Autoimmune Diseases: Molecular Pathogenesis and Therapeutic Targets

Abstract

Autoimmune diseases are a set of disorders in which the immune system attacks one's own tissues, leading to chronic inflammation, tissue damage, and systemic dysfunction. Affecting approximately 10% of the global population, these diseases impose significant health and economic burdens worldwide. The pathogenesis of autoimmune diseases is complex, involving not only genetic predisposition (e.g., human leukocyte antigen variants), environmental triggers (e.g., infections), and a dysregulated immune response but also various interacting components that contribute to the development of diverse clinical phenotypes. This review provides a comprehensive overview of common autoimmune diseases, covering their clinical manifestations, pathogenic mechanisms, and diagnostic approaches such as disease-specific autoantibodies. We also explore current therapeutic strategies, including commonly used broad-spectrum anti-inflammatory drugs, recent molecular-targeted therapies (e.g., Janus kinase inhibitors, monoclonal antibodies), and emerging cellular therapies such as chimeric antigen receptor T cells therapy and regulatory T-cell adoptive transfer. Incorporating knowledge from preclinical and clinical studies, this review synthesizes relevant information to inform about autoimmune diseases, bridge the gap from lab to clinic, and promote future advances through exploring precision medicine applications to meet clinical needs.

Keywords: autoimmune diseases; immune tolerance; pathogenesis; therapeutic strategies.

FIGURE 1

Common autoimmune diseases classified according to anatomical site. Abbreviations: AA, alopecia areata; AIG, autoimmune gastritis; AIH, autoimmune hepatitis; AIHA, autoimmune hemolytic anemia; AITD, autoimmune thyroid disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; SSc, systemic sclerosis; T1D, type 1 diabetes; IBD, inflammatory bowel disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; MS, multiple sclerosis; MG, myasthenia gravis.

FIGURE 2

Components of the immune system. The immune system comprises immune organs (central: bone marrow, thymus; peripheral: lymph nodes, spleen, mucosa‐associated lymphoid tissue), immune cells (innate: phagocytes, NK cells; adaptive: T and B lymphocytes), and immune molecules (antibodies, complement system, cytokines). These components collectively mediate immune defense, surveillance, and homeostasis. Dysregulation in any component can contribute to the pathogenesis of autoimmune disease.

FIGURE 3

The mechanism of T‐cell tolerance. Central tolerance is established in the thymus. Bone marrow‐derived progenitor cells mature into DP thymocytes within the thymic cortex, where thymic cortical epithelial cells (cTECs) regulate the positive selection of DP thymocytes. Following positive selection, single‐positive (SP) thymocytes migrate to the thymic medulla. There, they undergo further screening based on their affinity for self‐peptides presented by medullary thymic epithelial cells (mTECs). SP thymocytes exhibiting low affinity for self‐antigens are permitted to egress into the peripheral circulation or lymphoid tissues. Those with intermediate affinity may differentiate into regulatory T (Treg) cells, while the remains displaying high affinity for self‐peptides are eliminated via apoptosis. Impairment of negative selection in the thymic medulla can lead to the escape of autoreactive T‐cell clones into the periphery. The activation of autoreactive T cells and excessive T‐cell‐mediated immune response are limited by the FasL interaction. Treg cells exert immunosuppressive effects through multiple mechanisms, including the secretion of inhibitory cytokines (IL‐10, TGF‐β), cytotoxic molecules (granzyme B, perforin), and adenosine (ADO), as well as the expression of immune checkpoint molecules such as cytotoxic T lymphocyte associated protein‐4 (CTLA‐4) and the high‐affinity interleukin‐2 receptor α‐chain (CD25).

FIGURE 4

The development of autoimmunity. Under pathogenic conditions, healthy tissues expose self‐antigens to antigen‐presenting cells (APCs), leading to their activation and subsequent recruitment of T cells to specific sites. Following T‐cell migration, APCs capture, process, and present self‐antigens to T cells. On antigen recognition, T cells initiate the expression of key transcription factors induced by various cytokines, driving their differentiation into distinct subsets, including CD4+ T‐helper 1 (Th1) cells, Th2 cells, Th17 cells, T‐follicular helper (Tfh) cells, and CD8+ cytotoxic T lymphocytes (CTLs). These differentiated T cells secrete a broad array of cytokines, generating a cytokine storm that exacerbates tissue damage through a positive feedback loop. Autoantibody production is mediated by the interaction between CD4+ T‐helper cells and B cells. Once autoantibodies bind to target tissues, they induce multiorgan failure via multiple effector mechanisms, including antibody‐dependent cell‐mediated cytotoxicity (ADCC), antibody‐dependent cellular phagocytosis, and complement‐dependent cytotoxicity.

FIGURE 5

Therapeutic strategies for autoimmune diseases. Current treatments include broad‐spectrum anti‐inflammatory drugs (such as nonsteroidal anti‐inflammatory drugs and glucocorticoids), molecular‐targeted therapies (such as JAK inhibitors and anti‐TNF biologics), and emerging cell‐targeted approaches (such as CAR‐T therapy and Treg transfer). These strategies range from nonspecific immunosuppression to precise immune modulation, with newer therapies aiming to restore immune tolerance while minimizing side effects. The figure illustrates key drug classes, their molecular targets, and clinical applications across different autoimmune disorders.