Germ-line polymorphism of TCR genes and disease susceptibility--fact or hypothesis?
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Animals↗
Biomedical subjects
J Hillert
Publications and source records attributed to J Hillert.
An immunogenetic heterogeneity in multiple sclerosis.
Two clinical forms of multiple sclerosis (MS), primarily chronic progressive MS (PCP MS) and relapsing/remitting MS (R/R MS) have been shown to differ in several respects. The results of genomic HLA class II typing with restriction fragment length polymorphism analysis of 62 MS patients from Western Norway, 42 with R/R MS and 20 PCP MS, are reported on here. As in previous studies of Swedish patients, the haplotype DRw17(3), DQw2 was found to be five times more common in R/R MS than in PCP MS. This finding supports the hypothesis that R/R and PCP MS are immunogenetically separate entities. In contrast with a previous investigation of Norwegian MS patients, no association of MS with glutamine at position 34 of the HLA-DQ alpha chain or with defined sequences of the HLA-DQB1 gene was found.
Adult↗
T-cell receptor alpha chain germline gene polymorphisms in multiple sclerosis.
It has been proposed that genetic predisposition to multiple sclerosis (MS) and other diseases with autoimmune features is conferred by T-cell receptor (TcR) genes in addition to HLA class II genes. Although a family study has suggested linkage of susceptibility to MS to TcR genes, reports of disease associations with restriction fragment length polymorphism (RFLP)-defined alleles of TcR genes have been difficult to confirm, including a report of association of MS with TcR beta-chain gene RFLPs. We report here the distribution of three sets of RFLPs of the TcR alpha chain genes. Similar frequencies in patients and controls were observed for TaqI and BglII RFLPs of the TcR alpha constant segment (C alpha), the latter earlier reported to be associated with MS. A previously reported MS-associated PssI RFLP of the V alpha 12 and C alpha gene segments could not be confirmed. Our results indicate that these seemingly polymorphic restriction fragments are possibly the results of incomplete enzymatic cleavage of DNA in the RFLP analysis. We conclude that no convincing evidence exists for the association of MS with RFLPs of the TcR alpha or beta chain genes.
Alleles↗
Conjugal multiple sclerosis: immunogenetic characterization and analysis of T- and B-cell reactivity to myelin proteins.
We describe two families with conjugal multiple sclerosis. Onset of symptoms in the husbands occurred 11 and 17 years after onset of relapsing/remitting symptoms in their wives. There were no similarities regarding clinical manifestations of MS within each family. Evaluation of T-cell repertoire by enumeration of cells secreting interferon-gamma in response to proteolipid protein (PLP), myelin basic protein (MBP), and to various synthetic MBP peptides revealed similar patterns of T-cell reactivity within the families both in MS-affected parents and unaffected children. Genomic HLA-DR-DQ typing showed that T-cell reactivity was independent of HLA class II phenotype. Analysis of B-cell responses in blood showed low numbers of cells secreting IgG, IgA, or IgM antibodies against MBP, PLP, myelin-associated glycoprotein, and myelin-oligodendrocyte glycoprotein both in MS-affected and unaffected family members. In conclusion, our study of two families with conjugal MS has shown a dominant T-cell response against the same MBP peptide within the family both in MS-affected parents and unaffected children, and this T-cell response seems to be independent of the HLA class II phenotypes of the family members.
Adult↗
Association of rheumatoid arthritis with a dominant DR1/Dw4/Dw14 sequence motif, but not with T cell receptor beta chain gene alleles or haplotypes.
HLA-DR, HLA-DQ, and T cell receptor beta (TCR beta) chain gene polymorphisms were investigated in 43 patients with rheumatoid arthritis (RA), in 10 patients with Felty's syndrome (FS), and in 5 RA multicase families. RA was found to be strongly associated with a DRB1 gene sequence motif present in DR1, DR4-Dw4, and DR4-Dw14 alleles. Ninety-three percent of RA patients were positive for at least 1 of these alleles, providing strong support for the "shared epitope hypothesis." The frequency distribution of this sequence motif suggests a dominant mode of inheritance. All 10 FS patients were DR4-Dw4 positive. Different DR-DQ associations among DR4 positive RA and FS patients indicate heterogeneity in the genetic susceptibility to these 2 disease entities. Furthermore, analyses of TCR V beta 8, V beta 11, and C beta gene polymorphisms did not support the notion of an influence of TCR beta germline allotypes on RA susceptibility.
