Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome highlight T cell-initiated autoimmunity.

Abstract

Familial aggregation of primary Sjögren's syndrome (pSS), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and co-aggregation of these autoimmune diseases (ADs) (also called familial autoimmunity) is well recognised. However, the genetic predisposition variants that explain this clustering remains poorly defined. We used whole-exome sequencing on 31 families (9 pSS, 11 SLE, 6 RA and 5 mixed autoimmunity), followed by heterozygous filtering and cosegregation analysis of a family-focused approach to document rare variants predicted to be pathogenic by <i>in silico</i> analysis. Potential importance in immune-related processes, gene ontology, pathway enrichment and overlap analyses were performed to prioritise gene sets. A range from 1 to 50 rare possible pathogenic variants, including 39 variants in immune-related genes across SLE, RA and pSS families, were identified. Among this gene set, regulation of T cell activation (p=4.06×10^-7) and T cell receptor (TCR) signalling pathway (p=1.73×10^-6) were particularly concentrated, including <i>PTPRC</i> (<i>CD45</i>), <i>LCK</i>, <i>LAT-SLP76</i> complex genes (<i>THEMIS</i>, <i>LAT</i>, <i>ITK</i>, <i>TEC</i>, <i>TESPA1</i>, <i>PLCL1)</i>, <i>DGKD</i>, <i>PRKD1</i>, <i>PAK2</i> and <i>NFAT5</i>, shared across 14 SLE, RA and pSS families. TCR-interactive genes <i>P2RX7</i>, <i>LAG3</i>, <i>PTPN3</i> and <i>LAX1</i> were also detected. Overlap analysis demonstrated that the antiviral immunity gene <i>DUS2</i> variant cosegregated with SLE, RA and pSS phenotypes in an extended family, that variants in the TCR-pathway genes <i>CD45</i>, <i>LCK</i> and <i>PRKD1</i> occurred independently in three mixed autoimmunity families, and that variants in <i>CD36</i> and <i>VWA8</i> occurred in both RA-pSS and SLE-pSS families. Our preliminary results define common genetic characteristics linked to familial pSS, SLE and RA and highlight rare genetic variations in TCR signalling pathway genes which might provide innovative molecular targets for therapeutic interventions for those three ADs.