Olle Olerup

HLA‐DR15 is associated with lower age at onset in multiple sclerosis

To date, more than a dozen studies have investigated the role of HLA genes in determining clinical course and disease severity in multiple sclerosis (MS); in each of these studies, however, patient sample size has been small, and no consistent pattern has emerged from the results. For the present study, we determined HLA class II genotypes and catalogued clinical and demographic data for a total of 948 patients, making our data set the largest ever used to investigate HLA genes in MS. Our goals were both to investigate the impact of HLA‐DRB1 alleles on clinical course and disease severity in MS and to compare the frequencies of the established susceptibility allele DR15 in various clinicodemographic subgroups of MS patients. We found that, in addition to DR15, DR17 is positively associated with susceptibility to MS; that none of the HLA‐DRB1 alleles influences course or outcome in MS; that carriers of DR15 are prone to MS development at an earlier age than noncarriers; and that differences in DR15 positivity rates, after stratification for diagnostic category and examination results, seem to reflect a gradient of phenocopy contamination, with rates increasing in proportion to the degree of clinical or paraclinical verification of the MS diagnosis. Ann Neurol 2000;48:211–219

Increased frequency of autoimmune diseases in patients with primary sclerosing cholangitis

OBJECTIVES:Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown origin that mostly affects male patients with inflammatory bowel disease (IBD). The immune system is believed to be involved in the etiology/pathogenesis as these patients present with several immunological disturbances. Susceptibility to develop primary sclerosing cholangitis is partly determined by genes in the HLA complex. The aim of this study was to compare the prevalence of autoimmune disorders in IBD patients with and without PSC and to correlate the presence of autoimmune disorders in PSC to outcome and HLA association.METHODS:One hundred nineteen PSC patients were included in the study. Each PSC patient with IBD was matched to a IBD patient without PSC. The presence of autoimmune disorders was carefully evaluated in each group. Moreover, comparisons between PSC patients with and without autoimmune disorders were performed.RESULTS:Twenty-five percent of the PSC patients had at least one autoimmune disorder outside the liver and colon compared to 9% in the IBD group without PSC (p < 0.005). Nine of the PSC patients had two or more autoimmune diseases compared to only one patient in the IBD group (p < 0.02). The PSC patients with and without associated autoimmune disease did not differ in clinical presentation, outcome of PSC or HLA alleles. A significant overrepresentation of DRB1*03 was still present after excluding PSC patients with concomitant autoimmune diseases outside the liver and colon compared to a healthy Swedish control group.CONCLUSIONS:Autoimmune disorders are more frequent among PSC patients compared to IBD patients without liver disease. Associated autoimmune diseases in PSC patients does not influence the outcome or clinical presentation of PSC.

The CTLA-4 gene is associated with multiple sclerosis.

We have investigated whether three intragenic polymorphisms of the CTLA-4 gene, a C/T base exchange in the promoter (p.-318), an A/G substitution in exon 1 (p.49) and a dinucleotide repeat polymorphism in exon 4 (p.642), were associated with genetic susceptibility to multiple sclerosis (MS). We observed a significant association (p < 0.05) for homozygosity for the G49 allele in a case-control analysis of 378 MS patients and 237 controls, and a transmission disequilibrium (p < 0.02) for the G49 allele in 31 MS families. This was further corroborated by evidence for linkage by the affected pedigree member (APM) analysis (p < 0.0002) and a transmission distortion (p < 0.05) of the exon 4(642) polymorphism. Sequencing of the promoter, the first and second exons and the parts of the first intron revealed no further polymorphisms. Our results suggest that a dysregulation of CTLA-4-driven downregulation of T-cell activation could be involved in the pathogenesis of MS.

Multiple sclerosis is associated with genes within or close to the HLA‐DR‐DQ subregion on a normal DR15, DQ6, Dw2 haplotype

The HLA class II haplotype DR15, DQ6, Dw2 is associated with an increased risk for multiple sclerosis (MS). It has previously been shown that this haplotype extends to the HLA-DQA2 locus but not to the HLA-DP subregion. We report the distribution in 148 MS patients and 158 healthy controls of Taq I restriction fragments of the C4, cytochrome P-21 (CYP21), and HLA-B genes. Approximately 90% of the DR15,DQ6, Dw2 haplotypes extend to the C4/CYP21 loci and 50% to the HLA-B locus, indicated by a significant association of the haplotype with restriction fragments of these loci. However, there was no independent association in MS patients with these genes. This indicates that the susceptibility to MS is coded for by genes within or close to the HLA-DR-DQ subregion. Furthermore, the delineation of the DR15, DQ6, Dw2 haplotype is very similar in MS patients and control subjects. This observation supports the hypothesis that “normal” genes, common to all carriers of the DR15, DQ6, Dw2 haplotype, confer the increased genetic susceptibility to MS associated with this haplotype.

