTEs (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm and increased vascular permeability

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8
Q

How are mast cells activated

A

Mast cells are widely distributed throughout the connective tissue and become activated when there is damage to the tissue which results in activation of complement proteins c3a and c5a or cross-linking of cell surface IgE by antigen

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9
Q

Define Immediate and delayed response as it relates to mast cells

A

Immediate response involves the release of preformed histamine granules, which mediate vasodilation and increased vascular permiability

Delayed response involves production of arachadonic metabolites particularly lekoturienes

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10
Q

What are the three pathways by which complement cascade is activated

A

i. classical pathway - C1 binds IgG or IgM that is bound to antigen
ii. Alternative pathway - Microbial products directly activate compliment
Mannose-binding lectin (MBL) pathway - MBL binds to mannose on microorganism and activates complement

all 3 pathways result in production of C3 convertase which mediaters C3—>C3a (which then produces C5 convertase) C5—>C5a and C5 b. C5 b complexes with c6-9 to form the membrane attack complex (MAC)

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11
Q

what is the function of C3a, c5a , c3b and MAC

A

C3a and C5a (anaphylatoxins) trigger mast cell degranulation, resulting in histamine-mediated vasodilation and increased vascular permeability
C5a- chemotactic for neutrophils
C3b- opsonin for phagocytosis
MAC- lyses microbes by creating a hole in the cell membrane

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12
Q

what is Hageman factor (Factor XII

A

the hageman factor / Factor XII is an inactive proinflammatory protein produced in the liver . when exposed to subendothelial or tissue collagen it activates
i. coagulation and fibrinloytic systems
ii. complement
iii. kinin system- Kinin cleaves high molecular weight kininogen (HMWK) to bradykinin, which mediates vasodilation and increased vascular permeability (similar to histamine) as well as pain .

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13
Q

What are the key mediators for each cardinal sign of inflammation

A

Redness : vasodilation and increased blood flow (histamine, Prostaglandins and bradykinin

Swelling : leakage of fluid from postcapillary venules into the interstitial space (exudate) (histamine- causes endothelial cell contraction and tissue damage, resulting in endothelial cell disruption)

Pain : Bradykinin and PGE; sensitize sensory nerve endings

Fever : PGE2 raises temperature set point
Pyrogens (LPS from bacteria) causes macrophages to release IL-1 and TNF, which increase cyclooxygenase activity in perivascular cells of the hypothalamus.

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14
Q

Define the 5- step process by which Neutrophils arrive and carry out their function

A

Step 1 - Margination
vasodilation slows blood flow in the postcapillary venules .
cells marginate from center of flow to the periphery

Step 2 - Rolling
Selectin “speed bumps” are upregulated on endothelial cells.

P selectin release from Weibel palade bodies is mediated by histamine
E selectin is induced by Il-1 and TNF

Step 3-Adhesion
Cellular adhesion molecules (ICAM and VCAM) are upregulated on endothelium by IL-1 and TNF
Integrins are upregulated by C5a LTB4
Interactions between CAMs and integrins result in a firm adhesion of leukocytes to the vessel wall

Step 4- Transmigration and chemotaxis

Leukocytes transmigrate across the endothelium of postcaplillary venules and move towards its attractants (LTB4,C5a,IL-8 and bacterial products)

Step 5 - Phagocytosis

Consumption of pathogens or necrotic tissue; phagocytosis is enhanced by opsonins C3b and IgG )
Pseudopods extend from leukocytes to form phagosomes which are then internalized and fused with lysosomes to produce phagolysosomes

Step 6 ; Destruction of phagocytosed material

O2 dependent killing is the most effective mechanism
HOCL(bleach) generated by oxidative burst in tphagolysosomes destroys phagocytosed microbes .]

Step 7: Resolution
Neutrophils undergo apoptosis and disappear within 24hrs after the resolution of inflammatory stimulus

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15
Q

What enzymes are involved in the production of HOCL from o2 in phagolysosomes

A

NADPH oxidase converts O2 to O2-
Superoxide dismutase converts O2- to H2O2
Myeloperoxide converts H2O2 to HOCL

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16
Q

Clinical features of delayed umbillical cord seperation and recurrent infections which lack pus formation, indicate which autosomal recessive defect ?

