Lec7-8 Immunopathology/Amyloids Flashcards
4 main types of hypersensitivity reactions and examples
- Immediate [allergic], IgE mediated degranulation of mast cell
Ex. Asthma - Antibody dependent, IgG autoantibodies
Ex. Goodpasture syndrome - Immune complex, IgG/C3/Antigen mediated
Ex. Postinfectous GN, SLE, Vasculitis - Cell mediates, T cell mediated
Ex. Type I DM, Sarcoid
Two mech of immunologically-mediated disease
- hypersensitivity disease: react to foreign antigens via hyperreactive inflammatory response
- autoimmune disease: react to self antigens via normal inflammatory response
Bronchial asthma - what is it? What pathology?
- Type I hypersensitivity reaction
- Hypertrophy of bronchus smooth muscle
- Edema
- Leukocyte infiltration [eosinophils!]
- glandular hyperplasia and increased mucus secretion into bronchus lumen
- epithelial damage and sloughing
3 Subtypes of Type II Hypersentivitiy Rxns
Opsonization and phagocytosis
- may not have inflammation
Complement and Fc mediated inflammation
- neutrophil activation, inflammation, tissue injury
Abnormal physiological response
- no inflammation
- ex. receptors, myasthenia gravis [blocks acetylcholine receptors]
Goodpasture syndrome
Type II Hypersensitivity
- react to collagen IV in basement membrane
- complement and Fc receptor mediated
inflammation causes neutrophil activation
- glomeruler necrosis and acute inflammation
- leads to renal dysfunction
clinical: dark brown urine, high serum creatinine, coughing up blood, hematuria, hypertension, decreased glomerular filtration
Post-Streptococcal Glomerulonephritis
Type III hypersensitivity
- renal dysfunction, edema of eyelids, high BP, brown urine
- subepithelial immune complex deposits [granular deposits]
- may resolve on its own
Systemic Lupus Erythematosus [SLE]
Type III hypersensitivity
Reaction to nuclear antigens
- involves skin, joints, kidney, serosal membranes
- cannot resolve on its own, requires immunosuppressive therapy
5 most frequent sites immune complex deposition
skin: sun-exposure injury
glomerulus: high hemodynamic pressures + filtration function
synovium: mech trauma, high hemodynamic pressures + filtration function
endocardium: mechanical trauma, particularly valves
blood vessels: vascular turbulence, high pressure, particularly microvasculature + branch points of large BV
Type I Diabetes Mellitus
Target = Beta islet cells
Type IV hypersensitivity
Sarcoidosis
Type IV hypersensitivity
Causes Granulomas
Amyloid
pathologic accumulation proteinaceous substance deposited in extracellular space
Consists of insoluble aggregates fibrillar proteins, cross B pleated sheet
Diagnosis requires histologic identification
Amyloidosis
Group of diseases in which amyloids deposited
Amyloid properties
- result of protein misfolding
- self association of cross-B-pleated sheets form protofilament cores
- assembly of protofilaments create amyloid fibrils
- continuous non-branching fibers
- each fiber 4-6 fibrils in parallel array
- physical structure independent of clinical setting or chemical composition
Amyloid in histology
- composed of mostly protein fibrils
- stains blue-black with acidified iodine
- resembles cellulose or starch
- progressive extracellular accumulation
- pressure atrophy, functional disruption
- organs deformed, firm, enlarged
- amorphous, hyaline substance [H&E]
- pink-orange-red [congo red stain]
- red-green birefringence [polarized light]
What does congo red show?
amyloids show up eosinophilic in normal light
show up neony green in polarized light
AL amyloid
- misfolded form of immunoglobulin light chain
- deposits in plasma cells
- stimulus = unknown, possibly carcinogen
- get monoclonal B proliferation –> plasma cells –> lots of Ig light chains
- excess protein and limited proteolysis leads to aggregation
- primary systemic amyloidosis
- ex. multiple myeloma
AA amyloid
- from serum amyloid-associated protein [SAA]
- deposits in liver [acute phase response]
- stimulus = chronic inflammation
- get macrophage activation –> IL-1/6 –> liver cells
- excess SAA protein and limited proteolysis lead to aggregation
- secondary system amyloidosis
ex. chronic inflammatory conditions
B-amyloid [AB] - what disease type?
- from amyloid precursor protein [APP]
- cerebral deposits [plaques]
senile cerebral localized amyloidosis
ex. alzheimer disease
ATTR amyloid
- from Transthyretin [TTR]
- mutation [genetic syndrome, aging]
- mutant/abnormal protein aggregates
- senile/hereditary amyloidosis
ex. senile systemic/cardiac amyloidosis
Chemical Composition of Amyloid
95% major amyloid fibril protein
- AL, AA, AB, etc
5% minor components
- serum amyloid P component
- proteoglycans, glycosaminoglycans
Pathogeneisis of Amyloidosis
- Abnormal folding of protein, becomes unstable
- Self-associates into oligomers/fibrils, becomes insoluble
- Deposits in extracellular tissue, causes pressure atrophy
- Disrupts normal tissue function
Why do misfolded proteins turn into amyloids instead of being degraded in some people?
High level normal proteins [misfold when accumulate]
- increased production from aging
- decreased excretion
- decreased proteolysis
Mutation causes misfolding of abnormal proteins
- hereditary [ATTR] or acquire [prion]
Classification of Amyloidosis
Tissue distribution: either localized or systemic
If systemic:
- primary: due to plasma cell proliferation, clinically unrecognized
- secondary: due to chronic inflammatory disorder
Also can be hereditary/familial
Prognosis of generalize system amyloidosis
- progressive, unremitting
- median survival 2-5 yrs [primary < secondary]
- cardiac or renal complications
