The autoimmune targets in IPEX are dominated by gut epithelial proteins

Eriksson, Daniel; Bacchetta, Rosa; Gunnarsson, Hörður Ingi; Chan, Alice; Barzaghi, Federica; Ehl, Stephan; Hallgren, Åsa; Gool, Frédéric Van; Sardh, Fabian; Lundqvist, Christina; Laakso, Markku; Rönnblom, Anders; Ekwall, Olov; Mäkitie, Outi; Bensing, Sophie; Husebye, Eystein S.; Anderson, Mark S.; Kämpe, Olle; Landegren, Nils

doi:10.1016/j.jaci.2019.02.031

“…A handful of IPEX autoantibodies targeting antigens expressed in the intestine have been described, including harmonin (USH1C) and ANKS4B ( Eriksson et al, 2019 ; Kobayashi et al, 2011 ). In our data, enrichment of USH1C was observed in two IPEX patients, and this signal was fully correlated with anti-ANKS5B as previously described ( Figure 5—figure supplement 1 ; Eriksson et al, 2019 ).…”

Section: Resultsmentioning

confidence: 99%

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

Vazquez

¹

,

Mann

²

,

Bodansky

³

et al. 2022

eLife

Self Cite

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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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“…Their production can be genetically driven, as in patients with autoimmune polyendocrine syndrome type-1 (APS-1) due to germline mutations of AIRE, which controls the thymic expression of peripheral self-antigens and, thus, central T-cell tolerance [68][69][70] . They are also found in men with immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) due to mutations of FOXP3, encoding a protein that governs the development of regulatory T cells and thus, peripheral T-cell tolerance 71,72 , and in patients with combined T/B cell immunodeficiency due to hypomorphic mutations of RAG1 or RAG2 73 . Auto-Abs against type I IFN may also be produced in two overlapping conditions 74 of elusive etiology: thymoma 75 and myasthenia gravis 76,77 .…”

Section: From Inborn Errors To Their Phenocopymentioning

confidence: 99%

Human genetic and immunological determinants of critical COVID-19 pneumonia

Zhang

¹

,

Bastard

²

,

Karbuz³

et al. 2022

Nature

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This is a PDF file of a peer-reviewed paper that has been accepted for publication. Although unedited, the content has been subjected to preliminary formatting. Nature is providing this early version of the typeset paper as a service to our authors and readers. The text and figures will undergo copyediting and a proof review before the paper is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers apply.

show abstract

“…A handful of IPEX autoantibodies targeting antigens expressed in the intestine have been described, including harmonin (USH1C) and ANKS4B (Eriksson et al, 2019; Kobayashi et al, 2011). In our data, enrichment of USH1C was observed in 2 IPEX patients, and this signal was fully correlated with anti-ANKS5B as previously described (Figure 5 – Figure Supplement 1) (Eriksson et al, 2019).…”

Section: Resultsmentioning

confidence: 99%

Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq

Vazquez

¹

,

Mann

²

,

Bodansky

³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

The autoimmune targets in IPEX are dominated by gut epithelial proteins

Cited by 13 publications

References 16 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

Human genetic and immunological determinants of critical COVID-19 pneumonia

Autoantibody discovery across monogenic, acquired, and COVID19-associated autoimmunity with scalable PhIP-Seq

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