Immunogenetic heterogeneity of multiple sclerosis in Sardinia

Multiple sclerosis (MS) predisposition is thought to be influenced by a complex, yet unclear interaction of genetic and environmental factors. Studying ethnically selected populations may reduce genetic and environmental heterogeneities and help clarify the underlying mechanisms of MS susceptibility. Sardinians kept a homogeneous genetic structure and have among the highest MS frequency rates worldwide. Interestingly, MS in Sardinia is linked to otherwise rare HLA alleles. In this light, recent findings from epidemiological and immunogenetic studies of Sardinian MS are presented. Results confirm that, likely due to significant genetic differences at a microgeographic level, even in this homogeneous population MS is immunogenetically heterogeneous and tends to preferentially cluster in some more archaic areas of the island.     

The increasing incidence and prevalence of MS in a Sardinian province

OBJECTIVE: To verify incidence rates and their temporal trend in a homogeneous, ethnically, and genetically distinct population of central Sardinia (the Nuoro province). BACKGROUND: Intensive epidemiologic studies carried out in Sardinia since the 1970s have suggested that the prevalence and incidence of MS are much higher in this Mediterranean island compared with those found on mainland Italy. METHODS: The study area had a population of approximately 274, 000 people in the 1991 census. The authors adopted a complete enumerative approach by reviewing all possible sources of case collection available in the investigative area. RESULTS: Based on 469 MS patients, the mean annual incidence for 1955 to 1995 was 4.18 per 100,000 (or 4.3 per 100,000 if age- and sex-adjusted to the European population). The incidence, averaging 1.95 per 100,000 during 1955 to 1959, rose progressively over time, reaching rates of 6.6 in the quinquiennium 1985 to 1989 and 6.4 per 100,000 in 1990 to 1995. On December 31, 1994, the crude prevalence, based on 415 MS patients alive in the study area, was 151.9 per 100,000 (156.6 if adjusted to the European population). CONCLUSION: These incidence and prevalence rates are the highest to date that have been estimated for a large community in southern Europe, and they constitute some of the highest rates in the world. Based on other surveys, these results reinforce the position of Sardinia as a higher and rising prevalence area for MS compared with other Mediterranean populations. Genetic and social-historic data strengthen the hypothesis of the environmental role and genetic factors among Sardinians in determining the notable difference in MS frequency between Sardinians and other Mediterraneans.     

Multiple sclerosis and anti-Plasmodium falciparum innate immune response

Several epidemiological investigations conducted in Sardinia, insular Italy, indicate that the strong selective pressure of malaria along the centuries may have concurred to the elevated genetic MS-risk in this region. To test such hypothesis in an experimental setting, we have compared the immune response to P. falciparum (the causative agent of malaria) in Sardinian MS patients relative to their ethnic healthy controls and control MS patients of different ethnicity. To this purpose, the P. falciparum-driven peripheral mononuclear cell proliferation, the production of pro-inflammatory cytokines of the innate immunity such as TNF-alpha, IL-6 and IL-12 and the ability to inhibit the parasite growth have been tested in relation to HLA-DR alleles and TNF promoter polymorphisms known of being associated to MS. We found that P. falciparum-induced proliferation, cytokine production and parasite killing are significantly augmented in Sardinian MS patients as compared to controls (p<0.01). Additionally, a correlation is found with genes associated to Sardinian MS, namely the TNF(-376A) promoter polymorphism and the class II HLA-DRB1*0405 allele. In conclusion, we have found evidences that some genetic traits formerly selected to confer a protective responses to P. falciparum now partially contribute to the elevated MS susceptibility amongst Sardinians.     

