Valentino Taylor R, Chen Nan, Makhijani Priya, Khan Saad, Winer Shawn, Revelo Xavier S, Winer Daniel A
Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA.
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A8, Canada.
Immun Ageing. 2024 Nov 30;21(1):85. doi: 10.1186/s12979-024-00489-2.
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.
抗体在中和病原体方面发挥着作用，对免疫稳态至关重要。然而，消除自身反应性B细胞的中枢和外周检查点出现故障会破坏自身耐受性，并产生错误靶向自身抗原的自身抗体，从而导致炎症和自身免疫性疾病。虽然自身抗体在自身免疫性疾病和一些传染病中已得到充分研究，但其在肥胖和衰老等慢性疾病中的作用仍知之甚少。肥胖和衰老具有相似的免疫功能障碍特征，如体液反应减弱和慢性炎症加剧，这会破坏免疫耐受性并促进自身抗原产生，进而产生自身反应性B细胞和自身抗体。反过来，这些事件也可能导致肥胖和衰老的病理生理学变化、与这些病症相关的自身免疫性疾病，以及免疫衰老的发展，免疫衰老是一种与年龄相关的免疫功能下降，会增加对感染、慢性疾病和自身耐受性丧失的易感性。此外，肥胖和衰老过程中对抗原和细胞碎片的累积暴露会使促炎途径持续存在，将免疫衰老与其他衰老特征联系起来，如蛋白质稳态丧失和线粒体功能障碍。本综述探讨了肥胖和衰老过程中驱动自身抗体产生的机制，并讨论了这些情况下关键的假定抗原靶点。我们还探讨了新兴方法的治疗潜力，如CAR-T/CAAR-T疗法、疫苗和双特异性T细胞衔接器（BiTE），以应对衰老和肥胖中与自身免疫相关的病症。
