The Role of HLA in MS Susceptibility and Phenotype

Greer, Judith M.

doi:10.1007/7854_2014_357

Cited by 10 publications

(9 citation statements)

References 161 publications

(199 reference statements)

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“…Patients with neuromyelitis optica [15], neuromyelitis optica spectrum disorders [16], or longitudinally extensive spinal cord lesions extending over three or more vertebral segments were excluded. Patients with primary progressive MS (PPMS) were also excluded because of the low prevalence of PPMS in the Japanese population [10], as well as the association between PPMS and distinct HLA class II alleles from relapse-onset MS [17, 18]. Participants were recruited from the northern and southern parts of the Japanese archipelago, which spans 33–45° north (Additional file 1: Figure S1).…”

Section: Methodsmentioning

confidence: 99%

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

Nakamura

Matsushita

Sato

et al. 2016

J Neuroinflammation

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BackgroundHigher latitude and human leukocyte antigen (HLA)-DRB1*04:05 increase susceptibility to multiple sclerosis (MS) in the Japanese population, but their effects on disease severity are unknown. We aimed to clarify the effects of latitude and the HLA-DRB1 and HLA-DPB1 genes on disease severity in Japanese patients with MS.MethodsWe enrolled 247 MS patients and 159 healthy controls (HCs) from the northernmost main island of Japan, Hokkaido Island (42–45° north), and 187 MS patients and 235 HCs from the southern half (33–35° north) of the Japanese archipelago (33–45° north). We genotyped HLA-DRB1 and HLA-DPB1 alleles, compared demographic features, and analyzed factors contributing to differences in clinical and laboratory findings between MS patients from southern and northern Japan. The Multiple Sclerosis Severity Score (MSSS), which adjusts the Kurtzke’s Expanded Disability Status Scale score according to disease duration, was used to estimate disease severity.ResultsThe HLA-DRB1*04:05 and DRB1*15:01 alleles conferred susceptibility to MS in our Japanese population (pcorr = 0.0004 and pcorr = 0.0019, respectively). Southern patients had higher MSSS scores than northern patients (p = 0.003). Northern patients had higher frequencies of brain lesions meeting the Barkhof criteria (Barkhof brain lesions) and cerebrospinal fluid (CSF) IgG abnormalities than southern patients (p = 0.0012 and p < 0.0001, respectively). DRB1*04:05-positive MS patients had lower MSSS scores and lower frequencies of Barkhof brain lesions and CSF IgG abnormalities than DRB1*04:05-negative MS patients (p = 0.0415, p = 0.0026, and p < 0.0001, respectively). Multivariate analyses revealed that latitude and DRB1*04:05 were independently associated with the lowest quartile of MSSS and that latitude was positively associated with Barkhof brain lesions and CSF IgG abnormalities. DRB1*04:05 was negatively associated with these parameters. MSSS was decreased by 0.57 per DRB1*04:05 allele (p = 0.0198).ConclusionsLiving at a higher latitude and carrying the DRB1*04:05 allele independently lessens MS symptom severity as defined by MSSS. However, these factors influence the frequency of Barkhof brain lesions and CSF IgG abnormalities in opposite ways; higher latitude increases the frequency of Barkhof brain lesions and CSF IgG abnormalities, whereas DRB1*04:05 decreases them.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0695-3) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

Nakamura

Matsushita

Sato

et al. 2016

J Neuroinflammation

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“…The involvement of HLA in MS is supported by different studies that indicated an increased MS susceptibility is associated primarily with some HLA-DRB1 alleles, but also other alleles like HLA-DRB5 may influence the risk. In particular, HLA-DRB1*1501 is a DRB1 allele is considered the primary genetic risk factor for MS [ 41 ]. Elevated expression of HLA-DRB5 was found in MS and its expression was associated to the HLA-DRB1*1501 allele [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Could the Heat Shock Proteins 70 Family Members Exacerbate the Immune Response in Multiple Sclerosis? An in Silico Study

