10.2 Immunopathology: Hypersensitivity, Autoimmunity, Immunodeficiency & Transplant Rejection
Key Takeaways
Type I hypersensitivity is IgE and mast cell mediated (anaphylaxis, asthma); type II is antibody against cell or matrix antigens (hemolytic transfusion reaction, Graves, myasthenia); type III is immune-complex deposition (SLE, PSGN, serum sickness, Arthus); type IV is T-cell mediated (tuberculin test, contact dermatitis, granulomas).
SLE shows antinuclear antibodies (sensitive) and anti-dsDNA and anti-Smith antibodies (specific), low complement in active disease, and Libman-Sacks endocarditis.
X-linked (Bruton) agammaglobulinemia lacks B cells (BTK defect); DiGeorge syndrome lacks T cells (22q11 deletion, hypocalcemia); SCID lacks both; selective IgA deficiency is the most common primary immunodeficiency.
HIV destroys CD4 T cells; opportunistic infections appear as the CD4 count falls (Pneumocystis below 200, Toxoplasma below 100, CMV and MAC below 50).
Hyperacute rejection is due to preformed antibodies (minutes); acute rejection is T-cell or antibody mediated (weeks to months); chronic rejection causes vascular intimal fibrosis (months to years).
Why this area matters
The TOS lists "hypersensitivity disorders; autoimmune diseases; congenital immunodeficiency syndromes; acquired immunodeficiency associated with HIV, aging, malnutrition". These mechanisms connect Biochemistry (immunology), Microbiology (opportunistic infections), Medicine (rheumatology, allergy) and Pediatrics (recurrent infections). Learn each reaction by its mechanism and a classic example.
Hypersensitivity reactions
| Type | Mechanism | Timing | Examples |
|---|---|---|---|
| I (immediate) | Allergen cross-links IgE on mast cells and basophils, releasing histamine, leukotrienes and prostaglandins; a late phase follows with eosinophils | Minutes, then a late phase at 2 to 24 hours | Anaphylaxis, allergic rhinitis, atopic asthma, urticaria, food and drug allergy |
| II (antibody-mediated) | IgG or IgM binds antigens on cells or matrix, causing opsonization and phagocytosis, complement lysis, or receptor dysfunction | Minutes to days | ABO transfusion reaction, hemolytic disease of the newborn, autoimmune hemolytic anemia, ITP, Goodpasture syndrome, rheumatic fever, Graves disease (stimulating antibody) and myasthenia gravis (blocking antibody) |
| III (immune complex) | Antigen-antibody complexes deposit in vessels, glomeruli and joints, activating complement and recruiting neutrophils (fibrinoid necrosis) | Days to weeks | SLE, post-streptococcal glomerulonephritis, serum sickness, polyarteritis nodosa, Arthus reaction (local) |
| IV (T-cell mediated) | CD4 Th1 cells activate macrophages (granulomas), or CD8 cytotoxic T cells kill targets | 48 to 72 hours | Tuberculin (PPD) reaction, contact dermatitis (poison ivy, nickel), tuberculosis and leprosy granulomas, type 1 diabetes, multiple sclerosis, transplant rejection |
Autoimmunity
Autoimmune disease follows a loss of self-tolerance. Contributors are:
- failure of central deletion in the thymus (AIRE) or of peripheral anergy;
- defects in regulatory T cells (FOXP3);
- genetic susceptibility (HLA associations such as HLA-B27 in ankylosing spondylitis and HLA-DR4 in rheumatoid arthritis);
- environmental triggers, including molecular mimicry (streptococcal M protein and cardiac myosin in rheumatic fever) and tissue injury that exposes hidden antigens.
