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zPatho
2. Inflammation, Inflammatory Disorders, & Wound Healing
| Term | Definition |
|---|---|
| Acute Inflammation | Characterized by the presence of edema and neutrophils in tissue. Arises in response to infection or tissue necrosis. Immediate response with limited specificity (innate immunity). |
| Innate Immunity | Involved in acute inflammation. Immediate response with limited specificity. Includes: Epithelium, mucus, compliment, and cells (mast cells, macrophages, neutrophils, eosinophils, basophils). |
| Mediators of Acute Inflammation (5) | Toll-Like Receptors (TLRs), Arachidonic Acid (AA) metabolites, Mast cells, Complement, and Hageman Factor (Factor XII). |
| Toll-Like Receptors | Present on cells of innate immunity. Activated by Pathogen-Associated Molecular Patterns (PAMPs). TLR activation results in upregulation of NF-KappaB (a transcription factor) activating immune response genes. Also, present on cells of adaptive immunity. |
| CD14 | A TLR on macrophages that recognizes LipoPolySaccharide (a PAMP) on outer membrane of gram(-) bacteria. |
| Arachidonic Acid (AA) Metabolites | Released from cell membranes by Phospholipase A2, then acted upon by Cyclooxygenase (COX) (to produce prostaglandins) or 5-Lipoxygenase (to produce Leukotrienes). |
| Prostaglandins (PG) | Produced from AA by COX. PGI2, PGD2, PGE2 mediate vasodilation (at arteriole) and increase vascular permeability (at post-capillary venule). PGE2 also mediates fEEEver and pain. |
| Leukotrienes (LT) | Produced from AA by 5-Lipoxygenase. LTB4 attracts/activates neutrophils. LTC4, LTD4, & LTE4 (slow reacting substances of anaphylaxis) mediate smooth muscle contraction causing vasoconstriction, bronchospasm, & increased vascular permeability (pericytes). |
| Neutrophil attractors and activators | LTB4, C5a, IL-8, and bacterial products. |
| Mast Cells | Widely distributed in connective tissue. Activated by 1) trauma, 2) C3a & C5a, 3) cross-linking of surface IgE by antigen. Immediate response: release of histamine granules. Delayed response: production of AA metabolites (LTs). |
| Histamine | Released by activated Mast Cells. Mediate vasodilation of arterioles and increased vascular permeability of post capillary venules. |
| Complement | Proinflammatory serum proteins which circulate as inactive precursors. Activated via Classical Pathway, Alternative Pathway, and Mannose-binding Lectin (MBL) pathway. All pathways produce C3 convertase, C5 convertase, and C3a/b, C5a/b, and MAC. |
| Classical Pathway of Complement Activation | "GM makes Classic Cars - go C1." C1 binds IgG or IgM that is bound to pathogen. |
| Alternative Pathway of Complement Activation | Microbial products directly activate complement. |
| Mannose-Binding Lectin (MBL) Pathway of Complement Activation | MBL binds to mannose on microorganisms and activates complement. |
| Complement Activation Products | C3 convertase (C3 to C3a & C3b), C5 convertase (C5 [with C3b] to C5a & C5b). C5b complexes with C6-C9 to form Membrane Attack Complex (MAC). |
| C3a & C5a | Anaphylatoxins. Trigger mast cell degranulation (causing histamine mediated vasodialation and increased vascular permeability). |
| C5a | Chemotactic for neutrophils (and trigger mast cell degranulation) |
| C3b | Opsonin (protein marker) for phagocytosis |
| Membrane Attack Complex (C5-C9) | Lyses microbes by creating a hole in their cell membrane. |
| Hageman Factor (Factor XII) | Inactive proinflammatory protein produced in liver. Activated upon exposure to subendothelial or tissue collagen. Upon activation, it activates Coagulation and Fibrinolytic Systems, Complement, and Kinin System. Plays a big role in gram(-) sepsis and DIC. |
| 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. |
| Cardinal Signs of Inflammation | Redness (rubor) & Warmth (calor) - vasodilation from histamine, prostaglandins, and bradykinin. Swelling (tumor) - increased permiability from histomine and tissue damage. Pain (dolor) - Bradykinin and PGE2 sensitizing nerves. Fever - PGE2. |
| Physiology of a Fever | Pyrogens (e.g. LPS from bacteria) cause macrophages to release IL-1 and TNF, which increase Cyclooxygenase (COX) activity in perivascular cells of hypothalamus. More COX = more PGE2 which raises temperature set point. |
| Neutrophil Arrival and Function in Acute Inflammation (7 steps) | 1) Margination, 2) Rolling, 3) Adhesion, 4) Transmigration and Chemotaxis, 5) Phagocytosis, 6) Destruction of phagocytosed material, 7) Resolution |
| Step 1 of Neutrophil Arrival and Function - Margination | Vasodilation slows blood flow in postcapillary venules allowing cells to marginate from center of flow to periphery. |
