Immunoglobulin G heavy chain (Gm) allotypes in multiple sclerosis.

Pandey, Janardan P.; Goust, Jean‐Michel; Salier, Jean‐Philippe; Fudenberg, H. Hugh

doi:10.1172/jci110220

Cited by 82 publications

(16 citation statements)

References 24 publications

(10 reference statements)

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“…Although unusual, nonimmune neurological functions can be proposed, the implication of immune system genes (e.g., HLA-haplotype association and SH linkage) suggests an immunopathology in both the narcoleptic canines and humans. This condition would be consistent with the observed relationships in humans between HLA-associated autoimmune diseases and immunoglobulin heavy-chain polymorphisms (22)(23)(24)(25)(26)(27)(28)(29)(30). Involvement of immune mechanisms in the pathophysiology of narcolepsy and, by logical extension, in control of rapid-eye-movement sleep has been suggested previously (3,(6)(7)(8)(9).…”

Section: Methodssupporting

confidence: 87%

Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Mignot

Wang

Rattazzi

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Identification of genes determining narcolepsy susceptibility is important not only for understanding that disorder but also for possible clues to general sleep-control mechanisms. Studies in humans reveal at least one such gene related to the major histocompatibility complex and in dog anas-yet-unmapped single, autosomal recessive gene canarc-1. Gene markers for canarc-l were therefore sought by DNA restriction fragment length polymorphisms in our colony of narcoleptic dogs. A human ,I-switch immunoglobulin probe and the enzyme Hae III identified a gene cosegregating with canarc-l in backcrossed animals (logarithm of odds scores: m = 24, Z max = 7.2 at 0 = 0%). canarc-1 was also shown not to be tightly linked with the dog major histocompatibility complex (m = 40, Z < -2 at 0 < 4.8%). These results represent the mapping of a non-major histocompatibility complex narcolepsy gene and strongly suggest involvement of the immune system in the pathophysiology of that disease. Human narcolepsy is a sleep disorder characterized by excess daytime sleepiness, disturbed nocturnal sleep, and pathological manifestations of rapid eye movement sleep, including sleeponset rapid eye movement periods, cataplexy, sleep paralysis, and hypnagogic hallucinations. The cause and the pathogenesis of narcolepsy are unclear but involve both genetic and environmental factors (1, 2). One genetic factor appears in association with the major histocompatibility complex (MHC) haplotype HLA-DRw1S (DR2), Dw2, DQw6 (DQw1), which is present in 32.8% of Caucasian and 7.7% of Asian normal controls, respectively, compared with 90-95% of Caucasian and 100%o of Asian narcoleptic patients (1,(3)(4)(5).This finding has led to the hypothesis that narcolepsy may be an autoimmune disorder or that a gene encoding an essential protein for sleep control may be located within the MHC complex. Studies to date, however, have not found evidence for or against these hypotheses. None of the general tests of immunopathology described in other autoimmune disorders (peripheral blood erythrocyte sedimentation rate, C-reactive protein, complement, immunoglobulins and lymphocyte subpopulations, cerebrospinal fluid oligoclonal bands) have been found abnormal in narcoleptic patients (6-9), DNA studies have thus far failed to reveal differences between the DRw15 and DQw6 genes of narcoleptics and those of normals (10, 11), and numerous nonimmunological genes cloned within the MHC region do not seem related to sleep.The paucity of multicase families has hindered further genetic studies. Nevertheless, sufficient patients without the DRw15 (DR2) haplotype, as well as multiplex families with disease not linked to HLA, have been reported (1, 2), strongly suggesting the existence of human non-MHC nar- MATERIALS AND METHODSBackcrosses and Diagnosis of Narcolepsy. Canine narcolepsy is an autosomal recessive disorder with full penetrance. Cataplexy can be observed spontaneously or after induction, by using the food-elicited cataplexy test (12) in all adult animals born from nar...

