The immunogenetics of multiple sclerosis: A comprehensive review

Highlights

• The main susceptibility to MS maps to the class II region of HLA.

• Further studies are needed to fully account for the role of HLA in MS pathogenesis.

• New horizons include understanding the role of KIR and non-coding variation in MS.

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen (HLA) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA-DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS.

Introduction

Multiple sclerosis (MS) is a chronic neurological disease associated with central nervous system (CNS) inflammation and neurodegeneration mediated by the adaptive and innate arms of an unregulated immune response [1], [2]. MS pathology is characterized by well-demarked inflammatory infiltrates, breakdown of myelin sheaths, microglia activation, proliferation of astrocytes and gliosis, and variable grades of axonal degeneration linked to oxidative stress and mitochondrial injury [3], [4]. Demyelinated lesions are disseminated through the CNS, involving both the white and gray matter. MS is a common cause of progressive neurological deficits in young adults, but disease expression is heterogeneous, varying from a mild illness to a rapidly evolving, incapacitating disease requiring profound lifestyle adjustments.

The individual and socioeconomic consequences of this debilitating and unpredictable disease are stunning. Fifteen years after diagnosis more than 80% of patients have functional and/or cognitive limitations, and approximately half require assistance to walk [5]. Twelve FDA-approved treatments for MS are now available, and several others are in late phases of development. However, the effects of these therapies on the long-term prognosis of the disease are largely unknown [6]. Furthermore, these therapies have diverse safety and toxicity profiles, and in effect no comparative data exist to guide when to initiate, change, or even how to select amongst the available options. Furthermore, no therapy exists for the progressive forms of MS, the subtypes most responsible for disability and debilitation [7].