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The emerging role of Ikaros proteins in chronic inflammatory diseases

By Ana Ramon Vazquez - 12th Jun 2025

Reference: June 2025 | Issue 6 | Vol 11 | Page 18

Chronic inflammatory diseases (CIDs), like rheumatoid (RA) and psoriatic arthritis (PsA), inflammatory bowel disease (IBD), systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type 1 diabetes (T1D) are heterogeneous autoimmune diseases that share exacerbated immune responses and sustained inflammation as a common feature. CIDs have been recognised as the most significant cause of death in the world, with more than 50 per cent of all deaths being attributable to inflammation-related diseases.1

Generally, these are T cell-mediated diseases where different effector T helper (Th) cell subsets orchestrate cellular responses (typically subsets Th1, Th2, Th9, Th17, and Th22) causing chronic inflammation, cell recruitment and tissue destruction, in addition to other associated effects like fibrosis (involving Th2 and Th17). Typically, a breakdown in tolerance caused by an imbalance in the number and/or the functionality of specific T cell subsets is believed to mark the onset of these pathological processes.

Regulatory T (Treg) cells, on the other hand, are a T helper cell subset that are essential for maintaining peripheral tolerance, preventing autoimmunity, and limiting CIDs. These cells employ multiple mechanisms to mediate their suppressive effects, including the production of inhibitory cytokines such as interleukin-10 (IL-10) and transforming growth factor-β (TGFβ), as well as suppression through cytolysis and metabolic disruption.

Clinical relevance

The Ikaros family comprises five members of transcription factors – IKAROS, HELIOS, AIOLOS, EOS and PEGASUS – that control gene expression by binding as protein dimers to specific DNA sequences. They use different activating and repressing mechanisms to mediate their effects, depending on their interaction with other key transcriptional complexes. Their main role in lymphopoiesis and other cellular processes like proliferation, differentiation, cell cycle arrest, apoptosis, and tumourigenesis highlights their importance in maintaining the balance of T cell subsets and regulating immune responses.

Specific functions for some Ikaros proteins in determining Th cell identity in humans have been described. IKAROS protein, for instance, controls Th1 transcriptional programme repression and Th2 development. Consequently, germline heterozygous IKAROS gain-of-function mutations have been reported in patients presenting with Th2 cell-driven atopic and allergic diseases, dramatically reduced IL-2 production, and low Th1 and Treg cell counts.2-4 Conversely, EOS promotes Th1 differentiation and AIOLOS contributes mainly to Th17 development.5

Tregs are influenced by virtually all Ikaros family members; however, some specific functions have been ascribed to individual members, like phenotype stabilisation (HELIOS), control of suppressive function (AIOLOS), and function enhancement (EOS).6,7 In addition, the presence of HELIOS identifies natural thymic-derived Tregs (nTregs) over peripherally-induced Tregs (iTregs).8 Finally, PEGASUS has little or unknown contribution to T cell specification.

Ikaros as susceptibility genes

Genetic variants in the Ikaros genes have been linked to impaired T cell function, skewed differentiation, and increased disease activity, underscoring their association with various human chronic inflammatory and autoimmune diseases. As a result, Ikaros members have emerged as novel susceptibility genes for different CIDs including IBD, psoriasis, SLE, RA, and T1D.9-14

Missense DNA variants, which result in one amino acid being substituted for another in the protein, were found in the gene coding for IKAROS protein from several individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell proliferation.2 Single nucleotide polymorphisms (SNPs) on the Ikaros genes, although not evidently affecting the normal protein function, often result in a positive correlation with disease diagnosis: AIOLOS in RA, psoriasis, MS, and SLE – and IKAROS in primary Sjögren’s syndrome.11,13,15-17 Similarly, a SNP in the gene encoding EOS is associated with increased type 1 diabetes risk and the presence of serum insulin autoantibodies.14

Downregulation or loss-of-function mutations on Ikaros genes are a common feature in peripheral blood mononuclear cells (PBMCs) from SLE (HELIOS, IKAROS) and IBD (Ikaros10) patients.10,18-19 While in other cases, gene overexpression is observed in ulcerative colitis (IKAROS), SLE (AIOLOS) and RA (IKAROS and AIOLOS).20-22

However, the IKAROS gene expression in RA varied depending on the specific tissue examined, as IKAROS and AIOLOS were overexpressed in some peripheral blood mononuclear cell subsets and synovial membrane, but all Ikaros family members appeared consistently reduced in Treg cells.23

The clinical significance of aberrant IKAROS expression remains to be fully elucidated. In a clinical study describing higher HELIOS expression in T cells from a cohort of RA patients, no corresponding improvement in suppressive function was detected, although HELIOS contributes to maintain Treg function.24 In addition, these findings do not correlate with observations from engineered Treg cells in vitro, where co-expression of HELIOS and FOXP3 enhanced and stabilised their regulatory functions.

Homo- and hetero-dimerisation of Ikaros proteins is another important factor determining their functionality. A new hereditary heterozygous missense mutation was recently found in the AIOLOS gene in patients with an impaired adaptive immunity disorder. Mutant AIOLOS homodimers and AIOLOS–IKAROS heterodimers did not bind the canonical DNA sequence, a phenomenon driven by the mutant AIOLOS variant that hijacks IKAROS function.25

The gained ability of the mutant AIOLOS to specifically bind new DNA sequences would explain the pathological outcomes, but the mechanisms underlying the regulation of heterodimer and homodimer formation of Ikaros proteins and how functionality of AIOLOS-IKAROS heterodimers differ from IKAROS-IKAROS or AIOLOS-AIOLOS homodimers still needs to be investigated.

