Symposium on Multiple Sclerosis-Part IVIdentification of Multiple Sclerosis-Associated Genes
Section snippets
Human Leukocyte Antigens
Human leukocyte antigens (HLAs)-the human major histocompatibility determinants-function in self-recognition and immune interactions. These highly polymorphic genes are clustered on chromosome 6 and are divided into functionally distinct classes. Class I genes (HLA-A, B, and C) code for monomeric glycoproteins that are expressed on the surface of most nucleated cells in association with β2microglobulin. Class II genes include HLA-DR, DQ, and DP subregions. Each of these consists of A and B
T-Cell Receptor
Because MS seems to be a polygenic disease and the HLA association accounts for a relatively minor portion of the genetic influence (a relative risk of 2 to 4, in comparison with a relative risk of 20 to 40 in a sibling of a patient with MS), other susceptibility genes have been sought. As part of the trimolecular antigen recognition complex (T-cell receptor [TCR], HLA class II molecule, and antigen), the TCR is an obvious candidate.
One possibility is that a germline TCR locus confers
Myelin Basic Protein
Of several potential CNS antigens that may be important in MS, MBP has been the most extensively studied. By analogy to EAE, an autoimmune response against MBP is a credible pathogenic mechanism for MS. Autoimmunity to MBP could result from molecular mimicry or the release of MBP from its immunologically privileged site within the blood-brain barrier in susceptible persons. An immune response against MBP is detectable in the blood of most patients,58 occasionally in CSF,80 and possibly in the
Immunoglobulin
Immunoglobulin may be involved in the pathogenesis of MS. Increased levels of immunoglobulin are present in serum, CSF, and brain of patients with MS. MBP-reactive autoantibodies are often found in CSF.88 CSF IgG is oligoclonal and is often restricted to IgG class 1.89
The immunoglobulin heavy chain, encoded on chromosome 14, is highly polymorphic. Like the TCR, it consists of V, D, J, and C segments. The IgG C region includes class 1, 2, and 3 genes. Each of these classes is polymorphic (has γ
Complement
Complement is an important mediator of inflammation. Several observations support a role for complement in the pathogenesis of MS. Oligodendrocytes and progenitor cells (02A) from adult rat brains are susceptible to antibodyindependent complement-mediated Iysis.102 Deposition of complement in CNS vasculature of patients with MS is associated with disruption of the blood-brain barrier.103 Circulating immune complexes, depressed complement levels, and activated complement constituents have been
Tumor Necrosis Factor
TNF-α is a proinflammatory cytokine. TNF-a is directly toxic to myelin in vitro, causes selective injury to oligodendrocytes, and induces proliferation of astrocytes.115 TNF-a is present in active areas of demyelination in brains of patients with MS.116 Local TNF-a production in the CNS due to TH1-cell activation by any myelin antigen has been proposed to result in “bystander” demyelination. The level of TNF-α detectable in CSF correlates with disease severity and progression.117 Relapses may
Mitochondrial Mutations
Occasionally, patients with Leber's hereditary optic neuropathy (LHON) have additional neurologic symptoms, including spasticity and ataxia.134 A disorder indistinguishable from MS has been reported to occur in persons with a LHON-associated mitochondrial point mutation.135, 136 This This MS-like illness occurs in female patients, unlike LHON, which occurs preponderantly in male patients. Magnetic resonance imaging of the brain in such patients shows changes characteristic of MS, and
Other Genes
Polymorphic genes for transporters associated with antigen processing (TAP1 and are located are located between the HLADP and HLA-DQ subregions. Although one study found that two TAP2 AP2 alleles, when homozygous, were associated with MS in DR2-negative patients,141 other studies found no association with TAP1 API or T AP2 alleles or genotypes.142, 143, 144 Polymorphisms in genes for a large multifunctional protease (LMP2 and LMP7), also involved in antigen processing, were not associated with
Genomic Scans
The results of three entire genomic scans were reported concurrently in the August 1996 issue of Nature Genetics2, 3, 4 Because the mode of inheritance is polygenic, all three complete genome scans used model-independent affected sibling pairs identity-by-state approach to search for excess sharing of alleles between affected sibling pairs. The American study also used a non-model-dependent method, which incorporated data from unaffected members of the pedigrees (affected pedigree
Conclusion
Several candidate MS-susceptibility genes have been explored for association or linkage in families. To date, only the HLA complex has been widely accepted as a susceptibility locus. Both association and linkage with the HLA-DR15, DQ6 haplotype have been demonstrated. Although studies have determined the susceptibility locus to be between the DQA2 and TNF-a genes, strong linkage disequilibrium has prevented more precise localization. The DR15, DQ6 haplotype is neither sufficient nor necessary
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