small molecules

2026-07-16 | Approach to the patient with APS-1/APECED.

Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is a monogenic disorder of impaired central immune tolerance classically inherited in an autosomal recessive manner and caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene, leading to chronic mucocutaneous candidiasis (CMC) and multiorgan autoimmunity. Although hypoparathyroidism and adrenal insufficiency are among the most common and clinically consequential manifestations, it is increasingly recognized that several non-endocrine features - including autoimmune enteritis, urticarial eruption (termed APECED rash), enamel hypoplasia, autoimmune pneumonitis, and autoimmune hepatitis - often precede classical endocrinopathies, contributing to delayed diagnosis. Endocrinologists are often among the first specialists to encounter these patients and play a central role in early recognition and longitudinal care. Here we present five cases that illustrate the expanding clinical spectrum of APS-1, novel genetic mechanisms, key diagnostic challenges, and emerging therapeutic approaches. These cases highlight the importance of applying expanded clinical criteria and recognizing the limitations of standard genetic testing, including the need to consider deep intronic and dominant-negative AIRE variants. Finally, evolving mechanistic insights have established APS-1 as an interferon-γ (IFN-γ)-driven disease, providing a rationale for emerging targeted immunomodulatory therapies such as Janus kinase (JAK) inhibition with ruxolitinib. Early diagnosis enables proactive surveillance and may allow timely initiation of disease-modifying treatment.

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2026-07-15 | The autoimmune regulator (AIRE) is a target of the E3-Ubiquitin ligase Seven-in-absentia homolog 1 (SIAH1).

The autoimmune regulator (AIRE) is expressed in medullary thymic epithelial cells (mTECs) and is crucial for generating an immunocompetent T cell repertoire during central tolerance. Loss of AIRE function causes autoimmune polyglandular syndrome type 1 (APS-1), also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). Intracellular proteins are regulated by ubiquitination pathways. E3 ubiquitin ligases are specific proteins that confer selectivity to polyubiquitination, tagging proteins for proteasomal degradation while also performing other functions. In mTECs, peptides generated via the class I antigen-processing pathway are presented by HLA-I molecules to CD8 thymocytes to eliminate self-reactive T-cell precursors. AIRE induces promiscuous gene expression in mTECs, but little is known about the regulatory mechanisms of AIRE. Previously, we and others demonstrated that AIRE is an apoptosis inductor. Here, we demonstrate that AIRE increases the intracellular levels of SIAH-interacting protein (SIP), an adaptor protein of the SIAH E3 ubiquitin ligase family. We also show that AIRE interacts with SIAH1 in the human thymus. While AIRE contains two putative SIAH-interacting motifs, it interacts with SIAH proteins only through the sequence spanning residues 119-125. AlphaFold modeling indicated that the interaction between AIRE and SIAH1 is highly analogous to that observed between SIP and SIAH1, suggesting that both proteins compete for SIAH1 binding. The CARD domain and the SIAH-interacting motif is required to AIRE-mediated apoptosis. AIRE co-localized with SIAH proteins in the cytoplasm of HEK-293 cells. Finally, SIAH1 ubiquitinated AIRE, targeting it for proteasomal degradation. Collectively, these findings reveal a novel pathway for the degradation and regulation of AIRE.

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2026-05-03 | Assessment of levothyroxine sodium absorption: The possibility of ruling out malabsorption in a patient with autoimmune polyglandular syndrome

This article presents a complex clinical case of a 26-year-old female patient with autoimmune polyglandular syndrome type 2, comprising type 1 diabetes mellitus, primary adrenal insufficiency, and autoimmune thyroiditis with severe decompensated hypothyroidism (thyroid stimulating hormone 491.84 mU/L) despite treatment with high doses of levothyroxine sodium (L-T4) – 350 mcg/day. The key diagnostic challenge was to differentiate true L-T4 malabsorption from pseudomalabsorption caused by polypharmacy, non-adherence to the medication regimen, and psychosomatic disorders. To verify the cause, an L-T4 absorption test was performed using a 600 mcg dose of L-T4, with monitoring of free thyroxine (fT4) levels. The test results demonstrated an adequate increase in fT4 of more than 240% over 6 hours, which allowed for the exclusion of true malabsorption. Based on these findings, a comprehensive therapy correction was implemented: the sequence of drug administration was optimized (L-T4 to be taken strictly on an empty stomach with a subsequent interval before taking other medications), the glucocorticoid dose was reduced, insulin therapy was adjusted, and psychotherapeutic support was prescribed. This case highlights the critical importance of objectively assessing L-T4 absorption in patients with polyendocrinopathies to select the optimal pathway for achieving hypothyroidism compensation and to develop a personalized management plan.