Genes, environment, and susceptibility to multiple sclerosis

Multiple sclerosis (MS) is a chronic disease of the central nervous system affecting young adults and thus representing a major burden also for their families and communities. The etiology of MS is obscure and its pathogenesis is yet incompletely depicted. Increased evidences indicate a strong genetic contribution to MS susceptibility, although others support the view that it is also influenced by environmental factors, possibly related to still unidentified pathogens. MS appears to be more heterogeneous than previously believed at the immunological level, and new pathological studies indicate a series of subset of conditions under the common denominator MS. The use of genetically homogeneous and geographically isolated populations at high MS risk, such as that of Sardinia, insular Italy, becomes in principle a vital requirement to reduce biological variables and the intrinsic complexity of the disease. This review will focus on recent findings on the peculiarity of Sardinian MS concerning epidemiological, genetic, and environmental aspects. Epidemiological studies reveal a clear heterogeneous distribution of MS cases in the Northern province of Sassari which may not be uniquely assigned to genetic variations. Furthermore, a different immunogenetic profile, including the association with other immunomediated diseases, and a progressive change in clinical phenotype, including age at onset, are present in this island which gives us unexpected variations at the level of patients' cohort and territorial distribution, especially when the northern province is compared to the southern one. This renders MS etiopathogenesis more complex than formerly thought even in this selected and genetically stable population.     

Population frequency of HLA haplotypes contributes to the prevalence difference of multiple sclerosis in Ireland

BACKGROUND: A recent epidemiological study of multiple sclerosis in County Donegal in the northwest of Ireland and County Wexford in the southeast found a significant prevalence difference of 63.9/100,000 (95% CI 49.3-82.7/100,000) between the two regions (Z = 3.94, p 相似文献   

Lack of evidence for a role of the myelin basic protein gene in multiple sclerosis susceptibility in Sardinian patients

A link between myelin basic protein (MBP) polymorphism and multiple sclerosis (MS) has been reported in some populations but not in others. We analysed two polymorphisms in the 5' flanking region of the MBP exon 1 gene in MS patients from the founder population of Sardinia. Using the transmission disequilibrium test (TDT), MBP polymorphisms were analysed in 363 singleton MS families. No distortion in transmission of the tetranucleotide repeat (ATGG)12 and of the 1116–1540 nt alleles was found. Moreover, we discovered no epistatic effect of the MBP gene on the HLA/MHC DRB1,DQB1, DPB1 loci or on alleles defined by D6S1683 marker found to be associated with MS in Sardinians. We concluded that the MBP gene does not play a role in MS susceptibility in Sardinians. Received: 11 March 2002, Accepted: 18 June 2002 Correspondence to Professor Maria Giovanna Marrosu     

Genetic factors and the founder effect explain familial MS in Sardinia.

OBJECTIVE: To estimate the presence of familial aggregation and determine the contribution of genetic factors to familial clustering of MS in patients coming from Sardinia, a Mediterranean island considered a genetically homogeneous, isolated area having high disease incidence and prevalence. METHODS: Recurrence risk in siblings of 901 Sardinian patients and factors influencing risk (patient and sibling sex, patient age at onset, sibling birth cohort, and presence of affected relatives other than siblings) were examined. The presence of distant familial relationships among patients was evaluated by tracing the extended pedigrees of all patients with MS born in one Sardinian village. RESULTS: Twenty-three brothers and 36 sisters of the 2,971 siblings were affected with MS. Recurrence risk was greater in siblings of index patients with onset age less than 30 years (p < 0.01, increased risk 2.33 times) and having a relative with MS other than a sibling or parent (p < 0.01, increased risk 2.90 times). Pedigree analysis of patients from the village of L. showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in siblings of affected cases. CONCLUSIONS: Data from this study indicate that MS familial aggregation in Sardinians is influenced by genetic factors and that founder effect and the isolation of Sardinia can be considered causes of the enrichment of "etiologic" MS genes.     

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.     

Où en sont les études génétiques de la SEP ?

