TY - JOUR
T1 - Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome
AU - Pilarowski, Genay O.
AU - Cazares, Tareian
AU - Zhang, Li
AU - Benjamin, Joel S.
AU - Liu, Ke
AU - Jagannathan, Sajjeev
AU - Mousa, Nadeem
AU - Kasten, Jennifer
AU - Barski, Artem
AU - Lindsley, Andrew W.
AU - Bjornsson, Hans T.
N1 - Funding Information:
Specific funding for this work was provided via a grant to A.W.L. and A.B. from the Center for Pediatric Genomics, Cincinnati Children’s Research Foundation . H.T.B. is funded through an Early Independence Award from the National Institutes of Health ( DP5OD017877 ) and a grant from the Louma G. Foundation. G.P.’s salary is supported by a grant from the Louma G. Foundation. Confocal images ( Fig E7 , A) were taken at the Johns Hopkins Microscope Facility on a Zeiss LSM780-FCS microscope, which was supported by a National Institutes of Health grant ( S10OD016374 ).
Publisher Copyright:
© 2019 American Academy of Allergy, Asthma & Immunology
PY - 2020/3
Y1 - 2020/3
N2 - 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+/βGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d+/βGeo 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+/βGeo 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+/βGeo 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.
AB - 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+/βGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d+/βGeo 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+/βGeo 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+/βGeo 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.
KW - B-cell maturation
KW - B1 B cells
KW - ITGB7
KW - IgA
KW - KMT2D
KW - epigenetics
KW - gut lymphocyte homing
KW - hypogammaglobulinemia
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U2 - 10.1016/j.jaci.2019.11.034
DO - 10.1016/j.jaci.2019.11.034
M3 - Article
C2 - 31816409
AN - SCOPUS:85080842100
VL - 145
SP - 982
EP - 992
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
SN - 0091-6749
IS - 3
ER -