Cytosolic 5'-nucleotidase 1A autoimmunity in sporadic inclusion body myositis

The team applied two complementary unbiased approaches to a long-recognized but molecularly anonymous IBM autoantibody: mass spectrometry on muscle protein preparations enriched by IBM patient antibodies, and screening of IBM patient antibodies against a synthetic human peptidome covering essentially the entire human proteome. Both converged independently on cN1A.

Diagnostic test performance against 200 plasma and serum samples placed anti-cN1A at 70% sensitivity and 92% specificity for IBM at moderate reactivity, and 34% sensitivity at 98% specificity at high reactivity. Immunohistochemistry on 30 muscle biopsies localized cN1A reactivity to perinuclear regions and rimmed vacuoles — the same anatomical structures associated with IBM's degenerative pathology — providing tissue-level evidence that the autoimmune target colocalizes with the histopathological hallmarks.

The work reframes sporadic inclusion body myositis as a disease with a definable autoantibody-defined immune component, not a purely degenerative myopathy, and provides a mechanistic link between IBM's autoimmune and myodegenerative processes — a major nosological clarification for a disease historically classified at the boundary of these two categories. For autoantigen discovery programs working in under-served neuromuscular and rare autoimmune diseases, the study is a methodological template demonstrating how an unbiased screen against a proteome-spanning peptide library can convert a clinically suggestive but molecularly uncharacterized antibody reactivity into a fully defined autoantigen, immunodominant epitope map, and diagnostic test in a single integrated workflow.