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2026-05-01 | Multiomic Characterization of Treatment Response to JAK Inhibition in Patients with APECED

Background Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an inborn error of immunity caused by loss-of-function of the AIRE gene. Lack of AIRE impairs thymic negative selection of T cells, causing multiorgan autoimmunity, making APECED a prototypical disease for failed central tolerance. IFNγ secreted by T cells drives inflammation in APECED, and targeting IFNγ downstream signaling with JAK1/2 inhibitor ruxolitinib remits autoimmunity in the patients. How JAK inhibition affects tissue-specific responses at the single-cell level remains unclear. Methods In longitudinal samples from four APECED patients treated with ruxolitinib on a phase-II clinical trial at National Institutes of Health, we combined single-cell RNA sequencing (scRNAseq) from blood, enteritis-affected duodenum, and scalp skin affected by alopecia with serum proteome, autoantibody microarray, and metabolome to characterize tissue-specific autoimmune responses and their normalization upon JAK inhibition. Results In tissues affected by autoimmunity, we detected multifaceted cross talk between immune and stromal cells, ushering IFNγ-driven inflammation. Ruxolitinib downregulated expression of tissue-homing chemokines and antigen presentation by stromal cells and resulted in decreased accumulation of immune cells to the tissues, as well as dampening of pro-inflammatory responses. Normalization of tissue homeostasis ensued; for example, hair keratinocytes became detectable, aligning with clinical hair regrowth. Many of the transcriptional tissue changes were discernible by the serum proteome, and the treatment response was apparent in rejuvenation of proteome-based organ age. However, treatment was also associated with subclinical proteomic changes reflecting potential side effects of JAK inhibitors, including anemia, weight gain, and hypercoagulability. We expanded the proteome evaluation to 89 additional APECED patients affected by autoimmunity, identifying a patient cluster with the most severe clinical phenotype, highest autoantibody burden, and proteome-based premature aging of multiple organs. These patients had a distinct inflammatory profile, which, in addition to excess IFNγ, was characterized by heightened IL6 responses and TGFβ resistance, partly driven by alterations in sex hormone production. Conclusions Multiomic characterization of treatment response to JAK inhibition uncovers pathogenesis and normalization of tissue-specific autoimmunity. JAK inhibitors are increasingly used to target various immune pathways in inborn errors of immunity, and understanding their complex effects systemically and in the tissues is a prerequisite for safe and successful therapy.

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2026-05-01 | Prevention of Irreversible Autoimmune Endocrinopathies in APECED with Ruxolitinib

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic disorder of failed central tolerance caused by deleterious variants in the autoimmune regulator (AIRE) gene. Interferon-γ-driven inflammation in APECED underlies multiorgan autoimmunity and chronic mucocutaneous candidiasis and is targetable with JAK1/2 inhibition. Yet, whether early cytokine blockade can avert irreversible endocrine failure is currently unknown. Here, we describe two individuals with APECED who developed early autoimmune hypoparathyroidism and hypergonadotropic hypogonadism and in whom JAK1/2 inhibition halted progression and reversed biochemical and clinical abnormalities, preserving parathyroid and gonadal function. Specifically, patient 1 at the age of 2 years developed progressively declining intact parathyroid hormone (iPTH) levels that became undetectable within four months, while calcium and phosphorus levels remained normal, consistent with early, subclinical hypoparathyroidism. Ruxolitinib normalized iPTH levels and preserved calcium levels (Figure 1 A and B). Serum CXCL9 levels dropped and then increased, associated with a transient decline in iPTH levels; when the ruxolitinib dose was increased, iPTH increased, and CXCL9 dropped again and has remained normal after 18 months of treatment (Figure 1 C), suggesting that CXCL9 may be a potential biomarker of ruxolitinib efficacy in APECED. Ruxolitinib also remitted mycophenolate-refractory autoimmune hepatitis and recurrent oral candidiasis, which had occurred despite the absence of autoantibodies against IL-17A or IL-17F. Patient 2, at the age of 18 years, developed clinical and biochemical features of early hypergonadotropic hypogonadism. Screening labs showed declining anti-Müllerian hormone (AMH) and elevated follicle-stimulating hormone (FSH) and luteinizing hormone (LH). She reported severe hot flashes and oligomenorrhea with only three menses over five months, a reduction from her prior regular 28-day cycles. After initiation of ruxolitinib, hot flashes resolved while FSH, LH, and AMH normalized, and regular 28-day menstrual cycles were restored (Figure 2 A–C). Ruxolitinib caused no hematopoietic, hepatic, or renal toxicity in either patient. These findings provide, to our knowledge, the first clinical evidence that timely JAK–STAT pathway inhibition can intercept endocrine autoimmunity in APECED. More broadly, they advance a disease-interception paradigm in which early, pathway-directed cytokine blockade may alter the natural history of autoimmune endocrinopathies. Figure 1. Ruxolitinib reverses early hypoparathyroidism in patient 1. Data points in black represent time points before ruxolitinib initiation, while those in green and blue represent time points while receiving ruxolitinib at the indicated dose. A) Serum iPTH over time relative to ruxolitinib initiation. The dashed horizontal line represents the lower limit of normal for this assay. B) Total calcium levels over time relative to ruxolitinib initiation. C) Serum CXCL9 levels over time relative to ruxolitinib initiation. The dashed horizontal line marks the upper limit of normal for this assay. Figure 2. Ruxolitinib reverses premature ovarian failure in patient 2. Data points in black represent time points before ruxolitinib initiation, while those in green and blue represent time points while receiving ruxolitinib at the indicated dose. Serum AMH (A), FSH (B), and LH (C) levels over time relative to ruxolitinib initiation. The dashed lines represent the lower (A) or upper (B and C) limits of normal for these assays.