Alleles↗
No association with germline T cell receptor beta-chain gene alleles or haplotypes in Swedish patients with multiple sclerosis.
Multiple sclerosis (MS) has been reported to be associated with restriction fragment length polymorphism (RFLP)-defined alleles of the T cell receptor (TcR) alpha- and beta-chain genes. One hundred patients with MS, 23 with primarily chronic progressive MS and 77 with relapsing/remitting MS, as well as 100 controls were investigated with RFLP analysis of the V beta 8, V beta 11 and C beta TcR gene segments. No association was found with allelic patterns or, contrary to a previous report (Beall et al. (1989) J. Neuroimmunol. 21, 59-66), TcR beta-chain gene haplotypes. Subgrouping of patients according to clinical form of disease or MS-associated HLA class II alleles also failed to show associations to TcR beta-chain RFLPs. Thus, our results fail to confirm that TcR beta-chain gene haplotypes confer susceptibility to MS.
Gene Rearrangement, beta-Chain T-Cell Antigen Rece↗
No association with HLA-DR, -DQ or -DP alleles in Guillain-Barré syndrome.
The distribution of HLA class II alleles in Guillain-Barré syndrome (GBS) has previously been reported only for HLA-DR. We report here the results of genomic typing for HLA-DR, -DQ and -DP allelic variability by restriction fragment length polymorphism analysis in 49 patients with a history of GBS. No association was found to HLA-DR, -DQ or -DP alleles or HLA-DR-DQ haplotypes. Subgrouping of patients according to severity of disease, as measured by disability or muscular weakness, or response to plasmapheresis treatment, also failed to reveal significant associations. These data suggest that HLA class II genes do not confer susceptibility to GBS.
Adult↗
HLA class II-associated genetic susceptibility in multiple sclerosis: a critical evaluation.
Multiple sclerosis (MS) has, since the 1970s, been known to be associated with the HLA-Dw2 and -DR2 specificities in Caucasian Europeans and North Americans. By the use of genomic typing techniques, the association has been specified to be with the DRw15,DQw6,Dw2, i.e. the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. A significant DPw4 association in Scandinavian MS patients has been described in one report. However, this association has not been confirmed in several subsequent studies with patients from the same and other ethnic groups. During the last few years several reports, based on serological, RFLP and PCR-SSO data, have suggested that the HLA class II-associated MS susceptibility gene(s) may be more closely associated with the DQ than with the DR subregion. The observations that the HLA-DQB1 genes of MS patients share long stretches of sequence motifs and also carry DQA1 alleles encoding glutamine at position 34 of the DQ alpha chain have received considerable attention. It has been suggested that the susceptibility to develop MS might be determined by the corresponding DQ alpha-beta heterodimers either encoded in cis or in trans. We have investigated these issues in a large group of Swedish MS patients (n = 179). We found that the associations with the suggested DQB1 sequences and position 34 of the DQ alpha chain were due to linkage disequilibrium and secondary to the association with the DRw15,DQw6,Dw2 haplotype (p less than 10(-9) and p less than 10(-8), respectively). No overrepresentation of the implicated DQ alpha-beta heterodimers was observed in DRw15,DQw6,Dw2-negative patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Disease Susceptibility↗
The narcolepsy-associated DRw15,DQw6,Dw2 haplotype has no unique HLA-DQA or -DQB restriction fragments and does not extend to the HLA-DP subregion.
