Multiple sclerosis associates with LILRA3 deletion in Spanish patients

Abstract

The genetic susceptibility to multiple sclerosis (MS) is only partially explained, and it shows geographic variations. We analyse here two series of Spanish patients and healthy controls and show that relapsing MS (R-MS) is associated with a gene deletion affecting the hypothetically soluble leukocyte immunoglobulin (Ig)-like receptor A3 (LILRA3, 19q13.4), in agreement with an earlier finding in German patients. Our study points to a gene-dose-dependent, protective role for LILRA3, the deletion of which synergizes with HLA-DRB1*1501 to increase the risk of R-MS. We also investigated whether the risk of suffering R-MS might be influenced by the genotypic diversity of killer-cell Ig-like receptors (KIRs), located only B400 kb telomeric to LILRA3, and implicated in autoimmunity and defence against viruses. The relationship of LILRA3 deletion with R-MS is not secondary to linkage disequilibrium with a KIR gene, but we cannot exclude some contributions of KIR to the genetic susceptibility to R-MS.

Glycosylation in a Mammalian Expression System Is Critical for the Production of Functionally Active Leukocyte Immunoglobulin-like Receptor A3 Protein

“…This is consistent with our recent finding of the presence of abundant LILRA3 protein in sera of healthy individuals and its significant up-regulation by the anti-inflammatory cytokine IL-10 (6). This is further supported by recent reports showing an association of a lack of LILRA3 with an increased incidence of multiple sclerosis (8,9) and Sjögren syndrome (10), diseases characterized by chronic inflammation. Interestingly, we found a significant increase in LILRA3 in sera of patients with active rheumatoid arthritis (6) together with increased expression of activating and inhibitory LILRs in synovial tissue (7).…”

“…We proposed that LILRA3 may antagonize the effects of LILRA2, which is increased in highly inflamed synovial tissue (7). Interestingly, absence of a functional allele due to a natural gene deletion (4) has been shown to be strongly associated with increased incidence of multiple sclerosis (8,9) and Sjögren syndrome (10), both characterized by excessive inflammation, suggesting that LILRA3 may play a key role in the pathogenesis of chronic inflammatory diseases. Consistent with this, LILRA3 is strongly up-regulated by the anti-inflammatory cytokine IL-10 and down-regulated by proinflammatory cytokine TNF␣ (6).…”

HLA Class I Allelic Sequence and Conformation Regulate Leukocyte Ig-Like Receptor Binding

“…LILRA3 is not present on all leukocyte receptor complex haplotypes (64). LILRA3 deficiency has been associated with the development of Sjögren's syndrome and multiple sclerosis (66)(67)(68).…”

Functional and genetic diversity of leukocyte immunoglobulin-like receptor and implication for disease associations

“…First, LILRA3 deficiency is a risk factor for multiple sclerosis in the German and Spanish populations but not in the Polish population. [65][66][67] Second, homozygous LILRA3 deletion is associated with Sjögren's syndrome in German, whereas homozygous functional LILRA3 is associated with primary Sjögren's syndrome in Chinese. 68,69 Moreover, homozygosity for the LILRA3 non-deleted allele confers susceptibility to RA and SLE.…”