HLA-DQ is epistatic to HLA-DR in controlling the immune response to schistosomal antigen in humans

Hirayama, Kenji; Matsushita, Sho; Kikuchi, Ikuo; Iuchi, Masahiko; Ohta, Nobuo; Sasazuki, Takehiko

doi:10.1038/327426a0

Cited by 204 publications

(83 citation statements)

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“…It is interesting to note that monoclonal antibody directed against HLA-DQ also restored the immune response to Sj in vitro in nonresponders with HLA-DR2-DQw6-Dwl2 haplotype (Hirayama et al, 1987) (Fig. 4).…”

Section: Evidence For the Active Suppression And Epistatic Interactiomentioning

confidence: 89%

“…Actually there is no doubt that HLA-DR molecules are acting as the products of HLA-linked Ir-genes, because (1) HLA-DR molecules are the restriction elements in the interaction between CD4+ helper T cells and antigen presenting cells in the response to many antigens such as streptococcal cell wall antigen (SCW) Sone et aI., 1985;Hirayama et al, 1986), schistosomal antigen (Sj) (Hirayama et aL, 1987), Myeobacterium leprae antigen (ML) (Kikuchi et al, 1986) and so on, and (2) anti-HLA-DR monoclonal antibodies completely abolish the immune response to those antigens Sone et al, 1985;Hirayama et al, 1986;Kikuchi et al, 1986;Hirayama et al, 1987). However, genetic analysis of the immune response to those antigens in families or populations revealed that responsiveness is recessive and nonresponsiveness to those antigens is a dominant genetic trait which is tightly linked to HLA (Sasazuki et aI., 1980a;Sasazuki et al, 1983;Watanabe et al, 1988).…”

Section: Introductionmentioning

confidence: 99%

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HLA-linkedImmune suppression genes

Sasazuki

1990

Jap J Human Genet

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SummaryGenetic control of immune response was investigated by family and population analyses in humans. It was first recognized that there are high responders and low or non responders to natural antigens in human population. Family analysis revealed that low responsiveness to streptococcal cell wall antigen (SCW) was inherited as an HLA-linked dominant trait. CD8 + suppressor T ceils existed in low responders and depletion of the CD8 + T ceils from low responders could restore the strong immune response to SCW. Therefore the gene controlling the low response to SCW was designated as an immune suppression gene for SCW.Immune suppression gene for SCW was in strong linkage disequilibrium with particular alleles of HLA-DQ locus. The association between HLA-DQ alleles and low responsiveness mediated by CD8 + suppressor T cell was also observed for schistosomal antigen, Myeobacterium leprae antigen, tetanus toxoid, cryptomeria pollen antigen and hepatitis B virus surface antigen suggesting that low responsiveness to those antigens was also controlled by immune suppression genes. Anti-HLA-DR monoclonal antibodies inhibited the immune response to those antigens of high responders in vitro, but anti-HLA-DQ monoclonal antibodies did not. On the other hand, anti-HLA-DQ monoclonal antibodies restored the immune response in low responders. Therefore, it is suggested that HLA-DR upregulates immune response and that HLA-DQ downregulates it and that HLA-DQ is epistatic to HLA-DR in the regulation of immune response in humans. Furthermore, direct evidence for the differential in immune regulation between HLA-DR and DQ was obtained by analyzing the SCW specific T cell lines from low responders. SCW specific and HLA-DQ restricted CD4+ T cell lines could activate CD8 + suppressor T cells which in turn downregulate SCW specific CD4+ T cells whereas SCW specific and HLA-DR restricted CD4 + T cell lines could not activate CD8 + suppressor T cells. All these observation clearly demonstrated that the HLA-linked

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Section: Evidence For the Active Suppression And Epistatic Interactiomentioning

confidence: 89%

Section: Introductionmentioning

confidence: 99%

HLA-linkedImmune suppression genes

Sasazuki

1990

Jap J Human Genet

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“…However, their expression on antigen-presenting cells can be induced by interferon 7 [14], and infectious agents such as the Epstein-Barr virus [15]. It has been postulated that DQ molecules exercise epistatic action over DR molecules [16] and that they are the mediators of immunosuppression [17].…”

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confidence: 99%

Polymorphic structural features of modelled HLA-DQ molecules segregate according to susceptibility or resistance to IDDM

Routsias

Papadopoulos

1995

Diabetologia

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SummaryThe structural features of HLA-DQ alleles which are susceptible and resistant to insulin-dependent diabetes mellitus (IDDM) have been examined using a model of their three-dimensional structure obtained by energy minimisation, based on the published structure of HLA-DR1. The model shows DQ molecules to have an overall shape nearly identical to that of DR molecules, but with significant differences in the fine structure: 1) the antigen-binding groove of DQ molecules has a polymorphic first pocket; this pocket can be either amphiphilic or hydrophilic, 2) The [349-56 dimerisation domain of DQ is polymorphic: hydrophobic, or amphiphilic, or hydrophilic and positively charged, leading to spontaneous or T-cell receptor-induced homodimer formation, or difficulty of the formation of such dimers, respectively; 3) a prominent Arg-Gly-Asp loop is formed by some DQ alleles ([3167-169) and probably functions in cell adhesion. There are also small differences in the residues and sequences implicated in CD4 binding but the significance of these differences cannot be evaluated at present. All seven DQ alleles which confer susceptibility to IDDM posses a hydrophilic first pocket in the antigen-binding groove, a hydrophobic or amphiphilic [349-56 dimerisation patch that allows for spontaneous or T-cell receptor-induced dimerisation, and the Arg-Gly-Asp loop. By contrast, in the protective alleles at least one of these three features is absent. This segregation of phenotypes according to susceptibility or resistance can well explain the model of tighter autoantigen binding by the protective alleles compared to the susceptible alleles, previously proposed for the pathogenesis of IDDM. [Diabetologia (1995[Diabetologia ( ) 38: 1251[Diabetologia ( -1261

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“…The HLA plays an important role in controlling the immune system and is known to be associated with various diseases such as auto-immune diseases (Todd et al, 1988;Sasazuki et al, 1983), infectious diseases (Hirayama et al, 1987;Nishimura and Sasazuki, 1987) and virus-associated tumors (Burt et al, 1994).…”

Section: Discussionmentioning

confidence: 99%