Chapter 2 Flashcards
inflammation
inflammatory cells, plasma proteins, and fluid exit vessels into interstitial space;
acute and chronic inflammation
acute inflammation
edema and neutrophils in tissue;
response to infection or necrosis;
immediate response, limited specificity (innate immunity);
includes epithelium, mucus, complement, mast cells, macrophages, dendritic cells, neutrophils, basophils
toll-like receptors (TLR)
on innate immune cells;
activated by PAMPs (pathogen-associated molecular patterns) - CD14 of macrophage recognizes LPS of gram- bacteria;
upregulation of NF-kappaB and immune response genes;
TLRs also in adaptive immunity and chronic infection
Arachidonic Acid (AA) metabolites
AA from phospholipase A, acted on by cyclooxygenase or 5-lipoxygenase
cyclooxygenase
acts on AA to produce prostaglandins;
PGI2, PGD2, PGE2 mediate vasodilation of arteriole and vascular permeability of post capillary venule;
PGE2 causes pain and fever
5-lipoxygenase
acts on AA to produce leukotrienes;
LTB4 attracts and activates neutrophils;
LTC4, LTD4, LTE4 (reactive in anaphylaxis) cause vasoconstriction, bronchospasm, and vascular permeability
mast cells
activated by trauma, complement C3a and C5a, and cross-linked IgE;
immediate response - preformed histamine granule release (vasodilation, vascular permeability);
delayed response - AA metabolites (mostly LTs)
complement
proinflammatory serum proteins;
activated via:
classical pathway - IgG or IgM bind antigen;
alternative pathway - microbial product activation;
mannose-binding lectin - MBL binds mannose on microbes
major complement components
C3a and C5a (anaphylatoxins) - mast cell degranulation of histamine;
C5a - neutrophil chemotaxis;
C3b - opsonin for phagocytosis;
MAC - membrane attack complex (C5b + C6-9), holes in cell membrane to lyse microbe
Hageman factor
Factor XII, produced in liver;
activated by subendothelial tissue or collagen;
activates coagulation/fibrinolytic systems, complement, kinin system
bradykinin
made from high-molecular-weight kininogen;
causes vasodilation and vascular permeability (like histamine);
also causes pain
cause pain
PGE2 and bradykinin
mast cells activated by?
trauma;
C3a and C5a
cross-linked IgE
chemotactic for neutrophils
LTB4;
C5a;
IL8;
Bacteria products
opsonins
enhance phagocytosis by marking target cell;
IgG;
C3b
acute inflammation stages
fluid phase;
neutrophile phase;
macrophage phase
signs of inflammation
redness (rubor); heat (calor); swelling (tumor); pain (dolor); fever
redness and heat of inflammation
due to vasodilation;
via relaxation of arteriole smooth muscle - histamine, prostaglandins, bradykinin
swelling of inflammation
leakage of fluid from post capillary venule (exudate);
via histamine and tissue damage
pain of inflammation
bradykinin and PGE2, sensitize nerve endings
fever of inflammation
macrophages release IL-1 and TNF - increase cyclooxygenase activity in perivascular hypothalamus (temp control);
high PGE2 raises temp set point
neutrophil movement
margination; rolling; adhesion; transmigration and chemotaxis; phagocytosis; destruction of material; resolution
neutrophil margination
vasodilation slows blood flow;
cells move to periphery of blood flow
neutrophil rolling
endothelial cells upregulate selectin “speed bumps”;
P-selectin from Weibel-Palade bodies via histamine;
E-selectin from macrophages via TNF and IL-1;
selectins bind sialyl Lewis X on leukocytes
neutrophil adhesion
upregulation of ICAM and VCAM on endothelium by TNF and IL-1;
integrins of leukocytes upregulated by C5a and LTB4;
firm adhesion between CAMs and integrins;
leukocyte adhesion deficiency
defect of integrins;
leukocytes will not bind CAMs;
delayed separation of umbilical cord, increased circulating neutrophils, recurrent bacterial infections without pus
neutrophil transmigration and chemotaxis
neutrophils attracted by LTB4, C5a, IL-8, bacterial products
neutrophil phagocytosis
enhanced by opsonins;
pseudopods extend from leukocytes, form phagosomes, merge with lysosome
