Immunoregulatory role of saliva polymeric IgA1 in the pathogenesis of primary Sjögren’s Syndrome

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PROJECT SUMMARY/ABSTRACT To date, the pathogenesis of primary Sjögren’s Syndrome (pSS) is not well understood resulting in a 3 to 6 year delayed initial diagnosis. Serum anti-Ro/SSA autoantibodies and biopsy focus score are two key classification criteria of pSS by the 2016 ACR-EULAR1. Literature demonstrated that biopsy focus score is positively associated with the area of minor salivary gland fibrosis, common consequence of tissue damage and inflammation2,3. It is unclear whether tissue-resident lymphocyte infiltration or anti-Ro/SSA autoantibodies initiated autoimmune tissue destruction and orchestrated pSS disease progression. This proposal is to investigate the crosstalk between salivary anti-Ro52/SSA and salivary gland tissue destruction. We have developed a saliva-based electrochemical assay, electric field-induced release and measurement (EFIRM), that can screen, earlier detect, risk assess onset of pSS, alternative to the current ELISA blood-based serology assay. Preliminary data demonstrated: 1) EFIRM can directly detect and quantify salivary anti- Ro52/SSA autoantibodies in pSS patients; 2) Salivary and serum anti-Ro/SSA are correlated in pSS and Sicca patients; 3) Salivary anti-Ro52/SSA IgA1 correlate to salivary gland focus scores. IgA exists in two isotypes, IgA1 and IgA2, and IgA1 can further be subdivided into monomeric (mIgA1) and polymeric (pIgA1) subclasses4,5. Human serum IgA1 mostly exists as monomeric form (85-90%) whereas saliva secretory IgA1 are predominantly polymeric form (90-95%) secreted by polymeric Ig receptor (pIgR). Monomeric and polymeric IgA1 are structurally different due to the presence of galactose in the mIgA1, and absence in the pIgA14,6,7. The presence of galactose in mIgA1 can be detected using the galactose-specific legume lectin, Erythrina cristagalli lectin (ECL)8 whereas pIgA1 can be detected using the N-acetylgalactosamine binding lectin, Helix pomatia agglutinin (HPA)9. In addition to structural differences, mIgA1 and pIgA1 also exhibit differential immunoregulatory roles as immune suppressor5,7 and inducer10 respectively. We hypothesize that salivary pIgA1 anti-Ro52/SSA in pSS patients is associated with salivary gland tissue destruction, measured by biopsy focus score. Two Specific Aims are proposed to test this hypothesis. Aim 1 is to develop saliva-based anti-Ro52 mIgA1 and pIgA1 immunoassays. Aim 2 is to measure anti-Ro52 mIgA1 and pIgA1 in saliva of pSS, Sicca, and control subjects to investigate the correlation of saliva pIgA1 to salivary gland fibrosis and destruction. In future research plan, we will investigate the crosstalk between salivary pIgA1 anti-Ro52/SSA and tissue-resident immune T helper 17 cells12–14. Our studies are intended to determine the role of salivary autoantibody, anti-Ro52/SSA polymeric IgA1, in the context of salivary gland destruction in pSS patients.