Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies?

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.

Keywords: Autoimmune disease; GRAIL; IL-2 receptor signaling; environmental triggers; genetic susceptibility; neddylation; phosphor-S6; regulatory T cells.

Figure 1

Pathogenesis of autoimmune disease. Our working hypothesis is that the development of an autoimmune disease arises when three critical factors converge: genetic predisposition, exposure to an environmental trigger, and defects in immune regulation. In a genetically predisposed individual, the immune system’s response to an environmental pathogen, combined with defects in regulatory mechanisms, leads to autoimmunity. While the relative influence of each component may differ across individuals and specific diseases, the onset of autoimmune disease typically requires the intersection of all three elements, as illustrated in the Venn diagram. Among this triad, a defect in immune regulation is the only rational target for therapy. Our studies (described below) have identified a correctable defect in interleukin 2 receptor (IL-2R) signaling of regulatory T cells (Tregs) from patients with autoimmune diseases and allergic asthma. Created with BioRender.com.

Figure 2

Activation of Tregs by low-dose IL-2. Low-dose IL-2 activates the high affinity IL-2R to phosphorylate JAK1, that then phosphorylates STAT5 to drive the expression of genes required for Treg function. Created with BioRender.com.

Figure 3

Defective inhibition of IL-2 desensitization in the Tregs of SLE patients. The 25 SLE patients studied were selected from a clinic in Mexico City, irrespective of current disease status. These graphs represent Western blot data of pSTAT5 phosphorylation in Teffs and Tregs of the SLE patients and healthy sex and age-matched controls after stimulation with low dose IL-2 (1 ng/ml; 25 IU/ml) for the indicated amounts of time. Expression is shown as a percentage of pSTAT5 measured from 30 min-stimulated control Tregs. A defect in the inhibition of IL-2R desensitization is observed in the Tregs of SLE patients (red line) n=6 per group ***p < 0.001 by 2-way ANOVA. Fathman et al. (62).

Figure 4

Could a neddylation activating enzyme inhibitors (NAEi) such as MLN4924 or TAS4464 replace GRAIL to treat autoimmunity?

Figure 5

Tregs of healthy controls or an established T1D patient (who also had diminished GRAIL expression) were treated with low dose IL-2 (1 ng/ml) in the presence or absence of an NAEi (MLN4924; 400 uM). Like SLE, low dose IL-2 stimulated pSTAT5 expression is reduced in Tregs of T1D patients vs. controls (red line). Combination treatment of low dose IL-2 and the NAEi increased and prolonged pSTAT5 expression in the Tregs of T1D patients back to control Treg levels (solid black columns). The NAEi corrects for the GRAIL deficiency.