Pathoma: inflammation, inflammatory disorders, wound healing Flashcards
acute inflammation is characterized by
edema and neutrophils and tissue
arises in response to infection (to elim. pathogen) or tissue necrosis (to clear necrotic debris)
immediate response with limited specificity (innate immunity)
Toll-like receptors
present on cells of the innate immune system
activated by PAMPs (pathogen-associated molecular patterns)
activation results in up rgulation of NF-kB -> nuclear transcription factor that activates immune response genes leading to production of multiple immune mediators
also present on cells of adaptive immunity and are involved in mediating chronic inflammation
CD14
co-receptor for TLR4 on macrophages recognizes lipopolysaccharide on the outer membrane of G- bacteria
Arachidonic acid metabolites
released from phospholipidcell membrane by phospholipase A2 and then acted upon by COX or 5-lipoxygenase
COX produces
prostaglandins
PGI2, PGD2, and PGE2 - mediate vasodilation and increase vascular permeability
PGE2 also mediates pain and fever
5-lipoxygenase produces
leukotrienes
LTB4 attracts and activates neutrophils
LTC4, LTD4, LTE4 (slow reacting substances of anaphylaxis) mediate vasoconstriction, bronchospasm, and increased vascular permeability
Mast Cells
throughout connective tissue
activated by - tissue trauma
- complement proteins C3a and C5a
- cross-linking of cell-surface IgE by antigen
Immediate response of Mast Cells
release of preformed histamine granules, which mediate vasodilation of arterioles and increased vascular permeability
Delay response of Mast Cells
production of arachidonic acid metabolites - particularly leukotrienes
Complement
proinflammatory serum proteins that complement inflammation
Activation of complement occurs via 3 pathways
classical
alternative
mannose-binding lectin pathway
Classical Complement Pathway
C1 bind IgG or IgM that is bound to antigen
Alternative Complement Pathway
microbial products directly activate complement
mannose-binding lectin Complement Pathway
MBL binds to mannose on microorganisms and activates complement
All complement pathways result in production of
C3 convertase (C3 -> C3a and C3b) -> activates C5 convertase (C5 -> C5a and C5b) C5b complexes with C6-C9 to form the membrane attack complex
C3a and C5a
Anaphalytoxins
trigger mast cell degranulation -> histamine-mediated vasodilation and increased vascular permeability
C5a
chemotactic for neutrophils
MAC
lyses microbes by creating a hole in the cell membrane
Hageman Factor
Factor XII
inactive proinflammatory protein produced in the liver
activated upon exposure to subendothelial or tissue collagen
Activated Hageman Factor activates
coagulation and fibrinolytic systems
complement
kinin system - kinin cleaves high molecular weight kininogen(HMWK) to bradykinin, which mediates vasodilation and increase vascular permeability as well as pain
Cardinal Signs of Inflammation
Redness - rubor warmth - calor swelling - tumor pain - dolor fever
redness - rubor
warmth - calor
due to vasodilation - increased blood flow
occurs via relaxation of arteriolar smooth muscle, key mediator are histamine, prostaglandins, and bradykinin
swelling - tumor
leakage of luid from postcapillary venules into the interstitial space (exudate)
key mediators are histamine (causes endothelial cell contraction) and tissue damage (endothelial cell disruption)
pain - dolor
bradykinin and PGE2 sensitize sensory nerve endings
Fever
pyrogens (LPS from bacteria) cause macrophages to release IL-1 and TNF which increase cyclooxygenase activity in perivascular cells of the hypothalamus
increased PGE2 raises temperature set point
Neutrophil Arrival and Function
1) margination
2) rolling
3) adhesion
4) transmigration and chemotaxis
5) phagocytosis
6) destruction of phagocytosed material
7) resolution
margination
vasodilation slows blood flow in postcapillary venules
cells marginate from center of flow to the periphery
rolling
selectin is upregulated on endothelial cells
P-selectin release from Veibel-Palade bodies mediated by histamine
E-selectin - induced by TNF and IL-1
selectins bind sialyl Lewis X on leukocytes
interaction results in rolling of leukocytes along vessel wall
adhesion
ICAM and VCAM are upregulated on endothelium by TNF and IL1
integrins upregulated on leukocytes by C5a and LTB4
interaction creates firm adhesion of leukocytes to vessel wall
transmigration and chemotaxis
leukocytes transmigrate across the endothelium of postcapillary venules and move toward chemical attractants
