Summary:
Autoimmune diseases are chronic immune-mediated disorders in which the immune system mistakenly targets itself, leading to inflammation and tissue damage. They affect approximately 7-10% of the global population and include conditions such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and multiple sclerosis. These conditions share common biological features involving immune dysregulation and loss of tolerance to self-antigens. This study is a review that synthesises current evidence on the pathogenesis of autoimmune diseases, focusing on how genetic susceptibility, environmental exposures, and immune system dysfunction interact to drive disease development. The paper discusses that genetic risk for autoimmune diseases come from multiple genes rather than a single gene. Large genetic studies have found hundreds of small DNA variations that can slightly increase a person’s risk. Importantly, having genetic risk alone is usually not enough to cause disease, which means other factors are implicated. Environmental factors play a major role in triggering disease in people who are genetically susceptible. These include infections, diet, gut bacteria, hormones, and exposure to certain chemicals. For example, viruses like Epstein-Barr virus have been linked to lupus and rheumatoid arthritis because they can activate the immune system in ways that may accidentally trigger auto-immunity. Diet, metabolism, and changes in gut bacteria can also influence inflammation and immune balance. Early-life nutrition may also affect the risk of developing autoimmune disease later in life. The immune system is also implicated, as a key group of cells called regulatory T cells (Tregs) normally prevent the immune system from attacking itself. When these cells don’t work properly, autoimmune disease can develop. Recent research suggests that the problem is often not that there are fewer Tregs, but that they don’t function as intended. Overall, the study concludes that autoimmune diseases develop from a combination of genetic susceptibility, environmental triggers, and failure of immune regulation. A major focus is the dysfunction of T cells, and the authors suggest that future treatments should aim to restore normal immune tolerance rather than simply suppressing the immune system.
Abstract:
Autoimmune diseases are a diverse group of chronic disorders characterized by inappropriate immune responses against self-antigens, resulting in persistent inflammation and tissue destruction. Affecting an estimated 7–10% of the global population, these conditions include both systemic and organ-specific entities such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), type 1 diabetes (T1D), and multiple sclerosis (MS). Despite their clinical heterogeneity, autoimmune diseases share a common etiologic framework involving the convergence of genetic predisposition, environmental exposures, and immune dysregulation. Genome-wide association studies (GWAS) have identified hundreds of risk loci, most notably within the major histocompatibility complex (MHC), and highlighted the role of non-HLA genes regulating cytokine signaling, antigen presentation, and T cell tolerance. The majority of disease-associated variants lie in non-coding regulatory elements, suggesting that transcriptional dysregulation plays a central role in disease susceptibility. Yet, genetics alone does not determine disease onset—environmental factors such as infections, diet, microbiome alterations, and hormonal influences critically shape immune responses and may trigger disease in genetically susceptible individuals. Additionally, epigenetic modifications further compound these effects, creating lasting changes in gene expression and immune cell function. At the core of autoimmune pathogenesis lies immune dysregulation, particularly failure of peripheral tolerance maintained by regulatory T cells (Tregs). While Treg frequencies may appear normal in patients, emerging data indicate intrinsic signaling defects—especially impaired IL-2 receptor (IL-2R) signal durability—compromise Treg suppressive function. This dysfunction is linked to aberrant degradation of key IL-2R second messengers, including phosphorylated JAK1 and DEPTOR, due to diminished expression of GRAIL, an E3 ligase that inhibits cullin RING ligase activation. This review integrates recent insights across genetic factors, environmental triggers, and immune dysregulation to build a comprehensive understanding of autoimmune disease pathogenesis. We propose a novel therapeutic strategy targeting IL-2R signaling using Neddylation Activating Enzyme inhibitors (NAEis) conjugated to IL-2 or anti-CD25 antibodies. This approach selectively restores Treg function and immune tolerance without inducing systemic immunosuppression. By focusing on immune restoration rather than suppression, This therapy could provide an off the shelf therapy for many different autoimmune diseases.
Article Publication Date: 07/04/2025
DOI: 10.3389/fimmu.2025.1626082
