THEMIS – Systemic Lupus Erythematosus

Familial studies of autoimmunity have identified variants in key T cell receptor (TCR) signaling genes, including THEMIS, in families affected by systemic lupus erythematosus (SLE) alongside rheumatoid arthritis and primary Sjögren's syndrome. In a comprehensive study of 31 families, heterozygous filtering and cosegregation analysis revealed that rare variants in TCR pathway components, with THEMIS being one of the prioritized genes, were observed in 14 families (PMID:31848144).

The genetic evidence points to an autosomal dominant inheritance pattern for these variants, as heterozygous changes in THEMIS and other TCR-related genes were found to segregate with the disease phenotype. This observation is supported by the identification of a range of 1 to 50 rare possible pathogenic variants across affected families, with a subgroup exhibiting consistent segregation, particularly in the context of SLE (PMID:31848144).

Although no specific coding variant in THEMIS was directly highlighted in the mutation list, the recurring implication of THEMIS in these familial cohorts underscores its potential role in modulating T cell activation. The enrichment of rare variants in this gene among affected families serves as a robust indicator of its involvement in the pathogenesis of SLE.

Functional evidence further supports the contribution of THEMIS to disease pathology. Studies have demonstrated that allele-dependent expression differences in THEMIS in CD4+ T-cells can impact T cell activation and differentiation. Such findings are consistent with the known importance of TCR signaling in autoimmunity and complement the genetic data derived from familial studies (PMID:27438997).

There remains a degree of uncertainty at the variant-specific level for THEMIS; however, the convergence of both genetic and functional evidence provides a coherent narrative. This integration supports a strong gene–disease association where altered TCR signaling driven by THEMIS dysregulation contributes to the molecular etiology of SLE.

Overall, the combined data highlights that THEMIS is a substantial molecular contributor within the T cell signaling cascade, reinforcing its clinical relevance for diagnostic decision‑making and the future development of targeted therapeutics.

Key take‑home sentence: THEMIS alterations represent a significant genetic factor in familial systemic lupus erythematosus, exemplifying the role of T cell receptor signaling dysregulation in autoimmunity.

References

• Annals of the rheumatic diseases • 2020 • Germline genetic patterns underlying familial rheumatoid arthritis, systemic lupus erythematosus and primary Sjögren's syndrome highlight T cell‑initiated autoimmunity PMID:31848144
• PloS one • 2016 • Increased THEMIS First Exon Usage in CD4+ T-Cells Is Associated with a Genotype that Is Protective against Multiple Sclerosis PMID:27438997

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