| First Author | Pilarowski GO | Year | 2020 |
| Journal | J Allergy Clin Immunol | Volume | 145 |
| Issue | 3 | Pages | 982-992 |
| PubMed ID | 31816409 | Mgi Jnum | J:297985 |
| Mgi Id | MGI:6479480 | Doi | 10.1016/j.jaci.2019.11.034 |
| Citation | Pilarowski GO, et al. (2020) Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome. J Allergy Clin Immunol 145(3):982-992 |
| abstractText | 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(+/betaGeo)) mouse model and validated select findings in a patient with KS. RESULTS: Compared with wild-type littermates, Kmt2d(+/betaGeo) 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(+/betaGeo) 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(+/betaGeo) 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. |
