Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation

Narula, Mansi; Lakshmanan, Uma; Borna, Simon; Schulze, Janika; Holmes, Tyson H.; Harre, Nicholas; Kirkey, Matthew; Ramachandran, Akshaya; Tagi, Veronica Maria; Barzaghi, Federica; Grunebaum, Eyal; Upton, Julia; Kim, Vy Hong-Diep; Wysocki, Christian; Dimitriades, Victoria R.; Weinberg, Kenneth I.; Weinacht, Katja G.; Gernez, Yaël; Sathi, Bindu Kanathezhath; Schelotto, Magdalena; Johnson, Matthew; Olek, Sven; Sachsenmaier, Christoph; Roncarolo, Maria‐Grazia; Bacchetta, Rosa

doi:10.1016/j.jaci.2022.09.013

Cited by 17 publications

(40 citation statements)

References 57 publications

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“…Clinical data on this human cohort was previously published by Gambineri et al, 2018 . For the independent validation cohort ( Figure 5C ), all patient cohort data was collected and evaluated at Stanford under an IRB-approved protocol and was previously published by Narula et al, 2022 .…”

Section: Methodsmentioning

confidence: 99%

Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq

Vazquez

Mann

Bodansky

et al. 2022

eLife

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Phage Immunoprecipitation-Sequencing (PhIP-Seq) allows for unbiased, proteome-wide autoantibody discovery across a variety of disease settings, with identification of disease-specific autoantigens providing new insight into previously poorly understood forms of immune dysregulation. Despite several successful implementations of PhIP-Seq for autoantigen discovery, including our previous work (Vazquez et al. 2020), current protocols are inherently difficult to scale to accommodate large cohorts of cases and importantly, healthy controls. Here, we develop and validate a high throughput extension of PhIP-seq in various etiologies of autoimmune and inflammatory diseases, including APS1, IPEX, RAG1/2 deficiency, Kawasaki Disease (KD), Multisystem Inflammatory Syndrome in Children (MIS-C), and finally, mild and severe forms of COVID19. We demonstrate that these scaled datasets enable machine-learning approaches that result in robust prediction of disease status, as well as the ability to detect both known and novel autoantigens, such as PDYN in APS1 patients, and intestinally expressed proteins BEST4 and BTNL8 in IPEX patients. Remarkably, BEST4 antibodies were also found in 2 patients with RAG1/2 deficiency, one of whom had very early onset IBD. Scaled PhIP-Seq examination of both MIS-C and KD demonstrated rare, overlapping antigens, including CGNL1, as well as several strongly enriched putative pneumonia-associated antigens in severe COVID19, including the endosomal protein EEA1. Together, scaled PhIP-Seq provides a valuable tool for broadly assessing both rare and common autoantigen overlap between autoimmune diseases of varying origins and etiologies.

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Section: Methodsmentioning

confidence: 99%

Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq

Vazquez

Mann

Bodansky

et al. 2022

eLife

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“…For instance, in immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX) patients, deleterious mutations in FOXP3 result in a failure of Tregs to suppress autoimmunity. Intriguingly, T cells from IPEX patients can differentiate into Tr1 cells ( 146 ), and increased frequencies of Tr1 cells correlate with diminished disease severity ( 147 ). Another reason Tr1 cells may exist is the broad antigen specificity Tr1 cells can acquire.…”

Section: Importance Of Tr1 In the Face Of Other Regulatory T Cellsmentioning

confidence: 99%

Type 1 regulatory T cell-mediated tolerance in health and disease

2022

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Type 1 regulatory T (Tr1) cells, in addition to other regulatory cells, contribute to immunological tolerance to prevent autoimmunity and excessive inflammation. Tr1 cells arise in the periphery upon antigen stimulation in the presence of tolerogenic antigen presenting cells and secrete large amounts of the immunosuppressive cytokine IL-10. The protective role of Tr1 cells in autoimmune diseases and inflammatory bowel disease has been well established, and this led to the exploration of this population as a potential cell therapy. On the other hand, the role of Tr1 cells in infectious disease is not well characterized, thus raising concern that these tolerogenic cells may cause general immune suppression which would prevent pathogen clearance. In this review, we summarize current literature surrounding Tr1-mediated tolerance and its role in health and disease settings including autoimmunity, inflammatory bowel disease, and infectious diseases.