| Step 2 of Neutrophil Arrival and Function - Rolling | Selectin "speed bumps" are upregulated on endothelial cells interacting with Sialyl Lewis X on leukocytes slowing them down (rolling). |
| P-Selectin | Released from Weibel-Palade bodies. Mediated by histamine. Slow macrophages and neutrophils by interacting with Sialyl Lewis X on leukocytes. |
| Weibel-Palade bodies | Endothelial cells that release a W and a P: von Willebrande factor and P-selectin. |
| Step 3 of Neutrophil Arrival and Function - Adhesion | Cellular Adhesion Molecules (ICAM & VCAM) are upregulated on endothelium by TNF & IL-1. Integrins are upregulated on leukocytes by C5a and LTB4. Interactions between integrins and CAMs results in adhesion of leukocytes to vessel wall. |
| Leukocyte Adhesion Deficiency | AR defect of integrins (CD18 subunit). Clinical features: delayed separation of umbilical cord, increased circulating neutrophils (due to impaired adhesion of marginated pool of leukocytes in lung), and recurrent bacterial infections that lack pus. |
| Step 4 of Neutrophil Arrival and Function - Transmigration and Chemotaxis | Leukocytes transmigrate across endothelium of postcapillary venules and move towards chemical attractants. Neutrophils are attracted by bacterial products, IL-8, C5a, and LTB4. |
| Step 5 of Neutrophil Arrival and Function - Phagocytosis | Consumption of pathogens or necrotic tissue. Enhanced by opsonins (IgG and C3b). Pseudopods extend from leukocyte, "hug" pathogen to form Phagosome. Phagosome then merge with lysosomes to produce Phagolysosomes. |
| Chediak-Higashi Syndrome | AR protein trafficking defect. Traits: increased risk of pyogenic infections (impaired phagolysosome formation), Neutropenia, giant granules in leukocytes, defective primary hemostasis (abn dense granules in platlets), Albininsm, & Peripheral neuropathy. |
| Step 6 of Neutrophil Arrival and Function - Destruction of Phagocytosed Material | O2-dependent killing is most effective mechanism. O2 via NADPH oxidase to O2*- (oxidative burst). O2*- via Superoxide Dismutase (SOD) to H2O2. H2O2 to HOCl* (bleach) via Myeloperoxidase (MPO). O2-dependent killing via enzymes in leukocyte 2ndary granules. |
| Chronic Granulomatous Disease | Poor O2-dependent killing due to NADPH oxidase defect (XL or AR). Recurrent infection and granuloma formation with Catalase-Positive organisms (staph aureus, Pseudomonas cepacia, etc.). |
| Nitroblue tetrazolium Test | Screen test for Chronic Granulomatous Disease. Leukocytes given NBT dye, if color turns blue, then NADPH oxidase can convert to O2*-. If colorless, defective NADPH oxidase. |
| MPO deficiency | Defective conversion of H2O2 to HOCl*. Increased risk for Candida infections although most are asymptomatic. Nitroblue Tetrazolium Test is normal. |
| Secondary Granules in Marcrophages | Lysozyme |
| Secondary Granules in Eosinophils | Major Basic Protein |
| Step 7 of Neutrophil Arrival and Function - Resolution | Neutrophils undergo apoptosis and disappear within 24 hours of resolution. |
| Macrophages | Derived from monocytes in blood. Peak 2-3 days after inflammation begins. Arrive by same model as neutrophils. Phagocytize organisms via lysozyme in secondary granules. Manage next step of inflammation: Resolve, Continued acute, Abscess, or Chronic. |
| Resolution and Healing of Acute Inflammation | Managed by macrophages via IL-10 and TGF-Beta. |
| Continued Acute Inflammation | Managed by macrophages via IL-8 which recruits more neutrophils. Marked by persistent pus formation. |
| Abscess | Acute inflammation surrounded by fibrosis. Macrophages mediate fibrosis via fibrogenic growth factors and cytokines. |
| Acute to Chronic Inflammation | Macrophages present antigen on MHC (type II) to activate CD4+ helper T cells which secrete cytokines that promote chronic inflammation. |
| Chronic Inflammation | Delayed, more specific response. Characterized by presence of lymphocytes and plasma cells in tissue. Stimuli include: persistent infection, viral/mycobacterial/parasitic/fungal infection, autoimmune disease, foreign material, and some cancers. |
| T Lymphocytes | Produced in bone marrow. Develop in thymus into CD4 helpers or CD8 cytotoxic cells. Both use TCR complex (TCR & CD3) for antigen surveilance. Activation requires antigen/MHC complex binding and 2nd signal. |
| CD4 Helper T Cells | Recognize extracellular antigens via MHC class II presentation by APCs. B7 on APC binds CD28 on CD4 helper T providing 2nd activation. Activated CD4 helpers secrete cytokines and divide into TH1s and TH2s. |
| TH1 (CD4 Helper T Cells) | Activated CD4 Helper T Cells that secrete IL-2 (a T cell growth factor and CD8 T cell activator) and IFN-gamma (macrophage activator). |