neutrophils are attracted by bacterial products, IL8, C5a, and LTB4
phagocytosis
consumption of pathogens or necrotic tissue
enhanced by opsonins - IgG and C3b
destruction of phagocytosed material
O2-dependent killing is most effective mech
HOCL generated by oxidative burst in phagolysosomes destroys phagocytosed microbes
resolution
neutrophils undergo apoptosis and disappear within 24 hours after resolution of inflammatory stimulus
leukocyte adhesion deficiency is most commonly due to
AR defect of integrins (CD18 subunit)
delayed separation of umbilical cord, increased circulating neutrophils (due to impaired adhesion), and recurrent bacterial infection that lack pus formation
Chediak- Higashi
AR - protein trafficking defect impaired phagolysosome formation increased risk of pyogenic infections neutropenia giant granules in leukocytes defective primary hemostasis albinism peripheral neuropathy
chronic granulomatous disease
poor O2 dependent killing
due to NADPH oxidase defect ( x-linked or AR)
recurrent infection and granuloma formation with catalase + organisms (s. aureus, pseudomonas cepacia, serratia marcescens, nocardia, and aspergillus)
screen with nitroblue tetrazolium test - colorless if NADPH is defective, turns blue if it convers O2 to O2-
MPO deficiency
defective conversion of H2O2 to HOCL
increased risk for candida infections
Macrophages
predominate after neutrophils
peak 2-3 days after inflammation
derived from monocytes in the blood
IL-10 and TGF - B
anti-inflammatory cytokines produced by macrophages
involved in resolution and healing
continued acute inflammation
persistent pus formation
IL-8 from macrophages recruits additional neutrophils
Abscesses
acute inflammation surrounded by fibrosis
macrophages mediate fibrosis via fibrogenic growth factors and cytokines
macrophages in chronic inflammation
present antigen to activate CD4+ helper T cells which secrete cytokines that promote chronic inflammation
chronic inflammation is characterized by
presence of lymphocytes and plasma cells in tissue
delayed response, more specific adaptive immunity
chronic inflammation stimuli
persistent infection infection with viruses, mycobacteria, parasites, and fungi autoimmune disease foreign material some cancers
where are T lymphocytes produced
bone marrow as progenitor T cells
Further development of T cells occurs in the
thymus
T Cell receptor undergoes rearrangement and progenitor cells become CD4+ or CD8+ cells
-T cells use TCR complex (TCR and CD3) for antigen surveillance
- TCR complex recognizes antigen presented on MHC
- CD4+ - MHC II
- CD8+ - MHC I
- activation of T cells requires binding of antigen/MHC complex and an additional second signal
CD4+ helper T cell activation
extracellular antigen is phagocytosed, processed, and presented on MHC II, which is expressed by APCs
B7 on APC binds CD28 on CD4+ providing 2nd activation signal
activated CD4+ helper T cells secrete cytokines that help inflammation and are divided into 2 subsets - Th1 and Th2
Th1
secretes IFN-gamma (activates macrophage, promotes B cell class switching from IgM to IgG promotes Th1 and inhibits Th2
Th2
secretes IL-4 (facilitates B-cell class switching to IgE) IL-5 (eosinophil chemotaxis and activation, and class switching to IgA) IL-13 (function similar to IL-4)
CD8+ cytotoxic T-cell activation
intracellular antigen is processed and presented on MHC I, which is expressed by all nucleated cells and patelets
IL-2 from CD4+ Th1 cells provides 2nd activation signal
activated for killing
CD8+ killing occurs by
secretion of perforin and granzyme
perforin creates poes that allow granzyme to enter the target cell, activating apoptosis
expression of FasL, which binds Fas on target cells, activating apoptosis
B-Lymphocytes are produced where
bone marrow
undergo immunoglobulin rearrangements to become naïve B cells that express surface IgM and IgD
B-cell activation occurs via
antigen binding by surface IgM or IgD - maturation to IgM or IgD secreting plasma cells
B-cell antigen presentation to CD4+ helper T cells via MHC II
- CD40 receptor on B cell binds CD40L on helper T cell - 2nd signal
- helper T cell then secretes IL-4 and IL-5 (mediate B-cell isotype switching, hypermutation, and maturation to plasma cells
granulomatous inflammation
subtype of chronic inflammation
characterized by granuloma, which is a collection of epithelioid histiocytes(macs with abundant pink cytoplasm)
usually surrounded by giant cells ad a rim of lymphocytes
Non caseating granulomas
lack cental necrosis
