Professor of Pathology, Microbiology, and Medicine ImmunoPathology I R. Pat Bucy, MD, PhD Professor 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

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 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.

Granulomatous Inflammation Aggregation of macrophages with fibrosis Associated with chronic T cell and macrophage activation Antigen that is resistant to macrophage degradation

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 Scheme Mechanism 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

Alloantigen Recognition Direct Indirect Presentation Presentation Recipient APC Donor T Many endogenous peptides Donor peptide Recipient T cells

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)

Immune Complex IgE Ab T cells