Background/Purpose: Sjögren’s disease (SjD) is a systemic autoimmune disease characterized by immune-mediated damage to salivary and lacrimal glands. While autoantibodies against muscarinic type 3 receptor (M3R) have long been implicated in disease pathogenesis, their clinical relevance remains unclear. We hypothesized that pathogenic anti-M3R antibodies originate in inflamed salivary glands and are detectable in both circulation and saliva, where their presence correlates with objective measures of disease activity.

Methods: Recombinant monoclonal antibodies (mAbs) were generated from single cells infiltrating labial salivary glands of classified SjD, NSS (non-Sjögren’s sicca), and overlap SjD subjects and screened for binding to linear and conformational M3R epitopes. Monoclonal antibodies along with matched plasma and saliva samples, as well as an expanded plasma cohort, were screened using a conformational On-Cell Western assay. Functional effects were assessed via inhibition of M3R signaling in a cell-based activity assay. Associations with clinical features and disease activity were evaluated.

Results: A subset of IgG⁺ mAbs from SjD glands bound conformational M3R and inhibited signaling. These features were reflected in matched plasma and, to a lesser extent, saliva. In the larger cohort, plasma anti-M3R reactivity was significantly elevated in SjD and showed association with ocular staining scores, focus scores, and higher ESSDAI biological domain activity. ROC analysis supported moderate diagnostic potential (AUC = 0.736).

Conclusion: These findings demonstrate that anti-M3R antibodies are functionally relevant and detectable in both salivary gland tissue and the circulation. Their association with key glandular and systemic disease features underscores the importance of conformational assays in identifying clinically meaningful autoantibodies. These results suggest that anti-M3R reactivity may define distinct immunopathologic subtype within SjD and serve as a potential biomarker of disease activity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/functional-anti-m3r-autoantibodies-in-sjogrens-disease-from-gland-to-circulation/