Ikaros gene transcription

Some mechanisms of disease mediated by the Ikaros family have recently been identified that involve direct transcriptional control of genes that increase T cell activation and inflammatory cytokine production. Relevant studies on IKAROS, AIOLOS, and HELIOS in human T cells found that a defective repressive function over their target genes leads to increased cell responsiveness and sensitivity to external cues. This is suggestive that, ultimately, their transcriptional repression contributes to the control of autoimmune processes.

IKAROS was identified as a transcriptional repressor of the pore-forming calcium channel component ORAI3.26 This protein increased expression in naïve T cells derived from patients with RA and PsA. Consequently, stimulation with arachidonic acid, a known precursor of the biosynthesis of pro-inflammatory mediators, induced a calcium influx and phosphorylation of components of the T cell receptor signaling pathway, leading to an enhanced cellular responsiveness.

This process would also have a significant relevance in diseases where a consistent downregulation of Ikaros members is a signature feature, as found in Treg cells from RA patients, potentially rendering the cells more prone to activation.2,3 However, these mechanisms could be disease-specific, as although a down-regulated expression of Ikaros mRNA was observed in PBMCs from SLE patients, this was not correlated to an overexpression of ORAI3.

IKAROS and AIOLOS proteins were found to exert repressive transcriptional control over different genes that encode cytokines typically produced by T cells to activate additional immune cells and perpetuate inflammation. Using peripheral blood lymphocytes from healthy donors in vitro, it was demonstrated that IKAROS repressed CSF2 gene, which encodes granulocyte-macrophage colony-stimulating factor (GM-CSF).27

GM-CSF production correlates with disease severity in inflammatory and autoimmune diseases like IBD, RA, and MS. Another study showed that both IKAROS and AIOLOS were required for the control of IFN-γ overproduction in human Treg cells, indicating that they exert a repressive function over the transcription of the gene.28 IFN-γ is also a very relevant cytokine that plays a role in sustaining chronic inflammation.

Immune ageing is an important factor impairing adaptive immune responses that leads to cell immune malfunctioning and associated low-grade inflammation. A positive correlation between ageing and downregulation of HELIOS protein was found in T cells.29 Naïve T cells from aged individuals display a predisposition to turn into effector cells with increased STAT5 activity.

In addition, it was found that HELIOS also exerted a repressive function on the expression of CD25 gene. This gene encodes the surface receptor for IL-2 cytokine, that is required for T cell survival and proliferation. Therefore, loss of HELIOS in older age resulted in an overall amplified proliferative signal and differentiation.

Environmental factors like smoking, pollution, and intake of processed foods have been linked to exacerbation of RA symptoms, in part due to the ability of these factors to cause cell damage, inflammation, and oxidative stress. Ultimately, oxidative stress has been postulated to contribute to the hallmarks of ageing (examples include genomic instability, telomere attrition, and mitochondrial dysfunction) and to drive pathological pathways (like altered gene expression and arrested cell growth) that lead to age-related diseases. Therefore, it would be interesting to investigate if exposure to these factors could cause accelerated cell ageing through these mechanisms and subsequent degradation of HELIOS in T cells.

Ikaros therapeutic targeting

Targeted treatment options for CIDs are scarce, relying mainly on the use of disease-modifying antirheumatic drugs (DMARDs), biologics like anti-tumor necrosis factor-alpha (TNF-α) monoclonal antibodies, small molecule drugs like JAK-STAT inhibitors, and anti-inflammatory drugs (corticosteroids).

Furthermore, the clinical response to these treatments is often poor.30-33 A deeper investigation of disease-signalling pathways and better refinement of drug targets can potentially improve the poor response to current treatments and, ideally, shift diseased cells towards a more stable and homeostatic state.

Specific drugs that target the Ikaros family are thalidomide and its analogues, pomalidomide and lenalidomide. These compounds were originally developed as anti-inflammatory drugs and have long been known to reduce the production of TNF-α. They are collectively known as immunomodulatory imide drugs (IMiDs). They serve as potent protein degraders and emerged as one of the milestones for the treatment of multiple myeloma. Their molecular mechanism of action is based on prompting specific IKAROS and AIOLOS protein degradation through cereblon (CRBN) binding and subsequent proteasomal degradation of target proteins. Therefore, these drugs are commonly known as “molecular glues”.

Novel thalidomide analogues have emerged for use in the clinic. These cereblon E3 ligse modulating drugs (CELMoDs) bind CRBN with higher affinity than lenalidomide or pomalidomide.34

Some examples include avadomide (CC-122), iberdomide (CC-220), CC-885, and CC-92480. At present, they are being tested in clinical trials, both as monotherapy and in combination with other drugs (NCT01421524; NCT02773030; NCT03374085).

Another recent potent heterobifunctional molecule, NX-2127, that enables degradation of all known drug-resistant mutant forms of Bruton’s tyrosine kinase (a protein involved in B cell development), in addition to IKAROS and AIOLOS proteins, is currently in a first-in-human clinical trial (NCT04830137).

The mechanism of action of another selective degrader, NVP-DKY709, that targets HELIOS and spares IKAROS and AIOLOS, was recently characterised.35 Degradation of HELIOS with this compound made Tregs less inhibitory but also, exhausted effector T cells were more active in vitro, indicating that this could be a promising therapeutic option for settings other than chronic inflammatory conditions, where enhancing T cell activity is sought.

Another class of compounds that target HELIOS and are also the only reported EOS degraders (International Patent Applications WO 2019/038717 A1), are substituted 3-(1-oxoisoindolin-2-yl)piperidine-2,6-dione compounds. The activity of this class of compounds was recently validated in human Treg cells in vitro.

These studies have laid the foundation for future drug design with the objective of developing drugs with increased specificity for the various Ikaros family proteins.

References

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Author Bios

Ana Ramon Vazquez, Senior Postdoctoral Fellow, APC Microbiome Institute, University College Cork

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