Front Immunol 10: 2484

PMC: PMC6820504

Gut Antibody Deficiency in a Mouse Model of CVID Results in Spontaneous Development of a Gluten-Sensitive Enteropathy

Gregorio Gomez+7 authors

Supplementary Table 1

List of antibodies used.

Click here for additional data file.^{(32K, pdf)}

Supplementary Table 2

Differentially enriched fecal OTUs.

Click here for additional data file.^{(17K, xlsx)}

Supplementary Table 3

DE Ileal OTUs.

Click here for additional data file.^{(11K, xlsx)}

Supplementary Table 4

Differentially enriched ileal transcripts.

Click here for additional data file.^{(23K, xlsx)}

Supplementary Table 5

Differentially enriched OTUs in metronidazole-treated mice.

Click here for additional data file.^{(18K, xlsx)}

Click here for additional data file.^{(8.3M, pdf)}

^{Department of Pathology, Microbiology, and Immunology, University of South Carolina School of Medicine, Columbia, SC, United States}

^{School of Veterinary Medicine, University of Baghdad, Baghdad, Iraq}

^{Biology Department, University of Texas at Arlington, Arlington, TX, United States}

^{Department of Biomedical Sciences, College of Medicine, University of Houston, Houston, TX, United States}

^{College of Nursing and Health Innovation, University of Texas at Arlington, Arlington, TX, United States}

Edited by: Cecil Czerkinsky, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by: Karol Sestak, PreCliniTria, LLC., United States; Katri Lindfors, University of Tampere, Finland; Natalia Shulzhenko, Oregon State University, United States

*Correspondence: Jason L. Kubinak ude.cs.demcsu@kanibuK.nosaJ

This article was submitted to Mucosal Immunity, a section of the journal Frontiers in Immunology

Edited by: Cecil Czerkinsky, Institut National de la Santé et de la Recherche Médicale (INSERM), France

Reviewed by: Karol Sestak, PreCliniTria, LLC., United States; Katri Lindfors, University of Tampere, Finland; Natalia Shulzhenko, Oregon State University, United States

Received 2019 May 28; Accepted 2019 Oct 4.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

Primary immunodeficiencies are heritable disorders of immune function. CD19 is a B cell co-receptor important for B cell development, and CD19 deficiency is a known genetic risk factor for a rare form of primary immunodeficiency known as “common variable immunodeficiency” (CVID); an antibody deficiency resulting in low levels of serum IgG and IgA. Enteropathies are commonly observed in CVID patients but the underlying reason for this is undefined. Here, we utilize CD19^{mice as a model of CVID to test the hypothesis that antibody deficiency negatively impacts gut physiology under steady-state conditions. As anticipated, immune phenotyping experiments demonstrate that CD19}^{mice develop a severe B cell deficiency in gut-associated lymphoid tissues that result in significant reductions to antibody concentrations in the gut lumen. Antibody deficiency was associated with defective anti-commensal IgA responses and the outgrowth of anaerobic bacteria in the gut. Expansion of anaerobic bacteria coincides with the development of a chronic inflammatory condition in the gut of CD19}^{mice that results in an intestinal malabsorption characterized by defects in lipid metabolism and transport. Administration of the antibiotic metronidazole to target anaerobic members of the microbiota rescues mice from disease indicating that intestinal malabsorption is a microbiota-dependent phenomenon. Finally, intestinal malabsorption in CD19}^{mice is a gluten-sensitive enteropathy as exposure to a gluten-free diet also significantly reduces disease severity in CD19}^{mice. Collectively, these results support an effect of antibody deficiency on steady-state gut physiology that compliment emerging data from human studies linking IgA deficiency with non-infectious complications associated with CVID. They also demonstrate that CD19}^{mice are a useful model for studying the role of B cell deficiency and gut dysbiosis on gluten-sensitive enteropathies; a rapidly emerging group of diseases in humans with an unknown etiology.}

Keywords: CVID, primary immunodeficiency, dysbiosis, CVID enteropathy, gluten sensitivity

Abstract

Acknowledgments

We would like to thank Dr. June L. Round for her useful comments during manuscript preparation.

Acknowledgments

Footnotes

Funding. JK was supported by a NIAID K22 Award, NIH grant R21AI142409, NIH grant P20GM103641 (awarded to Prakash and Mitzi Nagarkatti), a Jeffrey Modell Foundation Specific Diseases Research Award, and a University of South Carolina ASPIRE-I Award. ADM was supported by the Iraqi Government through participation in the MOHESR Program. CO was supported by NIH/NIAMS R21AR067996.

Footnotes

Click here for additional data file.^{(32K, pdf)}Click here for additional data file.^{(17K, xlsx)}Click here for additional data file.^{(11K, xlsx)}Click here for additional data file.^{(23K, xlsx)}Click here for additional data file.^{(18K, xlsx)}Click here for additional data file.^{(8.3M, pdf)}

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