Translational and clinical immunologyAbnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome
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
In
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2024, Journal of Affective DisordersKrüppel-like factor 2 controls IgA plasma cell compartmentalization and IgA responses
2022, Mucosal ImmunologyCitation Excerpt :The downregulation of Itgβ7 is implicated in diseases such as the Kabuki syndrome, which is caused by mutations in the gene for the histone-lysine N-methyltransferase KMT2D57–59. In a haplo-insufficient KMT2D+/βGEO mouse model, reduced Itgβ7 expression resulted in abnormal PP size and numbers as well as impaired B and IgA+ PC populations, a phenotype similar to our B cell-specific KLF2 cKO mouse5,6,60. Both, the KMT2D+/GEO and KLF2 cKO mouse models exhibit a dysregulation of Itgβ7 resulting in IgA deficiency.
What can clinical immunology learn from inborn errors of epigenetic regulators?
2021, Journal of Allergy and Clinical ImmunologyCitation Excerpt :Some studies have explored the immune status and function in patients with KS. In the literature, there are around 48 case reports and 5 cohort studies, and the largest included 177 patients.51-54,57,142-144 Immunologic findings may actually be similar to those seen in individuals with CVID.52,145
Inhibition of KDM1A activity restores adult neurogenesis and improves hippocampal memory in a mouse model of Kabuki syndrome
2021, Molecular Therapy Methods and Clinical DevelopmentCitation Excerpt :We hypothesize that it may be possible to restore this balance with drugs that promote open chromatin states.8 Our laboratory characterized a mouse model of KS1 (Kmt2d+/βGeo) and found that these mice have many features that overlap with KS patient phenotypes, including craniofacial abnormalities, growth retardation, and immune dysregulation.9–11 These mice also demonstrate an ongoing deficiency of adult neurogenesis in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus and hippocampal memory defects.
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.
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Tareian Cazares is currently at Immunobiology Graduate Program, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio.
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Joel S. Benjamin is currently at Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, Calif.
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Ke Liu is currently at Xencor Inc, Monrovia, Calif.
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Sajjeev Jagannathan is currently at Therapeutic Innovation Center, Baylor College of Medicine, Houston, Tex.
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These authors contributed equally to this work.