| Disease | Key pathology and antibodies |
|---|---|
| Systemic lupus erythematosus | ANA (most sensitive); anti-dsDNA and anti-Smith (most specific); low C3 and C4 when active. Immune-complex nephritis (class IV diffuse proliferative is most severe), Libman-Sacks endocarditis, LE cells, malar rash, serositis, cytopenias. Antiphospholipid antibodies cause thrombosis and pregnancy loss. Drug-induced lupus (procainamide, hydralazine, isoniazid) shows anti-histone antibodies and spares the kidneys |
| Sjögren syndrome | Lymphocytic infiltration of salivary and lacrimal glands (dry eyes and mouth); anti-Ro (SS-A) and anti-La (SS-B); higher B-cell lymphoma risk |
| Systemic sclerosis (scleroderma) | Fibrosis of skin and viscera. Diffuse form: anti-Scl-70 (topoisomerase I), lung and kidney (renal crisis). Limited form (CREST): anti-centromere |
| Inflammatory myopathies | Dermatomyositis (heliotrope rash, Gottron papules, perifascicular atrophy, associated malignancy); anti-Jo-1 |
| Rheumatoid arthritis | Synovial pannus; rheumatoid factor and anti-CCP (more specific) |
Congenital (primary) immunodeficiencies
| Disorder | Defect | Clues |
|---|---|---|
| X-linked (Bruton) agammaglobulinemia | BTK mutation; B cells fail to mature | Boys over 6 months (maternal IgG gone); recurrent bacterial sinopulmonary infections, enteroviral and Giardia infections; absent tonsils and B cells |
| DiGeorge syndrome | 22q11 deletion; third and fourth pharyngeal pouch failure | Absent thymus (T-cell deficiency), hypocalcemic tetany, conotruncal heart defects, facial anomalies |
| Severe combined immunodeficiency (SCID) | X-linked IL-2 receptor common gamma chain, or adenosine deaminase deficiency (autosomal recessive) | Failure to thrive, chronic diarrhea, thrush, Pneumocystis; live vaccines dangerous; absent thymic shadow |
| Selective IgA deficiency | Most common primary immunodeficiency | Often asymptomatic; sinopulmonary and GI infections; anaphylaxis to IgA-containing blood products |
| Common variable immunodeficiency | Low immunoglobulins, often onset in adulthood | Recurrent infections, autoimmunity, lymphoma |
| Hyper-IgM syndrome | CD40 ligand defect (no class switching) | High IgM, low IgG, IgA and IgE; Pneumocystis |
| Wiskott-Aldrich syndrome | WAS gene, X-linked | Thrombocytopenia with small platelets, eczema, infections |
| Complement deficiencies | C5 to C9 (membrane attack complex); C1 esterase inhibitor | Recurrent Neisseria infections; hereditary angioedema |
Acquired immunodeficiency
- HIV uses gp120 to bind CD4 and the CCR5 or CXCR4 co-receptor, and destroys CD4 T cells, especially in gut lymphoid tissue. As CD4 counts fall, opportunistic infections and cancers appear:
- below 200/µL: Pneumocystis jirovecii;
- below 100/µL: Toxoplasma, Cryptococcus;
- below 50/µL: CMV retinitis, Mycobacterium avium complex;
- associated cancers: Kaposi sarcoma, primary CNS and B-cell lymphomas, invasive cervical cancer. Tuberculosis can occur at any CD4 count and is a common opportunistic infection among Filipinos living with HIV.
- Malnutrition, the most common cause of immunodeficiency worldwide, impairs cell-mediated immunity, causes thymic atrophy, and makes measles and tuberculosis severe.
- Aging (immunosenescence) causes thymic involution and fewer naive T cells, which leads to weaker vaccine responses and reactivation of herpes zoster and tuberculosis.
- Other causes: corticosteroids, chemotherapy, splenectomy (encapsulated bacteria), diabetes, chronic kidney disease, cancer.
Transplant rejection
| Type | Timing | Mechanism | Morphology |
|---|---|---|---|
| Hyperacute | Minutes | Preformed antibodies (ABO, HLA) | Thrombosis and ischemic necrosis of the graft |
| Acute | Weeks to months | Cellular (CD8 T cells, tubulitis) or antibody-mediated (vasculitis, C4d) | Reversible with immunosuppression |
| Chronic | Months to years | Mixed immune injury | Intimal fibrosis and vascular narrowing, interstitial fibrosis; irreversible |
| Graft-versus-host disease | After bone marrow or blood transfusion with T cells | Donor T cells attack host skin, gut and liver | Rash, diarrhea, jaundice; prevented by irradiating blood for at-risk recipients |
A child develops wheezing, urticaria and hypotension within minutes of eating shrimp. Which immune mechanism produced the reaction?
Type IV hypersensitivity: sensitized Th1 cells releasing interferon-gamma
Type II hypersensitivity: IgG binding to red cell antigens with complement lysis
Type III hypersensitivity: immune complexes deposited in small vessels
Type I hypersensitivity: allergen cross-linking IgE bound to mast cells, causing degranulation
A 9-month-old boy has recurrent pneumococcal pneumonia and otitis media. Flow cytometry shows almost no CD19+ B cells, and all immunoglobulin classes are very low. Tonsils are not visible. What is the most likely diagnosis?
Selective IgA deficiency
DiGeorge syndrome from a 22q11 deletion
Chronic granulomatous disease from an NADPH oxidase defect
X-linked (Bruton) agammaglobulinemia caused by a BTK defect
A kidney transplant recipient's graft turns cyanotic and mottled within minutes of reperfusion in the operating room. What is the mechanism?
Preformed recipient antibodies to donor antigens, with complement activation and thrombosis
Gradual intimal fibrosis and narrowing of the graft arteries over months to years after transplant
Cytotoxic T cells infiltrating tubules weeks after transplantation
Donor T cells attacking recipient tissues
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