Study of HLA as a predisposing factor and its possible influence on the outcome of multiple sclerosis in the sanitary district of Calatayud, northern Spain.

The relationship between multiple sclerosis (MS) and the HLA antigens DR2 and DQ1 is well recognised, but, in Spain, it has not been clearly defined. The aim of our study was to investigate the relationship between MS and HLA antigens in the sanitary district of Calatayud, northern Spain, and to correlate these antigens with the progression of the disease. Thirty-four patients were selected from a long-term (October 1990 to July 1996) prospective survey in the region where there was a prevalence rate of 58 per 100,000 population. The HLA antigens were determined in 31 patients. A control group of 895 people of Caucasian race was recruited from the same population. We performed serologic tests on all participants. Nucleotide typing was carried out in DR2-positive patients. The most frequent antigens in excess in MS were: A19 (odds ratio, OR: 2.29, p = 0.04), B5 (OR: 2.85, p = 0.02), B41 (OR: 7.65, p = 0.04), CW7 (OR: 3.4, p = 0.004), DR6 (OR: 6.18, p = 0.0001) and DR10 (OR: 3.4, p = 0. 004). The DR2 antigen was also more frequent in MS patients (39%) than in controls (19%; OR: 2.69, p = 0.01). All positive DR2 patients showed the DR15(2) split but not the DR16(2) split. The frequency of antigens CW4 and DR1 was lower in MS patients than in controls. The CW4 antigen was detected in 12% of the patients and in 33% of the controls (OR: 0.28, p = 0.04). The DR1 antigen was found in 20% of the controls and in none of the MS patients (OR: undefined, p = 0.01). The DQ1 antigen was observed in 68% of the patients and in 50% of the controls (OR: 2.1, p = 0.07). We did not find any relationship between HLA antigens and progression of the disease. Although we found that DR2 antigen is linked to MS, we also found other antigens related to the disease. This suggests a genetic heterogeneity in our geographic area. We also concluded that the DR1 antigen may play a protective role, as it was detected in 20% of the controls and in none of the MS cases.     

HLA antigens-linked genetic control in multiple sclerosis patients resistant and susceptible to infection

Patients with multiple sclerosis (MS) from the two Montreal MS clinics, were divided into two groups: one group of 61 patients (MS type I) who had no clinical history of susceptibility to recurrent respiratory tract infections and a second group of 58 patients (MS type II) who had persistent susceptibility to such infections since childhood. All patients were typed for the HLA tissue antigens. The HLA antigen frequencies of the total MS patient population, and of MS type I and MS type II patients were compared to those of a normal control population and each other. The HLA-DR2 and B7 antigen frequencies were significantly increased compared to the normal controls for all MS patients. MS type I patients had an increased frequency for HLA-Bw42 and DRw8 antigens; the frequency of HLA-A29 was lower than in the controls and MS type II patients. MS type II patients had a significantly increased frequency for DR3 and some HLA-DR3-associated phenotypes (A1 + DR3; B8 + DR3; A1 + B8 + DR3) as compared to controls and MS type I patients. These results are consistent with the existence of genes linked to the HLA antigens, such as immune response genes, which control the resistance or susceptibility of the patients to infection, and suggest that these HLA antigens could be associated with a difference in the evolution of MS, as observed in the MS type I and II patients [21].     

Multiple sclerosis,sleep latencies and HLA antigens

Summary The role of HLA antigens, and HLA-DR2 in particular, in the determination of mean sleep onset latencies (MSOLs) in multiple sclerosis (MS) was studied. It has been suggested that this antigen may play a part in the reduction of MSOLs, since nearly 100% of patients suffering from narcolepsy are DR2-positive. A multiple sleep latency test was performed in 37 patients suffering from MS without spontaneous complaints of sleep disturbances and who were typed for HLA-A, B, C, DR and DQ. The MSOL was reduced in a total of 21 patients, in only 7 of 15 DR2-positive patients and in 12 of 21 DQw1-positive patients. However, it was reduced in 13 of 16 B8- or B14-positive patients. In contrast with this, in the absence of an early sleep onset (MSOL >30 min), no HLA antigens were found to be over-represented when considered individually; only those patients positive for a group of cross-reacting HLA antigens (B5, B15, B18, B21 or B35) had an MSOL greater than 30min. These results suggest that the genes which code for the DR2 or DQw1 antigens, which are present in nearly 100% of narcoleptics, are not solely responsible for the appearance of an early sleep onset in MS.     

