HLA antigens and myasthenia gravis in Japan

Recent studies have noted an increased association of the histocompatibility antigen HLA-B8 with myasthenia gravis in Caucasian patients.The HLA types of 63 Japanese patients with myasthenia were compared to those of 271 controls. The present study was designed to assess correlations between HLA antigens, sex, age at onset, the presence of autoantibodies and thymic morphology.HLA-B12 was increased in Japanese patients, especially females with early age at onset, and in addition it was significantly correlated with thymic hyperplasia. HLA-B5 was frequently found in the patients with thymoma. Statistically the most frequent haplotype found in this disease was HLA-A10–HLA-B12.     

HLA antigens and myasthenia gravis in north India.

The HLA antigen distribution was studied in 37 north Indian patients with myasthenia gravis. The control group consisted of 118 normal, healthy individuals of the same ethnic group. The antigens showing the highest frequency were Bw21 (18.9% vs 4.2% p less than 0.005), Bw35 (24.3% vs 6.8%, p less than 0.005) and A9 (51.3% vs 30.5%, p less than 0.025). HLA-B8 was increased nearly two fold in the myasthenia gravis patients (RR = 2.4) and was confined mainly to the young females without thymoma. The possibility that Bw21 and Bw35 might be the markers for susceptibility to autoimmune disorders in India is discussed. The observations also support those of others that HLA-B8 linked susceptibility gene is more frequently found in myasthenia gravis patients with thymic hyperplasia.     

HLA class II genotypes in Mexican Mestizo patients with myasthenia gravis.

Myasthenia gravis is an autoimmune, heterogeneous disorder, characterized by the presence of antibodies against acetylcholine receptors at the neuromuscular junction. There is a strong evidence that an individual's genetic composition is an important predisposing factor for the development of the disease. To correlate HLA class II genotypes with thymic pathology in Mexican Mestizo patients who had been subjected to thymectomy. HLA class II genes were analyzed in 60 patients and in 99 healthy ethnically matched controls. Thymic hyperplasia, atrophy, thymoma, and normal histology were encountered in 56, 33, 8 and 2% of patients, respectively. HLA-DR11 was significantly increased in patients with thymoma compared with healthy controls (pC = 0.001, OR = 13.35, 95% CI 3.5-51.3), compared with the subgroup of hyperplasia patients (pC = 0.005, OR = 15.5, 95% CI 2.78-95.58) and with the atrophy subgroup (pC = 0.04, OR = 10.5, 95% CI 1.75-70.95). This study provides the evidence of an association between HLA class II alleles with clinical and genetic heterogeneity in myasthenia gravis, particularly in those with thymoma (HLA-DR11).     

Identification of genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis

HLA association with myasthenia gravis (MG) has been studied in a series of 114 patients using class I and class II genotyping after PCR amplification. Positive association was found with DR3, particularly in women (RR=2.6) and in early MG onset (RR=3.4). DRB1, DRB3, DQB1, DQA1 and B (B8 and B18_genotyping revealed that the association was predominantly with the B8 DRB1^*03 DRB3^*0101 DQB1^*0201 DQA1^*0501 ancestral haplotype. This haplotype frequency was also increased in patients with thymic hyperplasia (RR=3.5) and was greatly reduced in patients with thymona (RR=0.35). Sixteen out of 48 patients carrying this 8.1 ancestral haplotype showed absence of B8 (n=4) or of DR3 (n=12). HLA class II genotyping further revealed the existence of two other significant associations. MG was positively associated with the DQB1^*0604 allele (RR=3.4), particularly in patients with thymona (RR=5.7). Furthermore, the disease was negatively associated with DR1 in females (RR=0.32). These data suggest that MG is placed under the control of at least three distinct genes: (1) a class II predisposing gene in the 8.1 ancestral haplotype; (2) a thymona-associated class II allele on the DQB1^*0604 haplotype; and (3) a protective allele DR1.     

