MHC Class II & Multiple Sclerosis

Multiple Sclerosis (MS) is an Inflammatory DeMyelinating Disease of the Central Nervous System in which an AutoImmune response most probably contributes to PathoGenesis.

To date, the best characterized susceptibility-associated Gene has been mapped to the HLA complex. The HLA-DRB1*1501 - DRB5*0101 - DQA1*0102 - DQB1*0602 haplotype is both associated and linked to MS in different ethnic groups.

The locus within the HLA Class II region encoding the MS-susceptibility Gene is under intensive investigation.

Epidemiological studies, however, have suggested that Environmental Antigens also play a critical role in MS PathoGenesis.

One of the ways a pathogen could trigger AutoImmune Disease is via Immunological cross-reactivity or Molecular Mimicry.

This concept argues that a microbial peptide with certain degree of homology to a self peptide can stimulate pathogenic self-reactive specific T-Cells to cause an AutoImmune Disease.

Many Microbial agents have regions of sequences that may serve as binding motifs for HLA-DR2.

HLA Genetics and Molecular Mimicry may therefore be intimately interlinked in the disease process.

In the present review, we focus on the HLA association with MS and the role of Microbial Antigens in MS, with special reference to the Molecular Mimicry hypothesis.

Multiple Sclerosis (MS) is a presumed AutoImmune Disease of the Central Nervous System, shown to be associated with the HLA Class II haplotype DRB1*15,DQB1*06.

Carrying the HLA Class II haplotype DRB1*15, DQB1*06 increases the risk of MS by 3.6.

By adopting a Polymerase Chain Reaction (PCR)-based typing technique for HLA Class I and Class II Genes, 200 Swedish MS patients and 210 Swedish healthy controls were analyzed for their HLA alleles.

Additional HLA Class I alleles that increase and decrease the Genetic susceptibility to MS were identified:
1. HLA-A*0301 allele increases the risk of MS (odds ratio=2.1) independently of DRB1*15

2. DQB1*06, HLA-A*0201 decreases the overall risk (odds ratio= 0.52)

3. Presence of A*0201 reduces the risk of MS for DRB1*15 and DQB1*06 carriers from 3.6 to 1.5

Our findings are the first to identify a major modulating effect of HLA Class I alleles on the susceptibility to a human AutoImmune Disease; a phenomenon that has previously only been observed in animal models.

The PolyMorphism of the HLA Class II Genes was investigated in 97 patients with Multiple Sclerosis (MS) in Hokkaido, the northernmost main island of Japan.

Of these, 80 patients were classified as having conventional MS and 17 as having OpticoSpinal MS (OS-MS).

Our findings confirmed a previous report that the DPB 1*0501 allele is positively associated with OS-MS (P = 0.0043).

The frequency of DPB 1*0501 was also found to be higher in conventional MS patients than in controls (79% vs. 58%, P = 0.0084), although the differences were not statistically significant.

Our results indicate that OS-MS is a DPB 1*0501-associated subgroup of MS, and that DPB1*0501 is also correlated with risk of conventional MS in Japanese.

Objective
To look for HLA Class II alleles and haplotypes conferring susceptibility to Multiple Sclerosis (MS) in the Jewish population of Israel.

Design & Setting
Population-based cohort of Clinically Definite patients with MS tested prospectively over 7 years. Referral center in a Neurology clinic at a university hospital in the greater Jerusalem area in Israel.

Patients
A total of 162 consecutive patients with Clinically Definite MS from the 2 main ethnic Jewish groups in Israel:


• 104 Ashkenazi (80 with a Relapsing/Remitting or Secondary/Progressive and 24 with a Chronic Primary/Progressive course of the disease)
  
  
• 58 Non-Ashkenazi (36 with a Relapsing/Remitting or Secondary/Progressive course and 22 with a Chronic Primary/Progressive course of the disease), matched with 132 Ashkenazi and 120 Non-Ashkenazi healthy controls.

Main Outcome Measures
The relationship between the various MHC Class II alleles and haplotypes and MS

As defined by the polymerase chain reaction and sequence-specific OligoNucleotide probe hybridization, among the Ashkenazi and the Non-Ashkenazi Jewish sections and with respect to the different clinical courses of the disease.

Results
The haplotype DRB1*1501, DQA1*0102, DQB1*0602 was found to be associated with MS among both Ashkenazi and Non-Ashkenazi patients (P<.001 and P =.04, respectively).