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proteins

2026-07-17 | Palopegteriparatide Treatment for Hypoparathyroidism in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy - a Case Series and Literature Update

Abstract Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1), is an autosomal recessive disorder of thymic T cell negative selection that results in autoimmune destruction of various endocrine and extra-endocrine tissues. The classic clinical triad of the syndrome includes hypoparathyroidism (hypoPT), chronic mucocutaneous candidiasis (CMC), and adrenal insufficiency, while involvement of thyroid, pancreas, gonads, and ectodermal tissues are also frequently observed. Historically, treatment for hypoPT, the most common endocrine manifestation of APECED, has posed a unique challenge. Conventional therapy with oral calcium and active vitamin D analogues is often complicated by the presence of malabsorption and esophageal disorders, which are prevalent in APECED patients. Moreover, supplementation with oral calcium and active vitamin D analogues without correction of the underlying parathyroid hormone (PTH) insufficiency can result in renal and other soft-tissue calcifications. Short-acting PTH therapies, which have been used off-label in the treatment of hypoPT, fail to mimic normal parathyroid physiology due to their brief half-lives and can result in fluctuations of serum calcium levels between hypocalcemia and hypercalcemia. Long-acting PTH analogues have recently been developed to more closely mimic physiologic PTH activity. One such agent, palopegteriparatide, a prodrug of PTH (1,34), has shown promise to be the first hormone replacement therapy for hypoPT. We report our experience in four patients with APECED-associated hypoPT who initiated treatment with palopegteriparatide and were followed over the subsequent 4-15 month period. We observed a robust calcemic response to treatment during this follow-up window with wide fluctuations in serum calcium during this period of dose titration. These early observations highlight the effectiveness of palopegteriparatide in patients with APECED, enabling the discontinuation of oral calcium and active vitamin D supplements. They also highlight the question of whether etiology-specific differences in responsiveness may influence dose requirements and calcemic stability.

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2024-10-16 | A-9-Years-Old Female with Diabetes Mellitus Type 1 with Hyperthyroidism

Diabetes Mellitus Type 1 (DMT1) and thyroid disease can occur together, which is defined as a variant of autoimmune polyglandular syndrome type 3. It is known that the action of insulin and thyroid hormones affect cellular metabolism, thyroid hormones contribute to carbohydrate metabolism and pancreatic function. Since the thyroid gland plays a central role in the regulation of metabolism, abnormal thyroid function can have a major impact on the control of diabetes and poor glycemic control can cause alterations in thyroid hormone. A female, 9 years old, with decreased consciousness. Previous medical history, polyuria, increased appetite, and drastic weight loss. She also complained of sweating even in a cold room and was often emotional. On physical examination, there was fever, shortness of breath, tachycardia, and a soft and diffused slightly enlarged thyroid gland, with no bruit on auscultation. Laboratory tests showed blood glucose levels at 739 mg/dL, HbA1c 9.2%, C-peptide 0.2 ng/mL, TSH levels 0.01 µIU/mL, FT4 levels 2.77 ng/dL, the presence of metabolic acidosis, proteinuria, glucosuria, and ketonuria. Thyroid dysfunction will have a negative effect on DM control while poor glucose control will harm the work of thyroid hormones. Improvement in glycemic control and routine insulin injection with the right dose will reduce the risk of diabetic vascular and metabolic complications onset and progression.

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2024-07-12 | Increased frequency of microalbuminuria in patients with type 3 autoimmune polyglandular syndrome (APS) compared to isolated autoimmune type 1 diabetes mellitus: A real-life study.

The primary aim of the study was to evaluate the differences in metabolic control and chronic microvascular complications in patients with type 3 autoimmune polyglandular syndrome (APS3), compared to type 1 diabetes mellitus (T1DM) alone. Secondary aims were to evaluate the age of autoimmune thyroid disease (AIT) onset and the effects of levothyroxine treatment on metabolic control in patients with APS3. We retrospectively reviewed 276 patients with T1DM alone and 214 patients with APS3 and evaluated clinical and metabolic parameters and microvascular complications. Patients with T1DM showed a longer duration of diabetes (p = 0.001) and lower age of diabetes onset (p = 0.020) compared to patients with APS3. Female gender (p = 0.001) and microalbuminuria (p = 0.006) were significantly more frequent in patients with APS3 compared to T1DM. In addition, patients with APS3 showed higher AIT onset frequency in the 16-30 quartile age-range. Furthermore, APS3 patients treated with levothyroxine showed significantly better HbA1c values than non-treated patients (p = 0.001). We found that patients with APS3 showed positive microalbuminuria, earlier than T1DM. Patients with APS3 showed higher frequency of AIT age of onset in the 16-30 age-range and those treated with levothyroxine had better metabolic control, than untreated ones.

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2024-04-12 | Lessons From Prospective Longitudinal Follow-up of a French APECED Cohort.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome is a rare disease caused by biallelic mutations of the AIRE gene, usually presenting with the triad hypoparathyroidism-adrenal failure-chronic mucocutaneous candidiasis (CMC) and nonendocrine manifestations. The aim of this study was to determine the molecular profile of the AIRE gene, the prevalence of rare manifestations, and to characterize immunological disturbances in a French cohort. A national, multicenter prospective observational study to collect genetic, clinical, biological, and immunological data (NCT03751683). Twenty-five patients (23 families) were enrolled. Eleven distinct AIRE variants were identified, 2 of which were not previously reported: an intronic variant, c.653-70G > A, and a c.1066del (p.Arg356GlyfsX22) variant (exon 9). The most common was the Finnish variant c.769C > T (16 alleles), followed by the variant c.967_979del13 (15 alleles), which seemed associated with a less severe phenotype. Seventeen out of 25 patients were homozygote. The median number of clinical manifestations was 7; 19/25 patients presented with the hypoparathyroidism-adrenal failure-CMC triad, 8/13 showed pulmonary involvement, 20/25 had ectodermal dystrophy, 8/25 had malabsorption, and 6/23 had asplenia. Fifteen out of 19 patients had natural killer cell lymphopenia with an increase in CD4+ and CD8+ T lymphocytes and an age-dependent alteration of B lymphocyte homeostasis compared with matched controls (P < .001), related to the severity of the disease. All tested sera (n = 18) were positive for anti-interferon-α, 15/18 for anti-IL-22 antibodies, and 13/18 for anti-IL-17F antibodies, without clear phenotypic correlation other than with CMC. This first prospective cohort showed a high AIRE genotype variability, with 2 new gene variants. The prevalence of potentially life-threatening nonendocrine manifestations was higher with systematic screening. These manifestations could, along with age-dependent B-cell lymphopenia, contribute to disease severity. Systematic screening for all the manifestations of the syndrome would allow earlier diagnosis, supporting vaccination and targeted therapeutic approaches.