Chediak-Higashi syndrome
protein trafficking defect; impaired phagolysosome formation; risk of pyogenic infections; neutropenia (intramedullary neutrophil death); giant granules in leukocytes; defective primary hemostasis (dense platelet granules); albinism; peripheral neuropathy
neutrophil destruction of phagocytosed material
O2 dependent most effective;
HOCl made by oxidative burst:
1. O2 to superoxide by NADPH oxidase (oxidative burst)
2. superoxide to peroxide by superoxide dismutase (SOD)
3. peroxide to HOCl by myeloperoxidase (MPO)
chronic granulomatous disease
poor O2 dependent killing;
NADPH defect;
recurrent infection and granulomas with catalase+ org. (S. aureus, P. cepacia, S. marcescens, Nocardia, Aspergillus);
nitroblue tetrazolium test to screen
myeloperoxidase deficiency
defective conversion of peroxide to HOCl;
risk of candida infection (most are asymptomatic);
nitroblue tetrazolium test is normal (oxidative burst intact)
O2 independent killing
less effective than O2 dependent;
via enzymes present in leukocyte secondary granules (lysozyme, major basic protein)
neutrophil resolution
neutrophils undergo apoptosis within 24 hrs of resolution (pus)
macrophage phase
2-3 days after inflammation begins;
derived from monocytes;
travel similar to neutrophils;
phagocytosis with O2 dependent and independent destruction
outcome of macrophage phase of inflammation
resolution and healing - IL-10 and TGF-beta (anti-inflammatory from macrophages);
continued acute inflammation - IL-8 recruits more neutrophils, persistent pus;
abcess - acute inflammation surrounded by fibrosis via fibrogenic growth factors/cytokines;
chronic inflammation - activate CD4+ helper T cells to promote chronic inflammation
chronic inflammation
presence of lymphocytes and plasma cells in tissue;
delayed response;
specific (adaptive immunity);
via persistent infection, viruses, mycobacteria, parasites, fungi, autoimmune disease, foreign material, some cancers
T lymphocytes
progenitor T cells from bone marrow develop in thymus;
T cell receptor (TCR) rearranges to CD4+ (helper) or CD8+ (cytotoxic);
activation requires binding of antigen/MHC complex and 2nd signal
CD4+ helper T cell
extracellular antigen phagocytosed, processed, presented on MHC II via macrophages or dendritic cells;
B7 on antigen presenting cell bind CD28 on CD4+ cell (2nd signal;
secretes cytokines to aid inflammation;
TH1 helper T cell
secrete IFN-gamma - activates macrophages, B cell class switching from IgM to IgG, inhibits TH2 phenotype; CD8+ cell activated via IL-2
TH2 helper T cell
secretes IL-4 - activates B cell class switching from IgM to IgE;
IL-5 - eosinophil activatione, class switching to IgA;
IL-13 - similar to IL-4;
IL-10 inhibits TH1
CD8+ cytotoxic T cell
activation from intracellular antigen, IL-2 from TH1 cells;
activated for killing - via secretion of perforins and granzymes, expression of FAS ligand (activates apoptosis)
B lymphocytes
made in bone marrow;
immunoglobulin rearrangement to become naive B cell with surface IgM and IgD;
activation via IgM/IgD antigen binding or antigen presentation from CD4+ cell on MHC II
B cell activation from CD4+ cell
via MHC II;
CD40 on B cell bind CD40L on helper T cell (2nd signal);
helper T cell secretes IL-4 and IL-5 (class switching, hypermutation, maturation of plasma cells)
granulomatous inflammation
subtype of chronic inflammation;
granuloma - collection of epitheliod histiocytes (macrophages with pink cytoplasm) surrounded by giant cells and lymphocytes;
noncaseating and caseating subtypes
noncaseating granuloma
lack central necrosis;
from reaction to foreign material, sarcoidosis, beryllium exposure, Crohn disease, cat scratch disease
caseating granuloma
central necrosis from tuberculosis and fungal infections
granuloma formation
macrophages process/present antigen via MHC II to CD4+ helper cells;
macrophages IL-2 inducing helper T cells to form TH1;
TH1 secrete IFN-gamma to convert macrophages to epitheliod histocytes and giant cells
Digeorge syndrome
