Clinical, Pathological, Hla Antigen and Immunological Evidence for Disease Heterogeneity in Myasthenia Gravis

Compston, D. A. S.; Vincent, Angela; Newsom‐Davis, John; Batchelor, J. R.

doi:10.1093/brain/103.3.579

Cited by 444 publications

(198 citation statements)

References 0 publications

Supporting

Mentioning

176

Contrasting

Unclassified

Order By: Relevance

“…The reason for this discrepancy is not apparent. But the distinct immunogenetic heterogeneity in myasthenia gravis based on HLA types and autoimmune responses supports an idea that different immunogenetic bases underlie the autoimmune diseases such as myasthenia gravis and Type 1 diabetes [24,26].…”

Section: Discussionmentioning

confidence: 94%

“…Similarly, HLA-DR3 and HLADRw9 have recently been reported to be associated with Type 1 diabetes among Chinese, which are also different from HLA types of Caucasian patients [23]. Myasthenia gravis, which is an autoimmune disease directed to acetylcholine receptors of the neuromuscular junction, is similar in that its HLA-association varies among different ethnic groups; HLA-DR2 and DR3 in Caucasians [24], HLA-DR4 in Chinese [25], and HLADRw8 and DRw9 in Japanese [26]. These ethnic differences in HLA-association with Type I diabetes or myasthenia gravis might be derived from the difference in the distribution of HLA-DR antigens among the general population of the races; the prevalence of HLA-DR3 antigen is negligibly low not only in Type 1 diabetic patients but also in normal subjects, among Japanese as shown in the present study and previous studies [13,14,16], while it is considerably high even in the general population of Caucasians [18][19][20] and Chinese [23,25].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese ? HLA antigens and organ-specific autoantibodies

et al. 1989

View full text Add to dashboard Cite

Summary. HLA phenotypes and haplotypes in relation toorgan-specific autoantibody responses were studied in 82 Japanese patients with Type 1 (insulin-dependent) diabetes. HLA-DRw9 antigen and HLA phenotype of DRw9/X (X: not DR4) were increased in patients with organspecific autoantibodies other than islet cell antibody (CP<0.02, RR=4.02 and p<0.05, RR=2.30, respectively); whereas HLA-DR4 antigen and HLA phenotype of DR4/X (X: not DRw9) were increased in those without the autoantibodies (CP < 0.001, RR = 3.95 and p < 0.01, RR = 2.46, respectively). HLA haplotype of Bw61-DRw9 was increased in patients with the autoantibodies (p <0.005, RR=4.94), and HLA haplotype of Bw54-DR4 was increased in those without the autoantibodies (p < 0.001, RR= 5.52). The relative risk of HLA-DR4/DRw9 was the highest among all HLA-DR phenotypes or genotypes in patients either with or without the autoantibodies. No association was, however, found between the incidence of islet cell antibody and HLA-DR phenotypes. These findings suggest that Type 1 diabetes among Japanese is immunogenetically heterogeneous as is Type 1 diabetes among Caucasians; and the differences in HLA-association of Type 1 diabetes among ethnic groups might give a clue to understanding of a role of HLA-antigens in the development of Type 1 diabetes.

show abstract

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese ? HLA antigens and organ-specific autoantibodies

et al. 1989

View full text Add to dashboard Cite

show abstract

“…[18] Based on age at onset, HLA associations, AChR antibody positivity and thymic pathology the patients can be divided into early onset, late onset and thymoma-MG [ Table 1]. [19] In the older patients, the Human leukocyte antigen (HLA) association is less marked and the thymus is essentially normal for age. Despite these important subgroups, the disease mechanisms appear to be very similar (see below).…”