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2024-04-05 | Progressive Impairment of Prepubertal Growth in Children With APECED.

Subjects with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) have subnormal adult height. There are several potential APECED-related risk factors for suboptimal height attainment during childhood. To determine the growth patterns in children with APECED. This retrospective longitudinal study included 59 children with APECED from the Finnish national APECED cohort and assessed length/height and weight z-scores from birth to the end of prepuberty. Collectively, 59 children (30 [51%] girls) were included. Their median birth weight z-score (-0.60) was below the population average; 12 (20%) patients were born small for gestational age. Height attainment progressively declined from birth until the end of prepuberty (z-score -1.95), whereas weight-for-height z-score did not (+0.26). Of the 59 patients, 38 (64%) had all height z-scores below 0 during prepuberty, and 7 (12%) had z-scores below -2.0. Age at the end of prepuberty, number of APECED manifestations, duration of glucocorticoid treatment, and growth hormone deficiency correlated negatively with height z-score at the end of prepuberty (P < .0001; P = .041; P = .013; P = .034, respectively). Children with APECED had a progressive growth impairment from birth through prepuberty. Multiple predisposing risk factors were recognized, including disease severity and growth hormone deficiency. Timely interventions are needed to ensure optimal height attainment and new treatment options need to be developed.

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antibodies

2026-04-10 | Retinopathy caused by a primary immune regulatory disorder - the spectrum of AIRE-associated retinopathy: case series and literature review.

Retinal involvement in autoimmune polyendocrine syndrome type 1 (APS1), a rare monogenic autoimmune disorder caused by mutations in the AIRE gene, is increasingly recognised but remains poorly defined. Prior reports suggest a variable phenotype, ranging from mild changes to severe vision loss, often presumed untreatable. We explored the range of retinal phenotypes associated with AIRE gene deficiency in a multicentre case series of patients with APS1. We performed a retrospective case note review of patients with molecularly confirmed APS1 from tertiary ophthalmic centres. Clinical history, multimodal retinal imaging, electrophysiology, genetic data, and treatment regimens were analysed. Histopathology was available in one case postmortem. Records were reviewed from five unrelated female patients. Median age was 14 years at onset of ocular involvement and 33 years at most recent follow up. Some findings from two cases have been previously reported. Three distinct pathogenic AIRE variants contributing to biallelic genotypes were observed. Retinal findings ranged from structurally and functionally normal to advanced degeneration. One patient demonstrated sharp zonal atrophy on histopathology. Inflammatory features predominated in two cases, both showing durable vision preservation with periocular or systemic immunomodulation. One patient demonstrated four years of disease stabilisation with rituximab. No consistent genotype-phenotype correlation emerged. AIRE-associated retinopathy encompasses a diverse spectrum, from clinically silent to profound degeneration. Early, targeted immunomodulation might preserve vision in selected cases. These findings advocate for ophthalmic surveillance in APS1, and support further investigation into predictive biomarkers and possible tailored immunotherapy in this vision-threatening autoimmune disorder.

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2026-02-07 | Pediatric IPEX-Associated Dermatitis Responds To Dupilumab: Evidence from Skin Transcriptomics and Immune Profiling.

Immunodysregulation, Polyendocrinopathy, Enteropathy, and X-linked (IPEX) syndrome is a rare autoimmune disorder caused by mutations in the FOXP3 gene. Patients with IPEX frequently present with severe dermatitis, diabetes, and enteropathy. This study explores the efficacy of Dupilumab (an anti-IL-4Rα monoclonal antibody) in treating persistent, severe dermatitis in an IPEX patient refractory to conventional treatments like sirolimus. We conducted a clinical case study of a 2-year-old IPEX patient with refractory dermatitis. Whole-exome sequencing (WES) confirmed the FOXP3 mutation. Skin biopsies were analyzed for inflammatory gene expression by RNA sequencing and immunohistochemistry to characterize inflammatory pathways. Immune cell phenotyping was performed using flow cytometry pre- and post-treatment in peripheral blood mononuclear cells (PBMCs). The patient was treated with Dupilumab alongside sirolimus and prednisone. Clinical improvements were evaluated using the Eczema Area and Severity Index (EASI) score. Immunohistochemistry revealed elevated IL-13 expression. RNA sequencing of skin samples revealed upregulation of both Th1- and Th2-related genes, suggesting a dual inflammatory phenotype in IPEX dermatitis. The patient exhibited significant clinical improvement after 8 months of sustained Dupilumab therapy, with the EASI decreasing from 24.8 to 0.4. Flow cytometry demonstrated a reduction in Th1 and Th2 cell subsets post-treatment, accompanied by an increase in Treg and Th3 cell populations as well as enhanced expression of immunosuppressive markers such as CTLA-4 and CD39. Dupilumab appears promising as a therapeutic option for managing refractory dermatitis in IPEX, particularly by attenuating Th1/Th2 inflammation and promoting regulatory responses mediated by Treg and Th3 cells.

