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

Abstract

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 1/bGeo) mouse model and validated select findings in a patient with KS. Results: Compared with wild-type littermates, Kmt2d 1/bGeo 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 1/bGeo 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 1/bGeo 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 1 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.

Leveraging the Mendelian Disorders of the Epigenetic Machinery to Systematically Map Functional Epigenetic Variation

“…To verify these predictions at the phenotypic level, we measured serum IgA in the KS1/2 and wild-type mice. In agreement with the collective behavior of IgA-related genes, we found no difference in IgA levels between the KS2 and wildtype, while we recapitulated our previous result of IgA deficiency in KS1 mice 13 (Figure 5e; p = 0.8 for KS2 vs WT, p = 0.0008 for KS1 vs WT).…”

“…We then reasoned that we might gain more insight by focusing on two of the specific phenotypes seen in KS1: abnormal B-cell maturation, and IgA deficiency 13,20 . We set out to test if these are attributable to the collective dysregulation of multiple genes, or to the abnormal expression of a select few.…”

“…First, what biological samples are most appropriate to allow for non-ambiguous interpretation of the results? We propose the use of MDEM mouse models, which have been shown to closely recapitulate many aspects of the human phenotypes 13,16,17 . Importantly, using mice allows us to: a) eliminate multiple confounders such as the environment, genetic background, age, and sex, and b) maintain a consistent sampling of disease-relevant cell types between individuals.…”

“…We performed ELISAs on serum IgA from peripheral blood samples as previously described 13 . Tables Table 1 Figures Figure 1.…”

“…As a result, MDEMs may provide a unique lens into the causal relationship between epigenetic/transcriptomic variation and disease. Indeed, studies of Kabuki syndrome type 1 - one of the most extensively studied MDEMs to date - have begun unraveling the underpinnings of the neural 10 , growth 11 , cardiac 12 , and immune defects 13–15 seen in this disorder.…”