Multiple sclerosis and HLA class II susceptibility and resistance genes

Probes to the HLA class II genes DRβ, DQβ, and DQα were used to study DNA from unrelated Caucasian multiple sclerosis (MS) patients by sequential restriction fragment length polymorphism (RFLP) analysis in Taq1 restriction enzyme digests. Comparison of 104 patients and 108 controls, who were not matched for DR type, has identified for the first time a linked series of allele-specific RFLPs or allogenotypes which form an extended haplotype that is preferentially associated with MS. These allogenotypes include DRw15 or DR2(15);DQβlb, which corresponds at the DNA level to the DQwl (DQw6) serotype; a DQA1 allogenotype termed DQα1b; and a 2.2kb DX (DQA2) allogenotype termed DXαU (DQA2U). The role of HLA class II genes in susceptibility to MS was found to be complex. First, 23 of 104 MS patients showed DR-DQ linkages which were not observed in our control population. We suggest these anomalous associations may be important in the pathogenesis of MS. Second, homozygosity of a 2.0 KB DX (DQA2) gene, termed DXαL (DQA2L), Showed a strong negative association with MS. DXαL (DQA2L) is in strong linkage disequilobrium with DR1, 5(w11)7, and a subset of DR4, all of which also showed a negative association with MS, Since DXαL (DQA2L) does not code for any known product, DR1, 5(11), 4, and 7 become candidates for disease resistance genes. Third, in EcoR1 and EcoRV digests of DNA from both controls and patients homozygous for DQβ1b a number of different RFLP patterns were identified and these RFLPs patterns were identified and these RFLPs were associated with either relapsing-remitting or progressive MS. This suggests there may be HLA sequence differences between individuals bearing a particular class II allele and these may correlate with the clinical course of MS.     

HLA-DR beta, -DQ alpha, and -DQ beta restriction fragment length polymorphisms in multiple sclerosis

Restriction fragment length polymorphism (RFLP) studies were performed on DNA from unrelated Caucasian patients with multiple sclerosis (MS) using cDNA probes to the HLA class II genes DR beta, DQ alpha, and DQ beta. In a study of 34 patients and 34 controls who were not matched for DR type, we found that the DQ beta allele-specific RFLP or allogenotype, termed DQ beta lb, which corresponds at the molecular level to the DQwl serotype, is preferentially associated with MS. A significant disease association with DR2 was demonstrated by serology but this was not confirmed using DR2/Dw2-specific RFLPs. We suggest that DQ beta lb is largely responsible for HLA-associated susceptibility to MS and that the apparent MS-DR2 serological association is due to the strong linkage disequilibrium between DR2 and DQ beta lb. Homozygosity of one of the two allelic bands of the DX alpha gene, usually termed the DX alpha lower (DX alpha L) band (which cross-hybridizes with the DQ alpha probe), correlated with reduced susceptibility to MS. Similarly a 5.3 kb band identified by the DQ alpha probe in Mspl digests showed a negative correlation with MS. In an analysis of 27 DR2+ controls and 26 DR2+ patients it was found that these individuals all had DR2/Dw2-specific RFLPs and all had identical DR2/Dw2-associated DQ beta (DQ beta lb) and DQ alpha (DQ alpha lb) allogenotypes. We detected no polymorphisms of DR beta, DQ alpha, or DQ beta genes among the DR2+ MS patients which distinguished them from normals.(ABSTRACT TRUNCATED AT 250 WORDS)     

HLA antigens in Italian multiple sclerosis patients

We analyzed HLA-A,-C,-B,-DR and-DQ specificities in 104 Italian multiple sclerosis patients and in 905 healthy controls. The frequencies of HLA-A23, A26, Cw4, DR3 and, especially DR5 antigens were significantly higher in multiple sclerosis patients than in controls. Patients with progressive course were characterized by high frequencies of B7, B8 and DR3 antigens: Cw1 and DRw11 show a negative correlation with the extent of intrathecal IgG production. These data confirm that the HLA system may influence the clinical expression and the immune responses to the disease.

---

Sommario Abbiamo analizzato le specificità HLA del locus A, C, B, DR e DQ in 104 pazienti italiani affetti da Sclerosi Multipla e in 905 controlli sani. La frequenza degli antigeni A23, A26, Cw4, DR3 e soprattutto DR5 era aumentata in maniera significativa nei pazienti rispetto ai controlli. I pazienti con decorso progressivo erano caratterizzati da un'alta frequenza degli antigeni B7, B8 e DR3; Cw1 e DRw11 mostravano una correlazione negativa con l'estensione della produzione intratecale di IgG. Questi dati confermano che il sistema HLA può influenzare l'espressione clinica e le risposte immunitarie nella malattia.