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2025-12-22 | CARD8: An Emerging Genetic Cause of Autoinflammatory and CVID-Like Syndromes?

Introduction CARD8 encodes the caspase recruitment domain-containing protein 8, a negative regulator of the NLRP3 inflammasome and a modulator of innate immune signaling. Although not yet formally classified among inborn errors of immunity (IEIs), emerging evidence suggests a potential role of CARD8 variants in autoinflammatory syndromes and immune dysregulation. Case Presentations We describe three unrelated patients from different families with variable phenotypes involving autoinflammation and immune dysregulation. Patient 1: A 15-year-old female with an IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked)-like phenotype, including alopecia universalis, growth retardation, pubertal delay, and elevated serum IL-18 levels. A heterozygous frameshift variant in CARD8 (c.40delG, p.Glu14fs) was identified. Patient 2: A 3-year-old male presenting with neonatal lupus-like rash, severe atopic dermatitis, refractory autoimmune cytopenias, persistent hepatitis, and total villous atrophy on intestinal biopsy (Marsh 3b). A heterozygous frameshift variant (c.68dupG, p.Ser24fs) was detected. Patient 3: A 42-year-old female with adult-onset CVID (common variable immunodeficiency)-like phenotype, including recurrent pneumonia, chronic diarrhea, and persistent hypogammaglobulinemia requiring immunoglobulin replacement. A heterozygous missense variant (c.1093A&gt;C, p.Met365Leu) was identified. Discussion These cases illustrate the broad clinical spectrum associated with CARD8 variants, ranging from severe early-onset autoinflammatory disease to adult-onset humoral immunodeficiency. The presence of elevated IL-18 and multi-organ involvement supports dysregulated inflammasome activation as a key pathogenic mechanism. Importantly, heterozygous variants may result in incomplete penetrance and variable expressivity, complicating diagnosis and counseling. Conclusion CARD8 mutations should be considered in patients presenting with unexplained autoinflammation, immune dysregulation, or CVID-like phenotypes. Recognition of this spectrum may facilitate earlier diagnosis, appropriate therapeutic interventions targeting IL-1/IL-18 pathways, and genetic counseling for affected families.

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2025-11-12 | Use of Teplizumab to Modulate Stage 2 Type 1 Diabetes in Two Individuals With Autoimmune Polyendocrine Syndrome 1.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a rare, monogenic autoimmune disorder that may manifest as type 1 diabetes (T1D). Teplizumab, an anti-CD3 monoclonal antibody, delays progression of stage 2 T1D, but its effects in APS-1-associated diabetes are unknown. We report clinical responses of two adolescents with APS-1 and stage 2 T1D who received 14-day courses of teplizumab. In one patient, pancreatic MRI and spectral immune cell phenotyping were performed before and after treatment. Both patients exhibited improved glycemia. One who briefly required insulin recovered insulin independence 2 weeks after therapy. Pancreatic volume transiently increased, and circulating lymphocytes showed changes in homing receptors and senescence markers in the individual who underwent those studies. Nonpancreatic APS-1 manifestations were unchanged. Teplizumab may preserve β-cell function in APS-1-associated T1D. Larger studies are needed to define efficacy, durability, and immunologic and tissue mechanisms in this rare context.

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2025-11-01 | First-in-class anti-human CD45RC antibody targets CD45RChigh T and B cells to mitigate pathogenic immune responses.

CD45RC, an isoform of the transmembrane tyrosine phosphatase CD45, regulates T and B cell antigen receptor signaling and is highly expressed on Th1 precursors, Th1 cells, T effector memory CD45RA+ cells, and most B cells. Preclinical studies have shown that anti-CD45RC monoclonal antibodies (mAbs) can prevent or control diseases such as transplant rejection, graft-versus-host disease (GvHD), Duchenne muscular dystrophy (DMD), and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED or APS-1). However, their mechanism of action remained unclear. Here, we elucidate the mechanism of anti-human CD45RC mAbs, showing that it selectively induces apoptosis in CD45RChigh T and B cells through binding to cells expressing >24 CD45RC molecules/μm2. This interaction triggers intracellular signaling without cytokine release. Cytotoxicity by apoptosis is enhanced by crosslinking with a secondary antibody. The mAb also promotes antibody-dependent cellular phagocytosis by monocyte-derived macrophages, without inducing antibody-dependent cellular cytotoxicity or complement-dependent cytotoxicity, likely due to the length of CD45RC. In CD34+-humanized NSG mice, anti-CD45RC mAbs demonstrated dose-dependent depletion of CD45RChigh T and B cells and defined a minimum effective dose to prevent xenogeneic GvHD. These findings define the mechanism of action of this first-in-class anti-human CD45RC therapeutic mAb and supports its potential for the treatment of transplant rejection, GvHD, and autoimmune diseases.

