Abstract
Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a soluble immune regulatory molecule primarily expressed by monocytes and macrophages. A homozygous 6.7kbp LILRA3 gene deletion that removes the first seven of its eight exons is predicted to lead to lack of LILRA3 protein, although this has not been experimentally confirmed. Moreover, there are conflicting results with regards to the link between the LILRA3 homozygous genetic deletion and susceptibility to multiple sclerosis (MS) in different European populations. The aim of this study was to investigate whether LILRA3 gene deletion is associated with MS susceptibility in a North American cohort of European ancestry and assess if serum LILRA3 protein level is a marker of clinical subtype and/or disease severity in MS. A total of 456 patients with MS and 99 unrelated healthy controls were genotyped for the 6.7kbp LILRA3 gene deletion and levels of LILRA3 protein in sera determined by in-house sandwich ELISA. We showed that LILRA3 gene deletion was not associated with MS susceptibility and did not affect the age of disease onset, clinical subtype or disease severity. However, we discovered for the first time that homozygous LILRA3 gene deletion results in lack of production of LILRA3 protein. Importantly, LILRA3 protein level was significantly increased in sera of patients with MS when compared with control subjects, particularly in more severe type primary progressive MS. Multiple regression analysis showed that LILRA3 level in serum was one of the strongest independent markers of disease severity in MS, which potentially can be used as a diagnostic marker.
Highlights
Multiple sclerosis (MS) is a complex autoimmune disorder directed against components of CNS myelin or oligodendrocytes (OGD), probably initiated by environmental factors such as infections in genetically susceptible individuals [1,2,3,4,5]
In this study we aim to investigate whether Leukocyte immunoglobulin-like receptor A3 (LILRA3) gene deletion is linked with MS susceptibility in a North American cohort; we will for the first time i) assess whether LILRA3 null allele leads to lack of LILRA3 protein expression as predicted, ii) determine LILRA3 protein levels in patients with MS and healthy controls, and iii) investigate if LILRA3 protein levels correlate with clinical subtype, and/or disease severity in MS
The median age of disease onset for patients with primary progressive disease (PPMS) was 46 ± 9.8 years, which was older than patients with relapsing remitting disease (RRMS; 37 ± 10.2 years) or patients with secondary progressive disease (SPMS; 39 ± 10.3 years) but not statistically significant
Summary
Multiple sclerosis (MS) is a complex autoimmune disorder directed against components of CNS myelin or oligodendrocytes (OGD), probably initiated by environmental factors such as infections in genetically susceptible individuals [1,2,3,4,5]. About 85% of patients initially present with relapsing remitting disease (RRMS), which is characterised by recurrent and reversible neurological deficits [6, 7]. The majority of these patients will progress to the secondary progressive phase (SPMS) with continuous irreversible neurological decline [6, 7]. Variants in the Human Leukocyte Antigen (HLA) genes from the Major Histocompatibility Complex (MHC) in chromosome 6p21 have been consistently linked with MS susceptibility (reviewed in [4]). In some studies chromosome 19q13 has been found to be linked to MS [8, 9] and recent genome wide association studies have identified 110 MS risk variants in 103 discrete loci outside of the Major Histocompatibility Complex [4, 10,11,12,13,14]
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