A

Autosomal recessive deficiency of integrins (CD18 subunit) which results in leukocyte adhesion deficiency

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17
Q

Define Chronic Granulomatous disease (CGD)

A

CGDis characterized by poor O2 dependent killing
i. Due to NADPH oxidase defect (X-linked autosomal recessive)
ii. Leads to recurrent infection and granuloma formation with catalase-positive organisms , particularly (Stapyhlococous aureus,Pseudomonas cepacia, Serratia marcescens, Nocardia and Aspergillus )

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18
Q

How does Nitroblue Tetrazolium test for CGD

A

Leukocytes are incubated with NBT dye, which turns blue if NADPH oxidase can convert O2 to O2-, but remains colourless if NADPH oxydase is defective

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19
Q

Macrophages predominate after neutrophils and peak when ?

A

2-3 days

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20
Q

How do Macrophages arrive in tissue from blood vessels

A

Same way as neutrophils , Margination, Rolling, Adhesion, Transmigration

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21
Q

When macrophages phagocytose organisms how do they destroy phagocytosed material

A

O2 independent killing

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22
Q

What products are produced by macrophhages in the inflammatory process and what are their functions ?

A

Resolution and healing - Anti-inflammatory cytokines (IL-10 and TGF-B )
Continued acute inflammation - Il-8 produced by macrophages and recruit more neutrophils, marked by persistent pus formation.
Abscess- acute inflammation surrounded by fibrosis; macrophages mediate fibrosis by fibrinogenic growth factors and cytokines
Chronic Inflammation- Macrophages present antigen to activate CD4+ helper cells, which secrete cytokineonic inflammatios that promote chronic inflammation.

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23
Q

Define chronic inflammation

A

Characterized by the presence of lymphocytes and plasma cells in tissue
Delayed response, but more specific (adaptive immunity) than acute inflammation

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24
Q

Where are progenitor T cells produced

A

in the bone marrow

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25
Q

Where do T cells develop and what happens to develop them

A

Further development takes place in the thymus where T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4+ helper T cells or CD8+ cytotoxic T cells

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26
Q

What is the function of the TCR complex

A

TCR complex is comprised of T-cell receptor and CD3 and it is used for antigen surveillance.
TCR complex recognizes antigen presented on MHC molecules

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27
Q

What MHC molecule is recognized by CD4+ T cell ?

A

MHC class II

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28
Q

What MHC molecule is recognized by CD8+ T cell ?

A

MHC Class 1

29
Q

What are the requirements for T cell activation ?

A

binding of MHC/antigen complex and additional 2nd signal

30
Q

Explain CD4+ helper T cell activation

A
  1. Extracellular antigen (eg foreign proteins) is phagocytosed, processed and presented on MHC class II, which is expressed by APCs
  2. B7 on APCs binds CD28 on CD4+ helper T cells providing second activation signal
    3 Activated CD4+ helper T cells secrete cytokine that “help” inflammation and are divided into two subsets

TH1 subset: secretes IL-2 (T cell Growth factor and CD8+ T cell activator) and IFN-y (macrophage activator.
TH2 subset: secretes IL-4(Faclitates B cell class switching to IgG and IgE), IL-5(eosinophil chemotaxis, maturation of B cells to plasma cell and class switching to IgA), and IL-10(Inhibits TH1 phenotype)

31
Q

Explain what happens when CD8+ cytotoxic T cells are activated

A

Intracellular antigen (derived from proteins in the cytoplasm ) is processed and presented on MHC class I, which is expressed by all nucleated cells and platelets.

IL-2 from CD4+ TH1 cell provides 2nd activation signal
Cytotoxic T cells are activated for killing

32
Q

What is the mechanism by which cytotoxic CD8+ T cells kill

A

Secretion of perforin and granzyme , perforin creates pores that allow granzymes to enter target cell, activating apoptosis

Expression of FasL, which binds Fas on target cells, activating apoptosis .

33
Q

Which Ig molecules are expressed by immature B cells

A

IgM and IgD

34
Q

What are the two ways in which B cell activation occurs

A

Antigen binding by IgM or IgD, results in maturation to IgM and IgD secreting plasma cells

1st signal: B cell antigen presentation to CD4+ helper T cells via MHC class II
2nd signal : CD40 on B cells bind CD40L on helper T cell. Helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation and maturation to plasma cells)

35
Q

What is Granulomatous inflammation

A

A subtype of Chronic inflammation characterized by granuloma which is a collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm) usually surrounded by giant cells and a rim of lymphocytes.

36
Q

What are the steps involved in granuloma formation ?

