Ch 2 Pathoma Flashcards
Acute Inflammation characterized by
Presence of edema and neutrophils in tissue
Acute inflammation arises in response to
infection (to eliminate pathogen) or tissue necrosis (to clear necrotic debris) - it’s an immediate response with limited specificity
5 mediators of acute inflammation
TLRs, arachidonic acid metabolites, mast cells, complement, hageman factor (factor XII)
TLRs are present on
cells of innate immune system (macrophages, dendritic cells) - also present on cells of adaptive immunity (lymphocytes) so they play a role in acute and chronic inflammation
TLRs are activated by _______ and up regulate _______, a nuclear transcription factor that activates immune response genes
PAMPs (pathogen associated molecular patterns); NF-KB (acts as an on switch)
______ on macrophages recognizes LPS found on gram ______ bacteria
CD14 (a co-receptor for TLR4); negative (LPS acts as a PAMP)
Arachidonic acid is released by ________ and acted upon by ____ or _____ (2 possible pathways with distinct products)
phospholipase A2 (from phospholipid cell membrane); cyclooxyrgenase or 5-lipoxygenase
Cyclooxygenase produces ________ and 5-lipoxygenase produces ________.
prostaglandins; leukotrienes
Which three prostaglandins mediate vasodilation and increased vascular permeability and which one mediates pain and fever?
PGI2, PGD2, and PGE2; PGE2
4 key mediators that attract and activate neutrophils
LTB4 (leukotriene), C5a (complement), IL8 (cytokine), and bacterial products
LTC4, LTD4, and LTE4 (slow reacting substances of anaphylaxis) mediate these three things
vasoconstriction, bronchospasm, increased vascular permeability
Mast cells are activated by these three things
tissue trauma, complement proteins C3a and C5a, or cross linking of cell surface IgE by antigen
Immediate and delayed response of mast cells involve production of _______ and ______ respectively
histamine (which causes vasodilation and increased vascular perm); arachidonic acid metabolites particularly leukotrienes
Complement activations occurs via these three pathways
- classical - C1 binds IgG or IgM that is bound to antigen (GM makes classic cars); 2. alternative - microbe products directly activate complement; 3. MBL (mannose binding lectin) - MBL binds to mannose on microorganisms and activates complement
Complement activation pathways result in
production of C3 convertase (mediates C3 –> C3a and C3b), which in turn produces C5 convertase (mediates C5 –> C5a and C5b). C5b complexes with C6-C9 to form MAC (membrane attack complex - creates hole in microbe cell membrane)
This complement is chemotactic for neutrophils and this one is opsonin for phagocytosis
C5a; C3b
________ is an inactive pro inflammatory protein produced in the liver that is activated upon exposure to sub endothelial or tissue collagen
Hagemon factor (factor XII) (can lead to DIC)
Hagemon factor (factor XII) activates these three things
coagulation and fibrinolytic systems (can lead to DIC) - most impt; complement; kinin system (kinin cleaves high-molecular weight kininogen HMWK to bradykinin which mediates vasodilation and increased vascular perm and pain)
2 key mediators for pain
PGE2 and bradykinin
5 cardinal signs of inflammation
redness (rubor), warmth (calor), swelling (tumor), pain (dolor), and fever
The key mediators of redness and warmth are (3); the key mediators of swelling are (2); the key mediators of pain are (2)
histamine, prostaglandins, bradykinin; histamine, tissue damage; bradykinin and PGE2
Pathway of fever
pyrogens (like LPS from bacteria) cause macrophages to release IL1 + TNF –> increases COX activity in perivascular cells in hypothalamus –> increase PGE2
Leukocyte arrival in tissues (steps)
Margination, rolling, adhesion, and transmigration
Vasodilation slows blood flow in _________ which cause leukocytes to ________
postcapillary venules; marginate
Rolling occur by the up regulation of _______ on endothelial cells, which binds with ________ on leukocytes
selectin; sialyl Lewis X
This type of selectin is released from Weibel Palade bodies mediated by histamine; and this type of selectin is induced by TNF and IL1
