Description
Familial hemophagocytic lymphohistiocytosis (HLH) is a life-threatening cytokine storm syndrome caused by recessive, loss of function variants of genes in the pathway that controls the processing of cytolytic granule processing pathway genes. Heterozygous variants in these genes contribute to a secondary form of HLH (macrophage activation syndrome, MAS) that frequently develops in children with systemic juvenile idiopathic arthritis (sJIA). To evaluate the relationship between HLH gene variation and sJIA without MAS, HLH genes were sequenced and compared between 524 patients with sJIA and 2,924 control patients. The researchers identified an enrichment of rare HLH variants in people with sJIA compared with controls, driven by STXBP2 and UNC13D genes. In addition, people with sJIA carried two or more HLH variants more often than controls, driven largely by digenic combinations involving the gene LYST. However, only UNC13D displayed enrichment in people with MAS.
What is exciting about this article?
By studying a large international cohort, the researchers discovered previously unrecognized associations between rare HLH gene variation and uncomplicated sJIA. This suggests that HLH variants may contribute to the pathophysiology of sJIA, even without MAS, and that sJIA and HLH/MAS may not be distinct entities but instead represent a continuum of hyperinflammation.
Grant support
ZIA AR041198
Research Areas:
Research reported in this publication was supported by the Intramural Research Program of the NIHʼs National Institute of Arthritis and Musculoskeletal and Skin Diseases.