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