Abnormal Peyer patch development and B-cell gut homing drive IgA deficiency in Kabuki syndrome.
J Allergy Clin Immunol
; 145(3): 982-992, 2020 03.
Article
in En
| MEDLINE
| ID: mdl-31816409
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+/ßGeo) mouse model and validated select findings in a patient with KS.RESULTS:
Compared with wild-type littermates, Kmt2d+/ßGeo 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+/ßGeo 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+/ßGeo 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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Peyer's Patches
/
Abnormalities, Multiple
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B-Lymphocytes
/
Vestibular Diseases
/
Face
/
Hematologic Diseases
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
J Allergy Clin Immunol
Year:
2020
Type:
Article
Affiliation country:
Moldova