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STEP 1 Pathoma > Chapter 2 > Flashcards

Chapter 2 Flashcards

1
Q

Inflammation allows inflammatory cells and proteins to exist blood vessels and enter the interstitial space. It is divided into acute and chronic. What is it marked by?

A
  • edema and neutrophils in tissue
  • arises in repsonse to infection or necrosis
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2
Q

What are some mediators of acute inflammation?

A

Toll like receptors

Arachidonic acid metabolites

Mast cells

Complement

Coagulation

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3
Q

What are Toll like receptors?

A

These are present on cells of the innate immune system (e.g. macrophages and dendritic cells), activated by pathogen-assoicated molecular patterns (PAMPs) on microbes

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4
Q

How do TLRs recognize PAMPs?

A

CD14 ( a co-receptor) for TLR4 on macrophages recognized lipopolysacchardie (a PAMP) on the outer membrane of gram-negative bacteria

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5
Q

What does TLR activation cause?

A

upregulation of NF-kB, a nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators

NOTE: TLRs are also present on cells of adaptive immunity like lymphocytes

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6
Q

Arachidonic acid metabolites

A

AA is released from the phospholipid cell memrbane by phopsholipase A2 and then acted upon by COX-1/2 or 5-lipooxygenase

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7
Q

Action of COX-1/2 prodcued prostaglandins. Describe them

A

PGI2, PGD2, and PGE2 mediate vasodilation and increased vascular permeability

PGE2 also mediates pain and fever

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8
Q

5-Lipooxygenase produced leukotrienes. Describe these

A

LTB4 activated neurotrphils

LTC4-D4-E4 mediated vasconstriciton, bronchospasm, and increased vascular permeability

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9
Q

What are mast cells activated by?

A

tissue trauma, C3a or C5a, and cross-linking of cell-surface IgE by antigen

Acvtivation causes released of preformed histamine which mediate vasodilation or arterioles and vascular permeability

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10
Q

What are the 3 complement pathways?

A
  1. Classical Pathway- C1 binds IgG or IgM that is bound to antigen
  2. Alternative pathway-microbial products directly activate complemt
  3. Mannose-binding lecithin (MBL) pathway- MBL binds to mannose on microorganisms and activates complement

All pathways result in production of C3 convertase (mediated C3 to C3a and C3B), which in turn produced C5 convertase (C5- C5a/b). C5b compelxes with C6-9 to form the MAC

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11
Q

What do C3a and C5a do?

A

trgiger mast cell degranulation resultin in histamine-mediated vasodilation and increased vascular permeability

C5a is also a chemotractant for neutrophils

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12
Q

What are the cardinal signs of inflammation?

A

redness (rubor) and warmth due to vasodilation (more blood flow) from relaxation of arteriolar smooth muscle due to kistamine, prostaglandins, and bradykinin

swelling due to leakage of lfuids from postcapillary venules into the interstitial space (exudate)

pain (dolor) due to bradykinin and PGE2 sensitizing sensory nerve endings

fever (PGE2 and pyrogens cause macrophages to release Il-1 and TNF which increase COX activity in the hypothalamus)

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13
Q

Neutrophil activation. Steps 1 and 2

A

1) Vasodilation slows blood flow in postcapillary venules and cells marginate from the center of flow to the periphery
2) Selectins are upregulated on ednothelial cells (P-selectin release from Weibel-Palade bodies mediated by histamine and E-sleectin induced by TNF and IL-1). Selectins bind sialyl Lewis X on leukocytes and leukocyte ROLLING occurs along the vessel wall

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14
Q

Neutrophil activation. Steps 3 (Adhesion)

A

Cellular adhesion molecules suh as ICAM and VACM are upregulated on endothelium byTNF and IL-1, integrins are upregulated on leukocytes by C5a and LTB4. Interactions between CAMS and integrins results in firm adhesions of leukocytes to the vessel wall

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15
Q

What causes leukocyte adhesion deficiency?

