LILRA3 as a novel regulator of thrombioinflammation in antiphospholipid syndrome (APS)

JI Program: Exploratory

Few acquired states carry a higher risk of thrombosis than antiphospholipid syndrome (APS), a systemic autoimmune disease that impacts as many as 1-in-1000 individuals worldwide.  Neutrophil extracellular traps (NETs)—tangles of chromatin and microbicidal proteins ejected from dying neutrophils—appear to play a key role in the thromboinflammation inherent to APS.  Our Michigan Medicine team has characterized the transcriptome of APS neutrophils, where we discovered 4-fold upregulation of leukocyte immunoglobulin-like receptor A3 (LILRA3).  LILRA3 belongs to a family of surface receptors expressed especially by myeloidlineage cells, and best known for modulating HLA class I signaling.  Interestingly, the LILRA3 gene product is the only soluble receptor within the LILR family.  Another unique feature of LILRA3 is a 6.7-kb deletion polymorphism, resulting in a null allele when present.  Null-allele frequencies differ among ethnic groups:  0.560.84 (Asians), 0.17 (Europeans), and 0.10 (Africans).  Our PKUHSC team’s work in Han Asian individuals has found the null allele to be protective against rheumatoid arthritis and lupus.  This study will now be the first to characterize LILRA3 in a thromboinflammatory disorder (APS), leveraging unique expertise of Michigan Medicine and PKUHSC to (i) reveal novel APS-relevant biology, (ii) improve APS risk stratification, and (iii) lay the groundwork for future collaboration in pursuit of new APS biomarkers and therapies.