INTRODUCTION: Multiple Sclerosis (MS) is a multifactorial disorder caused by the interaction of environmental factors with a genetic predisposition. BACKGROUND: The chromosomal region comprising MHC contains one or several genes which contributes from 20 to 50 p. 100 to MS genetic predisposition. Other genes are unknown but are likely to have an individual contribution less than MHC. PERSPECTIVES AND CONCLUSION: Large DNA collections, high output genotyping facilities, a precise knowledge of the human genome and adequate statistical methods should allow the identification of MS predisposition genes.     

Multiple sclerosis epidemiology in Sardinia: evidence for a true increasing risk

OBJECTIVES: To update prevalence and incidence rates of MS among Sardinians. MATERIALS AND METHODS: The present work is a "spider" kind of population based survey, conducted over the interval 1968-97, on patients with MS (Poser criteria) living in the province of Sassari, Northern Sardinia (454,904 population). RESULTS: A crude total prevalence rate of 144.4 per 100,000, an onset-adjusted prevalence rate of 149.7 per 100,000 and an average annual incidence rate of 8.2 for the period 1993-7 were found. CONCLUSION: Repeated epidemiological assessments of MS in Sardinia over decades have shown that the island is at high risk for MS. The present work highlights that MS incidence in Sardinia has been increasing over time. Although a substantial and widely spread improvement in MS case ascertainment can be postulated as the reason for such observations, a comparison between our data and those recently reported from a more industrialized province in Northern Italy seems to prove an at least partially real increase in MS risk among Sardinians and favours the hypothesis of a MS "Sardinian focus" as related to its latitude.     

The prevalence of multiple sclerosis in the world: an update

The systematic study of multiple sclerosis (MS) in populations, started in 1929 by Sydney Allison, now consists of over 400 publications dealing with the prevalence of MS throughout the world. However, any attempt to redefine the pattern of geographical differences in MS frequency remains as difficult as ever. The comparison of prevalence studies carried out in different areas and times is made difficult by the variability in surveyed population sizes, age structures, ethnic origins and composition, and the difficult quantification of numerators, especially regarding the recognition of benign and very early cases. Additionally, complete case ascertainment depends on access to medical care, local medical expertise, number of neurologists, accessibility and availability of new diagnostic procedures, the degree of public awareness about MS, and the investigators' zeal and resources. Critical examination of the more recent data on MS prevalence leads to some revisions of previously held concepts, the most interesting of which is the appreciation of the greater influence of genetic factors on disease acquisition. The rarity of MS among Samis, Turkmen, Uzbeks, Kazakhs, Kyrgyzis, native Siberians, North and South Amerindians, Chinese, Japanese, African blacks and New Zealand Maoris, as well as the high risk among Sardinians, Parsis and Palestinians, clearly indicate that the different susceptibilities of distinct racial and ethnic groups are an important determinant of the uneven geographic distribution of the disease. The updated distribution of MS in Europe, showing many exceptions to the previously described north-south gradient, requires more explanation than simply a prevalence-latitude relationship. Prevalence data imply that racial and ethnic differences are important in influencing the worldwide distribution of MS and that its geography must be interpreted in terms of the probable discontinuous distribution of genetic susceptibility alleles, which can however be modified by environment. Because the environmental and genetic determinants of geographic gradients are by no means mutually exclusive, the race versus place controversy is, to some extent, a useless and sterile debate.     

Myelin basic protein-specific T-cell responses in identical twins discordant or concordant for multiple sclerosis