P-selectin (W-P bodies also release von Willebrand factor); E-selectin
CAMs are unregulated on endothelium by ___ and _____. Integrins are unregulated on leukocytes by ____ and _____
TNF and IL1; C5a and LTB4
Adhesion occurs by the interaction btwn _____ and ______
CAMs (on endothelium); Integrins (on leukocyte)
Leukocyte adhesion deficiency common cause and clinical presentation (3)
integrin defect (CD18 subunit); delayed separation of umbilical cord (neutrophils can’t come in after necrosis), increased circulating neutrophils (due to impaired adhesion of marginated pool), and recurrent bacterial infections that lack pus formation (pus is dead neutrophils sitting in fluid)
Phagocytosis is enhanced by _______
opsonins (C3b and IgG)
______ is a protein trafficking defect (autosomal recessive) characterized by impaired phagolysosome formation
Chediak-higashi syndrome
Clinical features of chediak higashi syndrome (6)
increased risk of pyogenic infections, neutropenia, giant granules in leukocytes, defective primary hemostasis, albinism (melanocytes can’t pass melanin to keratinocytes), peripheral neuropathy (can’t send proteins from cell body down long nerve)
O2 dependent killing pathway
O2 –(NADPH oxidase)–> O2^- –(SOD)–> H202 –(MPO)–> HOCl (bleach)
SOD = superoxide dismutase MPO = myeloperoxidase
_____ is characterized by poor O2 dependent killing due to _____ defect
CGD; NADPH oxidase
Chronic granulomatous disease leads to recurrent infection and granuloma formation with _______ organisms, particularly _____ (5)
catalase positive; staph aureus, psuedomonas cepacia*, serratia marcescens, nocardia, aspergillus
_____ is used to screen for CGD
Nitroblue tetrazolium test (NBT) - it turns blue if NADPH oxidase can convert O2 to O2^-
MPO deficiency causes increased risk for _____ infections; pts have a normal/abnormal NBT
Candida; normal (O2 to H2O2 is intact)
Neutrophils peak after _____, and macrophages peak ______ after inflammation begins
24 hours; 2-3 days
Macrophages destroy phagocytosed material via _______
O2 independent killing; use enzymes in secondary granules (ex: lysozyme)
Anti-inflammatory cytokines produced by macrophages (2)
IL10 and TGFB
______ from macrophages recruits additional neutrophils
IL8 (continued acute inflammation)
Abscesses are formed by _______ mediating fibrosis via fibrogenic growth factors and cytokines
macrophages
Macrophages present antigen to activate ____ which secrete cytokines that promote chronic inflammation
CD4+ helper T cells
Acute/chronic inflammation is characterized by the presence of lymphocytes and plasma cells in the tissue
chronic
Chronic inflammation stimuli include (5)
persistent infection (most common); infection with viruses, mycobacteria, parasites, and fungi; autoimmune disease; foreign material; and some cancers
T-Cell receptor complex includes both the TCR and ____
CD3
CD4+ T cells recognize antigens presented on MHC class ___ and CD8+ T cells on MHC class ____
II; I
Activation of T cells requires (2)
binding of antigen/MHC complex and an additional 2nd signal
2nd signal for activation of CD4+ helper T cells and for CD8+ cytotoxic t cells
B7 on APC binds CD28 on CD4+ helper T cell; IL-2 (secreted by CD4+ TH1)
TH1 secretes _____ (activating macrophage, promotes B cell class switching from IgM to IgG, promotes TH1 phenotype and inhibits TH2 phenotypes)
IFN-gamma
TH2 secretes _____ (facilitates B cell class switching to IgE) and ______ (eosinophil chemotaxis and activation, and class switching to IgA), and ______ (function similar to first one)
IL-4; IL-5; IL-13 (function similar to IL-4)
Two ways CD8+ cytotoxic T-cells kill
- secretion of perforin and granzyme; 2. expression of FasL, which binds Fas on target cells (both activate apoptosis)
B cell activation occurs in these two ways
Antigen binding by surface IgM or IgD (results in maturation to IgM or IgD secreting plasma cells); B cell antigen presentation to CD4+ helper T cells via MHC class II (CD40 receptor on B cell binds CD40L on helper T cell
What is the key cell of a granuloma?