     

The impact of HLA-A and -DRB1 on age at onset, disease course and severity in Scandinavian multiple sclerosis patients

The human leucocyte antigen (HLA) class II haplotype DRB1*15–DQB1*06 (DR15–DQ6) is associated with susceptibility to multiple sclerosis (MS), and HLA class I associations in MS have also been reported. However, the influence of HLA class I and II alleles on clinical phenotypes in MS has not yet been completely studied. This study aimed at evaluating the impact of HLA-A and -DRB1 alleles on clinical variables in Scandinavian MS patients. The correlation between HLA-A or -DRB1 alleles and age at onset, disease course and Multiple Sclerosis Severity Score (MSSS) were studied in 1457 Norwegian and Swedish MS patients by regression analyses and Kruskal–Wallis rank sum test. Presence of HLA-DRB1*15 was correlated with younger age at onset of disease (corrected P  = 0.009). No correlation was found between HLA-A and the variables studied. This study analysed the effect of HLA-A on clinical variables in a large Scandinavian sample set, but could not identify any significant contribution from HLA-A on the clinical phenotype in MS. However, associations between HLA-DRB1*15 and age at onset of MS were reproduced in this extended Scandinavian MS cohort.     

Influence of HLA on progression of optic neuritis to multiple sclerosis: results of a four-year follow-up study

BACKGROUND: Genetic predisposition in multiple sclerosis (MS) has always been a critical concern in aetiology and progress of the disease. The present study looks into the relations between human leukocyte antigen (HLA), optic neuritis (ON) and MS in the Iranian population. METHODS: Patients with potential diagnosis of acute ON underwent a standardized clinical examination for confirming the diagnosis. Selected patients were gathered for HLA typing and clinical follow up. RESULTS: Of the 55 patients, 46 (83.6%) were female. The mean age was 25(+/-7.3) with a range of 12-43. Twenty of the 55 (36%) were confirmed for the diagnosis of clinically definite MS (CDMS). Results show that A23, B21, A11 and B51 alleles were present in 4 (20%), 6 (30%), 2 (10%) and 1 (5%) of the CDMS patients, respectively. Ten (50%) and 17 (85%) CDMS patients were positive for HLA class II alleles, DR2 and DQ1, correspondingly. CONCLUSIONS: The study strongly suggests the association among DR2, A23 and B21 allele and the evolution of ON to MS. High prevalence of A23 and DR2 alleles in CDMS patients compared with the normal population may suggest an important role for these alleles in the development of MS. The study suggests B51 as a protective factor against development of ON in the normal population. In addition, results do not confirm previous studies considering A11 as a predisposing factor. The present study finally evokes that different classes of HLA have different roles in susceptibility to MS and confirms disease heterogeneity as an important emerging concept in MS.     

HLA and multiple sclerosis in Italy: a review of the literature

Summary HLA antigens of locus A, C, B, DR and DQ were typed in 104 Italian multiple sclerosis patients and in 905 healthy controls; the results have been compared with those published in the Italian literature. The Italian studies have been reviewed regarding the ethnic origin of the typed population and the corresponding prevalence of the disease. The data suggest a lack of association between A3 and B7 antigens and Italian multiple sclerosis and a relevance of other DR locus antigens (mainly DR4 and DR5), in addition to DR2, in the susceptibility to the disease.     

HLA-multiple sclerosis association in continental Italy and correlation with disease prevalence in Europe

The association with HLA-DRB1 alleles was tested in 609 Continental Italian MS patients and 836 controls. The phenotype frequency of DRB1*15 in the patients was significantly higher (0.316 vs. 0.112; p(c)<10(-6); Odds Ratio (OR)=3.64) with no dose effect. DRB1*10 was also significantly increased (OR=2.19; p(c)=0.047) and DRB1*07 decreased (OR=0.60; p(c)=1.3 x 10(-3)) independently of DR15 and of each other. We did not detect an influence of the DR phenotype on disease course, age at onset/diagnosis, gender or familiarity. No association with Class I was detected in a random subset of patients and controls. A comparison of the HLA association data in Northern and Southern European populations shows a parallel between disease prevalence and DR15 frequency.     