Although multiple sclerosis (MS) is thought to be an autoimmune disease, the target antigen of the immune response is unknown. Both myelin basic protein (MBP) and proteolipid protein (PLP) have been considered candidate autoantigens. Because the immune response to either foreign or self antigens is influenced by the genetic background of the host, the importance of these candidate antigens has been difficult to establish in humans because of genetic diversity. To eliminate genetic differences in MS patients and healthy controls, we have studied the MBP-specific T-cell response in 6 sets of identical twins, 3 of which were concordant and 3 discordant for MS. A total of 638 short-term T-cell lines were established and characterized for MBP-specific proliferative and cytotoxic activity, fine specificity, and human leukocyte antigen (HLA) restriction. Similar frequencies of MBP-specific T cells were observed in affected and unaffected individuals. A slightly higher percentage of cytotoxic T-cell lines was found in affected individuals. For most of the cell lines, the restriction elements were the HLA class II antigens that have been reported previously to be associated with MS; no important differences with respect to HLA restriction were found between the patients and healthy individuals. The peptide epitopes of MBP that were recognized most frequently by the T-cell lines were those previously shown to be immunodominant. Differences in specificity were seen in some discordant twins indicating that, despite genetic identity, the MBP-specific T-cell repertoire may be shaped differently. These findings indicate that differences in frequency, peptide specificity, or HLA restriction are not sufficient to implicate MBP-specific T cells in the pathogenesis of MS. However, the T-cell response to MBP may still represent one necessary component with disease occurring when this response is combined with other host characteristics such as regulation of cytokine-, adhesion molecule-, or HLA-antigen expression in the nervous system or immunoregulatory mechanisms.     

Genetic and environmental factors and the distribution of multiple sclerosis in Europe

Background: The observation that the incidence of multiple sclerosis (MS) increases further from the equator has prompted considerable interest in the factors that might underlie this latitude gradient. Potential candidates include population frequencies of disease‐associated Human Leukocyte Antigen (HLA) alleles which are the major genetic component of MS susceptibility. Ultraviolet (UV) exposure and smoking have also been implicated as key environmental risk factors. Methods: We used multiple sources of published data on MS prevalence, HLA allele frequencies, UV index and cigarette smoking to assess the contributions of both nature and nurture to the distribution of MS within Europe. Results: We observed that HLA alleles unequivocally interact with a population‐wide level to determine disease risk. The UV index and smoking behaviour was also shown to correlate with disease distribution in Europe. For countries with HLA, UV and smoking data, these three factors were shown to account for 75% of the variance in MS prevalence. Conclusions: Genetic (HLA) and environmental (UV and smoking) risk factors thus interact in a complex manner with each other to determine a large proportion of MS susceptibility within Europe.     

HLA antigens in drug-induced parkinsonism

The results of two epidemiological studies suggest a hereditary predisposition to develop drug-induced parkinsonism. We investigated human leukocyte antigen (HLA) antigen prevalence rates in patients with neuroleptic-induced parkinsonism. Fifty-two male, white, neuroleptic-treated, chronic in-patients with DSM-III-diagnosed schizophrenia were examined for the presence of parkinsonism. Subjects were tested for 23 type A, 43 type B, 4 type C, and 10 type DR HLA antigens. The group of schizophrenic patients with parkinsonism (n = 29) was compared with the group of schizophrenic patients without parkinsonism (n = 23). There were no significant differences between the two groups with respect to age, duration of neuroleptic exposure, or anticholinergic drug exposure. One HLA antigen, B44, was significantly more prevalent in the group with parkinsonism than in the group without parkinsonism. We derived a relative risk of 7.16 for drug-induced parkinsonism with HLA-B44 present in this group of schizophrenic patients. These data indicate that HLA-B44 may play a role in genetic or immunologic susceptibility to develop drug-induced parkinsonism in white schizophrenic individuals.     

Genetic aspects of multiple sclerosis

A large body of immunological, epidemiological, and genetic data indicate that tissue injury in multiple sclerosis (MS) results from an abnormal immune response to one or more myelin antigens that develops in genetically susceptible individuals after exposure to an as-yet undefined causal agent. A genetic component in MS is indicated by an increased relative risk to siblings compared to the general population, and an increased concordance rate in monozygotic compared to dizygotic twins. The past few years have seen real progress in defining the genetic basis of MS setting the stage for new approaches for the final characterization of the genes involved in MS susceptibility and pathogenesis. Whole genome screens conducted in different populations identified discrete chromosomal regions potentially harboring MS susceptibility genes, however, with the exception of the Major Histocompatibility Complex (MHC) on 6p21, no single locus generated overwhelming evidence of linkage. These results suggest a complex genetic etiology, including multiple genes of small to moderate effect and probable genetic heterogeneity. The identification and characterization of MS susceptibility genes and their correlation with disease phenotypes is likely to define the basic etiology of the disease, improve risk assessment, and influence therapeutics.     

