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

doi:10.1016/j.jaci.2019.11.034

Journal of Allergy and Clinical Immunology

Volume 145, Issue 3, March 2020, Pages 982-992

https://doi.org/10.1016/j.jaci.2019.11.034 Get rights and content

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.

Section snippets

Methods

For full methods, please see the Online Repository (available at www.jacionline.org).

Kmt2d^+/βGeo mice recapitulate clinical immune phenotypes seen in individuals with KS

IgA deficiency, disruption of terminal B-cell function, and splenomegaly have been described in patients with KS type 1.¹¹^,¹⁴ Therefore, we evaluated a mouse model of KS for evidence of immune dysfunction. We report serum IgA deficiency in Kmt2d^+/βGeo mice compared with wild-type littermates at 6.5 months (Fig 1, A). This IgA deficiency was accompanied by a modest elevation of serum IgM in mutant mice. However, we observed no significant differences in serum concentrations of the IgG subtypes

Discussion

Our results provide evidence that KMT2D plays a role in perinatal PP development, postactivation lymphocyte trafficking, and plasmablast terminal differentiation. Importantly, we report human data showing that an individual with KS has severely impaired PP development. Our work builds on prior reports that have shown that conditional deletion in B cells of a single copy of Kmt2d is sufficient to alter cell cycle regulation and enhance germinal center cell proliferation postvaccination.⁵^,⁶

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: 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).

: Disclosure of potential conflict of interest: H.T. Bjornsson and A.W. Lindsley are consultants for Millennium Therapeutics. A. Barski is a cofounder of Datirium, LLC. The rest of the authors declare that they have no relevant conflicts of interest.

^∗: Tareian Cazares is currently at Immunobiology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.

^‡: Joel S. Benjamin is currently at Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, Calif.

^§: Ke Liu is currently at Xencor Inc, Monrovia, Calif.

^‖: Sajjeev Jagannathan is currently at Therapeutic Innovation Center, Baylor College of Medicine, Houston, Tex.

^#: These authors contributed equally to this work.

View full text

Translational and clinical immunologyAbnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome

Background

Objective

Methods

Results

Conclusions

Section snippets

Methods

Kmt2d+/βGeo mice recapitulate clinical immune phenotypes seen in individuals with KS

Discussion

Mol Cell

J Allergy Clin Immunol

Gastroenterology

Dev Biol

Cell

Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome

Am J Med Genet A

Global identification of MLL2-targeted loci reveals MLL2’s role in diverse signaling pathways

Proc Natl Acad Sci U S A

UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells

Cancer Res

Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis

Nat Med

The histone lysine methyltransferase KMT2D sustains a gene expression program that represses B cell lymphoma development

Nat Med

A case of Kabuki make-up syndrome with EBV+Burkitt’s lymphoma

Acta Paediatr Jpn

Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome

Sci Transl Med

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Proc Natl Acad Sci U S A

Precocious chondrocyte differentiation disrupts skeletal growth in Kabuki syndrome mice

JCI Insight

Immunologic assessment and KMT2D mutation detection in Kabuki syndrome

Clin Genet

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

Kmt2d^+/βGeo mice recapitulate clinical immune phenotypes seen in individuals with KS