Pathogenic Interleukin-10 Receptor Alpha Variants in Humans - Balancing Natural Selection and Clinical Implications

被引：6

作者：

Aschenbrenner, Dominik ^{[1
,2
]}

Ye, Ziqing ^{[1
,3
]}

Zhou, Ying ^{[1
,3
]}

Hu, Wenhui ^{[3
]}

Brooks, Isabel ^{[1
]}

Williams, Isabelle ^{[1
]}

Capitani, Melania ^{[1
,4
]}

Gartner, Lisa ^{[1
]}

Kotlarz, Daniel ^{[5
,6
]}

Snapper, Scott B. ^{[7
,8
]}

Klein, Christoph ^{[5
,9
,10
,11
]}

Muise, Aleixo M. ^{[12
,13
,14
,15
]}

Marsden, Brian D. ^{[16
,17
]}

Huang, Ying ^{[3
]}

Uhlig, Holm H. ^{[1
,18
,19
]}

机构：

[1] Univ Oxford, John Radcliffe Hosp, Translat Gastroenterol Unit, Expt Med, Oxford OX3 9DU, England

[2] Novartis Pharma AG, Novartis Inst BioMed Res, Basel, Switzerland

[3] Fudan Univ, Natl Childrens Med Ctr, Dept Gastroenterol, Childrens Hosp, 399 Wanyuan Rd, Shanghai 201102, Peoples R China

[4] SenTcell Ltd, London, England

[5] Ludwig Maximilians Univ Munchen, Univ Hosp, Dr von Hauner Childrens Hosp, Dept Pediat, Munich, Germany

[6] Helmholtz Zentrum Munchen, Inst Translat Genom, German Res Ctr Environm Hlth, Neuherberg, Germany

[7] Boston Childrens Hosp, Boston, MA 02115 USA

[8] Harvard Med Sch, Boston, MA 02115 USA

[9] Ludwig Maximilians Univ Munchen, Gene Ctr, Munich, Germany

[10] Deutsch Zentrum Infekt Forsch DZI, Munich, Germany

[11] Deutsch Zentrum Kinder & Jugendgesundheit, Partner Site Munich, Munich, Germany

[12] Hosp Sick Children, SickKids Inflammatory Bowel Dis Ctr, Res Inst, Toronto, ON, Canada

[13] Hosp Sick Children, Cell Biol Program, Res Inst, Toronto, ON, Canada

[14] Dept Pediat, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[15] Univ Toronto, Hosp Sick Children, Toronto, ON, Canada

[16] Univ Oxford, Ctr Med Discovery, NDM, Oxford OX3 7DQ, England

[17] Univ Oxford, Kennedy Inst Rheumatol, NDORMS, Oxford OX3 7FY, England

[18] Univ Oxford, Dept Pediat, Oxford, England

[19] Univ Oxford, Biomed Res Ctr, Oxford, England

来源：

JOURNAL OF CLINICAL IMMUNOLOGY | 2023年 / 43卷 / 02期

关键词：

IL-10; IL10RA; natural selection; inflammatory bowel disease; INFLAMMATORY-BOWEL-DISEASE; CRYSTAL-STRUCTURE; LEISHMANIA-MAJOR; COMMON VARIANTS; SEVERE FEVER; IFN-GAMMA; CELLS; SUSCEPTIBILITY; INFECTION; IBD;

D O I：

10.1007/s10875-022-01366-7

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA. Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling.

引用

页码：495 / 511

页数：17

共 78 条

[11] Characteristics of Schistosoma japonicum infection induced IFN-γ and IL-4 co-expressing plasticity Th cells [J].