A

AR defect of integrins (CD18 subunit)- clinical features include delayed seperation of the umbilical cord, increased circulating neutrophils, and recurrent bacterial infections that lack pus formation

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16
Q

Neutrophil Activation. Step 4

A

Transmigration and Chemotaxis- leukocytes transmigrate across the endothelium or psotecapillaru veinules and move toward chemical attractants (chemotaxis)

NOTE: Neutrophils are attracted by bacterial products, IL8, C5a and LTB4

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17
Q

Neutrophil activation. Step 5

A

Phagocytosis- Consumption of pathogens or necrotic tissue (enhanced by opsonins such as IgG or C3b)- Pseudopods extend from leukocytes to form phagosomes, which are intenalized and merge with lysosomes to produce phagolyosomes

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18
Q

What is Chediak-Higashi syndrome?

A

a protein trafficking defect (AR) characterized by defective phagolyosome formation

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19
Q

How does Chediak-Higashi syndrome present?

A
  • increased risk of pyogenic infections
  • neutropenia (due to intamedullary death or neutrophils)
  • giant granules in leukocytes due to fusion of granules arising from the Golgi apparatus

Defective primary hemostasits to due to abnormally dense platelet granules

Abinism

Peripehral neuropathy

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20
Q

Neutrophil Activation. Step 6

A

Destruction of material

O2 dependent killing is the most effective mechanism. HOCl generated by the oxidative burst in phagolyosomes destroyed phagocytosized microbes

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21
Q

Describe the Oxidative burst

A

O2 is convertd to O2* by NADPH oxidase (oxidative burst)

O2* is converted to H2O2 by superoide dismutase

H2O2 is covnerted to HOCl (bleach) by myeloperoxidase (MPO)

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22
Q

What is chronic granulomatous disease (CGD)?

A

poor O2 dependent microbe killing due to NADPH oxidase deficiency (X-linked or AR) leading to recurrent infections anf granuloma formation with catalase positive organisms, particularly S. aureus, Pseudomonas, Serratia, Nocardia, and Aspergillus

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23
Q

How is CGD screened for?

A

Nirtoblue tetrazolium test (leukocytes are incubated with NBT dye which turns blue is NADPH oxidase can covnert O2 to O2*, but remains colorless in CGD

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24
Q

MPO deficiency results in defective conversion of hydrogen peroxide to HOCl. What is the result?

A

Increased risk for Candida infection; however most are asymptomatic

NBT is normal and the oxidative burst is intact

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25
Q

T or F. O2 indepedent killing is less effective than O2 dependent

A

T. Occurs via enzymes present in leukocyte secondary granules (e.g. lysosomes in macrophages and major basic protein in eosinophils)

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26
Q

Neutrophil Activation. Step 7

A

Neutrophil apoptosis within 24 hrs

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27
Q

When do macrophages dominate in inflammation?

A

After neutrophils, and peak 2-3 days after inflammation begins (derived from monocytes)

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28
Q

More about macrophages

A
  • Arive in tissue via margination, rolling, adhesion, and transmigration sequence
  • ingest organisms bia phagocytosis (augmented by opsonins) and destroy pahgocytosed material using enzymes like lyoszymes in secondary grnaules (O2 independent)
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29
Q

Macrophages also mediate the outcome of acute inflammation. What are the possibilities?

A
  1. Resoluation and healing- anti-inflammatory cytokines such as IL10 and TGF-B produced
  2. Continued acute inflammation- marked by persistent pus formation; IL8 from macrophages recruits additional neutrophils
  3. Abscess- acute inflammation surrounded by fibrosis; macrophages mediate fibrsis via fibrogenic growth factors
  4. Chronic inflammation- macrophages present antigens to activate CD4 helper T cells, which secrete cytkines that promote chronic inflammation
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30
Q

Describe chronic inflammation

A

Marked by the presence of lymphocytes and plasma cells in tissue

Delayed response, buy more specific (adpative immunity) than acute inflammation

Stimuli include persistent infection, infection with viruses, mycobacteria, parasites, or fungi, autoimmune disease, or foreign material

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31
Q

How are T lymphocytes produced?