HLA-DR and HLA-DQ are not markers for rapid disease progression in primary sclerosing cholangitis

BACKGROUND/AIMS The association between primary sclerosing cholangitis (PSC) and the HLA haplotype A1, B8, DR3, DQ2 is well established. During the last few years, several additional HLA associations have been suggested in PSC. Furthermore, two different HLA-DR specificities have been reported to be markers for rapid disease progression. Our aim was to critically evaluate all of the current and as yet mostly unconfirmed HLA class II issues in PSC. METHODS Seventy-five Swedish patients with PSC were HLA-DR and HLA-DQ genotyped. RESULTS Of the recently described HLA associations in PSC, the association with the DRB1*1301, DQA1*0103, DQB1*0603 haplotype was decisively confirmed, whereas the DRB1*04 specificity was only slightly under-represented and the frequency of DR2 was neutral. The association with codon 38 of DRB genes was secondary to the DRB3*0101 association. HLA-DR and HLA-DQ alleles were not found to be markers of disease progression. CONCLUSIONS The HLA-associated genetic susceptibility to PSC cannot be attributed to specific amino acid positions of the DR beta chains. The highly discrepant results obtained in two previously reported studies and the present investigation indicate that HLA class II alleles are not markers for a more aggressive clinical course in PSC.

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.

No association with germline T cell receptor β-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.

The HLA-DR3,DQ2 heterozygous genotype is associated with an accelerated progression of primary sclerosing cholangitis.

BACKGROUND An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. METHODS The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. RESULTS The DRB1*03,DQA1*0501, DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). CONCLUSION The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.Background: An improvement of prognostic models in primary sclerosing cholangitis (PSC) is needed. In particular, inclusion of prognostic markers that are independent of the disease stage would be advantageous. We investigated whether HLA class II genes associated with PSC are also related to disease progression. Methods: The study included 265 PSC patients from five European countries with a median follow-up of 9.1 years. The end-points were death (n = 38) or liver transplantation (n = 52). Thirty patients developed cholangiocarcinoma during follow-up. Results: The DRB1*03,DQA1*0501,DQB1*02 (i.e. DR3,DQ2) heterozygous genotype was associated with an increased risk of death or liver transplantation (hazard ratio = 1.63; 95% confidence interval (CI) = 1.06-2.52). The presence of a DQ6 encoding haplotype (DQB1*0603 or DQB1*0602) in DR3,DQ2 negative individuals was associated with a reduced risk of death or liver transplantation (hazard ratio = 0.57; 95% CI = 0.36-0.88). There was a trend towards an increased risk of developing cholangiocarcinoma among DR4,DQ8 positive patients, but this did not reach significance (odds ratio = 2.27; 95% CI = 0.78-6.62). Conclusion: The DR3,DQ2 heterozygous genotype is associated with a more rapid progression of PSC, whereas HLA-DQ6 is associated with a retarded disease progression. It is possible that the DR4,DQ8 haplotype is related to cholangiocarcinoma development.

Preferential Vβ3 usage by hepatic T lymphocytes in patients with primary sclerosing cholangitis

Abstract Background/Aims: Primary sclerosing cholangitis and primary biliary cirrhosis are two biliary destructive disorders characterized by prominent T lymphocyte infiltrates in areas of portal destruction. The specificity of the T cell is determined by the T cell receptor for antigens. The aim of this study was to investigate the preference by which certain Vα and Vβ gene segments are expressed by peripheral and hepatic T cells in primary sclerosing cholangitis and primary biliary cirrhosis. Methods: The usage of the α/βT cell receptor (TcR) V gene of liver infiltrating lymphocytes and peripheral blood lymphocytes from 12 primary sclerosing cholangitis patients, 10 primary biliary cirrhosis patients and healthy controls was investigated, using α/β TcR V gene product-specific monoclonal antibodies. HLA class II antigen typing with genomic typing technique was done in 1112 primary sclerosing cholangitis patients. Results: A significant difference between the studied groups of patients was an increase in the expression of Vβ3+ T cells in liver tissue from patients with primary sclerosing cholangitis compared to patients with primary biliary cirrhosis and healthy controls ( p Conclusions: Predominant TcR Vβ3 gene usage in liver tissue in primary sclerosing cholangitis may indicate the presence of a specific antigen in this tissue with the capacity of selectivity driving T cells, utilizing the Vβ3 gene segment product, in primary sclerosing cholangitis patients.

HLA polymorphisms and evolution

Polymorphisms within the human MHC are of interest to immunologists, for their functional significance, and to geneticists, as markers of populations. Here, Eleanor Riley and Olle Olerup describe how molecular analysis of the HLA complex is beginning to reveal the true extent of class II diversity, and demonstrate the use of this information to clarify the historical relationships between different human populations.