| TH2 (CD4 Helper T Cells) | Activated CD4 Helper T cells that secrete IL-4 (facilitates B-cell class switching to IgG and IgE), IL-5 (eosinophil chemotaxis and activation, maturation of B cells to plasma cells, and class switching to IgA), and IL-10 (inhibits TH1 CD4 Helpers). |
| CD8 Cytotoxic T-cells | Recognize intracellular antigens by their MHC class I. IL-2 from CD4 Helpers provide 2nd signal. Active CD8s kill via perforin & granzyme (perforin makes hole, granzyme activates apoptosis) & expression of FasL (binds Fas on target, activates apoptosis). |
| B Lymphocytes | Produced in bone marrow. Immunoglobulin rearrangement to become naive B cells. Activated by antigen binding IgM or IgD (results in IgM or IgD secreting plasma cell) or B cell presenting antigen to CD4 helper (CD40 on B binds CD40L on helper = 2nd signal). |
| IL-4 & IL-5 | Secreted by CD4 Helper T cells when bound to CD 40 on B cell (presenting antigen). Mediates B-cell isotype switching (from IgM and IgD to IgE, IgA, and IgG), hypermutation, and maturation to plasma cells. |
| Granulomatous Inflammation | Subtype of chronic inflammation. Characterized by granuloma surrounded by giant cells and a rim of lymphocytes. Divided into Caseating and Non-Caseating. |
| Granuloma | Collection of epithelioid histiocytes. Formed by macrophages presenting antigen to CD4 helpers, leads to macrophages secreting IL-12 (turning helpers into TH1s), TH1 secrete IFN-gamma (converting macrophages to epithelioid histiocytes and giant cells). |
| Epithelioid histiocytes | Tissue macrophages with abundant pink cytoplasm found in granulomas. |
| DiGeorge Syndrome | Developmental failure of 3rd & 4th pharyngeal pouches (due to 22q11 microdeletion). Lack of thymus (T-cell deficiency), Lack of parathyroid (hypocalcemia), and abnormalities of heart, great vessels, and face. |
| Severe Combined Immunodeficiency (SCID) | Defective Cell-mediated and Humoral immunity. Characterized by fungal, viral, bacterial, and protozoal infections (including opportunistic infections and live vaccines). Treatment is "bubble baby" (sterile isolation) and stem cell transplantation. |
| Causes of Severe Combined Immunodeficiency (SCID) | Cytokine receptor defects (cytokines needed for T/B cell proliferation/maturation), Adenosine Deaminase Deficiency (needed to secrete adenosine & deoxyadenosine. Buildup is toxic to lymphocytes), & MHC class II defiency - needed for CD4 helper activation. |
| X-Linked Agammaglobulinemia | Complete lack of immunoglobulin due to disordered B-cell maturation. Cause: mutated Bruton Tyrosine Kinase; X-linked. Presents after 6 months old with bacterial, enterovirus (ex. polio, coxsackie, etc), & Giardia infections. Avoid live vaccines (polio). |
| Common Variable Immunodeficiency (CVID) | Low immunoglobulin due to B or helper T defects. Risk for bacterial, enterovirus, and Giardia infections. Increased risk for autoimmune disease and lymphoma. |
| IgA Deficiency | Low serum and mucosal IgA. Most common immunoglobulin deficiency. Risk for mucosal infecton (especially viral); however most are asymptomatic. Associated with Celiac disease. |
| Hyper-IgM Syndrome | Elevated IgM due to mutated CD40L (on helper T) or CD40 receptor (on B cells). 2nd signal cannot be delivered to helper T cells (so cytokines needed for Ig class switching are not produced). Low IgA, IgG, and IgE result in recurrent pyogenic infections. |
| Wiskott-Aldrich Syndrome | Thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity). Due to WASP gene; X-linked. |
| C5-C9 deficiencies | Increased risk for Neisseria infection (N gonorrhoeae & N meningitidis). |
| C1 inhibitor deficiency | Results in Hereditary Angioedema (edema of skin and mucosal surfaces - especially periorbital). |
| Systemic Lupus Erythematosus | Systemic autoimmune disease. Damage via type II (cytotoxic) & type III (antigen-antibody complex) hypersensitivity. Common in AA females/females. Varied clinical features. ANA+ (sensitive) & dsDNA antibodies (specific). |
| Systemic Lupus Erythematosus Clinical Features | Fever/weight loss, Malar (butterfly) rash especially in sun, Arthritis, Pleuritis/pericarditis, CNS psychosis, Renal damage (diffuse proliferative glomerulonephritis - most common renal injury), Endo/myo/peri-carditis, Anemia/thrombocytopenia/leukopenia. |
| dsDNA antibody | Specific for Systemic Lupus Erythematosus |
| Antihistone antibody | Specific for Drug-induced SLE. Common drug inducers: Hydralazine, procainamide, and isoniazid. Remission with drug removal. |
| Antiphospholipid Antibody Syndrome |
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zackao1
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