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cell therapies

2026-06-26 | FOXP3 Mutations and Instability as Determinants of Regulatory T-Cell Plasticity in Endocrine Autoimmunity

Autoimmune endocrine diseases constitute a group of disorders characterized by immune-mediated destruction or dysfunction of hormone-producing glands. The pathogenesis of these diseases reflects a breakdown of immune tolerance in which regulatory T cells (Tregs) play a key role. The transcription factor forkhead box P3 (FOXP3) is a master regulator of Treg differentiation and suppressive function. Also, it is central to maintaining self-tolerance. Genetic mutations in FOXP3, including those responsible for immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome, highlight the critical role of FOXP3 in endocrine immune tolerance. Emerging evidence suggests that autoimmune endocrine disorders may reflect organ-specific destabilization of FOXP3 expression rather than complete Treg deficiency. The reversibility or irreversible loss of FOXP3 gene expression represents a key determinant of Treg plasticity and the persistence of autoimmune inflammation. This review proposes an integrated genetic–epigenetic model of FOXP3 instability and examines how the endocrine microenvironment shapes Treg plasticity. Genetic or epigenetic alterations affecting FOXP3 expression can impair Treg activity and precipitate endocrine organ-specific autoimmunity. Epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNA-mediated regulation that modulate FOXP3 transcriptional activity are discussed. From a translational perspective, the potential of FOXP3 as a biomarker for endocrine disease susceptibility and progression was summarized. Furthermore, therapeutic strategies employed for expanding or engineering functional FOXP3+ Tregs using antigen-specific vaccines, chimeric antigen receptors (CAR)-Tregs, gene therapy, or low-dose interleukin-2 (IL-2) were described.

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2026-05-01 | Human FOXP3 Isoforms in Health and Disease

Forkhead box P3 (FOXP3) is the master transcription factor of regulatory T cells (Tregs) and is essential for maintaining immune tolerance. FOXP3 is stably expressed in Tregs, driving their suppressive function, and it is transiently induced in conventional T cells (Tconv) upon activation, where it fine-tunes immune responses. In humans, but not in mice, FOXP3 is expressed as two major isoforms: the full-length protein (FOXP3FL) and an isoform lacking exon 2 (FOXP3Δ2), with additional variants such as FOXP3Δ7 and FOXP3Δ2Δ7 described. The precise contribution of each isoform to Treg development, stability, and function in health and disease remains incompletely defined, although clinical observations indicate that patients expressing only FOXP3Δ2 develop autoimmunity, highlighting a nonredundant role for FOXP3FL in Treg-mediated tolerance. Multiple studies have further associated increased FOXP3Δ2 expression with autoimmune disease and reduced Treg stability, suggesting that the relative abundance of FOXP3FL and FOXP3Δ2 may critically shape Treg function and the balance between tolerance and pathology. However, the physiological expression levels and ratios of FOXP3FL and FOXP3Δ2 in Tregs and activated Tconvs remain poorly characterized, hindering understanding of the distinct functions of these isoforms, the correlation of specific FOXP3 mutations with isoform expression patterns and disease severity, and the development of Treg-targeted and gene transfer–based therapies. To address this, we quantified isoform-specific expression in Tregs and activated Tconvs from healthy donors and in patients with loss-of-function mutations in FOXP3 that cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a severe monogenic disorder that typically presents in early infancy, affects male patients, and is almost uniformly fatal without definitive therapy. Our data indicate that FOXP3Δ2 is the dominant isoform in activated Tconvs and Tregs across both cohorts, with a FOXP3FL:FOXP3Δ2 ratio of 0.52 ± 0.08, suggesting that regulated co-expression of FOXP3 isoforms but not exclusive expression of a single isoform underpins effective Treg development and function. Consequently, therapeutic strategies for IPEX and autoimmunity should aim to restore a physiologic FOXP3 isoform balance rather than solely achieving full-length FOXP3 expression.

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2026-03-15 | Preclinical efficacy and safety assessment of engineered regulatory T cells for treatment of IPEX and other autoimmune disorders.

FOXP3 is an essential transcription factor driving lineage commitment and function of regulatory T cells (Tregs). We previously reported a proof-of-concept study describing engineered Tregs (EngTregs) generated using homology-directed repair-based editing of the FOXP3 gene in CD4+ T cells, resulting in constitutive, high-level endogenous FOXP3 expression leading to acquisition of a Treg phenotype and robust in vitro and in vivo suppressive function. Here, we expand this gene-editing strategy to integrate a functional FOXP3 cDNA to enable EngTreg therapy for immune dysregulation, poly-endocrinopathy, enteropathy, X-linked syndrome (IPEX), a devastating multiorgan autoimmune disorder mediated by mutations within the FOXP3 gene. We provide a detailed characterization of preclinical EngTreg generation, including gene targeting efficiencies, cell enrichment and expansion, analyses of potential off-target editing, and phenotypic and functional characterization, including in vitro suppression of effector T cells and in vivo reversal of graft-versus-host disease. Importantly, in parallel, we utilize syngeneic and humanized mouse models to demonstrate the safety of EngTregs in primary and secondary humoral responses and viral infection control, respectively. Our combined preclinical dataset strongly supports the efficacy and safety of EngTregs as a promising potential cellular therapeutic approach for IPEX and possibly other autoimmune disorders.

