MHC Class-II Molecules and Autoimmunity

Nepom, Gerald T.; Erlich, Henry A.

doi:10.1146/annurev.iy.09.040191.002425

Cited by 486 publications

(203 citation statements)

References 60 publications

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“…APS-2 is associated with DQA1*0501, DQB1*0201 (DQ2) [75] and because of linkage disequilibrium (non-random association), with A1, B8 and DR3 [75]. The HLA-association of the APS-2 is also found with individual disorders, such as Addison's disease and type 1A diabetes, when they appear as isolated conditions without evidence of other disorders of the syndrome [76].…”

Section: Mechanisms Of Diabetogenicity Of Hla Moleculesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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Type I (insulin-dependent) diabetes mellitus is a heterogeneous disease with major subdivisions termed Type 1A (immune-mediated) and Type 1B. Immunemediated diabetes is also heterogeneous with ªmono-genicº, oligogenic, and polygenic forms present in humans and in animal models. Single-gene mutations of two transcription factors have been recently identified in rare syndromes of autoimmunity with type 1A diabetes: autoimmune polyendocrine syndrome type 1 (APS-1) and X-linked polyendocrinopathy, immune dysfunction and diarrhoea (XPID). For more common forms of diabetes, susceptibility loci within the major histocompatibility complex and at the insulin locus have been identified. Both DQ* and DR* alleles provide susceptibility and certain alleles dominant protection. In the Diabetes Autoimmunity Study of the Young approximately 50 % of the siblings studied with the highest-risk HLA genotype develop anti-islet autoantibodies by age 3. Insulin could be a crucial autoantigen related to genetic susceptibility. The crystal structure of the high-risk allele, HLA-DQ8, complexed with an insulin peptide has just been reported. Insulin production by macrophage-dendritic cells within the thymus and lymphoid organs could underlie insulin gene polymorphisms influencing the risk of diabetes. Genome-wide scans for linkage in animal models and in humans have not conclusively identified other susceptibility genes though many loci have been implicated. We favour the hypothesis that HLA is a major determinant of susceptibility in animal models and in most families, and that the search for diabetogenes should concentrate on unique families to decrease heterogeneity and favour the eventual discovery of genes influencing risk. [Diabetologia (2002) 45:605±622]

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Section: Mechanisms Of Diabetogenicity Of Hla Moleculesmentioning

confidence: 99%

Genetic control of autoimmunity in Type I diabetes and associated disorders

2002

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“…The major histocompatibility complex (MHC) locus, localized on chromosome 17 in mice, is a region of highly polymorphic genes which encode many different proteins, including the MHC class I and class II molecules, complement, and tumour necrosis factor (TNF) [1]. It has been claimed that the MHC molecules may control immune responses to infectious agents, thus increasing susceptibility to infection [1].…”

Section: Introductionmentioning

confidence: 99%

“…It has been claimed that the MHC molecules may control immune responses to infectious agents, thus increasing susceptibility to infection [1]. However, exactly how this occurs is still unclear.…”

Section: Introductionmentioning

confidence: 99%

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Major Histocompatibility Complex Class II Region Confers Susceptibility to Staphylococcus aureus Arthritis

Abdelnour¹,

Zhao²,

Holmdahl

et al. 1997

Scand J Immunol

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The importance of the MHC class II region for the development of septic arthritis was studied in a murine model of haematogenously induced Staphylococcus aureus arthritis. In the first experiment MHC class II deficient mice (Ab ¹=¹ ) and their heterozygous (Ab þ=¹ ) littermates were intravenously inoculated with a single dose of toxic shock syndrome toxin-1 producing S. aureus LS-1 strain. The results demonstrate that the expression of class II MHC molecules increases the prevalence and severity of arthritis. To analyse the impact of MHC class II haplotypes on the disease onset and progression the authors used congenic C3H.NB, C3H.Q and C3H/HeJ mice in the second set of experiments. The results show that C3H/HeJ mice developed the highest frequency and the most severe course of arthritis compared with C3H.NB and C3H.Q animals. Immunohistochemical analysis of arthritic joints revealed equal number of macrophages, CD4 þ and CD8 þ lymphocytes in the inflamed synovia in all the congenic mice. In contrast, the number of MHC class II expressing cells was higher in the arthritic joints of C3H/HeJ mice compared with the congenic strains (P < 0.001). Furthermore, serum levels of proarthrtitogenic cytokines, such as tumour necrosis factor and interleukin-6 were higher in C3H/HeJ group. This study indicates that MHC class II expression is necessary for the development of S. aureus arthritis in mice and that different MHC class II haplotypes confer varying susceptibility for development of joint inflammation induced by staphylococci. A. Tarkowski,

