Review articleThe immunogenetics of multiple sclerosis: A comprehensive review
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].
Section snippets
MS epidemiology
In Europeans and their descendants, MS is the most common cause of non-traumatic neurological disability in young adults, affecting approximately 2.5 million people worldwide and more than 400,000 individuals in the US [8]. The prevalence of MS varies with geography and ethnicity. Indeed, with some notable exceptions, MS is more frequent in high latitude regions and northern European populations [9]. Notwithstanding difficulties in surveillance, MS is almost nonexistent in black Africans and
MS genetics
Evidence for a genetic component in MS pathogenesis is found in the clustering of affected individuals in families, high disease concordance rate in monozygotic twins, and differences in disease prevalence among different ancestral groups [17], [18], [19], [20], [21]. However, a simple model of inheritance for all MS is unlikely since neither the recurrence rate nor the twin concordance supports the presence of a Mendelian trait. On the other hand, there is a broad consensus that the disease is
The human leukocyte antigen [HLA] region and MS
A search for “multiple sclerosis” and “HLA” in Pubmed reveals over two thousand entries. The HLA (Box 1) association with MS, which was first described several decades ago [25], [26], is consistent with the idea that MS is, at its core, an antigen-specific autoimmune disease. The association of the HLA locus with MS risk has been observed across all populations studied, and in both primary progressive and relapsing-remitting patients. The primary signal within the MHC maps to the HLA-DRB1 gene,
HLA associations in other neurological diseases
By far the most well characterized association of HLA variation with neurological disease has been in MS, however there are important parallels observed in other neurological disease that may indicate some common pathogenic mechanisms or pathways. While other neurological diseases have been explored less fully for association with HLA, there exists strong evidence that variation in the region contributes to disease risk in particular disease, with some overlap with HLA associations MS. HLA has
Killer-immunoglobulin-like receptors (KIR) in MS
Killer-immunoglobulin-like receptors (KIR) are highly polymorphic receptors expressed on natural killer (NK) cells (Box 3). While clear association with variation in HLA has been established in MS, there has been limited examination of the role of NK cells or their receptors, including KIR. However, because HLA class I molecules serve as the primary ligand for many KIR, it is likely that the association signals observed for many diseases is related to KIR function. In MS, alleles of HLA-A, -B
Concluding remarks
MS is an example of a multifactorial, complex condition whose understanding has been transformed by advances in genomics, and specifically immunogenomics. Convergent epidemiological and laboratory results are consistent with a polygenic model of inheritance, while the data also supports the long-held view that MS susceptibility rests on the action of polymorphisms common in the population. The incomplete penetrance and moderate individual effect observed for most genetic associations in MS most
Acknowledgments
The authors are supported by grants from NINDS, NIAID, NIGMS, NHGRI, and the National Multiple Sclerosis Society. We thank Wesley Marin and Paul J. Norman for assistance with figures. We would like to dedicate this manuscript to our HLA mentors, Glenys Thomson and Chaim Brautbar.
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