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2025-07-01 | First Successful Fertility Preservation Using Oocyte Vitrification in Patient with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

Background/Objectives: Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autoimmune disorder caused by mutations in the AIRE gene. Approximately 60% of affected females develop premature ovarian insufficiency (POI) by age 30, often most commonly due to steroidogenic autoantibodies. Although APECED is typically diagnosed in childhood, its reproductive implications are underrecognized. This study reports a case of successful fertility preservation in an adult woman with APECED and reviews the relevant literature. Methods: We describe the clinical course of a 37-year-old woman with genetically confirmed APECED who underwent ovarian stimulation for fertility preservation. A comprehensive PubMed search was also conducted to identify English-language case reports on fertility preservation in APECED-associated POI. Results: The patient experienced menarche at age 13, adrenal insufficiency at 14, and menstrual irregularities from age 18. Genetic analysis confirmed an AIRE mutation (NM_000383: exon 11: c.1400+1G>A). Given her relatively high anti-Müllerian hormone level, she opted for fertility preservation and underwent six cycles of ovarian stimulation, resulting in the cryopreservation of 17 mature oocytes. During ovarian stimulation, multiple follicular developments were observed, but serum E2 levels remained low. The literature review identified fewer than 20 reported cases addressing fertility preservation in APECED, highlighting its rarity and the lack of standardized management. Conclusions: Although APECED frequently leads to early POI due to impaired steroidogenesis, residual ovarian function may persist. Early assessment of ovarian reserve and timely fertility counseling are crucial, even in asymptomatic patients or those diagnosed in childhood. Reproductive planning should be integrated into the long-term care of women with APECED.

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2024-10-01 | S4811 IPEX Syndrome With SBS and Its Novel Management Strategies

Introduction: IPEX syndrome stands for Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome caused due to mutations in forkhead box P3 FOXP3 gene which encodes a vital transcription factor for the maintenance of T -Reg cells. Activated T-cells infiltrate into the lamina propria and mucosa causing villous atrophy. Classic presentation includes severe intractable enteropathy leading to malabsorption (Enteropathy accounts for 95-98%), endocrinopathy (type -1 insulin dependent diabetes) and dermatitis (erythematous rash, eczema). There are other symptoms like recurrent infections leading to sepsis, hematologic and renal abnormalities etc. Below we discuss a case of IPEX with SBS and the novel treatment. Case Description/Methods: Here we present a case of milder variation of IPEX syndrome in a 28-year-old man, with FOXP3 mutation resulting in Crohn’s like IBD phenotype. Around age 6 years he underwent partial proctocolectomy and later around 13 years of age had total proctocolectomy, small bowel resection and ileostomy creation. Throughout his life he had severe sepsis, fistula formations and complications leading to multiple gut resections leading to short bowel syndrome. Along with enteropathy he had other autoimmune conditions like bronchiectasis, atrial fibrillation and pulmonary embolism. All were managed accordingly. Post operatively he's had persistent issues with wound healing, resulting in fistula formation through his midline incision. The current fistula has evolved to be essentially an externalized loop of bowel with 2 openings, secreting enteric contents. He has required multiple exploratory laparotomies in the past for management of fistulation and resulting obstructions. There is about 13ft of bowel remaining after multiple resections. He is currently dependent on total parenteral nutrition. Discussion: Novel management strategies with hematopoietic stem cell transplant and immunosuppression have shown finer results and better outcomes. Immunosuppression does help to an extent with infections and so do steroids. We plan to do a small bowel transplant either sequentially or in combination with bone marrow transplant. As a milder variant of this mutation, we anticipate this plan of treatment will have a favorable aftereffect.

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2025-08-14 | Precision T cell correction platform for inborn errors of immunity.

CRISPR-Cas9 gene editing is a promising tool to correct pathogenic variants for autologous cell therapies targeting inborn errors of immunity (IEI). Current strategies, such as gene knockout or cDNA knockin, address many single-gene defects but can disrupt gene expression, highlighting the need for precise correction platforms. While transplanting corrected autologous hematopoietic stem cells is a curative approach, it is unsuitable for patients with advanced disease, inflammation, or acute infections. As correcting T cells is an alternative therapeutic strategy for lymphoid IEIs, we present an efficient T cell single-nucleotide variant (SNV) correction platform based on homology-directed repair (HDR). By using STAT1 gain-of-function, cartilage hair hypoplasia, deficiency of ADA2, and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy as IEI models, we demonstrate that our platform achieves up to 80% correction, with resultant functional correction of the disease phenotype in the selected models. Furthermore, we performed safety profiling using GUIDE-seq, single-cell RNA sequencing, long-read genome sequencing, and proteomics analysis and detected no genomic, transcriptomic, or proteomic aberrations. This study establishes HDR-based SNV editing as a portable method for developing clinical autologous T cell therapies and represents a promising step toward a broad-spectrum gene correction platform for treating diverse monogenic immune disorders.

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2025-03-12 | The CRISPR-Cas9 System Is Used to Edit the Autoimmune Regulator Gene in Vitro and in Vivo.

