ImmunoPathology I
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Transcript of ImmunoPathology I
ImmunoPathology I
R. Pat Bucy, MD, PhDProfessor of Pathology, Microbiology, and
Medicine
Type I Hypersensitivity(AKA: Anaphylactic type, immediate hypersensitivity)
• Due to activity of IgE • Cross-linkage of Fce resulting in mast cell
degranulation• Anaphylaxis - local vs systemic• Skin test peaks in ~10 minutes• Normal function of IgE
Immediate Hypersensitivity (Type I)
Type II Hypersensitivity(AKA: Antibody mediated cytotoxic type)
• Ab coating of cells → phagocytosis & ADCC
• Ab + complement → direct lysis
• Ab interaction with cell surface receptor → activation or inhibition of bioactivity
Examples of Antibody-Mediated Diseases (Type II Hypersensitivity)
Disease Target Antigen Mechanisms of DiseaseClinicopathologic Manifestations
Autoimmune hemolytic anemia
Erythrocyte membrane proteins (Rh blood group antigens, I antigen)
Opsonization and phagocytosis of erythrocytes
Hemolysis, anemia
Autoimmune thrombocytopenic purpura
Platelet membrane proteins (gpllb:Illa integrin)
Opsonization and phagocytosis of platelets
Bleeding
Pemphigus vulgaris Proteins in intercellular junctions of epidermal cells (epidermal cadherin)
Antibody-mediated activation of proteases, disruption of intercellular adhesions
Skin vesicles (bullae)
Vasculitis caused by ANCA
Neutrophil granule proteins, presumably released from activated neutrophils
Neutrophil degranulation and inflammation
Vasculitis
Goodpasture syndrome Noncollagenous protein in basement membranes of kidney glomeruli and lung alveoli
Complement- and Fc receptor-mediated inflammation
Nephritis, lung hemorrhage
Acute rheumatic fever Streptococcal cell wall antigen; antibody cross-reacts with myocardial antigen
Inflammation, macrophage activation
Myocarditis, arthritis
Myasthenia gravis Acetylcholine receptor Antibody inhibits acetylcholine binding, down-modulates receptors
Muscle weakness, paralysis
Graves disease (hyperthyroidism)
TSH receptor Antibody-mediated stimulation of TSH receptors
Hyperthyroidism
Insulin-resistant diabetes
Insulin receptor Antibody inhibits binding of insulin
Hyperglycemia, ketoacidosis
Pernicious anemia Intrinsic factor of gastric parietal cells
Neutralization of intrinsic factor, decreased absorption of vitamin B12
Abnormal erythropoiesis, anemia
Type III Hypersensitivity(Immune complex type)
• Immune complex physical chemistry and IC deposition
• IC deposition in vessel walls and glomeruli – complement deposition and neutrophil
activation • Skin test peaks in ~10 hours
–Skin test called Arthus reaction
(Type III Hypersensitivity)
Disease Antigen InvolvedClinicopathologic Manifestations
Systemic lupus erythematosus
Nuclear antigens Nephritis, skin lesions, arthritis, others
Poststreptococcal glomerulonephritis
Streptococcal cell wall antigen(s); may be "planted" in glomerular basement membrane
Nephritis
Polyarteritis nodosa Hepatitis B virus antigen Systemic vasculitisReactive arthritis Bacterial antigens (Yersinia ) Acute arthritisSerum sickness Various proteins, such as foreign
serum protein (horse anti-thymocyte globulin)
Arthritis, vasculitis, nephritis
Arthus reaction (experimental)
Various foreign proteins Cutaneous vasculitis
Examples of Immune Complex-Mediated Diseases
Type IV Hypersensitivity(Cell mediated type)
• Delayed Type Hypersensitivity (DTH) - CD4+ T cell mediated macrophage and endothelial activation
• Granulomatous inflammation - continual T cell drive with lack of complete M digestion of Ag
• Cytolytic T Lymphocytes (CTL) - direct lysis of target cells involving TCR recognition at effector phase
• NK cell activity - no specific recognition (no TCR). Require IL-2 and perhaps other cytokines.
• Technical difficulties in experimental determination of cellular vs Ab mediated immune mechanisms.