A

Produced in bone marrow as progenitor T cells, further developing in the thymus where the T-cell receptor (TCR) undergoes rearrangement and progenitor cells become CD4 helper T cells or CD* cells

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32
Q

T cells use their TCR complexes (TCR and CD3) for antigen surveillance and recognize antigens presented on MHC molecules.

A

CD4= MHC class II

CD8= MHC class I

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33
Q

How are T cells activated?

A

requires 1) binding of antigen/MHC complex and 2) an additional 2nd signal

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34
Q

How are CD4 T cells activated?

A

Extracellular anitgens are pahgocytosed, processed, and presented MHC class II, which is expressed by APCs. B7 on the APC binds to CD28 on the CD4 cell providing the 2nd signal.

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35
Q

What do CD4 T cells do?

A

secrete cytokines that help inflammation

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36
Q

Describe TH1 helper T cells

A

secreted IFN-y (activates macrophages, promotes B cell class switching from IgM to IgG, promotes the Th1 phenotype and inhibits Th2 phenotype)

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37
Q

Describe TH2 helper T cells

A

secrete IL-4 (facilitates B-cell class switching to IgE), IL-5 (promotes class switching to IgA and eosinophil chemotaxis), and IL-13 (similar to IL-4)

38
Q

How are CD8 T cells activated?

A

Intracellular antigens (derived from proteins in the cytoplasm) are processed and presented on MHC class I, which is expressed by all nucleated cells and platelets. Il-2 from CD4 TH1 cells provide the 2nd signal of activation.

39
Q

How do CD8 T cells kill?

A

Secretion of perforin and granzyme; perforin creates pores that allow granzyme to eter the target cell to activate apoptosis

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

40
Q

How do B cells develop?

A

Immature B cells produced in the bone marrow and udnergo immunoglobulin rearrangements to become naive B cells that express surface IgM and IgD

41
Q

How are B cells activated?

A

Antigen binding by surface IgM or IgD results in maturation to IgM or IgG secreting plasma dells

B-cell antigen presentation to CD4 helper T cells via MHC class II- CD40 receptor on B cells binds to CD40L on helper T cells, providing the 2nd activation signal. Helper T cells then secrete Il4 and Il5 to mediate B cell isotype switching and maturation to plasma cells

42
Q

What is granulomatous inflammation?

A

A subtype of chronic inflammation marked by granuloma (epitheliod histiocytes)- divided into caseating and noncaseating subtypes

43
Q

Noncaseating grnaulomas lact central necrosis (rxn to foregin body, sarcoidosis, beryillum exposure, Crohn disease, and cat scratch disease)

Caseating granulomas classic in TB and fungal infections

A
44
Q

How are granulomas formed?

A
  1. macrophages process and process antigens via MHC class II to CD4 helper T cells and the interaction leads macrophages to secreted I12, inducing CD4 cells to differentiate into the Th1 subtype.
  2. The Th1 T cells then secretes IFn-y which converts macrophages to epitheliodi histiocytes and giant cells
45
Q

What causes DiGeorge syndrome?

A

Development fialure of the 3rd and 4th pharyngeal pouches due to 22q11 microdeletion

46
Q

How does DiGeorge syndrome present?

A

T cell deficiency (lack of thymus)

hypocalcemia (lack of PTH)

abnormalities of the heart, great vessels, and face

47
Q

What is severe combined immunodeficiency (SCID)?

A

Defective cell-medated and humoral immunity

48
Q

What are some causes of SCID?

A
  1. Cytokine receptor defects-cytokine signaling is neccessary for maturation of B and T cells
  2. Adenosine deaminase (ADA) deficiency- ADA is needed to deaminate adenosine and deoxyadenosine for excretion as waste products- buildup is toxic to lymphocytes
  3. MHC Class II deficiency
49
Q

How does SCID present?

A

susceptibility to fungal, viral, abcterial, and protozoal infections, including live vaccines

Tx: sterile isolation (bubble boy) and stem cell transplant

50
Q

What causes X-linked agammaglobinemia?