The genetic epidemiology of multiple sclerosis

Multiple sclerosis (MS) is a debilitating immunological and neurodegenerative disorder. Epidemiological studies have provided overwhelming evidence of complex genetic susceptibility to MS. However, with the exception of the human leukocyte antigen (HLA) locus, genetic studies have failed to consistently identify significant linkage or association with genes that modulate MS disease expression. Numerous functional candidate gene studies, linkage genomic screens, and locational candidate gene studies have been performed in an attempt to identify additional loci. However, these methods have demonstrated insufficient power to consistently identify genes or epigenetic factors for MS. More current approaches integrate information from a variety of sources (e.g. consistent linkage data, gene expression profiling, and functional characterization studies) and utilize high throughput methods (e.g. genotyping high density markers, utilizing pooling schemes and performing new statistical analyses) in an attempt to overcome power issues. The following article presents a review of MS genetics research and a brief overview of methods that are currently being developed and utilized for fine localization of MS loci, such as the method employed in the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) study that is presented elsewhere in this journal. It is the hope of researchers that these methods will lead to the identification of susceptibility genes for MS that aid in elucidating pathogenic mechanisms and potential therapeutic strategies for this debilitating disease.     

Sardinian multiple sclerosis is associated with HLA-DR4: a serologic and molecular analysis

HLA haplotypes in 45 unrelated Sardinian multiple sclerosis patients and in six multiplex families were defined, using both serologic and restriction fragment length polymorphism (RFLP) analysis. In unrelated MS patients, we found an association with HLA-DR4 (p less than 0.01, relative risk = 2.5) and DQw3 (p less than 0.04, relative risk = 2.2). Using a beta-DR cDNA probe, we observed no variation of the DR4 RFLP profile in sporadic or related MS patients compared with DR4-specific pattern in controls. Using a beta-DQ cDNA probe, we identified two DQw3 patterns (DQw3.1 and DQw3.2) with similar frequency in patients and in controls. No specific RFLPs were observed in association with different disease courses. The frequency of haplotype sharing in affected members of multiplex families was not different from that expected by chance. This study shows that Sardinian MS patients carry predominantly the HLA-DR4 allele, in contrast to the DR2 prevalence reported in Caucasian populations. The lack of association with HLA haplotypes in affected members of multiplex families may indicate that genetic factors outside the HLA system play a substantial role in families with MS.     

Multiple sclerosis in the tropics: genetic association to STR's loci spanning the HLA and TNF

Clear evidence has been presented correlating gene polymorphisms at 6p21.3-21.4 (containing HLA and TNF) and the predisposition to acquire multiple sclerosis (MS). In a previous study, we found that polymorphisms at HLA DQAI were associated with being or not being predisposed to MS in individuals inhabiting the tropics, where the prevalence of MS is significantly lower than in subtropical areas. Here, we tested the hypothesis that polymorphisms at D6S276, D6S265, D6S273 and D6S291 microsatellite loci are in strong linkage disequilibrium with a major genetic factor predisposing to MS. These microsatellites span the 6p21.3 region with intervals of 5 cM establishing particular landmarks for the HLA and TNF loci. Thirty-five MS patients and 35 controls, age, sex, social, ethnically and geographically matched healthy individuals, were studied. After testing the fit of gene frequencies to the normal distribution and performing the correlation for multiple comparisons, we found significant differences among the case and the control frequencies for the allele 202 belonging to the marker D6S276 (Pc=0.00455) and for the allele 114 belonging to the marker D6S265 (Pc=0.0084). For these two alleles at different loci, we found higher frequencies in the cases than in the controls. A nonsignificant p value was found in testing the existence of linkage disequilibrium among the studied loci in the cases and in the controls. In conclusion, the current study adds evidence to the established association among polymorphisms of genes located at 6p21.3-21.4 and MS. Furthermore, because of the distribution of the tested microsatellite loci, the more probable critical region could be correlated with the TNF neighborhood.     