A
  1. Macrophage process and present antigen via MHC class II to CD4+ helper T cells
    2 Interaction leads macrophages to secrete IL-12, inducing CD4+ helper T cells top differentiate into TH1 subtype
    3 TH1 subtype secrete IFN-y, which converts macropahges to epithelioid histiocytes and giant cells
37
Q

What is DiGeorge Syndrome

A

Developmental failure of 3rd and fourth pharyngeal pouch
Presents with T cell deficiency (Lack of thymus), hypocalcemia(lack of parathyroids) and abnormalities of the heart, great vessels and face

38
Q

What are some causes of non-caseating granulomas

A

(lack central necrosis)
1. reaction to foreign materials
2.Sarcoidosis
3.beryllium exposure
4.Crohn Disease
5.Cat scratch dx

39
Q

What are some causes of caseating granuloma ?

A

(exhibit central necrosis)
1.TB and fungal infections

40
Q

Define SCID (Severe Combined Immunodeficiency)

A

Defective cell-mediated and humoral immunity
Characterized by susceptibility to fungal, bacterial and protozoal infections, including opportunistic infections and live vaccines
Treatment is with sterile isolation (bubble baby) and stem cell transplantation

41
Q

What are the etiologies of SCID

A

Cytokine receptor defects - Cytokine signalling is necessary for proliferation and maturation of B and T cells

Adenosine Deaminase (ADA) deficiency - ADA is necessary to deaminate adenosine and deoxyadenosine for excretion of waste products, build up of adenosine and deoxyadenosine is toxic to lymphocytes

3 MHC Class II deficiency - MHC class II is necessary for CD4+ helper T cell activation and cytokine production

42
Q

Define X-Linked agammaglobulinemia

A

A complete lack of immunoglobulin due to disorder in B cell maturation
1 Naive B cells cannot mature to plasma cells
Due to mutated Tyrosine Kinase , X-Linked

43
Q

What are some important factors about presentation of X-linked agammaglobulinemia ?

A

Presents after 6months of age (when mothers immunity disappears)
recurrent bacterial, enterovirus (polio and coxsackievirus) and Giardia Lamblia infections
Live vaccines (eg. Polio) must be avoided

44
Q

Common Variable Immunodeficiency (CVID)

A

Low Immunoglobulin due to B-cell or helper Tcell defects
Increased risk for bacterial, enterovirus(eg. polio and coxsackie) and Giardia Lamblia
Usually presents in late childhood

45
Q

Children with CVID are at an increased rick for ?

A

Lymphoma and autoimmune dx

46
Q

IgA deficiency

A

Low serum and mucosal IgA (most common IG deficiency)
Increased rick for mucosal infection, especially viral, however most patients are asymptomatic

47
Q

Hyper-IgM syndrome

A

Characterized by elevated IgM and Low IgA,IgE,IgG (result in recurrent pyogenic infections due to poor opsonization), especially at mucosal sites

results from mutated CD40L(on helper T cells or CD40 receptor on Bcell

  1. second signal cannot be delivered to helper T cell during B cell activation
  2. Consequently, cytokines necessary for immunoglobulin class switching are not produced .
48
Q

Wiskott-Aldrich Syndrome

A

Characterized by thrombocytopenia, eczema and recurrent infections (defective humoral and cellular immunity)
Mutation in WASP gene; X-Linked

49
Q

Complement deficiencies

A

C5-C9-Increased risk for Neisseria infection(N meningitidis and N gonorrhoea
C1 inhibitor deficiency results in hereditary angioedema, characterized by edema of the skin (especially periorbital) and mucosal surfaces

50
Q

What are the ways in which Autoimmune diseases arise (ie loss of self tolerance)

A

Self-reactive lymphocytes are regularly generated but undergo apoptosis (negative selection) in the Thymus (Tcells) or bone marrow (Bcells) or become anergic (due to recognition of antigen in peripheral lymphoid tissue with no 2nd signal)

51
Q

What are the two mechanisms that mediate the systemic autoimmunity in patients with SLE

A

Autoantibodies against the host damage multiple tissues via type II hypersensitivity (cytotoxic) and Type III hypersensitivity (antigen-antibody complex)

52
Q

Clinical features of SLE

A

Malar “butterfly” rash, esp on exposure to sunlight
discoid rash
Arthritis
Pleuritis and pericarditis
CNS psychosis
Renal damage - diffuse proliferitive glomerulonephritis is the most common (hematuria) can also be nephrotic (proteinuria)
Endocarditis,myocarditis, or pericarditis (can affect any layer of the heart)
i. Libman sacs endocarditis is a classic finding characterized by small sterile deposits on both sides of the mitral valve
Anemia, thrombocytopenia and leukopenia(due to autoantibodies against cell surface proteins
Renal failure and infection re common causes of death