HLA antigens and acetylcholine receptor antibody in the subclassification of myasthenia gravis in Hong Kong Chinese.

Thirty seven Chinese adults and 23 children in Hong Kong with myasthenia gravis were tested for HLA-A and -B antigens and acetylcholine receptor (AChR) antibody. HLA BW46 had a significantly increased prevalence in patients with juvenile onset ocular myasthenia gravis. Only one third of the juvenile ocular patients had AChR antibodies and the titres were generally low. In the adult patients taken as a whole there was a non-significant increase in the prevalence of HLA B5 and HLA B15. HLA BW46 was more prevalent in adult patients without AChR antibody and less prevalent in patients with AChR antibody but the findings were not statistically significant. It is suggested that ocular myasthenia gravis is determined by a pathological mechanism for which susceptibility is determined by HLA BW46. There was a strong correlation between ocular myasthenia gravis and Graves' disease in the adult patients. The possibility that ocular myasthenia gravis is accentuated by a BW46-associated predisposition to ocular Graves' disease is considered.     

Immune disease and HLA associations with myasthenia gravis.

In the late 1950's laboratory and clinical evidence suggested that myasthenia gravis was an autoimmune disorder. Since then a voluminous literature has developed documenting the many immunological abnormalities that occur in this condition. Recent findings point to a central disorder of immunoregulation. It is postulated that the disease occurs as a result of host genetic and environmental influences-the latter being, as yet unidentified and possibly a virus.     

DNA restriction fragment length polymorphism of HLA-DR2: Correlation with HLA-DR2-associated functions

HLA-DR2 can be divided into at least 3 distinct HLA-D clusters which correlate with structural differences within the HLA-D region. Further, a functional counterpart of this subdivision has been previously identified. The presence of a particular DR beta 2 polypeptide chain correlated precisely with the susceptibility of measles virus-infected HLA-DR2 homozygous typing cell lines to lysis by measles virus-specific, HLA class II-restricted CTL clones. To determine if a genetic basis for these functional differences could be detected, the degree of polymorphism at the DNA level within the serologically defined HLA-DR2 haplotype has been examined. By using DNA probes for DR beta and DQ beta 4 of the 5 HLA-D clusters of HLA-DR2 could be distinguished and a RFLP pattern was identified which correlates with known immunological functions associated with these various D types. In addition, this technique of 'molecular genotyping' was used to investigate a limited panel of patients with multiple sclerosis (MS) who were HLA typed as either HLA-DR2,2 or HLA-DR2,blank. The RFLP profile of the HLA-DR2 Dw2 D type was found in all of these MS patients.     

Tumour necrosis factor-alpha polymorphism and secretion in myasthenia gravis.

The mechanism behind the association between MHC genes and myasthenia gravis (MG) is not fully understood. In the present study we studied the associations with polymorphisms at HLA-DR3, HLA-B8 and TNF-alpha genes in Swedish patients and healthy individuals. The TNF-alpha-308 allele 2 was associated with female patients having disease onset before the age 40 and with thymic hyperplasia. Analysis of strongest associations between MG and alleles close to TNF-alpha indicated that the association of TNF-alpha was possibly stronger than for HLA-DR3 and nearly the same as for HLA-B8. Peripheral blood mononuclear cells from patients positive for TNF-alpha -308 allele 2 had higher secretion of TNF-alpha when stimulated by anti-CD3 antibodies. Our results indicate that a subgroup of MG patients who have been previously shown to be associated with MHC genes may have a higher inducible TNF-alpha level in vivo, thus resulting the pathological changes in the thymus and the early onset of MG.     