Although mutations in the AIRE gene in patients with autoimmune polyendocrine syndrome type 1 (APS-1) syndrome are associated with the onset of this autoimmune disease, much of what is known about its mechanisms has been obtained through studies with Aire mutant Mus musculus mouse model or with Aire mutant medullary thymic epithelial cells (mTEC) cultured in vitro. The in vivo murine model was soon established, and ten mutant strains are currently described. Most Aire mutant mice were obtained through homologous recombination, which generated Aire knockout (KO) animals. Nevertheless, long-term cultures of mTECs from APS-1 patients or Aire mutant mice are difficult to establish. The CRISPR-Cas9 system to edit Aire in a murine mTEC line in vitro and mouse embryo has been successfully used to overcome this. The ribonucleoprotein (RNP) complexes composed of the guide RNA (gRNA), the Cas9 enzyme, and single-stranded oligonucleotides (ssODN) were designed to target Aire exons 6 and 8 separately. The CRISPR-Cas9 makes it possible to produce NHEJ-derived indels or HDR-derived mutations. Efforts are being concentrated on using RNP complex rather than plasmid vectors, as RNP makes recurrent NHEJ-derived mutations among in vitro and in vivo editions. One recurrent mutation was described in the Aire exon 6 (del 3554G) and the other in the exon 8 (del 5676_5677TG), i.e., the exon 6 mutation was kept in an mTEC clone edited in vitro and in vivo in a mouse, and the exon 8 mutation was kept in several mTEC clones in vitro. In contrast, none of the mutations obtained with the nickase system (plasmid expression vector) were recurrent, indicating the participation of the RNP complex in recurring mutation, which offers advantages, as it does not involve recombinant plasmids and does not generate a genetically modified organism but rather a mutant animal or cell.

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2024-10-25 | Uncovering ASO-Targetable Deep Intronic AIRE Variants: Insights and Therapeutic Implications.

High-throughput DNA sequencing has accelerated the discovery of disease-causing genetic variants, yet only in 10-40% of cases yield a genetic diagnosis. Increased implementation of genome sequencing has enabled a deeper exploration of the noncoding genome and recognition of noncoding variants as major contributors to disease. In a recent study, we identified a deep intronic variant in the AutoImmune REgulator (AIRE) gene (c.1504-818 G>A) as the cause of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a life-threatening monogenic autoimmune disorder most often caused by biallelic AIRE defects. This deep intronic variant disrupts normal splicing AIRE , causing pseudoexon inclusion and altered protein function. By developing an antisense oligonucleotide (ASO) targeting the pseudoexon sequence, we restored normal AIRE transcript in vitro, thereby revealing a potential genotype-specific candidate treatment. Our study illustrates key aspects of intronic variant detection, validation, and candidate ASO development. Herein, we briefly highlight the growing potential of ASO-based therapies for deep intronic variants, addressing the unmet need of personalized, genotype-specific therapies in diseases lacking curative options.

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2024-09-18 | A deep intronic splice-altering AIRE variant causes APECED syndrome through antisense oligonucleotide-targetable pseudoexon inclusion.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a life-threatening monogenic autoimmune disorder primarily caused by biallelic deleterious variants in the autoimmune regulator (AIRE) gene. We prospectively evaluated 104 patients with clinically diagnosed APECED syndrome and identified 17 patients (16%) from 14 kindreds lacking biallelic AIRE variants in exons or flanking intronic regions; 15 had Puerto Rican ancestry. Through whole-genome sequencing, we identified a deep intronic AIRE variant (c.1504-818 G>A) cosegregating with the disease in all 17 patients. We developed a culture system of AIRE-expressing primary patient monocyte-derived dendritic cells and demonstrated that c.1504-818 G>A creates a cryptic splice site and activates inclusion of a 109-base pair frame-shifting pseudoexon. We also found low-level AIRE expression in patient-derived lymphoblastoid cell lines (LCLs) and confirmed pseudoexon inclusion in independent extrathymic AIRE-expressing cell lines. Through protein modeling and transcriptomic analyses of AIRE-transfected human embryonic kidney 293 and thymic epithelial cell 4D6 cells, we showed that this variant alters the carboxyl terminus of the AIRE protein, abrogating its function. Last, we developed an antisense oligonucleotide (ASO) that reversed pseudoexon inclusion and restored the normal AIRE transcript sequence in LCLs. Thus, our findings revealed c.1504-818 G>A as a founder APECED-causing AIRE variant in the Puerto Rican population and uncovered pseudoexon inclusion as an ASO-reversible genetic mechanism underlying APECED.

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2024-09-06 | T cell correction pipeline for Inborn Errors of Immunity

CRISPR/Cas9 gene editing technology is a promising tool for correcting pathogenic variants for autologous cell therapies for Inborn Errors of Immunity (IEI). The present IEI correction strategies mainly focus on the knock-in of therapeutic cDNAs, or knockout of the disease-causing gene when feasible. These strategies address many single-gene defects but may disrupt gene expression and require significant optimization for each newly discovered IEI-causing gene, highlighting the need for complementary platforms that can precisely correct diverse pathogenic variants. Here, we present a safe and efficient T cell single nucleotide variant (SNV) correction pipeline based on homology-directed repair (HDR), suitable for diverse monogenic mutations. By using founder mutations of Deficiency of ADA2 (DADA2), Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and Cartilage Hair Hypoplasia (CHH) as IEI models, we show that our pipeline can achieve up to 80% bi-allelic editing, with resultant functional correction of the disease phenotype in patient T cells. We do not find detectable pre-malignant off-target effects or karyotypic, transcriptomic or proteomic aberrations upon profiling patient T cells with GUIDE-seq, single cell RNA sequencing, PacBio based long-read whole genome sequencing, and high-throughput proteomics. This study demonstrates that HDR-based SNV editing is a safe and effective option for IEI T cell correction and that it could be developed to an autologous T cell therapy, as the presented protocol is scalable for a GMP-compatible workflow. This study is a step towards the development of gene correction platform that targets a broad number of monogenic mutations.

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