Among the Non-Ashkenazi patients, a new association of haplotypes DRB1*1303, DQA1*05, and DQB1*030 with MS was detected (P = .03).

The MS susceptibility alleles, DRB1*1501, DQA1*0102, and DQB1*0602, were found in association with the Ashkenazi patients (P<.001, P=.02, and P=.01, respectively).

DRB1*1501 and DRB1*1303 were more frequently observed among the Non-Ashkenazi patients (P = .03, P = .04, respectively).

On subdivision of the patients into clinical subgroups, associations of DRB1*0801, DQA1*0102, DQA1*0401, and DQB1*0602 with Chronic Primary/Progressive MS among the Ashkenazi patients were evident (P = .03, P = .04, P = .04 and P = .05, respectively).

Whereas DRB1*1501, DRB1*03011, and DQB1*0602 were associated with Relapsing/Remitting or Secondary/Progressive among the Non-Ashkenazi patients (P = .05, P = .05, and P = .03, respectively).

Conclusions
This study, unlike previous ones, is the first to show a significant association between MHC Class II alleles and MS in the Jewish population.

The association with the HLA-DR2-related haplotype is similar to that among Non-Jewish white patients with MS.

Moreover, our data support the possibility that DRB1*1501 is the susceptibility allele responsible for the association between this haplotype and MS in the Jewish population.

Our study also underscores differences in HLA profiles between Ashkenazi and Non-Ashkenazi patients, and between the different clinical courses of the disease.

The latter may indicate that the clinical courses of MS are influenced by the Genetic background.

Objective
To verify whether MultiAllelic PolyMorphisms belonging to HLA Class II Genes are linked to Multiple Sclerosis (MS) in the Italian population, we studied 28 multiplex MS families originating from different areas of Italy.

Design
Allelic characterization was carried out by analysis of RFLPs and OligoNucleotide typing.

Results
Evidence supporting the existence of linkage between MS susceptibility and the MHC Class II loci DRB1, DQA, 1and DQB1 was provided using two non-parametric tests, affected sib-pair analysis, and Affected-Pedigree-Member (APM) analysis.

Conclusions
The APM analysis also suggested the existence of Genetic heterogeneity for the HLA Class II loci and MS susceptibility in our series.

Linkage disequilibrium between MS susceptibility and the haplotype DRB1*1501, DQA1*0102, DQB1*0602 was demonstrated by applying the transmission linkage disequilibrium test to our families.

Finally, lod score analysis suggests that in our Italian families, MS susceptibility is conferred by MHC Class II alleles according to a low-penetrance autosomal recessive mode of inheritance.

Multiple Sclerosis (MS) is a complex trait with a sibling relative risk (lambda(sibs)) between 18 and 36. We report a multistage Genome scan of 552 sibling pairs from 442 families, the largest MS family sample assessed for linkage.

The first stage consisted of a Genome scan for linkage with 498 MicroSatellite markers at an average spacing of 7 cM in 219 sibling pairs.

The second stage involved further GenoTyping of markers from positive regions in an independent sample of 333 affected sibling pairs.

The global distribution of Allele sharing for all markers showed a shift towards greater sharing within the affected sibling pair group but not in the discordant sibling pair group.

This shift indicates that the number of contributing genetic factors is likely to be moderate to large.

Only markers at Chromosome 6p showed significant evidence for linkage (MLOD=4.40), while other regions were only suggestive (1p, 2q, 5p, 9q, 11p, 12q, 18p, 18q and 21q) with MLODs greater than 1.0.

The replication analysis involving all 552 affected sibling pairs confirmed suggestive evidence for five locations, namely, 2q27 (MLOD=2.27), 5p15 (MLOD=2.09), 18p11 (MLOD=1.68), 9q21 (MLOD=1.58) and 1p31 (MLOD=1.33).

Suggestive linkage evidence for a previously reported location on Chromosome 17q (MLOD=1.67) and a prior association with marker D17S789 was replicated.

We showed that the overall excess Allele sharing we observed for the entire sample was due to increased Allele sharing within the DRB1*15 negative subgroup alone.

This observation is most consistent with a model of genetic heterogeneity between HLA and other genetic loci.

These findings offer guidance for future genetic studies including dense SNP linkage disequilibrium analysis.

Variation in Major Histocompatibility Complex genes on chromosome 6p21.3, specifically the Human Leukocyte Antigen HLA-DR2 or -DRB1*1501 -DQB1*0602 extended haplotype, confers risk for Multiple Sclerosis (MS).

