Genetics of autoimmune neuroinflammation

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Detection of gene variants affecting the risk for multiple sclerosis provides insights into mechanisms central for autoaggressive neuroinflammation. Major histocompatibility complex (MHC) class II genes, and probably also MHC class I genes, regulate both human multiple sclerosis and rodent experimental autoimmune encephalomyelitis. However, the functional understanding of the MHC regulation requires further experimentation. Genome scans in human multiple sclerosis have failed to demonstrate significant non-MHC loci with genome-wide significance, but approximately 50 such loci have been described in different rodent experimental autoimmune encephalomyelitis models. Positional cloning of individual rodent genes is difficult, but genes or small genome regions now emerge. Association studies in large human cohorts are needed to confirm the human relevance of rodent genes and such cohorts will also be used for single nucleotide polymorphism-based whole-genome screening. It is realistic to assume that several non-MHC genes regulating autoimmune neuroinflammation, including target tissue responses, will be pinpointed in the next ten years. At the moment there are a few hot candidates, including MHC2TA, PRKCA and IL7R.

Introduction

A genetic predisposition to multiple sclerosis (MS) is supported by twin studies, demonstrating concordance rates for monozygotic twins of around 30%, whereas dizygotic twins display 2–4% [1]. There is a lack of effective and selective treatments in MS because of insufficient knowledge of pivotal disease mechanisms. Gene positioning in monogenic disorders has given enormous insights into pathogenesis and in many cases offered prevention and treatment. Large efforts have therefore been spent on dissecting the genetic basis of MS.

The most recent and largest MS linkage study failed to show any significant linkage, apart with the human major histocompatibility complex (MHC), known also as human leukocyte antigens (HLA) system [2•]. An important conclusion from this and previous linkage studies is that MS-related genes have low odds ratios. Possible reasons include genetic heterogeneity, implying that a large number of different genes might dispose for the same end phenotype in form of MS. This is indeed the case in experimental models for MS, as discussed below. A second reason is that linkage analysis is not sensitive enough for detection of genes with modest effects. These genes might instead be detected by association analysis of large cohorts (thousands) of patients and controls. Until now, most association studies have been extremely underpowered. The genotyping of large sets of individuals by applying HapMap single nucleotide polymorphism (SNP) whole-genome screening with chip technology is now a possibility. However, even such a screening might not be dense enough to unravel crucial genes [3•]. The immense number of comparisons will also generate false-positive results. An alternative approach is to build high-density SNP map on candidate genes generated in experimental models under the assumption that some pathogenic mechanisms might be shared by different species.

Section snippets

Genetics

To date, the MHC (HLA) remains the strongest and most convincingly linked gene region in MS and experimental autoimmune neuroinflammation. It was shown that the HLA-DRB1*15 allele confers a 2–3-fold increase of risk for MS [4, 5•]. Later, it became apparent that also other DR alleles are disease predisposing, such as DRB1*17 [6, 7]. A recent study has identified a disease protective allele, DRB1*14 [8•]. Studies in African Americans have pinpointed the MHC influence to the HLA-DRB1*15 gene and

Selected potential immune mechanisms for the MHC (HLA) influence

A hierarchy of influences by different MHC alleles in autoimmune neuroinflammation, similar to what is now apparent in MS, was demonstrated in MHC-congenic rats in experimental autoimmune encephalomyelitis (EAE) [12]. Interestingly, some alleles displayed encephalitogenic potential towards several different myelin antigens, with options for epitope spreading as a potential reason for relapsing disease. A promiscuous, rather than restricted, binding of many different myelin antigen epitopes by

The human species

Despite the so far slow progress in this field, a few examples of potential risk genes start to be reported. In the human 17q locus, there are protein kinase Cα (PRKCA) gene variants in both Finnish and Canadian populations, increasing the risk for MS with odds ratios of about 1.3 and 1.6, respectively [21•]. The 17q was also the starting point for analysis of a cluster of CC chemokine ligands, which were found to be associated with MS risk [22•].

A selection of 66 candidate genes on the basis

Experimental gene mapping and comparative genetics

To date, 19 whole-genome scans aiming at identifying EAE-regulating regions (quantitative trait loci, QTLs) have been performed in rodents, 14 in mice [24, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] and five in rats [40, 41, 42, 43, 44]. Following the criteria of significance, reproducibility and overlap, the number converges to approximately 50 EAE QTLs (Figure 1). Considering that many of these QTLs, as discussed below, often comprise more than one gene, this gives perspective on the

Sharing of risk genes

Susceptibility genes have been suggested to be shared among different organ-specific diseases [59, 60]. If so, common therapeutic strategies against the mechanism regulated by the gene would hypothetically be possible. Disease-specific genes would be equally important to find, in view of future development of disease-specific therapy. To date, we have been able to simultaneously fine-dissect two genomic regions for EAE and experimental arthritis. A c-type lectin cluster [48•] and Ncf-1 [53]

Genetics of target tissue responses

The magnitude and quality of the nervous tissue reaction in response to a damaging neuroinflammatory process is of relevance in at least two aspects. First, the particular features of the glial response as well as the relative susceptibility of nerve cells might be important for determining the extent of resulting tissue injury. Second, the local inflammatory reaction is likely to act as a modifier on the immune system through the expression of immune-related molecules, such as MHC antigens,

Conclusions

The gene hunt in MS has evoked many frustrations during the past decade. An important reason for this is the low or modest impact of a single polymorphic gene on disease with estimated odds ratios in the range 1.0–1.5. It might be argued that such low risks might be unimportant. However, such odds ratios, which translated into a 10–50% increased risk for morbidity on the population level, are substantial, and if larger sets of risk genes are present in an individual, there are options for

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors of this review have received support by the Swedish Research Council, Bibbi and Nils Jensen's Foundation, Torsten and Ragnar Söderberg's Foundation, the Montel William's Foundation, The Swedish Association of Persons with Neurologically Disabilities and 6th Framework Program of the European Union, NeuroproMiSe (LSHM-CT-2005-018637) and EURATools (LSHG-CT-2005-019015).

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