epithelioid histiocyte (macrophage with abundant pink cytoplasm) - often also find giant cells and a rim of lymphocytes
Caseating granulomas exhibit exhibit/lack central necrosis and are characteristic of ______ (2)
exhibit; TB and fungal infections
Noncaseating granulomas exhibit/lack central necrosis. Common etiologies include _____ (5)
lack; rxn to foreign material, sarcoidosis, beryllium exposure, Crohn disease, and cat scratch disease
Steps to forming a granuloma (3)
Macrophage process and present antigen via MHC class II to CD4+ helper T cells, which cause macrophages to release IL-12 inducing CD4+ t cells to differentiate to TH1 subtype; 3. TH1 cells secrete IFNgamma which converts macrophages to epithelioid histiocytes and giant cells
DiGeorge’s syndrome is a developmental failure of the _________ due to a ____ microdeletion
3rd and 4th pharyngeal pouches; 22q11
DiGeorge’s syndrome clinical presentations (3)
T-cell deficiency (lack of thymus), hypocalcemia (lack of parathyroids), abnormalities of heart, great vessels, and face
Severe Combined Immunodeficiency (SCID) results in defective _____ and _____ immunity
cell mediated (T cell) and humoral (B cell)
3 etiologies of SCID
cytokine receptor defects (necessary for proliferation and maturation of b and t cells); adenosine deaminase deficiency* (necessary to dominate adenosine and deoxyadenosine which otherwise build up and are toxic to lymphocytes); MHC class II deficiency (necessary for CD4+ helper t cell activation and cytokine production and subsequent CD8+ t cell and B cell development)
SCID is characterized by susceptibility to ______ infections including opportunistic and live vaccines. And tx
fungal and viral (t cell defect), bacterial, and protozoal (b cell defect) - tx is sterile isolation and stem cell transplantation
X-linked agammaglobulinemia
complete lack of immunoglobulin due to disordered b cell maturation (due to mutated bruton tyrosine kinase)
X-linked agammaglobulinemia presents with
recurrent bacterial, enterovirus, and Giardia lamblia infections (maternal ABs present during first 6 mo of life are protective) - avoid live vaccines
Immunodeficiency disorder due to low immunoglobulin due to B cell or helper T cell defects
Common variable immunodeficiency (CVID)
CVID presents with increased risk for
bacterial, enterovirus, and giardia lamblia infections and increased risk for autoimmune disease and lymphoma
IgA deficiency presents with increased risk for
mucosal infection, especially viral (most common Ig deficiency; most pts are asymptomatic) - IgA protects against mucosal enteric infxns
Wiskott-Aldrich Syndrome cause and triad presentation
due to a mutation in WASP gene (x-linked); characterized by thrombocytopenia, eczema, and recurrent infxns (defective humoral and cellular immunity) - bleeding is major cause of death
Increased risk of Neisseria infection (N gonorrhoeae and N meningitidis) is caused by
C5-C9 deficiencies (complement deficiency)
______ deficiency results in hereditary angioedema (edema of skin especially periorbital and mucosal surfaces)
C1 inhibitor
causes over activation of C1 –> over activation of complement –> increased vasodilation, vascular permeability, and edema (inflammation)
Central tolerance vs peripheral tolerance
central occurs in areas where lymphocytes develop (thymus or bone marrow); peripheral occurs in other tissues
central tolerance in thymus leads to apoptosis or generation of regulatory t cells; in bone marrow leads to receptor editing or apoptosis
peripheral tolerance leads to anergy or apoptosis of both t and b cells
AIRE mutations
AIRE is a TF that causes dendritic cells in thymus to express self-antigen to ensure T-cells aren’t created that bind to self; mutations lead to autoimmune polyendocrine syndrome (hypoparathyroid, adrenal failure, and chronic candida infxns)
_____ suppress autoimmunity by blocking T cell activation (by expressing CTLA4, which competes with CD28 on t cells to bind B7 on APCs) and producing anti-inflammatory cytokines (IL-10, TGF-B)
Regulatory T cells
They are CD4+, CD25+ (IL-2 receptor), and FOXP3+ (a TF needed for dvlpmnt and maintenance)
FOXP3 mutations lead to _______
IPEX syndrome (Immune dysfunction, Polyendocrinopathy, Enteropathy, X-linked)
Why autoimmune disorders are more common in women?
