Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies?
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-spe...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-08-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1626082/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850036924380610560 |
|---|---|
| author | Manoj Kumar Manoj Kumar Linda Yip Fangyuan Wang Saci-Elodie Marty C. Garrison Fathman |
| author_facet | Manoj Kumar Manoj Kumar Linda Yip Fangyuan Wang Saci-Elodie Marty C. Garrison Fathman |
| author_sort | Manoj Kumar |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9039852e04f145cfb40d081279b7b3cf |
| institution | DOAJ |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-9039852e04f145cfb40d081279b7b3cf2025-08-20T02:57:00ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-08-011610.3389/fimmu.2025.16260821626082Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies?Manoj Kumar0Manoj Kumar1Linda Yip2Fangyuan Wang3Saci-Elodie Marty4C. Garrison Fathman5Department of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Radiology, School of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United StatesDepartment of Medicine, School of Medicine, Stanford University, Palo Alto, CA, United StatesAutoimmune 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.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1626082/fullAutoimmune diseasegenetic susceptibilityenvironmental triggersregulatory T cellsIL-2 receptor signalingGRAIL |
| spellingShingle | Manoj Kumar Manoj Kumar Linda Yip Fangyuan Wang Saci-Elodie Marty C. Garrison Fathman Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? Frontiers in Immunology Autoimmune disease genetic susceptibility environmental triggers regulatory T cells IL-2 receptor signaling GRAIL |
| title | Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? |
| title_full | Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? |
| title_fullStr | Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? |
| title_full_unstemmed | Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? |
| title_short | Autoimmune disease: genetic susceptibility, environmental triggers, and immune dysregulation. Where can we develop therapies? |
| title_sort | autoimmune disease genetic susceptibility environmental triggers and immune dysregulation where can we develop therapies |
| topic | Autoimmune disease genetic susceptibility environmental triggers regulatory T cells IL-2 receptor signaling GRAIL |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1626082/full |
| work_keys_str_mv | AT manojkumar autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies AT manojkumar autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies AT lindayip autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies AT fangyuanwang autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies AT sacielodiemarty autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies AT cgarrisonfathman autoimmunediseasegeneticsusceptibilityenvironmentaltriggersandimmunedysregulationwherecanwedeveloptherapies |