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
Prognosis localized or familial amyloidosis
15-20 years
longer than generalized
treatment for amyloidosis
- reduce precursor protein synthesis
- inhibit fibrillogenesis
- amyloid can rarely be resorbed
Origins of autopsy
- 18th century
- Giovanni Battista Morgagni
- first great autopsy pathologist
- publicly opposed galileo’s theories
19th century autopsy
Marie-Francois Xavier Bichat = father of histology
Rudolph Virchow: said cellular derangement is at basis of disease
Does histamine lead to transudate or exudate? Why?
- Histamine is a vasodilator and increases vascular permeability
- Causes cells and fluid to leave = exudate
Type III hypersenstivity mechanism and pathology?
- circulating immune complex is deposited in kidney
- activated inflammatory pathway in kidney
- causes vasculitis [fibrinoid necrosis]
Type IV hypersensitivity examples, mech, pathology?
examples: type I diabetes, sarcoidosis, contact dermatitis, transplant rejection
mech: CD4 or CD8 T cell activation
pathology: granulomas
Type II hypersensitivity examples, mech, pathology?
examples: goodpastures, autoimmune hemolytic anemia, graves
immune mech: antigen on cell surface or tissue surface
pathology: complement activation or acute inflammation
Definition of polyp
growth protruding above epithelial surface
Clinical signs of bronchial astham
- wheezing, breathlessness, tight chest, cough
clinica sign of systemic analphylaxi
- itching, hives, difficult breathing, diarrhea, shock
What is myasthenia gravis
- type II hypersensitivity
- blocks acetylcholine receptor
what is grave’s disease
- stimulates TSH receptor
- type II hypersensitivity
what type of hypersensitivity is autoimmune hemolytic anemia?
- type II
- attacks red cell antigen
What type of hypersensitivity is post-strep glomerulonephritis?
type III
What type of hypersensitivity shows granular immunofluorescence and which linear?
Type III is granular
Type II is linear [goodpasture]
What is multiple myeloma? What amyloidosis associated?
- cancer of plasma cells where overproduce one type of abnormal antibody
- overproduction of antibody can lead to AL amyloidosis
What disease associated with AL amyloid?
multiple myeloma
What disease associated with AA amyloid?
chronic inflammatory conditions [rheumatoid arthritis
If you see subepithelial deposits in glomerulus what should be first thought?
post stre glomerulonephritis
What is heparin?
An anticoagulant
What are schistocytes?
Fragmented RBC
a sign of disseminated intravascular coagulation
Most likely cause arterial thrombus?
Endothelial injury
What inflammatory cell involved primarily in bronchial asthma?
eosinophils
What form of amyloid associated with alzheimers? What precursor?
AB amyloid, from APP
What type of necrosis is associated with type III hypersensitivity
fibrinoid necrosis
How do you tell if a granuloma in lung is sarcoid or TB?
- granulomas of sarcoid have no central necrosis, those of TB do
- sarcoid granulomas often surrounded by fibrosis [scar tissue]
What are 4 diseases that cause granulomas and where?
in lung: sarcoidosis, TB
in intestine: crohns
in skin: leprosy