53
Q

ANA, Antihistone antibody and dsDNA are antibodies found in SLE what is their qualitative difference

A

ANA-highly sensitive
dsDNA- highly specific
antihistone antibody- Drug induced Lupus (hydralazine,procainamide,isoniazid- removal of drug results in remission)

54
Q

Define Antiphospholipd antibody syndrome (associated with ~ 30% of SLE)

A

autoantibodies against protein bound to phospholipids
Anticardiolipin and lupus anticoagulant are the most common antibodies
i. Lead to false positive syphillis test and falsely elevated PTT lab studies, respectively
Result in arterial and venous thrombosis including DVT, hepatic vein thrombosis, placental thrombosis(recurrent pregnancy loss) and stroke
Requires lifelong anticoagulation

55
Q

Sjogren’s Syndrome

A

Autoimmune destruction of lacrimal and salivary glands (Type-Iv hypersensitivity-Lympphocyte mediated wiith fibrosis)
recurrent dental carries in an older woman, dry mouth (xerostomia) dr eyes (keratoconjunctivitis)
Increased risk for B-cell(marginal zone lymphoma, which presents as unilateral enlargement of the parotid gland late in dx course

56
Q

What are the antibodies associated with Sjogren’s syndrome?

A

ANA and ribonucleoprotein antibody (SS-A/Ro and SS-B/La

57
Q

Define Scleroderma

A

Autoimmune tissue damage with activation of fibroblasts and deposition of collagen (fibrosis)

58
Q

Explain diffuse Scleroderma

A

Exhibits skin and early visceral involvement
Almost any organ can be involved ; esophagus is commonly affected, resulting in disorderer motility (dysphagia of solids and liquids)
Characterized by ANAand anti-DNA topoisomerase I (Scl-70) antibody

59
Q

Explain localized scleroderma

A

This type exhibits local skin and visceral involvement

Prototype is CREST syndrome (Calcinosis,Raynaud syndrome,Esophageal dysmotility,Sclerodactyly,Telengiectasias of the skin)

60
Q

What antibody characterizes mixed connective tissue disease

A

Serum antibodies against U1 ribonucleoprotein

Mixed features of SLE , Polymyositis and systemic sclerosis

61
Q

What is a labile tissue and what are some types of labile tissues

A

Tissue that posseses regenerative capacity via stem cells that continuously cycle eg. skin(stem cells in basal layer),bone marrow(hematopoietic stem cells) and small and large bowel(stem cells in mucosal crypts)

62
Q

What is stable tissue and list some types of stable tissues

A

this is tissue comprised of quiescent cells (G0), can reenter the cell cycle to regenerate tissue when necessary
Classic example is Liver regeneration by compensatory hyperplasia after resection . each hepatocyte produces additional cells and then re-enters quiesence

63
Q

What is Permanent tissue and what is an example

A

Lack significant regenerative capacity (eg, myocardium,nerve,skeletal muscle )

64
Q

What are the steps in tissue repair

A

1st: Granulation Tissue formation; consists of fibroblasts (deposit type II collagen),capillaries(provide nutrients) and myofibrils(provide contraction at wound site)

2nd: Scar formation: collagenase removes type II collagen and requires zinc as a cofactor, Type III collagen is then replaced with type I collagen .

Type II collagen is pliable and present in embryonic tissue,granulation tissue,uterus and keloid
Type 1 collagen has tensile strength and is present in the skin , bone,tendons and most organs .

65
Q

Which metal is necessary for the replacement of type III collagen with type I collagen

A

zinc

66
Q

Growth factors are important in regeneration and repair of tissues , interaction of GF with receptors results in gene expression and cellular growth. Name % of these growth factors and their uses

A

TGF a - epithelial and fibrinoid
TGF B - important fibrinoblast growth factor also inhibits inflammation
Platelet derived growth factor: growth factor endothelium,smooth muscle and fibroblasts
Fibroblast growth factor: important for angiognesis; also mediates skeletal development
Vascular enothelial growth factor: important for angiogenesis

67
Q

What are some causes of delayed wound healing

A

Infection (most common cause is S aureus )
Vitamin C, Copper or zinc deficiency
other causes: foreign body,ischemia,diabetes and malnutrition

68
Q

why does copper cause delayed wound healing

A

copper is a cofactor for lysyl oxidase, which crosslinks lysine and hydroxylysine to form stable collagen

69
Q

What is keloid

A

Excess production of scar tissue out of proportion to the wound

characterized by excess type III collagen
More common in african americans
Classically affects ear lobes,face and upper extremities

Pathoma (4 decks)

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