Section: Generalized Acetylcholine Receptormentioning

confidence: 99%

Autoimmune disorders of the neuromuscular junction

Lang

Vincent

2009

Current Opinion in Pharmacology

View full text Add to dashboard Cite

The neuromuscular junction (NMJ) is a prototypic synapse although its structure is rather different from those of the central nervous system (CNS). The unmyelinated motor nerve terminals are separated from the postsynaptic membrane by a cleft that contains a basal lamina. This includes many proteins such as collagens, laminins, fibronectin and perlecan which help anchor some of the key elements involved in NMJ The neuromuscular junction (NMJ) is a specialized synapse with a complex structural and functional organization. It is a target for a variety of immunological disorders and these diseases usually respond well to immunotherapies. The understanding of the immunological basis of myasthenia gravis, the most common neuromuscular junction disorder, has improved in the recent years. Most patients have antibodies to the acetylcholine receptor (AChR), but around 10% have AChR antibodies that are only identified by novel methods, and up to 5% have muscle-speciÞ c kinase antibodies which deÞ ne a different subgroup of myasthenia. The spectrum of antibodies and their pathophysiological aspects are being elucidated. Even though less common, Lambert Eaton myasthenic syndrome (LEMS) is important to recognize. The abnormality in LEMS is a presynaptic failure to release enough packets of ACh, caused by antibodies to the presynaptic voltage-gated calcium channels. More than half these patients have a small cell carcinoma of lung. Acquired neuromyotonia (NMT) is a condition associated with muscle hyperactivity. Clinical features include muscle stiffness, cramps, myokymia, pseudomyotonia and weakness. The immune mechanisms of acquired NMT relate to loss of voltage-gated potassium channel function. This review will focus on the important recent developments in the immunemediated disorders of the NMJ.Key words: Gravis, Lambert Eaton myasthenic syndrome, neuromyotonia, neuromuscular junction, autoimmunity, acetylcholine receptor, voltage-gated channel development and function; for instance acetylcholine esterase (AChE) is localized via ColQ, a collagen-like molecule, to the basal lamina. Agrin and neuregulins, secreted from the nerve terminal, are bound by the basal lamina and interact with their receptors, playing an important role in the location of postsynaptic membrane proteins, voltage-gated calcium channels and the dystroglycans. The postsynaptic membrane at the NMJ forms a series of deep folds. The acetylcholine receptors (AChRs) are found at the top one-third of these folds, whereas the voltage-gated sodium channels are anchored at the bottom of the folds. The development of the NMJ is a fascinating area of research [1] and many of the proteins involved are relevant to disease ([ Figure 1] for a simple representation).The nerve action potential opens voltage-gated calcium channels (VGCCs) that are located in the motor nerve terminal [ Figure 1]. The resulting influx of calcium leads to the release of about 30 (in human muscle) individual packets of acetylcholine (ACh). Some of the ACh is hydrolysed by AChE but about 65%...

show abstract

“…17 The HLA-DR3-B8 haplotype was also associated with increased titers of anti-AChR autoantibodies. 12 Owing to the strong linkage disequilibria across the HLA complex, it is suspected that an allele of a linked locus, rather than DR3 itself, is responsible for these associations. 21,22 Regarding the titers of anti-AChR autoantibodies, work in progress from our laboratory points to an allele of a microsatellite marker in the central region of HLA, designated as TNFD*1, as explaining the variance of autoantibody titers better than DR3.…”

Section: Genetics Of Autoantibodies In Myasthenia Gravis M Giraud Et Almentioning

confidence: 99%

“…Thymus anomalies are also a major factor of clinical and biological heterogeneity of the disease. 12,13 As is the case for most autoimmune diseases, MG has a complex genetic control. 14 The extended HLA-A1-B8-DR3 haloptype, also called the 8.1 ancestral haplotype, 15 has long been associated with the form of MG with thymus hyperplasia, 16 defining the MYAS1 locus.…”

Section: Introductionmentioning

confidence: 99%

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

et al. 2004

View full text Add to dashboard Cite

Autoantibodies against the muscle acetylcholine receptor (AChR) play an essential role in the pathophysiology of autoimmune myasthenia gravis (MG). Their serum titers, however, vary considerably among patients. Our aim was to investigate whether their variation might be explained by genetic factors. Using different methods, we have obtained strong evidence for a threelocus association influencing autoantibody titers in MG patients with thymus hyperplasia or with a normal thymus. Two of the loci, one encoding the AChR a-subunit, the other encoding the a-chain of the class II antigen-presentation molecule, HLA-DQ, demonstrated interaction to determine high autoantibody titers. The third locus was associated with the 8.1 ancestral HLA haplotype. It exerted an additive effect and it is posutlated to have a nonantigen specific immunoregulatory function. Our study demonstrates for the first time that polymorphism of an autoantigen gene may quantitatively modify the immune response against it. Altogether, the data lend support to a three-gene model to explain autoantibody expression in a subset of MG patients.

show abstract

Clinical, Pathological, Hla Antigen and Immunological Evidence for Disease Heterogeneity in Myasthenia Gravis

Cited by 444 publications

References 0 publications

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese ? HLA antigens and organ-specific autoantibodies

Immunogenetic heterogeneity in Type 1 (insulin-dependent) diabetes among Japanese ? HLA antigens and organ-specific autoantibodies

Autoimmune disorders of the neuromuscular junction

Genetic control of autoantibody expression in autoimmune myasthenia gravis: role of the self-antigen and of HLA-linked loci

Contact Info

Product

Resources

About