Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Pilarowski, Genay O.^1,3  Cazares, Tareian^4,11  Zhang, Li³  Benjamin, Joel S.^1,3,12  Liu, Ke^5,13  Jagannathan, Sajjeev^4,14  Mousa, Nadeem⁴  Kasten, Jennifer⁶  Barski, Artem^4,7,8  Lindsley, Andrew W.^4,8  Bjornsson, Hans T.^2,3,9,10 

[1] Johns Hopkins Sch Med, Predoctoral Program Human Genet, Baltimore, MD USA

[2] Johns Hopkins Sch Med, Dept Pediat, Baltimore, MD USA

[3] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Baltimore, MD USA

[4] Cincinnati Childrens Hosp Med Ctr, Div Allergy & Immunol, Cincinnati, OH 45229 USA

[5] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH 45229 USA

[6] Cincinnati Childrens Hosp Med Ctr, Div Pathol, Cincinnati, OH 45229 USA

[7] Cincinnati Childrens Hosp Med Ctr, Div Human Genet, Cincinnati, OH 45229 USA

[8] Univ Cincinnati, Dept Pediat, Coll Med, Cincinnati, OH 45221 USA

[9] Univ Iceland, Fac Med, Reykjavik, Iceland

[10] Landspitali Univ Hosp, Dept Genet & Mol Biol, Reykjavik, Iceland

[11] Cincinnati Childrens Hosp Med Ctr, Immunobiol Grad Program, Cincinnati, OH 45229 USA

[12] Stanford Univ, Dept Neurol & Neurol Sci, Sch Med, Stanford, CA 94305 USA

[13] Xencor Inc, Monrovia, CA USA

[14] Baylor Coll Med, Therapeut Innovat Ctr, Houston, TX 77030 USA

关键词: KMT2D;    hypogammaglobulinemia;    gut lymphocyte homing;    ITGB7;    epigenetics;    B-cell maturation;    B1 B cells;    IgA;   

DOI  :  10.1016/j.jaci.2019.11.034

来源: Elsevier

【 摘 要 】

Background: Kabuki syndrome (KS) is commonly caused by mutations in the histone-modifying enzyme lysine methyltransferase 2D (KMT2D). Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. Objective: We sought to understand the mechanisms driving KS-associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). Methods: We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d(+/beta Geo)) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d(+/beta Geo) mice demonstrated deficiencies in multiple B-cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. The bone marrow, spleen, and intestine of Kmt2d(+/beta Geo) mice contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in the mesenteric lymph node and Peyer patches. Kmt2d(+/beta Geo) mice have decreased size and numbers of Peyer patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Conclusions: Kmt2d haploinsufficiency has broad deleterious effects on B-cell differentiation, specifically hampering gut lymphocyte homing and IgA(+) plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS, and these results provide new mechanistic insights into the pathogenesis of KS-associated immune deficiency.

【 授权许可】

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