A LILRB1 variant with a decreased ability to phosphorylate SHP-1 leads to autoimmune diseases
Thivaratana Sinthuwiwat, Supranee Buranapraditkun, Wuttichart Kamolvisit, Siraprapa Tongkobpetch, Wanna Chetruengchai, Chalurmpon Srichomthong, Adjima Assawapitaksakul, Chureerat Phokaew, Patipark Kueanjinda, Tanapat Palaga, Tadech Boonpiyathad, Kanya Suphapeetiporn, Nattiya Hirankarn, Vorasuk Shotelersuk
Abstract
Inborn errors of immunity are known to cause not only immunodeficiencies and allergies but also autoimmunity. Leukocyte immunoglobulin-like receptor B1 (LILRB1) is a receptor on leukocytes playing a role in regulating immune responses. No phenotypes have been reported to be caused by germline mutations in LILRB1. We aimed to identify the causative variant in a three-generation family with nine members suffering from one of the three autoimmune diseases-Graves' disease, Hashimoto's thyroiditis, or systemic lupus erythematosus. Whole-genome linkage study revealed a locus on chromosome 19q13.4 with the maximum LOD score of 2.71. Whole-exome sequencing identified a heterozygous missense variant, c.479G > A (p. G160E) in LILRB1, located within the chromosomal-linked region, in all nine affected members. The variant has never been previously reported. Jurkat cells transfected with the mutant LILRB1, compared with those with the wild-type LILRB1, showed decreased phosphorylation of both LILRB1 and its downstream protein, SHP-1. Flow cytometry was used to study immunophenotype and revealed that LILRB1 was significantly lower on the surface of activated regulatory T lymphocytes (Treg) cells of patients. Single-cell RNA sequencing showed substantially increased M1-like monocytes in peripheral blood mononuclear cells of affected individuals. This study, for the first time, implicates LILRB1 as a new disease gene for autoimmunity.