Mapping of a susceptibility gene for multiple sclerosis to the 51 kb interval between G511525 and D6S1666 using a new method of haplotype sharing analysis

Multiple sclerosis (MS) is a complex disease that is partly genetic in origin. Although an association of MS with specific human leukocyte antigen (HLA) types has been known for almost 30 years, the nature of this relationship has remained unclear. Furthermore, genetic resolution sufficient to implicate a specific gene in the HLA region has not been achieved. Many loci in the HLA region have been found to be significantly associated with MS, which is largely explained by the extended haplotype sharing and varying marker informativity of the region. We have determined 248 haplotypes of MS patients from the population of the northern Netherlands and 226 haplotypes of their relatives as controls using a set of 22 microsatellite markers covering the HLA region. The data were analyzed using standard association methods and a new statistical method, haplotype sharing statistics (HSS). Haplotype sharing statistics determines the extent of haplotype sharing for all pairs of haplotypes of patients and of controls and calculates the difference in mean haplotype sharing between patients and controls. Haplotype sharing was found to be significantly greater among patients than among controls in a region of 1.1 Mb between markers G511525 and TNFα. The involvement of this region is also supported by association analysis and the transmission/disequilibrium test (TDT). Within this region, HSS, which is largely independent of association and TDT, indicated the interval of 51 kb between G511525 and D6S1666 as that most likely to contain a susceptibility gene for MS. As DQB1 is the sole gene known in this interval at present, the results of our analysis suggest that this gene plays a role in the pathogenesis of MS. Electronic Publication     

The T-cell response to myelin basic protein in familial multiple sclerosis: Diversity of fine specificity,restricting elements,and T-cell receptor usage

Indirect evidence suggests that an autoimmune response to myelin basic protein (MBP) may be involved in the pathogenesis of multiple sclerosis (MS). In MS, several reports have suggested that restricted T-cell populations respond to MBP, as in inbred rodents with the MS disease model experimental allergic encephalomyelitis. In experimental allergic encephalomyelitis, the T-cell repertoire to MBP varies between strains, and in MS it is likely that the response to MBP is also best defined under conditions where genetic differences between subjects are controlled. In this report, the fine specificity of the T-cell response to MBP was assessed in three families, each with multiple individuals affected with MS. We found that (1) comparable frequencies of MBP-reactive T-cell lines were obtained from peripheral blood of MS patients and their healthy siblings. Human leukocyte antigen (HLA) identical sibling pairs discordant for MS had similar frequencies of MBP-reactive T-cell lines. (2) A broad spectrum of MBP epitopes was recognized by T-cell lines from all individuals studied. Within a family, the fine specificity of MBP recognition showed little or no overlap between individuals, even between HLA identical siblings. (3) Recognition of MBP epitopes occurred in the context of different HLA class II alleles. At least four DR alleles each served as restricting elements for recognition of P82—101 or the carboxy terminal region of MBP, two regions thought to be important in the human T-cell response to the molecule. No relationship between the use of a particular DR allele and a response to a particular region of MBP could be established. (4) Apparently random expression of different T-cell receptor Vβ gene families by MBP-reactive T-cell lines was present, with little overlap by different lines reponding to the same region of MBP, or between different individuals belonging to the same family. These results demonstrate that the frequency and fine specificity of T-cell responses to MBP in peripheral blood is independent of the MS phenotype.