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“…These glycoproteins consist of an ␣-and a ␤-chain associated as heterodimers on the cell surface of antigen-presenting cells such as B cells and macrophages. They play a central role in the regulation of the immune system 1 in transplantation biology, 2,3 as well as in susceptibility to a number of diseases, including autoimmune disorders 4,5 and certain cancers. 6,7 The HLA-D region contains several class II genes and has three subregions: HLA-DR, -DQ and -DP according to the position of gene.…”

mentioning

confidence: 99%

Simultaneous Genotyping of DRB1/3/4/5 Loci by Oligonucleotide Microarray

Xiaohe²,

Ye³

et al. 2005

The Journal of Molecular Diagnostics

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Matching of the HLA antigens for donor-recipient in transplantation, disease predisposition or protection, population studies, and forensic testing requires accurate but simple typing methods. Here, we describe a DNA-based tissue-typing assay that determines the haplotype of the DRB1/3/4/5 loci in hybridization of oligonucleotide array after sample amplification. Using this multianalyte DNA hybridization system, we analyzed seven regions of exon 2 of DRB loci that have single-base discrimination. Thirtysix oligonucleotide probes complementary to the alleles of interest were immobilized on each microslide. The efficiency and specificity of identifying DRB genotypes using the oligonucleotide arrays was evaluated by blinded analysis of 147 samples from reference standards and subjects. The established method provides a rapid and inexpensive DRB "low-resolution" typing tool for prescreening a large number of samples. (J Mol Diagn 2005, 7:592-599)The human leukocyte antigen (HLA) class II molecules of the human major histocompatibility complex are encoded on the short arm of human chromosome 6p21.3 in the HLA-D region. These glycoproteins consist of an ␣-and a ␤-chain associated as heterodimers on the cell surface of antigen-presenting cells such as B cells and macrophages. They play a central role in the regulation of the immune system 1 in transplantation biology, 2,3 as well as in susceptibility to a number of diseases, including autoimmune disorders 4,5 and certain cancers. 6,7 The HLA-D region contains several class II genes and has three subregions: HLA-DR, -DQ and -DP according to the position of gene. For HLA-DR, one gene coding for the DR ␣-chain, DRA, and one gene coding for ␤-chain, DRB1, is always present. Depending on the DRB1 type, a DRB3, DRB4, or DRB5 may also be present and may be accompanied by pseudogenes. With the exception of the DRA molecule, the genes encoding the functional class II molecules are highly polymorphic with virtually all of the variability localized to the second exon. This exon encodes the amino-terminal extracellular domain, which functions as the antigen binding site for processed peptides.With respect to the multiple functions of the HLA antigens, adequate typing analyses are extremely important. Matching for donor-recipient in transplantation and typing for disease predisposition or protection, for population studies, as well as for paternity or other forensic testing are all applications demanding an accurate but simple typing method. Traditionally, HLA antigens were tested by serological typing. Recent advances in DNA technology have vastly improved the detail to which HLA antigens can be characterized. Several different DNAbased techniques have been developed to improve HLA-class II typing such as polymerase chain reaction (PCR)-restriction fragment length polymorphism, 8 PCR sequence-specific oligonucleotide probe (PCR-SSOP), 9 reverse dot blot hybridization, 10 PCR with sequence specific primers (PCR-SSP), 11,12 oligonucleotide array, 13,14 multiplex primer extension, 15...

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MHC Class-II Molecules and Autoimmunity

Cited by 486 publications

References 60 publications

Genetic control of autoimmunity in Type I diabetes and associated disorders

Genetic control of autoimmunity in Type I diabetes and associated disorders

Major Histocompatibility Complex Class II Region Confers Susceptibility to Staphylococcus aureus Arthritis

Simultaneous Genotyping of DRB1/3/4/5 Loci by Oligonucleotide Microarray

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