reaction to foreign material sarcoidosis beryllium exposure Crohn disease cat scratch disease
caseating granulomas
central necrosis
characteristic of tuberculosis and fungal infections
steps involved in granuloma formation
1) macrophages process and present antigen via MHC II to CD4+ helper T cells
2) interaction leads macrophages to secrete IL-12 - inducing CD4+ to differentiate into Th1 subtype
3) Th1 cells secrete IFN-gamma - converts macs to epithelioid histiocytes and giant cells
Primary Immunodeficiencies
Digeorge Syndrome Severe Combined Immunodeficiency X-Linked Agammaglobulinemia Common Variable Immunodeficiency IgA Deficiency Hyper IgM Syndrome Wiskott-Aldrich Syndrome Complement Deficiencies
Digeorge Syndrome
developmental failure of the third an fourth pharyngeal pouches - due to 22q11 microdeletion
presents with T-cell deficiency (lack of thymus)
hypocalcemia (lack of parathyroids)
and abnormalities of heart, great vessels, and face
SCID
defective cell-mediated and humoral immunity
cytokine receptor defects adenosine deaminase (ADA) deficiency MHC II deficiency
susceptibility to fungal, viral, bacterial, and protozoal infections
Tx - sterile isolation (bubble boy) and stem cell transplantation
cytokine receptor defects
necessary for proliferation and maturation of B and T cells
adenosine deaminase (ADA) deficiency
necessary to deaminate adenosine and deoxyadenosine for excreation as waste
buildup is toxic to lymphocytes
MHC II deficiency
necessary for CD4+ activation and cytokine production
X-Linked Agammaglobulinemia
complete lack of immunoglobulin due to disordered B cell maturation
pre and pro B cells cannot mature
X-linked - mutated Bruton tyrosine kinase
presents at 6 months after maternal antibodies are done
recurrent bacterial, enterovirus, and giardia lamblia infections
Avoid live vaccines (polio)
Common Variable Immunodeficiency
low immunoglobulin due to B cell or helper T cell defects
increased risk for bacterial, enterovirus, and giardia lamblia infections in late childhood
increased risk for autoimmune disease and lymphoma
IgA Deficiency
low serum and mucosal IgA
most common immunoglobulin deficiency
increased risk for mucosal infection - esp. viral
most pts are asymptomatic
Hyper IgM Syndrome
elevated IgM
mutated CD40L (on T helper Cells) or CD40 R (on B cells)
2nd signal cannot be delivered to helper T cells during B cell activation -> cytokines required for immunoglobulin class switching are not produced
low IgA, IgG, and IgE -> recurrent pyogenic infections (due to poor opsonization) especially at mucosal sites
Wiskott-Aldrich Syndrome
characterized by thrombocytopenia, eczema, and recurrent infections (defective humoral and cellular immunity)
bleeding is major cause of death
mutation in WASP gene
X-linked
Complement Deficiencies
C5-C9 deficiencies
increased risk for Neisseria infection (gonorrhoeae and meningitides)
C1 inhibitor deficiency -> hereditary angioedema, characterized by edema of the skin (esp. periorbital) and mucosal surfaces
Central tolerance in the thymus leads to
T-cell apoptosis or generation of regulatory T cells
AIRE mutations -> autoimmune polyendocrine syndrome
central tolerance in the bone marrow leads to
receptor editing or B-cellapoptosis
peripheral tolerance leads to
anergy or apoptosis of T and B cells
Fas apoptosis pathway mutations result in autoimmune lymphoproliferative syndrome (ALPS)
Regulatory T cells suppress autoimmunity by blocking
T-cell activation and producing anti-inflammatory cytokines - IL-10, TGF-B
CD25 polymorphisms assoc. with autoimmunity (MS and type I DM
FOXP3 mutations -> IPEX syndrome
Autoimmune disorder etiology
more common in women - estrogen may decrease apoptosis of self reactive B cells
HLA B27 and PTPN22 association
SLE
antigen-antibody complexes damage multiple tissues (type III HSR)
poorly cleared apop. debris activates self-reactive lymphocytes -> produces antibodies to host nuclear antigens
Can effect any tissue
SLE common findings
fever, weight loss, fatigue, lymphadenopathy, and Raynaud phenomenon
malar rash or discoid rash - esp. after exposure to sunlight
oral or nasopharyngeal ulcers
arthritis
serositis
psychosis or seizures
renal damage
anemia, thrombocytopenia, or leukopenia (type II HSR)
Libmann-Sacks endocarditis
antinuclear antibody
anti-dsDNA or anti-Sm antibodies
anti-phospholipid AB assoc with 1/3 of pts -> characterized by hypercoagulable state
Anti-histone antibody
characteristic of drug-induced lupus
procainamide, hydralazine, and isoniazid
ANA is positive by definition (anti-nuclear antibody)