developmental failure of 3rd and 4th pharyngeal pouches (22q11 microdeletion);
T cell deficiency (lack of thymus);
hypocalcemia (lack of parathyroid);
abnormalities of heart, great vessels, face
severe combined immunodeficiency disease (SCID)
defective cell mediated and humoral immunity (T and Be cells); cytokine receptor defects (necessary for B/T cell maturation); adenosine deaminase (ADA) deficiency - buildup of adenosine and deoxyadenosine toxic to lymphocytes; MHC II deficiency (helper T activation, cytokine production); susceptible to fungal, viral, bacterial, protozoal infections; sterile isoloation (bubble baby) with stem cell transplant
x-link agammaglobulinemia
disordered B cell maturation - complete lack of immunoglobulin;
mutated Bruton tyrosine kinase;
after 6 months of life (maternal antibodies present before);
recurrent bacterial, enterovirus (polio and coxsackievirus), and Giardia infections
common variable immunodeficiency (CVID)
B/helper T cell defects - low immunoglobulin;
risk of bacterial, enterovirus, Giardia infection in late childhood;
risk of autoimmune disease and lymphoma
IgA deficiency
low serum and mucosal IgA;
most common immunoglobulin deficiency;
risk of mucosal infections (celiac disease)
hyper-IgM syndrome
elevated IgM;
mutated CD40 (helper T cell) or CD40 receptor (B cell);
2nd signal not delivered to helper T cells, disabling class switching;
low IgA, IgG, and IgE cause recurrent pyogenic infections at mucosal sites
Wiskott-Aldrich syndrome
thrombocytopenia, eczema, recurrent infections (defective humoral and cellular immunity);
death from bleeding;
mutation in WASP gene (x-linked)
complement deficiencies
C5-C9 deficiencies - risk of Neisseria infections;
C1 inhibitor deficiency - hereditary angioedema (especially periorbital skin and mucosal surfaces)
autoimmune disorders
immune mediated damage of self; loss of self-tolerance; more common in women during childbearing age; usually an environmental trigger; progressive with relapses and remissions
autoimmune loss of self-tolerance
central tolerance in thymus leads to thymocyte apoptosis or regulatory T cell generation;
central tolerance in bone marrow leads to receptor editing or B-cell apoptosis;
peripheral tolerance leads to anergy or apoptosis;
regulatory T cells stop autoimmunity by blocking T cell activation and making IL-10/TGF-beta (anti-inflammatory);
autoimmune polyendocrine syndrome
from AIRE mutation;
no central tolerance in thymus;
hypoparathyroid, adrenal failure, chronic candida infections
autoimmune lymphoproliferative syndrome (ALPS)
FAS apoptosis pathway mutation;
no peripheral tolerance
regulatory T cells
CD25 polymorphisms associated with MS and Type I DM;
FOXP3 mutations cause IPEX (immune dysregulation, polyendocrinopathy, enteropathy, x-linked)
systemic lupus erythematosus (SLE)
chronic, systemic autoimmune disease;
mostly middle-aged females (AA and Hispanic);
antigen-antibody complex damage tissue (type III hypersensitivity);
almost any tissue involved;
hypercoagulabe state;
drug induced lupus from antihistone antibody
antigen-antibody complex in SLE
UV damage, apoptosis poorly cleared;
self-reactive lymphocytes activated, produce antibodies to host antigens;
complexes taken up by dendritic cells;
activate TLRs, amplify immune respone (IFN-alpha);
deposit on tissues, damage via complement;
deficiency of early complement proteins
SLE findings
Raynaud sign;
malar butterfly rash, discoid rash (sunlight);
oral, nasopharyngeal ulcers;
arthritis;
serositis (pleuritis and pericarditis);
psychosis, seizures;
renal damage (diffuse proliferative glomerulonephritis) most common and severe injury;
anemia, thrombocytopenia, leukopenia (type II hypersensitivity);
Libman-Sacks endocarditis (plaques on mitral valve);
antinuclear antibody (ANA);
antiphospholipid antibody in SLE
targets proteins bound to phospholipids;
anticardiolipin (false + VDRL and RPR syphilis tests);
anti-beta2-glycoprotein I;
lupus anticoagulant (false elevated PTT);
antiphospholipid antibody syndrome
