Identification and Characterization of Adipose Tissue-Derived Human Antibodies With “Anti-self” Specificity

Abstract

We have previously shown that the human obese adipose tissue (AT) contributes to increased secretion of adipocyte-specific IgG antibodies in individuals with obesity. This occurs without any exogenous stimulation, because the ongoing process of cell death in the obese AT leads to the release of "self" antigens able to induce chronic stimulation of B cells. We have identified several mechanisms responsible for the release of "self" antigens, such as hypoxia, cell cytotoxicity, and DNA damage. In this paper, we confirm and extend our initial observation on a different cohort of individuals, and we show that also the plasma of these individuals is enriched in IgG antibodies with specificities for adipocyte-derived antigens. Adipocyte-specific IgG secreted in the obese AT are significantly correlated with those present in plasma. Using immunoprecipitation and mass spectrometry, we have identified these antigenic specificities. The antigens are almost exclusively intracellular or cell-associated, usually not recognized as "self" antigens, but they are released by cells dying in the AT. We also show for the first time that the adipocytes in the obese AT contribute to the secretion of IgG autoimmune antibodies and this seems to be due to their expression of the antigen-presenting molecules CD1d and, to a much lesser extent, MHC class II, as our mechanistic experiments performed in mice have shown. These results may lead to the development of novel therapeutic strategies to control autoimmunity.

B Cells with a Senescent-Associated Secretory Phenotype Accumulate in the Adipose Tissue of Individuals with Obesity

“…These results altogether suggest that obesity induces B cells characterized by a higher metabolic profile which is needed to support their increased IA and function, including the production of pro-inflammatory mediators that support local and systemic inflammation. The higher metabolic phenotype of B cells from the AT is also associated with increased secretion of IgG antibodies with autoimmune specificity, as we have previously shown [29,30].…”

“…B cells are among the first immune cell types that infiltrate the obese AT in both mice [ 41 , 42 , 43 ] and humans [ 30 ], where they secrete pro-inflammatory mediators, regulate inflammatory T cells and macrophages, and secrete pathogenic IgG antibodies with autoimmune specificities [ 29 , 43 ]. Therefore, depletion of systemic [ 43 ] or AT-derived [ 41 ] B cells, through intra-peritoneal or intra-AT injection with an anti-CD20 depleting monoclonal antibody, has shown to significantly improve metabolic and immunological function of the tissue in mice.…”

Hyper‐metabolic B cells in the spleens of old mice make antibodies with autoimmune specificities

“…Our studies with human B cells have shown that higher intrinsic inflammation in unstimulated B cells from elderly individuals, as compared to B cells from young individuals, is positively associated with the secretion of IgG antibodies with autoimmune specificity [ 16 ]. This occurs because B cells from elderly individuals are already pre-activated, a status leading to spontaneous secretion of autoimmune antibodies, also observed in autoimmune diseases [ 17 ], and in the obese adipose tissue [ 18 , 19 ].…”

“…In this paper we evaluated the metabolic profile of B cells isolated from the spleens of young and old mice, with the aim to identify metabolic pathways associated with intrinsic B cell inflammation and with the secretion of autoimmune antibodies. We focused on the secretion of autoimmune antibodies because our recent human B cell results [ 16 ] have shown that higher intrinsic inflammation in unstimulated B cells from elderly individuals induces a “pre-activation” status associated with the secretion of IgG antibodies with autoimmune specificities, similar to what has been observed in autoimmune diseases [ 17 ], and in the obese adipose tissue at least for some specificities [ 18 , 19 ]. In order to identify the B cell subset(s) driving the phenotype and function of B cells in the splenic B cell pool of old mice, we sorted the major splenic B cell subsets, Follicular (FO) and Age-associated B cells (ABCs).…”

Obesity Accelerates Age Defects in Mouse and Human B Cells

“…More recently, we have shown that the human obese AT contributes to increased secretion of adipocyte-specific IgG antibodies and this occurs without any stimulation, likely because the ongoing process of cell death in the obese AT leads to the release of “self” antigens, that are almost exclusively intracellular or cell-associated, able to chronically stimulate B cells ( 28 ). Adipocyte-specific IgGs secreted in the obese AT are significantly correlated with those present in the plasma ( 79 ).…”