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“…It is important to note, however, that our data are cross sectional with variable follow-up periods and rely on comprehensive reporting of symptoms by referring clinicians. A recent study on 15 individuals with IPEX syndrome showed that demethylation at the TSDR increased [23].…”

Section: Discussionmentioning

confidence: 98%

“…In individuals with IPEX syndrome, functional Tregs are largely absent, and one of the most typical Treg markers, intracellular antibody staining of FOXP3, may no longer work [21]. At the same time, the number of cells counted by other Treg surface markers (e.g., CD4( +), CD25( +), and CD127(low)) may no longer reflect fully functional Tregs [1,10,21,22] which are highly variable in individuals with IPEX syndrome [23]. Indeed, a breakdown of correlation between surface Treg markers and FOXP3 TSDR demethylation was recently shown in 15 IPEX patients whose FOXP3 expression was independent of TSDR demethylation [23].…”

Section: Discussionmentioning

confidence: 99%

“…At the same time, the number of cells counted by other Treg surface markers (e.g., CD4( +), CD25( +), and CD127(low)) may no longer reflect fully functional Tregs [1,10,21,22] which are highly variable in individuals with IPEX syndrome [23]. Indeed, a breakdown of correlation between surface Treg markers and FOXP3 TSDR demethylation was recently shown in 15 IPEX patients whose FOXP3 expression was independent of TSDR demethylation [23]. We were not able to measure regulatory T cell number or function in our cohort to assess whether TSDR quantification is related to Treg function in our cohort, as we were not able to obtain fresh samples for analysis.…”

Section: Discussionmentioning

confidence: 99%

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FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome

Wyatt

Olek²,

Franco

et al. 2023

J Clin Immunol

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Pathogenic FOXP3 variants cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, a progressive autoimmune disease resulting from disruption of the regulatory T cell (Treg) compartment. Assigning pathogenicity to novel variants in FOXP3 is challenging due to the heterogeneous phenotype and variable immunological abnormalities. The number of cells with demethylation at the Treg cell-specific demethylated region (TSDR) is an independent biomarker of IPEX. We aimed to investigate if diagnosing IPEX at presentation with isolated diabetes could allow for effective monitoring of disease progression and assess whether TSDR analysis can aid FOXP3 variant classification and predict disease course. We describe a large genetically diagnosed IPEX cohort (n = 65) and 13 individuals with other monogenic autoimmunity subtypes in whom we quantified the proportion of cells with FOXP3 TSDR demethylation, normalized to the number with CD4 demethylation (%TSDR/CD4) and compare them to 29 unaffected controls. IPEX patients presenting with isolated diabetes (50/65, 77%) often later developed enteropathy (20/50, 40%) with a median interval of 23.5 weeks. %TSDR/CD4 was a good discriminator of IPEX vs. unaffected controls (ROC-AUC 0.81, median 13.6% vs. 8.5%, p < 0.0001) with higher levels of demethylation associated with more severe disease. Patients with other monogenic autoimmunity had a similar %TSDR/CD4 to controls (median 8.7%, p = 1.0). Identifying increased %TSDR/CD4 in patients with novel FOXP3 mutations presenting with isolated diabetes facilitates diagnosis and could offer an opportunity to monitor patients and begin immune modulatory treatment before onset of severe enteropathy.

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Epigenetic and immunological indicators of IPEX disease in subjects with FOXP3 gene mutation

Cited by 17 publications

References 57 publications

Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq

Autoantibody discovery across monogenic, acquired, and COVID-19-associated autoimmunity with scalable PhIP-seq

Type 1 regulatory T cell-mediated tolerance in health and disease

FOXP3 TSDR Measurement Could Assist Variant Classification and Diagnosis of IPEX Syndrome

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