hypercoagulable state from antiphospholipid antibodies (lupus anticoagulant);
arteriole/venous thrombosis;
recurrent pregnancy loss (placental vein thrombosis);
cerebral thrombosis (stroke);
associated with SLE
drug induced SLE
antihistone antibody;
procainamide, hydralazine, isoniazid;
remission with removal of drugs
Sjogren syndrome
autoimmune distruction of lacrimal, salvary gland;
lymphocyte-mediated with fibrosis (type IV hypersensitivity);
associated with rheumatoid arthritis;
lymphocytic sialadenitis;
risk of B-cell lymphoma (unilateral parotid enlargement);
ANA can cause neuropathy, neonatal lupus and congenital heart block
scleroderma
autoimmune sclerosis of skin and visceral organs;
autoimmune mesenchymal damage leads to collagen deposition;
endothelial dysfunction causes inflammation (secretion of growth factors (TGF-beta and PDGF);
perivascular fibrosis leads to organ damage;
limited and diffuse type
CREST syndrome
limited type scleroderma (limited skin involvement); calcinosis; raynaud sign; esophageal dysmotility; sclerodactyly; telangiectasias of skin
diffuse scleroderma
any organ involved;
associated with antibodies to DNA topoisomerase I;
commonly:
vessels (raynaud);
GI tract (esophageal dysmotility and reflux);
lungs (interstitial fibrosis and pulmonary HTN);
kidneys (scleroderma renal crisis);
mixed connective tissue disease
mixed features of SLE, systemic sclerosis, and polymyositis;
ANA with serum antibodies to U1 ribonucleoprotein
wound healing
initiated when inflammation begins;
combination of regeneration and repair
regeneration
replace damaged tissue with native tissue;
depends on tissue regenerative capacity;
labile tissue
possess stem cells and continuously cycle:
- bowels (stem cells in mucosal crypts);
- skin (stem cell in basal layer);
- bone marrow (hematopoietic stem cells);
- lung (type 2 pneumocyte)
stable tissue
cells are quiescent but can reenter cell cycle as needed:
liver compensatory hyperplasia after partial resection
permanent tissue
lack regenerative potential (myocardium, skeletal muscle, neurons)
repair
replace damaged tissue with fibrous scar when regenerative stem cells are lost or when tissue lack regen capacity;
granulation tissue leads to collagen and scar
granulation tissue
consists of fibroblasts (type III collagen), capillaries (nutrient supply), and myofibroblasts (wound contraction);
type III collagen replaced with type I collagen via collagenase (requires zinc cofactor)
collagen types
I: bone, skin, tendons, most organs
II: cartilage
III: granulation tissue, embryonic tissue, uterus, keloids
IV: basement membrane
mechanism of regen/repair
paracrine signaling via growth factors;
macrophages secrete growth factors target fibroblasts;
results in gene expression, cell growth
growth factors of regen/repair
TGF-alpha - epithelial and fibroblast growth factor;
TGF-beta - fibroblast growth factor, inhibits inflammation;
platelet-derived growth factor - for endothelium, smooth muscle, fibroblasts;
fibroblast growth factor - for angiogenesis, skeletal development;
vascular endothelial growth factor (VEGF) - angiogenesis
normal wound healing
primary intention - wound edges brought together, minimal scar;
secondary intention - granulation tissue fills defect, myofibroblasts contract wound, form scar
delayed wound healing
infection (S. aureus most common); Vit C, copper, zinc deficiency; foreign body; ischemia; diabetes; malnutrition
Vitamin C, copper, zinc in wound healing
Vitamin C - cofactor in hydroxylation of proline and lysine procollagen residue (collagen cross-linking);
copper - cofactor of lysyl oxidase (stable collagen cross-linking);
zinc - collagenase cofactor, replace type III collagen with type I
dehiscence
rupture of wound, common after abdominal surgery
hypertrophic scar
excess production of scar tissue localized to wound area (type I collagen)
keloid
excess production of scar tissue disproportional to wound;
excess type III collagen;
genetic predisposistion;
earlobes, face, upper extremities