Previous studies of DRB1 variation and both MS susceptibility and phenotypic expression have lacked statistical power to detect modest genotypic influences, and have demonstrated conflicting results.

Results derived from analyses of 1339 MS families indicate DRB1 variation influences MS susceptibility in a complex manner.

DRB1*15 was strongly associated in families (P=7.8x10(-31)), and a dominant DRB1*15 dose effect was confirmed (OR=7.5, 95% CI=4.4-13.0, P < 0.0001).

A modest dose effect was also detected for DRB1*03; however, in contrast to DRB1*15, this risk was recessive (OR=1.8, 95% CI=1.1-2.9, P=0.03).

Strong evidence for under-transmission of DRB1*14 (P=5.7x10(-6)) even after accounting for DRB1*15 (P=0.03) was present, confirming a protective effect.

In addition, a high risk DRB1*15 genotype bearing DRB1*08 was identified (OR=7.7, 95% CI=4.1-14.4, P < 0.0001), providing additional evidence for trans DRB1 allelic interactions in MS.

Further, a significant DRB1*15 association observed in Primary/Progressive MS families (P=0.0004), similar to Relapsing/Remitting MS families, suggests that DRB1-related mechanisms are contributing to both phenotypes.

In contrast, results obtained from 2201 MS cases argue convincingly that DRB1*15 genotypes do not modulate age of onset, or significantly influence disease severity measured using Expanded Disease Disability Score and disease duration.

These results contribute substantially to our understanding of the DRB1 locus and MS, and underscore the importance of using large sample sizes to detect modest genetic effects, particularly in studies of genotype-phenotype relationships.

Multiple Sclerosis (MS) is a common inflammatory disease of the Central Nervous System unsurpassed for variability in disease outcome.

A cohort of sporadic MS cases (n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity.

Genotyping sets of Benign and Malignant MS patients showed that HLA-DRB1*01 was significantly underrepresented in Malignant compared with Benign cases.

This allele appears to attenuate the progressive disability that characterizes MS in the long term.

The observation was doubly replicated in:
1. Sardinian Benign and Malignant patients and
2. A cohort of affected sibling pairs discordant for HLA-DRB1*01

Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1*01 allele compared with their disease-concordant siblings who did not.

The findings were additionally supported by similar transmission distortion of HLA-DRB1*04 subtypes closely related to HLA-DRB1*01.

The protective effect of HLA-DRB1*01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1*1501.

A high-density (>700) SNP examination of the MHC region in the Benign and Malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus.

We conclude that HLA-DRB1*01, previously implicated in disease resistance, acts as an independent modifier of disease progression.

These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.

The most important confirmed genetic factor of susceptibility to Multiple Sclerosis (MS) has been identified in the HLA Class II region.

The hypothesis that several genes, including HLA Class II, may influence the prognosis of patients with MS has been proposed.

In a recent study, using low intermediate resolution typing, we found that some HLA alleles may predict disease severity as assessed by Magnetic Resonance Imaging (MRI) measures.

The aim of this study was to examine the relationship between high-resolution typing of HLA alleles and disease severity as measured by Brain MRI quantitative markers of DeMyelinating and destructive pathology in patients with MS.

In 41 MS patients (27 Relapsing/Remitting, 7 Secondary/Progressive, and 7 Primary/Progressive), we performed high-resolution typing of alleles HLA-DRB1*04, -DQB1*03, -DRB1*15, -DQB1*06, and of haplotypes -DRB1*04-DQB1*03 and -DRB1*15 -DQB1*06.

These alleles and haplotypes were associated with higher susceptibility to MS in a recently published case-control study conducted in the Friuli-Venezia-Giulia region, Italy.

Of 41 included patients, 13 were men and 28 were women. Mean age was 43.3 (SD 11.4) years, mean disease duration 10.3 (SD 7.8) years, and mean EDSS 2.3.

DNA extraction and genomic typing were obtained with the sequence-specific primers method using primer pairs that amplified the HLA alleles.

All patients underwent a 1.5-T MRI examination of the Brain. Disease severity was assessed by clinical measures [Expanded Disability Status Scale (EDSS)] and MRI measures.

T₂- and T₁-Lesion Volumes (LVs) and Brain Atrophy measures [fractions of Brain Parenchyma (BPF), Gray Matter (GMF), and White Matter (WMF)] were calculated.