A

Complete lack of immunoglobulin due to disorderd B-cell maturation (pre and pro-B cells cannot mature) due to mutated Bruton tyrosine kinase (X-linked)

51
Q

How does X-linked agammaglobinemia present?

A

Presents after 6 months of life with recurrent bacterial, enterovirus (e.g. polio and coxsackievirus), and Giardia lamblia infections (maternal Abs present during first 6 months are protective)

Avoid live vaccines (e.g. polio)

52
Q

What causes common variable immunodeficiency (CVID)?

A

low immunoglobulin due to B cell or helper T cell defects leading to an increased risk of bacterial, etnerovirus, and Giardia infections, especially in late childhood (increased risk of autoimmune disease and lymphoma too)

53
Q

What is the most common immunoglobulin deficiency?

A

IgA deficiency- risk of mucosal infection, especially viral but most pts are aymptomatic

54
Q

Describe Hyper IgM syndrome

A

Elevated IgM due to mutated CD40L on helper T cells or CD40 receptors on B cells (no second signal for B cell activation and no class switching)

Low IgA, IgG, and IgE result in recurrent pyogenic infections due to poor opsonization, especially as mucosal sites

55
Q

What disease is marked by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity) and has a major cause of death due to BLEEDING?

A

Wiskott Aldrich Syndrome

56
Q

What causes Wiskott Aldrich Syndrome?

A

WASP gene mutation; X linked

57
Q

C5-9 deficiency places one at risk for what?

A

Neisseria infections

58
Q

How does C1 inhibitor deficiency present?

A

HANE (hereditary angioedema)

59
Q

How do autoimmune disorders arise?

A

Self-reactive lymphocytes are regularly generated but develop central or peripheral tolerance- in AI, these fail

60
Q

What causes autoimmune polyendocrine syndrome?

A

AIRE mutation

61
Q

What cause autoimmune lymohproliferative syndrome (ALPS)?

A

Fas apoptosis pathway mutations

62
Q

How do Tregs work?

A

They block autoimmunity by blocking T-cell activation and producing anti-inflammatoru cytokines such as IL10 and TGF-B

63
Q

____ polymorphisms are associated with autoimminuty in MS and type I DM

A

CD25

64
Q

What causes IPEX syndrome (Immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked)?

A

FOXP3 mutations

65
Q

Describe Lupus

A

This is a chronic, systemic autoimmune disease marked by flares and remissions

Common in middle aged black women

66
Q

Pathogenesis of Lupus

A

Antigen-Ab complexes damage multiple tissues via type III rxns

Poorly-cleared apoptoic debris activates self reactive lymphocytes when then produce Abs to host nuclear antigens and these complexes are taken up by dendritic cells

67
Q

Symptoms of Lupus

A

-fever, weight loss, fatigue, LAD, and Raynaud’s phenomenon

malar butterfly rash

oral ulcers

arthritis

serositis

psychosis or seziures

renal damage

Libman-Sacks Endocarditis

etc.

68
Q

What is antiphospholipid syndrome?

A

syndrome of hypercoaguable state due to antiphospholipid Abs presenting with recurrent arterial and venous thromboss and pregancy losses

69
Q

Common causes of death with lupus?

A

renal failure

infection

coronary atherosclerosis

70
Q

What is Sjogren Syndrome?

A

Autoimmune disease of the lacrimal and salivary glands marked by lymphocyte mediated damage (type IV rxn) and fibrosis

71
Q

How does Sjogren Syndrome present?

A

dry eyes (ketatoconjunctivitis sicca), dry mouth and reucrrent dental caries in an older woman , 50-60 yo

72
Q

What abs are seen with Sjogren Syndrome?

A

ANA

Anti-SSB/La and Anti-SSA/Ro (assocaited with neuropathy)

73
Q

What is systemic slcerosis?

A

AI disease marked by sclerosis of the skin and visceral organs classically in middle aged women.

74
Q

What causes systemic slcerosis?