Almost all patients with cataplectic narcolepsy are DR2-positive. It has been suggested that the non-DR2 allele/haplotype might not be neutral with respect to disease susceptibility. It has also been reported that Taq I DQA and Bam HI, Eco RI, Eco RV, and Pst I DQB restriction fragments might differentiate between narcoleptic and healthy DR2-positive individuals. In the present study, HLA class II gene polymorphisms were investigated by restriction fragment length polymorphism (RFLP) analysis in 47 Swedish patients with cataplectic narcolepsy, 100 random controls, and DR2-associated homozygous cell lines. All patients had Taq I DRB-DQA-DQB patterns corresponding to the DRw15,DQw6,Dw2 haplotype. The non-DR2 haplotype was found to be neutral. This genotyped group of patients allows firm rejection of a recessive mode of inheritance and supports a dominant or additive model. No DQA or DQB RFLPs were found that could differentiate between DR2-positive narcoleptics, DRw15,DQw6,Dw2-positive controls, or Dw2-homozygous cell lines. No significant Msp I HLA-DP association was found. No linkage disequilibrium was observed between the DRw15,DQw6,Dw2 haplotype and alleles of the DP subregion in patients or controls. Thus, the HLA-D region-associated narcolepsy susceptibility gene may be located telomeric to the HLA-DP subregion. No RFLPs have been observed that can locate the narcolepsy susceptibility gene closer to the DQ than to the DR subregion.
Genetic Linkage↗
The HLA-D region-associated MS-susceptibility genes may be located telomeric to the HLA-DP subregion.
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Genetic Predisposition to Disease↗
Primarily chronic progressive and relapsing/remitting multiple sclerosis: two immunogenetically distinct disease entities.
HLA class II gene polymorphism was investigated in 100 patients with clinically definite multiple sclerosis (MS) by restriction fragment length polymorphism analysis of Taq I-digested DNA using DRB, DQA, and DQB cDNA probes. Twenty-six patients had primarily chronic progressive MS and 74 had relapsing/remitting MS. The latter group included patients with a secondary progressive evolution of symptoms. Both clinical forms of MS were found to be associated with the DRw15,DQw6 haplotype. In addition, primarily chronic progressive MS was positively associated with the DQB1 restriction fragment pattern seen in DR4,DQw8, DR7,DQw9, and DRw8, DQw4 haplotypes, as well as negatively associated with the Taq I DQB1 allelic pattern corresponding to the serological specificity DQw7. Relapsing/remitting MS was positively associated with the DQB1 allelic pattern observed in the DRw17,DQw2 haplotype. These three DQB1 alleles are in strong negative linkage disequilibria with DRw15. The two susceptibility markers of each clinical form of MS act additively in determining the genetic susceptibility, as the relative risks for individuals carrying both markers roughly equal the sum of respective risks. Different alleles of the DQB1 locus defined by restriction fragment length polymorphisms contribute to susceptibility and resistance to primarily chronic progressive MS as well as to susceptibility to relapsing/remitting MS. The observed immunogenetic heterogeneity between the different clinical forms of MS favors the hypothesis that primarily chronic progressive MS and relapsing/remitting MS are two distinct disease entities.
Alleles↗
Association and linkage analysis of candidate chromosomal regions in multiple sclerosis: indication of disease genes in 12q23 and 7ptr-15.
Four recent genome-wide screen studies in multiple sclerosis (MS) identified a number of candidate regions for susceptibility genes in addition to the HLA complex in 6p21. However, none of these regions provided formally significant evidence for genome-wide linkage. We have investigated such regions in 46 Swedish multiplex MS families, 28 singleton families, 190 sporadic MS patients and 148 normal controls by parametric and nonparametric linkage and association analysis. One microsatellite marker, in 12q23, provided evidence for association in addition to suggestive transmission distortion and slightly positive linkage. In addition, a marker in 7ptr-15 showed a significant transmission distortion as well as a highly significant score in affected pedigree member analysis, but not quite significant deviations in association analysis. One of three markers in 5p, a region implicated in all four previous studies, showed a weakly positive lod score, but no other evidence of importance. Markers in 2p23, 5q11-13, 6q25, 7q21-22, 11q21-23, 13q33-34, 16p13.2, 18p11.32-23, Xp21.3 provided little or no evidence of importance for MS. In summary, these data support the importance of genome-wide screens in the identification of new candidate loci in polygenic disorders.
Alleles↗