Case report: Thymoma-associated GAD65 autoimmunity: a unifying mechanism for multi-organ injury involving nervous, endocrine, and renal systems

TL;DR

A man with a thymoma developed multiple autoimmune conditions linked to GAD65 antibodies, suggesting a single autoantigen can cause multi-organ damage.

Contribution

This case identifies GAD65 as a paraneoplastic pan-autoantigen that can drive cross-organ autoimmunity through molecular mimicry.

Findings

High-titer GAD65 antibodies were associated with neurological, endocrine, and renal autoimmune manifestations.

Epitope mapping revealed molecular mimicry between GAD65 and proteins in the kidney and thyroid, explaining cross-reactivity.

IVIG treatment reduced GAD65 antibody levels and improved clinical symptoms, supporting a causal role of autoimmunity.

Abstract

Thymomas are well-established disruptors of central immune tolerance, yet their capacity to drive systemic autoimmunity via a single autoantigen remains incompletely characterized. We report a 59-year-old male who, following resection of a Masaoka stage IIb type B2 thymoma, developed sequential neurological, endocrine, and renal manifestations over 18 months. Clinical evaluation confirmed stiff-person syndrome (SPS) with axial muscle hypermetabolism on PET-CT, latent autoimmune diabetes (HbA1c 11%), subclinical hypothyroidism (TSH 15.28 μIU/mL), and distal renal tubular acidosis (dRTA) evidenced by severe hypokalemia (K+ 2.4 mmol/L) and inappropriately alkaline urine (pH 7.5). All three syndromes were associated with persistently high-titer glutamic acid decarboxylase 65 (GAD65) autoantibodies (>500 nmol/L in serum). Epitope mapping identified molecular mimicry between the GAD65 peptide ²60PEVKEK²65 and homologous sequences in renal H+-ATPase and thyroid peroxidase, providing a mechanistic basis for multi-organ cross-reactivity. Treatment with intravenous immunoglobulin (IVIG) led to a 53.6% reduction in serum and an 80% decline in cerebrospinal fluid GAD65 antibody levels, paralleling clinical improvement. This case illustrates how thymoma-induced loss of tolerance to GAD65 can trigger widespread autoimmune injury through conformational epitope spreading, positioning GAD65 as a paraneoplastic pan-autoantigen. High-titer GAD65 antibodies may serve as a biomarker for systemic involvement, supporting early multidisciplinary surveillance in thymoma patients.

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