12.3 Disorders of the Immune System

Why immune disorders are a scored Pathology topic

Disorders of the immune system are 14% of the Pathology domain (Pathology is 16% of Part I, Session 2). Official bullets are hypersensitivity reactions, autoimmune diseases, and immunologic deficiencies. Microbiology immunology (/study-guides/nbce-part1/microbiology-host-pathogens/immunology) covers cells, antibodies, complement, vaccines, and serology. This section is immunopathology: which hypersensitivity type, which autoantibody, which missing limb of host defense. Physiology already listed circulating leukocytes; here the same cells produce tissue lesions.

Quick Answer: I = IgE mast cell (anaphylaxis, atopy). II = antibody to surface or receptor (MG, Graves, Goodpasture, AIHA). III = complexes (SLE nephritis, serum sickness, Arthus). IV = T cells (PPD, contact dermatitis, MS, Hashimoto, TB granuloma). SLE is III+II. RA is T-cell synovitis plus ACPA. HIV needs CD4 plus CCR5 or CXCR4.

Hypersensitivity types I–IV

Hypersensitivity is tissue damage from an otherwise adaptive immune effector. The Gell and Coombs four types still organize Part I stems. Types I–III are antibody-mediated; type IV is T-cell-mediated. All except the first encounter (sensitization) require prior adaptive priming.

Type I mechanism in steps. Sensitization: allergen presented to CD4 Th2 cells → IL-4 class-switch to IgE → IgE occupies FcεRI. Reexposure: crosslinking dumps preformed histamine (vasodilation, leak, itch, bronchoconstriction) and synthesizes cysteinyl leukotrienes (prolonged bronchospasm). The late phase is eosinophilic and can remodel bronchi. Systemic anaphylaxis is airway edema plus shock from leak and vasodilation; epinephrine is the physiologic antagonist (α1 vascular tone, β2 bronchodilation, mast-cell stabilization)—pathology wants the mechanism, not a prescription pad. Skin testing produces a wheal-and-flare in minutes.

Type II mechanisms split. (1) Opsonization and phagocytosis: IgG-coated RBCs or platelets (warm autoimmune hemolysis, ITP). (2) Complement MAC: some transfusion reactions. (3) ADCC: NK cells via FcγR. (4) Anti-receptor: Graves IgG stimulates TSH receptor (hyperthyroidism, pretibial myxedema, orbitopathy); myasthenia IgG blocks and down-regulates nicotinic receptors (fatigable weakness). Goodpasture IgG against the noncollagenous domain of type IV collagen in glomerular and alveolar basement membranes produces a linear IF pattern and lung-kidney hemorrhage—contrast the granular IF of immune-complex (type III) glomerulonephritis.

Type III needs complexes formed in slight antigen excess so they stay soluble, deposit in filtering or turbulent beds (glomerulus, synovium, skin, small arteries), fix complement, and attract neutrophils. Serum sickness is systemic (fever, urticaria, arthralgia, proteinuria about 1–2 weeks after a foreign protein or drug). The Arthus reaction is local immune-complex vasculitis in a primed host injected subcutaneously with antigen. Fibrinoid necrosis of vessel walls is the histologic signature.

Type IV is the PPD you sat through: previously primed Th1 cells recognize peptide on MHC II, release IFN-γ, and activate macrophages—induration at 48–72 hours is cellular infiltrate, not antibody. Contact dermatitis is a hapten (catechols of poison ivy) on self proteins. Granulomatous type IV is the TB tubercle. CD8 effectors kill viral and some autoimmune targets (β cells, thyroid epithelium, oligodendrocytes).

A stem that peaks in minutes with urticaria and wheeze is type I. A stem with hours, hemolysis, or receptor blockade is type II. A stem with vasculitis, hypocomplementemia, and granular GN is type III. A stem with 48-hour induration or granulomas is type IV.

Autoimmunity: failure of tolerance

Tolerance is the learned failure to attack self. Central tolerance deletes or receptor-edits high-affinity self-reactive clones: thymic negative selection (AIRE lets medullary epithelium express peripheral antigens; AIRE failure is APS-1) and bone-marrow editing of B cells. Peripheral tolerance uses anergy (costimulation missing), FoxP3 Tregs, and Fas–FasL deletion. Autoimmunity is that machinery failing plus a genetic (often HLA) and environmental (infection, UV, smoking, citrullination) trigger.

Systemic lupus erythematosus

SLE is the prototype multi-organ autoimmune disease of young women. Defective clearance of apoptotic debris exposes nuclear antigens; B cells make antinuclear antibodies (ANA). Pathologically it is type III (immune-complex dermatitis, vasculitis, wire-loop glomerulonephritis) plus type II (autoimmune hemolysis, thrombocytopenia, antiphospholipid antibodies against β2-glycoprotein I/cardiolipin). UV light apoptoses keratinocytes and drives photosensitivity.

Libman–Sacks endocarditis is sterile vegetations on both surfaces of the mitral valve. Immune complexes consume complement: low C3/C4 during flares. Do not call SLE a type I disease because of malar “rash”—the malar erythema is immune-complex and photosensitivity, not IgE.

