15.5 Immunological System Pathology: Autoimmune, Amyloid, and Systemic Immune-Mediated Disease

15.5 Immunological System Pathology

The blueprint's immunological-system pathology competency asks the student to identify the etiology, risk factors, complications, and clinical characteristics of immunodeficiency, hypersensitivity, autoimmune disease, amyloidosis, and systemic infections whose pathogenesis runs through the immune system. The earlier immunology chapter taught the mechanisms (Gell-Coombs types, tolerance breakdown, complement). Here the focus is the disease.

1. Autoimmune Connective-Tissue Diseases

Systemic lupus erythematosus (SLE) is a type III immune-complex disease with a striking female predominance. ANA is the sensitive screen (essentially all patients positive); anti-dsDNA correlates with nephritis and disease activity; anti-Sm is highly specific. Characteristic findings include a malar (butterfly) rash, Libman-Sacks nonbacterial verrucous endocarditis, lupus nephritis (Class IV proliferative is the most severe), and antiphospholipid antibodies causing thrombosis and recurrent fetal loss. The kidney lesion ranges from mesangial to membranous to diffuse proliferative; immune-complex deposition is visible as 'wire-loop' lesions and granular immunofluorescence.

Rheumatoid arthritis (RA) is a chronic symmetric polyarthritis of small joints. It targets MCP and PIP joints, sparing the DIP (the reverse of osteoarthritis's Heberden nodes). Anti-cyclic citrullinated peptide (anti-CCP) antibodies are more specific than rheumatoid factor; synovial hyperplasia produces a destructive pannus that erodes cartilage and bone. Extra-articular features include rheumatoid nodules (over extensor surfaces), vasculitis, and Felty syndrome (RA + splenomegaly + neutropenia).

Sjögren syndrome is exocrine gland lymphocytic infiltration producing xerophthalmia and xerostomia; anti-Ro/SSA and anti-La/SSB are the serologic markers; there is a markedly increased risk of B-cell lymphoma (mucosa-associated lymphoid tissue, MALT) over time.

Progressive systemic sclerosis (scleroderma) causes diffuse fibrosis. Diffuse disease (anti-Scl-70/topoisomerase I) involves skin and internal organs early, including renal crisis; limited disease (anti-centromere) is the CREST syndrome (Calcinosis, Raynaud, Esophageal dysmotility, Sclerodactyly, Telangiectasia). Anti-RNA polymerase III identifies the diffuse form with the highest renal-crisis risk.

Rheumatic fever is a type II/III disease two to three weeks after group A streptococcal pharyngitis (elevated ASO titers). Jones criteria: carditis (most serious), migratory polyarthritis, subcutaneous nodules, erythema marginatum, Sydenham chorea. Mitral valve damage leads to chronic rheumatic heart disease.

Myasthenia gravis (type II, anti-AChR, often with thymoma) produces fatigable weakness improving with rest; Goodpasture syndrome (type II, anti-GBM, linear immunofluorescence) causes hematuria and hemoptysis.

2. Diseases of Amyloids

Amyloidosis is extracellular deposition of misfolded β-pleated-sheet proteins. All types stain Congo red with apple-green birefringence and fluoresce under thioflavin.

A patient with a plasma-cell disorder, macroglossia, and restrictive cardiomyopathy has AL amyloidosis; a patient with chronic tuberculosis or rheumatoid arthritis and nephrotic-range proteinuria has AA amyloidosis. Distinguishing the type matters because AL is treated with anti-myeloma regimens while AA is treated by controlling the underlying inflammation.

3. Other Autoimmune and Hypersensitivity-Mediated Diseases

Granulomatous inflammation (type IV) appears in sarcoidosis and Crohn disease; transplant rejection is hyperacute (antibody, minutes), acute (cellular, weeks), or chronic (vascular, months-years). The hypersensitivity mechanisms are detailed in section 12.3; here the diseases are named so a vignette can be recognized. Sarcoidosis, a noncaseating granulomatous disease of unknown cause, preferentially affects the lungs (bilateral hilar lymphadenopathy) and produces elevated angiotensin-converting enzyme.

4. Systemic Infectious Diseases (Immune-Mediated Presentations)

Several blueprint-listed systemic infections are best understood through the immune response they provoke; organism details are in the microbiology chapter.

• Fifth disease (erythema infectiosum) — parvovirus B19; 'slapped-cheek' rash; arthritis in adults; can cause aplastic crisis in sickle cell disease and hydrops fetalis.
• Measles — prodromal Koplik spots on buccal mucosa, descending maculopapular rash, risk of SSPE years later.
• Rubella — postauricular and suboccipital lymphadenopathy, mild rash; teratogenic (congenital rubella syndrome: deafness, cataracts, cardiac defects).
• Roseola infantum — HHV-6, high fever for 3–4 days followed by rash as fever defervesces; febrile seizures are the common complication.
• Mumps — parotitis; can cause orchitis (with risk of infertility) and aseptic meningitis.
• Scarlet fever — group A strep pyrogenic exotoxin; strawberry tongue and sandpaper-like rash; precedes rheumatic fever and glomerulonephritis.
• Infectious mononucleosis — EBV infection of B cells; atypical lymphocytes (reactive T cells), positive heterophile antibody, splenic enlargement with rupture risk.
• Toxoplasmosis — Toxoplasma gondii (cat vector); congenital triad of choroidoretinitis, hydrocephalus, intracranial calcifications; ring-enhancing lesions in HIV.
• Haemophilus influenzae type b — epiglottitis ('cherry red'), meningitis in unvaccinated children.
• Influenza — seasonal viral respiratory infection with systemic cytokine-mediated symptoms; superimposed staphylococcal pneumonia is a major complication.

Board signal: a young woman with malar rash, nephritis, and a positive ANA with anti-dsDNA → SLE; a dry-eyed woman with anti-Ro and parotid swelling → Sjögren; a dialysis patient with carpal-tunnel syndrome → β2-microglobulin amyloidosis.