We used General Linear Model analysis (GML), controlled for age, disease duration, and treatment status, to compare the MRI measures according to allele and haplotype status.

The following significant results were found:

HLA-DRB1*1501 positive patients had significantly lower GMF (0.493 vs 0.526, p < 0.001), lower BPF (0.784 vs 0.815, p = 0.018), and higher T₁-LV (2.8 vs 0.7ml, p = 0.036);

-DQB1*0301 positive patients had significantly higher T₂-LV (34.1 vs 0.7ml, p = 0.041), and showed a trend for lower BPF (0.790 vs 0.846, p = 0.064);

-DQB1*0302 positive patients had significantly lower T₁-LV (2.4 vs 0.9ml, p = 0.016); and

-DQB1*0602 positive patients had significantly lower GMF (0.492 vs 0.521, p = 0.007) and lower BPF (0.781 vs 0.811, p = 0.023).

No differences were found in the indices of MRI disease severity according to HLA haplotype associations.

Both in correlation and in regression analyses, we observed significant associations between HLA-DRB1*15011 and lower GMF.

And, BPF and higher T₁-LV, between -DQB1*0301 and higher T₂-LV and disease duration, between -DQB1*0302 and lower GMF and higher T₁- and T₂-LV, between -DQB1*0602 and lower GMF and BPF, and between -DQB1*0603 and higher T₁-LV and EDSS.

High-resolution HLA genotyping analysis revealed a robust relationship between alleles HLA-DRB1*1501, -DQB1*0301, -DQB1*0302, -DQB1*0602, and -DQB1*0603, and more severe damage on Inflammatory and NeuroDegenerative MRI measures.

Objective
Multiple Sclerosis (MS) is approximately twice as common among women as men.

If men have greater physiologic resistance to MS, they might theoretically require stronger genetic predisposition than women to overcome this resistance.

In this circumstance, men would be expected to transmit the disease more often to their children, a phenomenon known as the Carter effect.

The authors evaluated whether the Carter effect is present in MS.

Methods
The authors studied 441 children (45 with definite MS) of an affected father or mother (197 families of interest) from 3598 individuals in 206 multiplex pedigrees. The authors compared transmission of MS from affected men with transmission from affected women.

Results
Fathers with MS transmitted the disease to their children more often (transmitted: 18, not transmitted: 99) than mothers with MS (transmitted: 27, not transmitted: 296) (p = 0.032; OR: 1.99, 95% CI: 1.05, 3.77).

Adjusting for both the sex of the affected child and multiple transmissions from a single affected parent, the sex of the affected parent remained as an independent risk factor for transmission of MS to children, fathers transmitting more often than mothers (p = 0.036; OR: 2.21, 95% CI: 1.05, 4.63).

Conclusions
The authors have demonstrated the Carter effect in Multiple Sclerosis (MS).

These observations may be explained by greater genetic loading in men that leads to relative excess paternal vs maternal transmission.

Linkage analysis in genetic studies of MS may be more informative if patrilineal transmission were given additional weighting.

Objective
Genetic and environmental factors have important roles in Multiple Sclerosis (MS) susceptibility. The precise nature of these factors and mode of inheritance remains unknown.

A female predominance is universally found. Recently, offspring of affected fathers were reported to be more likely to have MS than those of affected mothers. This was attributed to the Carter effect, which is seen in polygenic disorders.

The Carter effect predicts that affected parents of the sex lesser affected by a disease/trait are more genetically loaded for risk alleles and thus transmit these more often to their offspring.

This hypothesis was tested in a population-based Canadian MS cohort.

Methods
Using the longitudinal Canadian database, we identified 3,088 nuclear families with one affected parent and a total of 8,401 offspring, of which 798 had MS.

Transmission to daughters and sons from affected mothers and fathers was compared.

Results
There was equal transmission of MS from affected fathers vs affected mothers (9.41% vs 9.76%).

Stratifying by gender of affected parent there were no differences in the female:male sex ratio of affected (2.46% vs 2.41%, p = 0.88) or unaffected offspring (0.91% vs 0.95%, p = 0.46).

Conclusions
We observed equal disease transmission to offspring from affected mothers and affected fathers.

No difference in the female:male sex ratio of affected offspring, and previously no difference in sibling recurrence risk by gender of parent affected.

These findings show no evidence for the Carter effect and do not support the hypothesis of polygenic inheritance of Multiple Sclerosis susceptibility by parent.