Human leukocyte antigen DR1 in Japanese and Turkish patients with schizophrenia

The main focus of this review has been to discuss the probable causes of the higher frequency of HLA DR1 antigen in patients with schizophrenia from Japan and Turkey, and also to see whether there was an impact of belonging to the Ural-Altaic language group. A general medline search on the terms HLA and schizophrenia was used as the method to determine HLA studies in patients with schizophrenia. Most of the findings were inconsistent regarding the increased or decreased frequencies of different Class I and II antigens. However, there were interesting results, which have been consistently repeated in several Japanese studies and in a Turkish study. HLA DR1 antigen was statistically significantly increased in Japanese and Turkish patients with schizophrenia. As Japanese and Turkish languages belong to the Ural-Altaic language group, HLA DR1 antigen might have a specific association with schizophrenia in Japanese and Turkish patients. Searching the frequency of HLA DR1 antigen in patients with schizophrenia in other members of Ural-Altaic language group is necessary to support this hypothesis. Other language groups (e.g. Indo-European) should be assessed as well.     

Intrathecal humoral immune response in HAM/TSP in relation to HLA haplotype analysis

Introduction – In HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), we correlated human leukocyte antigen (HLA) haplotypes to the fine specificities of intrathecally synthesized IgG antibodies against HTLV-1. Patients and methods – HLA haplotypes of HAM/TSP patients were determined by the standard NIH microcytotoxicity test and family HLA studies. IgG antibodies against HTLV-1 synthetic peptides in paired CSF and serum were measured by enzyme immunoassay, and intrathecal synthesis of antibodies was evaluated. Results – HAM/TSP patients with particular HLA haplotypes (A24Cw7B7DR1DQ5, A2Cw7B7DR1DQ5, A24Cw-B52DR15DQ6, A11Cw1B54DR4DQ4, and A24CwlB54DR4DQ4) showed more frequently intrathecal synthesis of antibodies against HTLV-1 synthetic peptides, especially against HTLV-1 env gp21 synthetic peptides. Conclusion – In HAM/TSP, a retrovirus-induced human chronic inflammatory disease of the CNS, this is the first report to provide evidence that the intrathecal antiviral immune response is influenced by immunogenetic factors of the HLA complex.     

HLA and anti-GQ1b IgG antibody in Miller Fisher syndrome and Guillain-Barré syndrome

We investigated serological human leukocyte antigen (HLA) types in patients with histories of Miller Fisher syndrome (MFS) and Guillain-Barré syndrome (GBS) with ophthalmoplegia, in whom serum anti-GQ1b IgG antibody was present during the acute phase. We examined class I antigens (A, B and C) in 32 patients and class II antigens (DR and DQ) in 30, but found no association. We conclude that particular serologically defined HLA types are not preferred for the immunoresponse of anti-GQ1b IgG antibody in MFS and GBS.     

HLA-DRB1 and multiple sclerosis in Argentina

Background:  The association of multiple sclerosis (MS) with HLA DR subtypes, and particularly human leukocyte antigen (HLA)-DRB1*15 has been a consistent finding across nearly all Caucasian MS populations. In South America, scarce data exist about this issue. As the complete characterization of the HLA association range around the world is important to understand the role of this locus in MS susceptibility, we analyzed the frequency of HLA-DRB1* allelic groups in an MS population in Argentina.
Methods:  HLA-DRB1 locus was genotyped using PCR and sequence-specific primer amplification in 61 MS patients born in Buenos Aires, Argentina and 1216 healthy controls. Allele frequencies were compared between groups.
Results:  The HLA-DRB1*15 allele frequency significantly differed between controls and patients (13.5% and 33.9% respectively, P  < 0.001, OR 2.51, 95% CI: 1.7–3.0). The other allele frequencies did not show significant differences between patients and controls.
Conclusions:  The present HLA class II population study is in accordance with other Caucasian MS surveys which have found that HLA-DRB1*15 allele is strongly associated with MS disease. In Argentina, this is the first study performed to analyze the association of HLA-DRB1*15 and MS susceptibility in a Caucasian population and therefore contributes with new data to the immunogenomic global MS map.     

Familial bipolar disorder and multiple sclerosis: a three-generation HLA family study

The coexistence of bipolar disorder (BD) and multiple sclerosis (MS) is well known. Manic symptoms may represent initial symptoms of MS, at least in some cases, and follow the MS-HLA phenotype frequencies. The purpose of this study was to examine the possible relation of BD and MS based on an HLA family study of a woman with BD and comorbid MS, with family history of BD. Five members of the family from three generations (the patient, her mother, her brother, and her two daughters) were examined regarding the two disorders and the HLA class I and II specificities, performed by serology and molecular techniques. Her deceased father, her brother, and her older daughter suffered from BD. Moreover, in her brother, BD and MS comorbidity was diagnosed. The three affected members and the nonaffected grandmother share the same class I and II, HLA-A2, B18, CW8, DR2, DQ1 haplotype. The shared class II, HLA-DR2, DQ1 haplotype among affected individuals, which is well known to be associated with MS in Caucasians, suggests a possible susceptibility locus for BD, mapped on chromosome 6, very close to the HLA region, underlying the clinical comorbidity of the two disorders.     

