Pathoma 2 Flashcards
inflammation - overview
*allows inflammatory cells, plasma proteins (eg. complement), and fluid to exit blood vessels and enter the interstitial space
*divided into acute (neutrophils) and chronic (lymphocytes) inflammation
acute inflammation - basic principles
*characterized by the presence of edema & neutrophils in the tissue
*arises in response to infection (to eliminate pathogens) or tissue necrosis (to clear necrotic debris)
*immediate response with limited specificity (innate immunity)
mediators of acute inflammation: toll-like receptors (TLRs)
*present on cells of the innate immune system (eg. macrophages & dendritic cells)
*activated by pathogen-associated molecular patterns (PAMPs) that are commonly shared by microbes
*TLR activation requires upregulation of NF-kappaB, 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 (eg. lymphocytes) and play an important role in mediating chronic inflammation
mediators of acute inflammation: arachidonic acid metabolites
*arachidonic acid (AA) is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase:
1. cyclooxygenase produces PROSTAGLANDINS (PGs)
2. 5-lipoxygenase produces LEUKOTRIENES
prostaglandins (PGs) produced by cyclooxygenase from arachidonic acid
*PGI2, PGD2, PGE2 mediate VASODILATION and increased vascular permeability
*PGE2 also mediates fever & pain
leukotrienes (LTs) produced by 5-lipoxygenase from arachidonic acid
*LTB4 attracts and activates neutrophiles
*LTC4, LTD4, LTE4 mediate VASOCONSTRICTION, bronchospasm, and increased vascular permeability
mediators of acute inflammation: mast cells
*widely distributed throughout connective tissue
*activated by: 1) tissue trauma; 2) complement proteins C3a and C5a; or 3) cross-linking of cell-surface IgE by antigen
*immediate response involves release of preformed histamine granules, which mediate vasodilate of arterioles and increased vascular permeability
*delayed response involves production of arachidonic acid metabolites, particularly leukotrienes
mediators of acute inflammation: complement
*proinflammatory serum proteins that “complement” inflammation
*circulate as inactive precursors; activation occurs via: classical, alternative, and mannose-binding lectin pathways
classical pathway of complement activation
*C1 binds IgG or IgM that is bound to antigen, activating complement cascade
alternative pathway of complement activation
*microbial products directly activate complement
mannose-binding lectin pathway of complement activation
*MBL binds mannose on microorganisms and activates complement
result of complement activation (regardless of pathway of activation)
*all pathways result in production of:
C3 convertase (mediates C3 → C3a and C3b)
C5 convertase (mediates C5 → C5a and C5b)
formation of MAC complex
roles of complement proteins: C3a and C5a
*anaphylatoxins
*trigger mast cell degranulation resulting in histamine-mediated vasodilation and increased vascular permeability
*C5a is also chemotactic for neutrophils
roles of complement proteins: C3b
*opsonin for phagocytosis
roles of complement proteins: MAC complex
*lyses microbes by creating holes in the cell membrane
mediators of acute inflammation: Hageman factor
*an inactive proinflammatory protein produced in the liver
*activated upon exposure to subendothelial or tissue collage; in turn activates:
1. coagulation and fibrinolytic systems
2. complement
3. kinin system
cardinal signs of inflammation: redness (rubor) and warmth (calor)
*due to vasodilation, which results in increased blood flow
*occurs via relaxation of arteriolar smooth muscle
*key mediators are histamine, prostaglandins, and bradykinin
cardinal signs of inflammation: swelling (tumor)
*due to leakage of fluid from postcapillary venules into the interstitial space (exudate)
*key mediators are histamine & tissue damage
cardinal signs of inflammation: pain (dolor)
*bradykinin and PGE2 sensitize sensory nerve endings
cardinal signs of inflammation: fever
*pyrogens (e.g. LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase COX activity in perivascular cells of the hypothalamus
*increased PGE2 raises temperature set point in the hypothalamus
leukocyte adhesion deficiency
*autosomal recessive defect of integrins CD18 subunit
*clinical features include:
-delayed separation of umbilical cord
-increased circulating neutrophils
-recurrent bacterial infections that LACK pus formation
Chediak-Higashi Syndrome
*a protein trafficking defect characterized by impaired phagolysosome formation
*autosomal recessive
*clinical features include:
-increased risk of pyogenic infections
-neutropenia
-giant granules in leukocytes
-defective primary hemostasis
-albinism
-peripheral neuropathy
chronic granulomatous disease (CGD)
*characterized by poor O2-dependent killing, due to NADPH oxidase defect (X-linked or autosomal recessive)
*leads to recurrent infection and granuloma formation with CATALASE-POSITIVE organisms: Staph aureus, Pseudomonas / Burkholderia cepacia, Serratia marcescens, Nocardia, and Aspergillus
*nitroblue tetrazolium test (NBT) is used to screen for CGD (remains COLORLESS if NADPH oxidase is defective)
normal mechanism of O2-dependent killing of microbes by neutrophils
*HOCl generated by oxidative burst in phagolysosomes destroys phagocytosed microbes
1. O2 is converted to O2- (superoxide) by NADPH oxidase
2. superoxide is converted to hydrogen peroxide (H2O2) by superoxide dismutase
3. H2O2 is converted to HOCl by myeloperoxidase (MPO)
TH1 subset of CD4+ T cells
*secrete:
1. IL-2 (T-cell growth factor and CD8+ T cell activator)
2. IFN-gamma (macrophage activator)
TH2 subset of CD4+ T cells
*produce:
1. IL-4 (class switching to IgG and IgE)
2. IL-5 (eosinophil chemotaxis and activation, maturation of B cells to plasma cells, and class switching to IgA)
3. IL-10 (inhibits TH1 phenotype)
CD8+ T cells
*perform cytotoxic killing via:
1. secretion of perforins and granzyme, inducing apoptosis of the target cell
2. expression of FasL, binds Fas on target cell, activating apoptosis
granulomatous inflammation
*characterized by formation of a granuloma, composed of:
1. epithelioid histiocytes (macrophages with abundant pink cytoplasm
2. surrounded by giant cells and rim of lymphocytes
*divided into caseating (central necrosis) and noncaseating (lack central necrosis) subtypes
steps involved in granuloma formation
*macrophages present antigen via MHC II to CD4+ helper T cells
*macrophages secrete IL-12, inducing CD4+ helper cells to differentiate into TH1 subtype
*TH1 cells secrete IFN-gamma, which converts macrophages to epithelioid histiocytes & giant cells
note - occurs in both caseating and non-caseating granulomas
DiGeorge Syndrome - overview
*developmental failure of the 3rd and 4th pharyngeal pouches
*due to 22q11 microdeletion
*presents with:
1. T-cell deficiency (lack of thymus)
2. hypocalcemia (lack of parathyroids)
3. abnormalities of heart, great vessels, and face
X-linked agammaglobulinemia - overview
*complete lack of immunoglobulin due to disordered B-cell maturation (naive B cells cannot mature into plasma cells)
*due to mutated Bruton tyrosine kinase
*presentation: after 6 months of life, recurrent bacterial, enterovirus, and Giardia infections
*must AVOID live vaccines
hyper-IgM syndrome
*characterized by elevated IgM
*due to mutated CD40L or CD40 receptor
*cytokines necessary for Ig class switching not produced
*low IgA, IgG, and IgE result in recurrent pyogenic infections, especially at mucosal sites