Chiricosta

Bramantı

Mazzon

2020

Genes

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Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system. It represents one of the main causes of neurological disability in young people. In MS, the autoimmune response is directed against myelin antigens but other possible bio-molecular markers are investigated. The aim of this work was, through an in silico study, the evaluation of the transcriptional modifications between healthy subjects and MS patients in six brain areas (corpus callosum, hippocampus, internal capsule, optic chiasm, frontal and parietal cortex) in order to identify genes representative of the disease. Our results show the upregulation of the Heat Shock Proteins (HSPs) HSPA1A, HSPA1B, HSPA7, HSPA6, HSPH1 and HSPA4L of the HSP70 family, among which HSPA1A and HSPA1B are upregulated in all the brain areas. HSP70s are molecular chaperones indispensable for protein folding, recently associated with immune system maintenance. The little overexpression of the HSPs protects the cells from stress but extreme upregulation can contribute to the MS pathogenesis. We also investigated the genes involved in the immune system that result in overall upregulation in the corpus callosum, hippocampus, internal capsule, optic chiasm and are absent in the cortex. Interestingly, the genes of the immune system and the HSP70s have comparable levels of expression.

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“…In some patients, lesion distribution appears to correlate closely to the HLA type of the patients and the dominant myelin antigen-specific T cell reactivity restricted by those HLA types (1, 2). In other cases, we have noted that patients who have another coexisting autoimmune disease often tend to have a similar lesion distribution, HLA restriction, and T cell myelin antigen reactivity pattern when compared to other patients who have the same combination of autoimmune diseases.…”

Section: Introductionmentioning

confidence: 91%

“…The two main types of AITD, Graves’ disease (hyperthyroidism) and Hashimoto’s thyroiditis (hypothyroidism), have both been linked primarily to carriage of the HLA-DRB1*03-DQB1*02-DQA1*0501 (DR3) genotype in Caucasians (17). MS is generally thought of as involving linkage to HLA-DRB1*15:01; however, around 40% of MS patients are negative for DRB1*15:01 (1), and HLA-DRB1*03 has also been reported to confer an increased risk for development of MS (18). Interestingly, studies on NMOSD patients from Caucasian, Afro-Caribbean, and Indian populations have all found an association with HLA-DRB1*03 (19–21).…”

Section: Introductionmentioning

confidence: 99%

Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease

2017

Self Cite

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Several lines of evidence suggest a definite and unique link between CNS demyelinating diseases and autoimmune thyroid disease (AITD). The aim of the current study was to systematically compare the clinical and laboratory features of patients with coexistent AITD and CNS demyelinating disease with those of patients with just CNS demyelinating disease. Forty-four patients with coexisting CNS demyelinating disease and AITD were identified and their clinical and radiological features were recorded. Blood and DNA were collected and tested for HLA type and for the response of T cells and antibodies to a variety of antigens. Patients with multiple sclerosis (MS) without AITD and healthy individuals were included as controls. Patients with coexisting AITD and CNS demyelinating disease were almost exclusively female (43/44) and had prominent spinal cord involvement as the main neurological finding. The HLA molecules carried by individuals with CNS demyelinating disease and AITD differed from both other MS patients and healthy individuals. Furthermore, patients with both CNS disease and AITD showed less T cell reactivity than patients with MS alone to myelin proteolipid protein, but, compared to other groups, showed elevated levels of T cell reactivity to the calcitonin gene-related peptide, which is present in both the CNS and the thyroid, and elevated levels of T cell and antibody to the leucine-rich repeat-containing G-protein coupled receptor 4 (LGR4), a molecule that is expressed in the brainstem and spinal cord, and which is a homolog of the thyroid-stimulating hormone receptor. We suggest that reactivity of autoreactive immune cells in these patients against antigens present in both the thyroid and the spinal cord is a potential mechanism underlying the pattern of lesion development in the CNS in patients with coexisting AITD and MS and might indicate a novel mechanism of disease pathogenesis in these patients.

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The Role of HLA in MS Susceptibility and Phenotype

Cited by 10 publications

References 161 publications

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

Latitude and HLA-DRB1*04:05 independently influence disease severity in Japanese multiple sclerosis: a cross-sectional study

Could the Heat Shock Proteins 70 Family Members Exacerbate the Immune Response in Multiple Sclerosis? An in Silico Study

Reactivity to Novel Autoantigens in Patients with Coexisting Central Nervous System Demyelinating Disease and Autoimmune Thyroid Disease

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