HLA,anti-DNA,and complement in myasthenia gravis

Twenty-seven patients (18 females and 9 males) with myasthenia gravis were HLA-A, -B, -C, and -D typed, and the results were analyzed with relation to evidence of immunodeficiency, thymic disease, and associated autoimmune processes. An association of A1, B8, and DRW3 appeared to identify a group of 8 females with higher mean anti-DNA, lower mean C4, and lower mean E. coli antibody titer than other females in whom CW4 (with or without BW35) was common (6 of the remaining 10 females were in this category). Antiacetylcholine receptor (anti-AChR) autoantibody and reduced serum lgM and isohemagglutinin titers were not clearly related to particular HLA specificities. These results suggest that HLA-A1, -B8, -DRW3, and -CW4 may be related to associated phenomena rather than playing a major role in the development of anti-AChR and myasthenia gravis.     

Congenital myasthenia gravis: clinical and HLA studies in two brothers.

Two brothers with congenital myasthenia gravis are described. In both, ptosis and ophthalmoplegia responded poorly to oral anticholinesterase therapy and to thymectomy. The brothers had two different HLA haplotypes and neither had the HLA-A1-B8-DW3 haplotypes which are commonly associated with myathenia gravis in adult-onset cases.     

Involvement of HLA in clinical courses of myasthenia gravis

The relationship between the histocompatibility leukocyte antigen (HLA) phenotypes and the clinical course of myasthenia gravis (MG) was studied in 53 Japanese patients with MG. The frequency of HLA-DRw9 antigen was high in the MG patients who did not need immunosuppressive therapy but only anticholinesterase agents (RR = 4.52; CP less than 0.02), who achieved remission of the disease (RR = 2.98; CP less than 0.05) or who showed a decrease in AChR antibody (Ab) titer (RR = 6.32; CP less than 0.0002), whereas the frequency of HLA-DRw8 antigen was increased in MG patients who underwent immunosuppressive therapy (RR = 4.03; CP less than 0.01), who did not have remission (RR = 4.75; CP less than 0.1) or who showed an increase in AChR Ab titer (RR = 6.48; CP less than 0.01). These data suggest that immunogenetic heterogeneity in MG might be reflected in its clinical course.     

Correlation of HLA and myasthenia gravis in a Brazilian population

Based on the fact that Brazilian ethnic groups are mixed and therefore different from caucasian, chinese or japanese populations the authors studied the HLA antigen distribution in 37 myasthenic patients. The control group consisted of 69 healthy individuals of the same population studied in the same laboratory. The antigens HLA B8 showed the highest relative risk for female, younger than 40 years old, with thymic hyperplasia. Also the HLA B8 and A1 showed high frequency for black myasthenic patients.     

HLA and acetylcholine receptor antibody in patients with myasthenia gravis]

Human leucocyte antigen (HLA) and acetylcholine receptor antibody (AchRab) titer in the serum assayed were in 106 and 100 patients with myasthenia gravis (MG), respectively. 93 of the total patients had both HLA and AchRab assays. There is a strong association between HLA Bw46, Cx46 antigens and the patients with MG. The AchRab level in the patients with positive Bw46, Cx46 antigen is significantly lower than that of the patients with negative Bw46 Cx46 antigen. The geometric means (G) of AchRab were 2.99 and 4.74, respectively, P less than 0.05. From our study, We think the patients with MG could be divided into two groups, according to the clinical presentation, the AchRab level and the association with HLA Bw46, Cx46 antigens. The first group is that who present ocular muscular myasthenia, childhood or adolescence onset, lower level of AchRab titer and strong association with HLA Bw46 and Cx46. The second one is that who have general muscular myasthenia, adult onset, higher level of AchRab titer and no association with Bw46 and Cx46.     

Absence of cellular hypersensitivity to muscle and thymic antigens in myasthenia gravis.

Humoral antibodies to skeletal muscle and its components and to thymus have been demonstrated in the sera of patients with myasthenia gravis. A role for cellular hypersensitivity to similar antigens in the pathogenesis of the disease has been suggested by some reports of the presence of cellular immunity. A detailed immunological study using muscle and thymic antigens, including those prepared from the patients' own tissues, failed to confirm these findings. It is suggested that previous reports of cellular hypersensitivity represent the demonstration of an epiphenomenon.