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Section: Methodssupporting

confidence: 87%

Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Mignot

Wang

Rattazzi

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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“…However, Bulman et al (60) found no association and Haile et al (61) found no linkage between Gm markers and MS. Gaiser et al (28) reported an association between a DNA polymorphism of IgG3 and MS, but found no association between IgG1 and MS. Furthermore, the IgG3 association was with the opposite allele of IgG3 reported elevated in MS patients in the previous studies (57)(58)(59).…”

Section: Resultsmentioning

confidence: 65%

“…Geographical stratification and local variation in ethnic composition has been suggested as a possible explanation, as well as the possibility that different environmental factors may involve different MS susceptibility loci. However, as different results in association studies between MS and the CH region have been reported for MS patients from the same geographical regions (28,57,61,62), other explanations including incompatible control groups, may be more probable.…”

Section: Resultsmentioning

confidence: 89%

“…The results of these studies have been inconsistent. Several studies reported an elevation of the IgG marker Gm"'7;21 haplotype in MS patients (57)(58)(59). However, Bulman et al (60) found no association and Haile et al (61) found no linkage between Gm markers and MS. Gaiser et al (28) reported an association between a DNA polymorphism of IgG3 and MS, but found no association between IgG1 and MS.…”

Section: Resultsmentioning

confidence: 99%

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Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region.

Walter¹,

Gibson²,

Ebers³

et al. 1991

J. Clin. Invest.

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15 immunoglobulin heavy chain constant (CH) and variable region (VH) polymorphisms were selected to span the entire length of the heavy chain cluster. These polymorphisms were examined in 34 sib pairs concordant for multiple sclerosis (MS) and in 23 sporadic MS patients. Allele frequencies were calculated for the 2 MS patient groups and compared with those found in a control population from the same geographical location and of similar ethnic background. No significant association was found between MS and the 7 CH region polymorphisms examined. However, a significant correlation between the MS phenotype and a VH2 family polymorphism was observed in both MS patient populations (familial MS patients x2 = 8.16, P < 0.005; sporadic MS patients x2 = 8.90, P < 0.005). One allele of the VH2-5 gene segment was found to be overrepresented in both MS groups. VH2-5 has recently been physically mapped close to the CH region, between 180 and 360 kb away. These results indicate that a locus near or within the CH-proximal VH region is associated with increased susceptibility to MS. (J. Clin.

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“…It has also been suggested that, in the same ethnic group, susceptibility to MS is associated with the presence of certain combinations of alleles (haplotypes) at another series of immune response loci that code for the heavy chains of immunoglobulin Gl to G4 subclasses, i.e., the socalled Glm to G4m loci on chromosome 14. Specifically, the Gm'2; haplotype is overrepresented in MS (9)(10)(11). Finally, MS susceptibility may be under the simultaneous influence of at least two unlinked genetic systems (12).…”

Section: Introductionmentioning

confidence: 99%

Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

Salier¹,

Sesboüé²,

Martin-Mondiere³

et al. 1986

J. Clin. Invest.

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In some Caucasian populations, multiple sclerosis (MS) susceptibility has been independently related to given alleles of HLA or Gm systems that respectively code for majorhistocompatibility complex class I and II antigens or immunoglobulin G heavy chains. Whether given combinations of alleles at both series of loci simultaneously influence MS susceptibility and/or severity was investigated by comparing 147 French MS patients and 226geographically-matched healthy controls. The G2m(-23)/HLA-B35 phenotype and Glm(-1)/HLA-B7(-)/HLA-DR2 phenotype were respectively associated with significant protection against (relative risk = 0.05) and susceptibility to (relative risk = 43) MS. When considering MS severity, the presence of HLA-B7 antigen correlated with a more severe disease in Gmn/Gm3 heterozygous patients, but not in Gm33/Gm3 homozygous patients.Conversely, an HLA-B12-associated milder disease was restricted to Gm3/Gm3 homozygotes. These results demonstrate the combined influence on MS of genetic loci that are unlinked but immune response-associated. Combined Gm and HLA typing is very likely able to serve as a prognostic indicator in this disease.

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Immunoglobulin G heavy chain (Gm) allotypes in multiple sclerosis.

Cited by 82 publications

References 24 publications

Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Genetic linkage of autosomal recessive canine narcolepsy with a mu immunoglobulin heavy-chain switch-like segment.

Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region.

Combined influences of Gm and HLA phenotypes upon multiple sclerosis susceptibility and severity.

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