estrogen may reduce apoptosis of self-reactive B cells
Wound healing occurs via a combination of ______ and ______
regeneration and repair
Three types of regenerative capacity and tissues that exhibit each type
Labile (small/large bowel - stem cells in crypts, skin - stem cells in basal layer, bone marrow - hematopoietic stem cells);
Stable (liver - regenerate tissue only when necessary, otherwise the cells are quiescent (G0));
Permanent (myocardium, skeletal muscle, neurons - lack regenerative potential)
_____ formation is the initial phase of repair
granulation tissue
Granulation tissue consists of these 3 major things
fibroblasts (deposit type III collagen), capillaires (provide nutrients), and myofibroblasts (contract wound - aka make it smaller)
In scar formation, type ____ collagen is replaced with type ____ collagen
III; I
(III is pliable and present in granulation tissue, embryonic tissue, and keloids - I has high tensile strength and is found in skin, bone, tendons)
Regeneration and repair are mediated by paracrine signaling via growth factors that interact with receptors and result in gene expression and cellular growth. Name 5 examples of mediators.
TGF-alpha (epithelial and fibroblast GF)
TGF-beta (fibroblast GF; inhibits inflammation)
PDGF (GF for endothelium, smooth muscle and fibroblasts)
Fibroblast GF (impt for angiogenesis; mediates skeletal development)
Vascular endothelial GF (VEGF - impt for angiogenesis (growing bv’s))
Delayed wound healing occurs in
Infection (most common); vitamin C, copper, or zinc deficiency (all involved in strengthening collagen); foreign body, ischemia, diabetes, and malnutrition
zinc is a cofactor for collagenase, which replaces type III collagen of granulation tissue with type I
______ is excess production of scar tissue that is out of proportion to the wound and is characterized by excess _______. (genetic predisposition in african americans)
Keloid; type III collagen
classically affects earlobes, faces, and upper extremities
An autoimmune disease in which flares and remissions are common, classically arises in middle aged females, can present with a malar butterfly rash or discoid rash
Systemic lupus erythematosus (SLE)
A sensitive test for SLE and 2 highly specific tests for SLE
Antinuclear antibody (ANA); Anti-dsDNA or anti-Sm antibodies
This autoimmune disorder causes destruction of lacrimal and salivary glands and often presents with dry eyes, lymphocytic sialadenitis, and ANA + anti-SSA/SSB + rheumatoid factor
Sjogren syndrome
This autoimmune disorder is characterized by hardening of the skin and visceral organs - fibroblast activation leads to deposition of collagen
systemic sclerosis (Scleroderma)
endothelial dysfunction leads to inflammation (increased adhesion molecules), vasoconstriction (increased endothelin and decreased NO), and secretion of growth factors (TGF-B and PDGF which both can activate fibroblasts)
Limited type or diffuse type of systemic slcerosis presents with CREST syndrome
Limited; CREST = calcinosis/anti-Centromere antibodies, Raynaud’s, Esophageal dysmotility, Sclerodactyly (tight skin), and Telangiectasias of skin (red marks from dilated capillaries)
Diffuse type is highly associated with antibodies to DNA topoisomerase I
This autoimmune disease is characterized by ANA along with serum antibodies to U1 ribonucleoprotein
Mixed connective tissue disease (has mixed features of SLE, systemic sclerosis, and polymyositis)
Which hypersensitivity reaction is characterized by IgE-related release of chemical mediators from mast cells and basophils?
Type I (immediate) - anaphylactic type
Which hypersensitivity reaction is mediated by sensitized T lymphocytes?
Type IV (cell mediated type) - delayed type = granuloma formation by CD4+ TH1-cells; cytotoxic type - CD8+ destroy antigen containing cells
Type III hypersensitivity reaction are characterized by the formation of _______.
Immune complexes (antibody-antigen complexes) - deposit in tissue resulting in inflammation and tissue injury
Which hypersensitivity reaction is characterized by IgG and IgM antibody directed against a specific target cell or tissue with complement usually involved?
Type II (antibody mediated) - complement dependent cytotoxicity results in lysis of cell; antibody dependent cell mediated cytotoxicity (ADCC) causes killing of antibody coated cells
Anaphylaxis and asthma are what type of hypersensitivity reaction?
Type 1
Serum sickness and autoimmune diseases like SLE and rheumatoid arthritis, and glomerulonephirits are what type of hypersensitivity reaction?
Type III
Name 4 types of type II hypersensitivity reactions
Transfusion reactions, hemolytic anemia, graves disease, and myasthenia gravis
Name 5 types of type IV hypersensitivity reactions
Graft rejection, viral infection, immune reaction to tumors, granulomatous disease, and delayed skin reactions (poison ivy)