Dual-label immunocytochemistry of the active multiple sclerosis lesion: major histocompatibility complex and activation antigens

Fresh-frozen autopsy material containing active inflammatory lesions from 9 different patients with multiple sclerosis (MS) was analyzed by immunocytochemistry using a panel of monoclonal antibodies, and a dual-label immunocytochemical method was developed which permitted the simultaneous detection of two different surface markers on a single cell. We now report the following. (1) The predominant T-cell phenotype within MS lesions is CD2,3,8. This phenotype marks the suppressor-cytotoxic subset. (2) These cells do not express the natural killer cell marker NKH-1, which is present on a subset of CD8-positive cells in peripheral blood. (3) The infiltrating cell expresses class I (HLA A, B, C), but not class II (DR and DQ), major histocompatibility complex (MHC) molecules. (4) Other T-cell surface molecules, including the activation antigens interleukin-2 receptor, Ta1, and T11-3, as well as the marker 2H4, are largely not expressed. (5) Endothelial cells express both class I and class II MHC molecules and the 4B4 molecule in both MS and control tissue. (6) Astrocytes within the vicinity of MS lesions are predominantly class II MHC-negative. These results demonstrate that the T-cell infiltrate present in MS tissue on autopsy has a restricted phenotypic profile, but they also raise the possibility that, within this population, few activated effector cells are present.     

Immunogenetic heterogeneity and associated autoimmune disorders in myasthenia gravis: a population-based survey in the province of Ferrara, northern Italy

Introduction - The well-established relationship between myasthenia gravis (MG) and HLA antigens varies among different ethnic groups. In Caucasians B8 and/or DR3 alleles have been found associated with young MG women without thymoma and with high titres of acetylcholine-receptor antibody (AChR Ab). An increased frequency of haplotype HLA-A3, B7 and/or DR2 has been observed in older MG patients with low AChR Ab levels. So far, there is no convincing evidence for an association between a specific haplotype HLA and ocular MG or MG with thymoma. MG subjects often show other concurrent autoimmune disorders suggesting a more general inherited predisposition to autoimmunity. We performed a community-based study to verify the HLA-A, B, C, DR and DQ profile on ethnically homogeneous MG patients and with the aim to estimate the frequency of concurrent autoimmune diseases and to compare HLA phenotypes to autoimmune status in different MG patients groups. Methods - Forty-seven patients, living in the province of Ferrara, were followed-up in our neurologic department and typed for HLA Antigens. In addition a set of immunological laboratory tests was performed. Results - We found a trend towards an increased B8 and DR3 frequencies in total affected population; an association between B8 allele and early onset of generalized MG sustained by thymic hyperplasia. The DR3 allele is statistically associated with the presence of additional autoimmune disorders. Conclusions - Our data support the hypothesis of a genetically-based heterogeneity of the disease and show an increased prevalence of associate autoimmune conditions in MG patients.     

HLA antigens and progression of multiple sclerosis. Part II

The HLA-A, -B, -C and -D were determined in 200 multiple sclerosis (MS) patients, 64 of whom underwent a CSF examination. Their frequencies were correlated with the rate of disease progression and with factors thought to influence disease progression, including onset age, type of clinical course and intrathecal IgG synthesis. No correlation was found between HLA haplotypes and progression rate or type of disease course. Patients starting MS after age 31 years carried the DR2 determinant more frequently (P = 0.016) than patients with onset before this median age. Although the greatest proportion of patients with an IgG index greater than 1.5 or more than 15 oligoclonal bands in their CSF were DR2 carriers, no statistical difference was found in the intrathecal IgG synthesis of HLA-DR2 (+) and (-) patients.     

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.     

HLA and prognosis in multiple sclerosis

The patients of a multiple sclerosis (MS) incidence cohort with 25 years of longitudinal follow-up were typed for HLA-DR and DQ. This type of cohort provides reliable data for gene frequencies and prognostic studies. The influence of sampling bias, mainly due to mortality during the long follow-up, was accounted for. A positive association between MS and DR15,DQ6 was confirmed, but this haplotype did not influence prognosis. There was no difference in haplotype frequency between relapsing-remitting and primary chronic progressive MS. DR17,DQ2 was significantly over-represented in the quartile with the most malignant course. The haplotype DR1,DQ5, which was found rather less frequently in MS patients, also tended to be associated with a poorer prognosis.