PA8.3-5 | HLA, Transplantation, Autoimmunity & SLE — Summary & Reflection

REFLECT

Think about the 28-year-old woman from the hook scenario with joint pain, malar rash, foamy urine, and ANA 1:640.

1. Which additional autoantibodies would you request to confirm the diagnosis, and which specific test result would most concern you regarding her kidneys?
2. Her C3 is 45 mg/dL (normal 90–180) and C4 is 6 mg/dL (normal 16–47). What does this tell you about her disease activity and the underlying mechanism?
3. If her biopsy shows wire-loop lesions and full-house immunofluorescence, which WHO/ISN class is this, and what does it mean for her prognosis and treatment?
4. A classmate says: 'Her ANA is positive, so she must have SLE.' Why is this reasoning incomplete?

Write your responses briefly before reviewing the teaching points in your reference text.

KEY TAKEAWAYS

HLA/MHC: Class I (A, B, C) on all nucleated cells — presents endogenous peptides to CD8+ CTLs. Class II (DR, DP, DQ) on APCs — presents exogenous peptides to CD4+ helper T cells. Extreme polymorphism drives both disease associations (HLA-B27/AS, DR3/DR4 in SLE and T1DM) and transplant matching challenges.

Transplant rejection: Three types — Hyperacute (preformed antibody, complement, minutes–hours, prevent with crossmatch), Acute cellular (T-cell infiltrate, weeks–months, treat with steroids/ATG), Acute humoral (de novo DSA, C4d, antibody-mediated), Chronic (fibrosis + transplant arteriopathy, years, no specific therapy). GVHD = donor T cells attack host, occurs in bone marrow transplants.

Autoimmunity: Loss of central (thymic deletion, AIRE) and peripheral (anergy, T_reg, ignorance) tolerance. Failure mechanisms: molecular mimicry, bystander activation, epitope spreading, genetic susceptibility (HLA, CTLA4, PTPN22), environmental triggers.

Organ-specific vs systemic: Hashimoto, Graves, T1DM, MG, pernicious anaemia (organ-specific) ↔ SLE, RA, systemic sclerosis, Sjögren (systemic).

SLE pathogenesis: Impaired clearance of apoptotic nuclear debris → sustained ANA production (anti-dsDNA, anti-Sm most specific) → Type III immune-complex deposition → complement consumption (low C3/C4 = active disease). Multisystem: malar rash, non-erosive arthritis, nephritis (wire-loop lesions = Class IV worst), Libman–Sacks endocarditis, haematologic cytopenias, serositis, neuropsychiatric. ANA sensitive (>95%) but not specific; anti-dsDNA + anti-Sm = specific.