sjogren syndrome
autoimmune destruction of lacrimal and salivary glands
lymphocyte mediated damage (type IV HPR) with fibrosis
dry eyes, mouth and recurrent dental caries in an older woman
can be primary or assoc. with rheumatoid arthritis
lymphocytic sialadenitis on lip biopsy is a diagnostic criterion
sjogren syndrome is characterized by what antibodies
ANA and anti-ribonucleoprotein antiodies
systemic sclerosis (scleroderma)
autoimmune disorder characterized sclerosis of skin and visceral organs - middle aged females
fibroblast activation leads to deposition of collagen
autoimmune damage to mesenchyme is possible initiating event
endothelial dysfunction leads to inflammation, vasoconstriction, and secretion of growth factors (TGF-B and PDGF)
fibrosis, initially perivascular, progresses and causes organ damage
systemic sclerosis (scleroderma)
limited type
skin involvement is limited to hands and face with late visceral involvement Prototype is CREST syndrome Calcinosis/anti-centromere ABs Raynaud phenomenon esophageal dysmotility sclerodactyly telangiectasias of the skin
systemic sclerosis (scleroderma)
diffuse type
skin involvement is duffuse with early visceral involvement
any organ can be involved
commonly:
vessels (Raynaud’s)
GI tract (esophageal dysmotility and reflux)
lungs (interstitial fibrosis and pulmonary hypertension)
kidneys (scleroderma renal crisis)
highly assoc. with ABs to DNA topoisomerase I (anti-Scl-70)
Mixed connective tissue disease
autoimmune-mediated tissue damage with mixed features of SLE, systemic sclerosis, and polymyositis
characterized by ANA along with serum ABs to U1 ribonucleoprotein
wound healing - regeneration
replacement of damaged tissue with native tissue, dependent on regenerative capacity of tissue
three types of tissue based on regenerative capacity
labile, stable, and permanent
labile tissues
possess stem cells that continuously cycle to regenerate tissue
small and large bowel (stem cells in mucosal crypts)
skin (stems in basal layer)
bone marrow (hematopoietic stems)
stable tissues
cells that are quiescent but can reenter the cell cycle to regenerate when necessary
permanent tissues
lack significant regenerative potential
myocardium
skeletal muscle
neurons
wound healing - repair
replacement of damaged tissue with fibrous scar
when regenerative stem cells are lost (deep skin cut) or when a tissue lacks regenerative capacity (healing after myocardial infarction)
initial phase of repair
formation of granulation tissue
consists of fibroblasts(deposit type III collagen)
capillaries (provide nutrients)
and myofibroblasts (contract wound)
scar formation
type III collagen is replaced with type I collagen
type III collagen
pliable and present in granulation tissue, embryonic tissue, uterus, and keloids
type I collagen
high tensile strength
present in skin, bone, tendons, and most organs
collagenase
removes type III collagen
requires zinc as cofactor
TGF-alpha
epithelial and fibroblast growth factor
TGF-B
important fibroblast growth factor, also inhibits inflammation
platelet-derived growth factor
growth factor for endothelium, smooth muscle, and fibroblasts
fibroblast growth factor
important for angiogenesis, also mediates skeletal development
vascular endothelial growth factor - VEGF
angiogenesis
regeneration and repair is mediated by
paracrine signaling via growth factors
primary intention
wound edges are brought together (suturing)
minimal scar formation
secondary intention
edges are not approximated
granulation tissue fills the defect
myofibroblasts then contract the wound - forming a scar
delayed wound healing occurs in
infection (S. Aureus is most common)
vitamin C, copper and zinc deficiency
foreign body, ischemia, diabetes, and malnutrition
vitamin C deficiency
important cofactor in the hydroxylation of proline and lysine procollagen residues
hydroxylation is necessary for eventual collagen cross-linking
copper deficiency
cofactor for lysyl oxidase
which cross-links lysine and hydroxylysine to form stable collagen
zinc deficiency
cofactor for collagenase
replaces the type III collagen of granulation tissue with stronger type I collagen
dehiscence
rupture of a wound
most commonly seen after abdominal surgery
hypertrophic scar
excess production of scar tissue that is localized to the wound
keloid
excess production of scar tissue that is out of proportion to the wound characterized by type III collagen genetic predisposition (African americans) classically affects earlobes, face, and upper extremities
