Secretion of autoimmune antibodies in the human subcutaneous adipose tissue.

Daniela Frasca,Bonnie B Blomberg,Maria Romero,Alain Diaz,Seth Thaller,Calogero Caruso

doi:10.1371/journal.pone.0197472

Daniela Frasca, Bonnie B Blomberg + Show 4 more

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https://doi.org/10.1371/journal.pone.0197472

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Abstract

The adipose tissue (AT) contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies. In this study we show that adipocytes in the human obese subcutaneous AT (SAT) secrete several pro-inflammatory cytokines and chemokines, which contribute to the establishment and maintenance of local and systemic inflammation, and consequent suboptimal immune responses in obese individuals, as we have previously shown. We also show that pro-inflammatory chemokines recruit immune cells expressing the corresponding receptors to the SAT, where they also contribute to local and systemic inflammation, secreting additional pro-inflammatory mediators. Moreover, we show that the SAT generates autoimmune antibodies. During the development of obesity, reduced oxygen and consequent hypoxia and cell death lead to further release of pro-inflammatory cytokines, “self” protein antigens, cell-free DNA and lipids. All these stimulate class switch and the production of autoimmune IgG antibodies which have been described to be pathogenic. In addition to hypoxia, we have measured cell cytotoxicity and DNA damage mechanisms, which may also contribute to the release of “self” antigens in the SAT. All these processes are significantly elevated in the SAT as compared to the blood. We definitively found that fat-specific IgG antibodies are secreted by B cells in the SAT and that B cells express mRNA for the transcription factor T-bet and the membrane marker CD11c, both involved in the production of autoimmune IgG antibodies. Finally, the SAT also expresses RNA for cytokines known to promote Germinal Center formation, isotype class switch, and plasma cell differentiation. Our results show novel mechanisms for the generation of autoimmune antibody responses in the human SAT and allow the identification of new pathways to possibly manipulate in order to reduce systemic inflammation and autoantibody production in obese individuals.

Highlights

The increase in the frequency of obesity is a worldwide phenomenon associated with several chronic diseases
We have evaluated several mechanisms which may be responsible for the release of “self” antigens, which stimulate class switch and the production of autoimmune IgG antibodies
Because we detected Germinal Center (GC) B cells in the subcutaneous AT (SAT), and we detected the presence of cytokines promoting isotype class switch in the SAT, we evaluated if the adipocyte-conditioned medium (ACM) was able to induce mRNA expression of activationinduced cytidine deaminase (AID), the enzyme of CSR and SHM, and BLIMP-1, the transcription factor involved in plasma cell differentiation [57]

Summary

Introduction

The increase in the frequency of obesity is a worldwide phenomenon associated with several chronic diseases. It is known that aging induces a significant increase in adipose tissue (AT) mass and redistribution of body fat with increased Visceral Adipose Tissue (VAT) and ectopic VAT deposition [11, 12] These are all strongly associated with poorer health conditions in elderly individuals, including the development of Insulin Resistance (IR) which increases with age, as reviewed in [13]. Our prior studies in mice have shown that the VAT, which increases in size with aging, contributes to systemic and B cell intrinsic inflammation, reduced B cell responses and secretion of autoimmune antibodies. Conversion of the AT from an insulin sensitive (IS) to an IR state during obesity involves expansion of adipocyte volume and remodeling of extracellular matrix components (collagens, elastins and the associated blood vasculature) This involves a concomitant increase in the secretion of adipokines, pro-inflammatory cytokines and chemokines, which are involved in the recruitment of immune cells to the AT. We have measured the expression of transcription factors and membrane markers (T-bet and CD11c) responsible for the production of these antibodies in the SAT, as well as the release of cytokines known to promote isotype class switch

Study participants

Results and discussion

Conclusions