A

Fibroblast activation leads to deposition of collagen (AI dmaage to the mesenchyme is a possible initiating event)

Endothelial dysfunction leads to inflammation, vasocontriction, and secretion of growth factors such as TGF-B and PDGF

Fibrosis, initially perivascular, progresses and causes organ damage

75
Q

What are the types of systemic slcerosis?

A

Limited

Diffuse

76
Q

Limited systemic sclerosis

A

Skin involvment in limited to the hands and face with late visceral involvement

CREST syndrome: Calcifications/anti Centromere Abs, Raynauds, Esophageal dysmotility, Sclerodactylyl, Telangiectasias of the skin

77
Q

Diffuse systemic sclerosis

A

Skin involvement is diffuse with early visceral involvement (of any organ)

commonly involved organs include: Vessels (Raynauds), Gi tract, lungs (interstitial fibrosis and pulmonary HTN), kidneys (Scleroderma renal crises)

78
Q

Diffuse systemic sclerosis has a high assocaition with what Abs?

A

DNA topoisomerase I (anti Scl 70)

79
Q

Wound healing begins when inflammation starts and occurs via a combo of regeneration and repair. Describe the regenerative capacity of cells.

A

Labile, stable, and permnanent

80
Q

Describe labile tissues

A

These possess stem cells that continuously cycle to regenerate the tissue (includes the small and large bowel (stem cells in crypts), skin (stem cells in basal layer), and bone marrow (hematopoitic stem cells))

81
Q

Describe stable tissues

A

Compromised of cells that are quiescent (Go) but can reenter the cell cycle to regenerate tissue when needed (class example is regeneration fo the liver by compensatory hyperplasia after partial resection- each ehaptocyte produces additional acells nd then reenters quiescence.

82
Q

Describe permanent tissues (regeneration)

A

These lack significant regenerative potential (e.g. myocardium, skeletal muscle, and neurons)

83
Q

Wound repair occurs via replacement of damaged tissue with a fibrous scar and this occurs when regenerative stem cells are lost (e.g. deep skin cut) or when a tissue lacks regenerative capacity (e.g. healing after an MI). Describe this process

A

1) Grnaulation tissue formation is the initial phase of repair- consists of fibroblasts (deposit type III collagen), capilalries (provide nutrients) and myofibroblasts (contract wound)
2) Eventually results in scar formation in which type III collagen is replaced with type I collagen

84
Q

Type III collagen is pliable and present in grnulation tissue, embryonic tissue, uterus, and keloids

Type I collagen has high tensile strength and is present in skin, bone, tendons, and most organs

A

Collagenase removes type III collagen and requires zinc as a cofactor

85
Q

What mediates tissue regeneration and repair?

A

Meidated by paracrine signaling via growth factors (e.g. macrophages secrete growth factors that target fibroblasts). Interaction of growth faactors with receptors (e.g. epidermal growth factor with growth factor receptor) results in gene expression and cellular growth

Ex of mediators include TGF-a (epipthelial and fibroblast growth factor), TGF-B (important fibroblast growth factor; inhibits inflammation), PDGF (growth factor for endothelium, smooth muscle and fibroblasts), and VEGF for angiogenesis

86
Q

Cutaneous healing occurs via primary or secondary intention. Describe primary intention

A

Wound edges are brought togehter (e.g. suturuing) leading to minimal scar formation

87
Q

Describe 2ndary intention

A

Edges are not approximated and granulation tissue fills the defect, myofibroblasts then contract the wound, forming a scar

88
Q

Delayed wound healing leads to infection, most commonly ________

A

S. aureus

89
Q

What is the role of Vit C in wound healing?

A

Need cofactor for the hydorxylation or proline and lysine procollagen residues; hydroxylation is needed for eventual collagen cross-linking

90
Q

What is the role of copper in wound healing?

A

co-factor for lysyl oxidase, which cross-links lysine and hydroxylysine to form stable collagen

91
Q

What is the role of zinc in wound healing?

A

cofactor for collagenase, which replaces type III collagen of granulation tissue with stronger type I collagen

STEP 1 Pathoma (18 decks)

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