The immunogenetic landscape of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is typically considered an acquired disease; nevertheless, a growing body of evidence suggests that, particularly in patients with severe disease and early onset, SLE may be due to single-gene mutations. To identify Inborn Error of Immunity genes that can cause monogenic SLE, we conducted a literature review. For each gene, we evaluated the plausibility of the reported association and defined the prevalent pathological pathway implicated in disease pathogenesis.

In the latest International Union of Immunological Societies (IUIS) classification, SLE is mentioned as a phenotype in only a subset of the genes identified in this review as SLE-related. At least 25 additional genes included in the most recent IUIS classification have also been recently linked to SLE and should be analyzed in patients with suspected monogenic SLE.

Genes related to different immunological pathways (from innate to adaptive immunity) can influence SLE development. A detailed clinical history, including previous infections, and a complete immunological evaluation should be performed in all patients with SLE at diagnosis, especially when monogenic SLE is suspected. Given the large number of genes and pathways associated with SLE, next-generation sequencing should be preferred over Sanger sequencing.