The role of autoantibodies in bridging obesity, aging, and immunosenescence

Abstract

Antibodies are essential to immune homeostasis due to their roles in neutralizing pathogenic agents. However, failures in central and peripheral checkpoints that eliminate autoreactive B cells can undermine self-tolerance and generate autoantibodies that mistakenly target self-antigens, leading to inflammation and autoimmune diseases. While autoantibodies are well-studied in autoimmune and in some communicable diseases, their roles in chronic conditions, such as obesity and aging, are less understood. Obesity and aging share similar aspects of immune dysfunction, such as diminished humoral responses and heightened chronic inflammation, which can disrupt immune tolerance and foster autoantigen production, thus giving rise to autoreactive B cells and autoantibodies. In return, these events may also contribute to the pathophysiology of obesity and aging, to the associated autoimmune disorders linked to these conditions, and to the development of immunosenescence, an age-related decline in immune function that heightens vulnerability to infections, chronic diseases, and loss of self-tolerance. Furthermore, the cumulative exposure to antigens and cellular debris during obesity and aging perpetuates pro-inflammatory pathways, linking immunosenescence with other aging hallmarks, such as proteostasis loss and mitochondrial dysfunction. This review examines the mechanisms driving autoantibody generation during obesity and aging and discusses key putative antigenic targets across these conditions. We also explore the therapeutic potential of emerging approaches, such as CAR-T/CAAR-T therapies, vaccines, and BiTEs, to tackle autoimmune-related conditions in aging and obesity.

Keywords: Aging; Autoantibodies; Chronic inflammation; Immunosenescence; Obesity.

Fig. 1

Aging- and obesity-related risk factors contributing to the generation of autoreactive B cells and autoantibodies. A) Autoreactive B cells can be generated throughout the B cell development, from hematopoietic stem cells in the BM to various mature, differentiated B cells. In the BM, central tolerance mechanisms, including receptor editing, clonal deletion, and anergy, reduce the autoreactivity of immature B cells, which resulted mostly from the random V(D)J recombination. In the spleen (shown here) and lymph nodes, clonal deletion or anergy remove transitional B cells (spleen) or naïve B cells that strongly bind self-antigens and B cells lacking the costimulatory signals from CD4 + T_H cells or CD4 + T_FH cells. However, obesity- and aging-related risk factors, including several hallmarks of aging, promote the release of autoantigens and compromise the self-tolerance, facilitating the generation of autoreactive B cells and augmenting the function of existing autoreactive B cells. B) In various tissues and organs, including the gastrointestinal tract and kidneys, ectopic lymphoid structures, such as TLS, can potentially provide a niche for autoreactive B cells, facilitating their ability to promote local and systemic inflammation. The resulting pro-inflammatory factors and autoantibodies drive tissue damage in multiple organs, further fueling the ongoing inflammation and systemic diseases. ANCA = anti-neutrophil cytoplasm antibody; Abeta = amyloid beta; ASCA = anti-Saccharomyces cerevisiae antibodies; BCR = B cell receptor; BTK = Bruton tyrosine kinase; COL1A1 = collagen 1 A; CSR = class switch recombination; DMD = Dystrophin; FN1 = fibronectin; FYN = tyrosine-protein kinase Fyn; GC = germinal center; GRP78 = Glucose regulated protein 78; GP2 = Glycoprotein 2; HSP60 = Heat shock protein 60; MyHC = Myosin Heavy Chain; OmpC = outer membrane porin C; PLIN1 = Perilipin 1; SASP = senescence-associated secretory phenotype; SC5D = Sterol-C5-desaturase; SHM = somatic hypermutation; TLS = tertiary lymphoid structures; USP4 = Ubiquitin specific protease 4

Fig. 2

Potential therapies targeting autoimmune components during aging and obesity. With next-generation autoAb detection methods, such as PhiP-Seq, antigen arrays, and REAP, playing a central role in providing a more detailed atlas of autoAbs, therapies traditionally used for autoimmune diseases can be repurposed to conquer the autoAbs and autoantigens generated during obesity and aging. T cell-based therapies targeting autoreactive B cells, antibody-based therapies targeting pro-inflammatory factors, and tolerance-inducing vaccines based on anti-idiotypic antibodies and antigen-encoding mRNA vaccines, are emerging techniques that are gaining increasing research focus. PhiP-Seq = phage immunoprecipitation sequencing; REAP = rapid extracellular antigen profiling; CAR-T = Chimeric antigen receptor T cells; CAAR-T = Chimeric autoantibody receptor T cells; BiTEs = Bispecific T cell engagers; SAAs = senescence-associated antigens

Fig. 3

A vicious cycle of immune dysregulation during obesity and aging mediated by autoantibodies. During obesity and aging, the generation of autoantibodies depends on various interconnecting mechanisms, including ones that directly contribute to alteration in B cell functions and antibody structures, as well as several hallmarks of aging that promote the formation of autoantigens. The autoantibodies then play a critical role in fueling chronic inflammation that eventually contributes to immunosenescence, which continues to drive age-related diseases and metabolic syndromes. While obesity-related autoantibodies can contribute to metabolic syndromes, and age-related autoantibodies can contribute to age-related diseases (denoted as solid arrows), metabolic syndromes and age-related diseases can potentially create niches for the generation of age-related and obesity-related autoantibodies, respectively (denoted as dashed arrows). As a result, a vicious cycle between metabolic syndromes and age-related diseases forms and can exacerbate each other when driven by immunosenescence and chronic inflammation associated with autoantibodies. AGE = Advanced glycation end product; DAMPs = Danger-associated molecular patterns; PAMPs = Pathogen-associated molecular patterns; HFD = High-fat diet; SHM = Somatic hypermutation