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首页> 外文期刊>The British journal of psychiatry : >Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility
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Nfkb2 variants reveal a p100-degradation threshold that defines autoimmune susceptibility

机译：NFKB2变体显示P100-降级阈值，定义自身免疫敏感性

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摘要

NF-kappa B2/p100 (p100) is an inhibitor of kappa B (I kappa B) protein that is partially degraded to produce the NF-kappa B2/p52 (p52) transcription factor. Heterozygous NFKB2 mutations cause a human syndrome of immunodeficiency and autoimmunity, but whether autoimmunity arises from insufficiency of p52 or I kappa B function of mutated p100 is unclear. Here, we studied mice bearing mutations in the p100 degron, a domain that harbors most of the clinically recognized mutations and is required for signal-dependent p100 degradation. Distinct mutations caused graded increases in p100-degradation resistance. Severe p100-degradation resistance, due to inheritance of one highly degradation-resistant allele or two subclinical alleles, caused thymic medullary hypoplasia and autoimmune disease, whereas the absence of p100 and p52 did not. We inferred a similar mechanism occurs in humans, as the T cell receptor repertoires of affected humans and mice contained a hydrophobic signature of increased self-reactivity. Autoimmunity in autosomal dominant NFKB2 syndrome arises largely from defects in nonhematopoietic cells caused by the I kappa B function of degradation-resistant p100.
机译：NF-κB2/p100（p100）是一种κB（I-κB）蛋白的抑制剂，该蛋白被部分降解以产生NF-κB2/p52（p52）转录因子。杂合子NFKB2突变导致人类免疫缺陷和自身免疫综合征，但自身免疫是否由突变p100的p52或IκB功能不足引起尚不清楚。在这里，我们研究了携带p100基因突变的小鼠，这是一个包含大多数临床公认突变的结构域，是信号依赖性p100降解所必需的。不同的突变导致p100降解抗性的分级增加。由于一个高度降解抗性等位基因或两个亚临床等位基因的遗传，严重的p100降解抗性导致胸腺髓质发育不全和自身免疫性疾病，而p100和p52的缺失则没有。我们推断，在人类中也存在类似的机制，因为受影响的人类和小鼠的T细胞受体序列包含一个疏水性信号，表明自身反应性增强。常染色体显性NFKB2综合征中的自身免疫主要由抗降解p100的IκB功能引起的非造血细胞缺陷引起。

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    Wirasinha Rushika C.; Davies Ainsley R.; Srivastava Monika; Sheridan Julie M.; Sng Xavier Y. X.; Delmonte Ottavia M.; Dobbs Kerry; Loh Khai L.; Miosge Lisa A.; Lee Cindy Eunhee; Chand Rochna; Chan Anna; Yap Jin Yan; Keller Michael D.; Chen Karin; Rossjohn Jamie; La Gruta Nicole L.; Vinuesa Carola G.; Reid Hugh H.; Lionakis Michail S.; Notarangelo Luigi D.; Gray Daniel H. D.; Goodnow Christopher C.; Cook Matthew C.; Daley Stephen R.;

  • 作者单位

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Walter &

    Eliza Hall Inst Med Res Melbourne Vic Australia;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    NIAID Lab Clin Immunol &

    Microbiol Div Intramural Res NIH 9000 Rockville Pike Bethesda MD;

    NIAID Lab Clin Immunol &

    Microbiol Div Intramural Res NIH 9000 Rockville Pike Bethesda MD;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Childrens Natl Med Ctr Div Allergy &

    Immunol Washington DC 20010 USA;

    Univ Utah Dept Pediat Salt Lake City UT USA;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

    NIAID Fungal Pathogenesis Sect Lab Clin Immunol &

    Microbiol NIH 9000 Rockville Pike Bethesda;

    NIAID Lab Clin Immunol &

    Microbiol Div Intramural Res NIH 9000 Rockville Pike Bethesda MD;

    Walter &

    Eliza Hall Inst Med Res Melbourne Vic Australia;

    Univ New South Wales Garvan Inst Med Res Sydney NSW Australia;

    Australian Natl Univ John Curtin Sch Med Res Dept Immunol &

    Infect Dis Canberra ACT Australia;

    Monash Univ Monash Biomed Discovery Inst Infect &

    Immun Program Clayton Vic Australia;

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  • 正文语种 eng
  • 中图分类 精神病学;
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