GranulomatousInflammation
• Aggregation of macrophages with fibrosis
• Associated with chronic T cell and macrophage activation
• Antigen that is resistant to macrophage degradation
Examples of T-Cell-Mediated (Type IV) Hypersensitivity
Disease Specificity of Pathogenic T cellsClinicopathologic Manifestations
Type 1 diabetes mellitus
Antigens of pancreatic islet βcells (insulin, glutamic acid decarboxylase, others)
Insulitis (chronic inflammation in islets), destruction of βcells; diabetes
Multiple sclerosis Protein antigens in CNS myelin (myelin basic protein, proteolipid protein)
Demyelination in CNS with perivascular inflammation; paralysis, ocular lesions
Rheumatoid arthritis Unknown antigen in joint synovium (type II collagen?); role of antibodies?
Chronic arthritis with inflammation, destruction of articular cartilage and bone
Peripheral neuropathy; Guillain-Barré syndrome?
Protein antigens of peripheral nerve myelin
Neuritis, paralysis
Inflammatory bowel disease (Crohn's disease)
Unknown antigen; may be derived from intestinal microbes
Chronic inflammation of ileum and colon, often with granulomas; fibrosis, stricture
Contact dermatitis Environmental chemicals, e.g., poison ivy (pentadecylcatechol)
Dermatitis, with itching; usually short-lived, may be chronic with persistent exposure
Relationship of antibody vs cell mediated hypersensitivity
• Radical difference in assay/detection methodology
• Usually both are present in a strong immune response
• Presence of antibody can be a marker of a specific T cell mediated lesion
• Passive transfer is the key experimental approach to determine primary cause of response.
Classification SchemeMechanism vs Antigen
• Classical system focuses on mechanism– Don’t know all mechanisms (especially early)– Actual disease mechanisms overlap
• Alternative system focused on antigen drive– The kinetic course of antigen concentration is the
key immunoregulatory entity. – Often don’t know the specific driving antigens– Infection, environmental, tumors, iatrogenic, self.
Leprosy• Two forms of disease; one bug
(Mycobacterium leprae).• Tuberculoid leprosy - intense immune
response with low organism load• Lepromatous leprosy - suppressed immune
response with high organisms load• Different cytokine patterns in T cell
response correlate with forms of disease
Contact Dermatitis• Exposure of the skin to multiple agents can cause
sensitization. On repeated exposure, an eczematous eruption occurs.
• Histologically, the lesion is a mononuclear infiltrate, epidermal spongiosis (intercellular edema), and vesicle formation (bullae).
• Depends on ability covalently conjugate to proteins.
• Exposure to poison ivy is a common example of this process.
Penicillin Allergy• Since penicillin is fairly reactive with proteins,
sensitization is common. • Depending on the idiosyncratic nature of the immune
response and subsequent exposure, several clinical syndromes may develop.
• Formation of IgE can result in systemic anaphylaxis after penicillin therapy (particularly after intravenous administration).
• Formation of IgG and drug conjugates of serum proteins (albumin) can lead to a "serum sickness" syndrome, involving fever, skin rash, lymphadenopathy, and edema. Occasionally arthritis, nephritis, and vasculitis may result.
• Conjugation to red blood cells with high dose IV therapy and IgG formation can result in development of hemolytic anemia.
Tumor Antigens for CD8+ T cells
Organ/Tissue Transplants
RecipientAPC
DonorAPC
T T
Alloantigen RecognitionDirect
PresentationIndirect
Presentation
Recipient T cells
Manyendogenous
peptides
Donorpeptide
Mechanisms of transplant rejection (classical)
• No “real” physiologic mechanism (evolutionarily selected)
• Hyperacute rejection• Acute vascular rejection• Acute cellular rejection• Chronic rejection
Mechanisms of transplant rejection• Cytotoxic damage to endothelial cells with
coagulation• “DTH” in interstitium - CD4+ T cells & M
activation• CTL activity on parenchymal cells (tubules,
cardiomyocytes, bile ducts, hepatocytes)• T cell mediated arteritis with intimal proliferation
and infarction• ADCC and NK cell activity in interstitium • Antibody mediated injury to endothelia with
intimal proliferation and infarction
Clinical Monitoring of Allograft Rejection
• Kidney - serum creatinine/Biopsy• Heart - Blind Biopsy• Liver - Bilirubin, transaminases/Biopsy• Lung - Pulmonary Function tests/Biopsy• Pancreas - No good method, (urinary
amylase, or cytology)
IgE AbImmuneComplex T cells