Paraneoplastic encephalomyelitis in a patient with small cell lung carcinoma is mediated by antibodies against Hu antigen (ANNA-1). The Hu proteins are RNA-binding proteins normally expressed only in neurons. Why does SCLC trigger anti-Hu autoimmunity?

• A SCLC cells express Hu proteins due to their neuroendocrine lineage, which breaks central tolerance by presenting neuronal antigens in a peripheral, immunologically accessible context ✓
• B SCLC secretes IL-6, which directly activates B-cells to produce anti-Hu antibodies by polyclonal stimulation
• C SCLC cells release exosomal Hu protein that activates Toll-like receptors on dendritic cells, bypassing adaptive immunity
• D Hu antigen in SCLC is expressed only after chemotherapy-induced tumor lysis, exposing sequestered neuronal proteins

Explanation

SCLC, derived from neuroendocrine precursor cells, aberrantly expresses neuronal proteins including Hu, which are normally sequestered behind the blood-brain barrier. When SCLC expresses these proteins in a peripheral lymphoid-accessible environment, immune tolerance is broken and an adaptive T-cell and antibody response targets both the tumor and neurons expressing the same antigens. This onconeural antigen mechanism underlies all paraneoplastic neurological syndromes. IL-6 polyclonal activation and TLR-exosome pathways are not the established mechanism. Anti-Hu responses occur before chemotherapy.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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Written and medically reviewed by the StethoPrep medical team.