Rheumatoid arthritis

RA is a chronic, symmetric, inflammatory polyarthritis of synovial joints driven by CD4 T cells, macrophages, and B cells. Smoking and periodontal bacteria citrullinate proteins; anti-citrullinated peptide antibodies (ACPA / anti-CCP) are more specific than rheumatoid factor (IgM against the Fc of IgG). HLA-DR4 shared epitope presents citrullinated peptides. Cytokines TNF, IL-1, and IL-6 activate synoviocytes; a pannus of inflamed synovium erodes cartilage and bone. Extra-articular: rheumatoid nodules (palisading granulomas), serositis, vasculitis, Felty syndrome (RA, splenomegaly, neutropenia).

Cervical fact for a spinal-anatomy-literate candidate: pannus and erosive disease at C1–C2 can destroy the transverse ligament and allow atlantoaxial subluxation. That is the same joint complex you studied in axial arthrology (/study-guides/nbce-part1/spinal-anatomy-axial/axial-arthrology), now as an immune lesion. Osteoarthritis is wear-and-remodeling without ACPA or pannus; seronegative spondyloarthritis is HLA-B27 and enthesitis, not rheumatoid factor.

Hashimoto thyroiditis

Hashimoto (chronic lymphocytic) thyroiditis is the most common cause of hypothyroidism in iodine-sufficient regions. CD8 T cells kill follicular epithelium (type IV); antibodies to thyroid peroxidase (TPO) and thyroglobulin are markers and contribute to antibody-dependent damage. The gland is firm, lymphocytic, with Hurthle (oncocytic) cells and germinal centers. Transient thyrotoxicosis can occur when stored hormone leaks (hashitoxicosis). Long-standing Hashimoto raises risk of thyroid B-cell lymphoma. Contrast Graves: type II stimulating antibody, diffuse hyperfunction, pretibial myxedema, orbitopathy—not a destructive lymphocytic gland.

Myasthenia gravis

Myasthenia gravis (MG) is type II autoimmunity against the postsynaptic nicotinic acetylcholine receptor (a subset have anti-MuSK). Antibodies block acetylcholine binding, fix complement, and accelerate receptor internalization. Safety factor at the neuromuscular junction collapses with repetition: fatigable weakness, ptosis, diplopia, bulbar and respiratory risk. Association: thymic hyperplasia in younger patients, thymoma in older. Ice-pack or acetylcholinesterase-inhibitor testing is clinical; pathology is the receptor and the thymus. Lambert–Eaton is the opposite polarity: antibodies to presynaptic P/Q calcium channels, often paraneoplastic small-cell lung carcinoma, and strength that may improve with use.

Multiple sclerosis

MS is a CD4 Th1/Th17-driven (type IV) attack on CNS myelin, with later CD8 and macrophage stripping of internodes. Plaques favor periventricular white matter, optic nerves, brainstem, and cervical cord. CSF oligoclonal IgG bands are clonal antibody inside the CNS, not the effector that starts demyelination. Clinical localizers: internuclear ophthalmoplegia (MLF), relative afferent pupillary defect (optic nerve), Lhermitte symptom (cervical cord). Separate MS from compressive myelopathy (disc, tumor, atlantoaxial subluxation): compression is a mass-effect lesion, not an autoimmune plaque. Charcot triad (nystagmus, scanning speech, intention tremor) is historic; the mechanism to memorize is T-cell demyelination with relative axonal sparing early, axonal loss later.

Immunodeficiencies: primary versus secondary

Primary (congenital) immunodeficiencies are gene defects presenting in childhood (or adulthood for milder lesions). Secondary are acquired: malnutrition, aging, diabetes, cancer, cytotoxics, corticosteroids, splenectomy, protein-losing states, and HIV.

Secondary immunodeficiency from splenectomy loses opsonization of encapsulated organisms (pneumococcus, meningococcus, H. influenzae). Steroids kill lymphocytes and blunt macrophage function. Malnutrition is still the world’s most common immunodeficiency.

HIV

Human immunodeficiency virus is a lentivirus (RNA retrovirus). gp120 binds CD4 plus a chemokine coreceptor: CCR5 on macrophages and memory T cells (R5, early, sexually transmitted strains; CCR5-Δ32 homozygotes are relatively resistant) or CXCR4 on T cells (X4, later). gp41 mediates fusion. Reverse transcriptase makes DNA; integrase inserts it; memory CD4 cells and macrophages are reservoirs. Acute infection can look like mononucleosis with a high viral load and a transient CD4 dip; a latent period of years follows as lymph-node CD4 cells are slowly destroyed. AIDS is a CD4 count <200 cells/µL or an AIDS-defining opportunistic illness regardless of count.

Malignancies: Kaposi sarcoma (HHV-8), aggressive B-cell lymphomas (EBV), HPV-driven cervical and anal carcinoma. Diagnosis is antibody/antigen immunoassay then RNA or differentiation assay—serology details belong to microbiology. Pathology wants the receptor, the cell destroyed (CD4 helper, which collapses both cell-mediated and, eventually, T-dependent antibody responses), and why granulomatous and viral defenses fail first.

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