Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

doi:10.1084/jem.20231152

. 2024 Nov 4;221(11):e20231152.

doi: 10.1084/jem.20231152. Epub 2024 Oct 1.

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

Jérémie Rosain^{1

2

3

4}, Tom Le Voyer^#^{1

2

3

5}, Xian Liu^#⁶, Adrian Gervais^#^{1

2}, Laura Polivka^#^{7

8}, Axel Cederholm^#⁹, Laureline Berteloot^#¹⁰, Audrey V Parent^#⁶, Alessandra Pescatore^#¹¹, Ezia Spinosa^#¹¹, Snezana Minic^#^{12

13}, Ana Elisa Kiszewski^#^{14

15}, Miyuki Tsumura^#¹⁶, Chloé Thibault^#^{1

2}, Maria Esnaola Azcoiti^#^{1

2}, Jelena Martinovic^#¹⁷, Quentin Philippot^#^{1

2}, Taushif Khan^#¹⁸, Astrid Marchal^#^{1

2}, Bénédicte Charmeteau-De Muylder^#¹⁹, Lucy Bizien^#^{1

2}, Caroline Deswarte^#^{1

2}, Lillia Hadjem²⁰, Marie-Odile Fauvarque²¹, Karim Dorgham²², Daniel Eriksson²³, Emilia Liana Falcone^{24

25}, Mathilde Puel⁴, Sinem Ünal^{1

2}, Amyrath Geraldo^{1

2}, Corentin Le Floc'h^{1

2}, Hailun Li^{1

2}, Sylvie Rheault^{25

26}, Christine Muti²⁷, Claire Bobrie-Moyrand²⁸, Anne Welfringer-Morin⁷, Ramsay L Fuleihan²⁹, Romain Lévy^{1

2

3

30}, Marie Roelens^{2

4}, Liwei Gao^{1

2}, Marie Materna^{1

2}, Silvia Pellegrini³¹, Lorenzo Piemonti³¹, Emilie Catherinot³², Jean-Christophe Goffard³³, Arnaud Fekkar^{1

2

34}, Aissata Sacko-Sow³⁵, Camille Soudée^{1

2}, Soraya Boucherit^{1

2}, Anna-Lena Neehus^{1

2}, Cristina Has^{36

37}, Stefanie Hübner³⁶, Géraldine Blanchard-Rohner³⁸, Blanca Amador-Borrero³⁹, Takanori Utsumi¹⁶, Maki Taniguchi¹⁶, Hiroo Tani^{40

41}, Kazushi Izawa⁴², Takahiro Yasumi⁴², Sotaro Kanai⁴³, Mélanie Migaud^{1

2}, Mélodie Aubart^{1

2

44}, Nathalie Lambert⁴, Guy Gorochov^{22

45}, Capucine Picard^{2

4

46}, Claire Soudais⁴⁶, Anne-Sophie L'Honneur⁴⁷, Flore Rozenberg⁴⁷, Joshua D Milner²⁹, Shen-Ying Zhang^{1

2

3}, Pierre Vabres⁴⁸, Dusan Trpinac⁴⁹, Nico Marr^{18

50}, Nathalie Boddaert¹⁰, Isabelle Desguerre⁴⁴, Manolis Pasparakis⁵¹, Corey N Miller⁶, Cláudia S Poziomczyk⁵², Laurent Abel^{1

2

3}, Satoshi Okada¹⁶, Emmanuelle Jouanguy^{1

2

3}, Rémi Cheynier¹⁹, Qian Zhang^{1

2

3}, Aurélie Cobat^{1

2

3}, Vivien Béziat^{1

2

3}, Bertrand Boisson^{1

2

3}, Julie Steffann⁵³, Francesca Fusco¹¹, Matilde Valeria Ursini¹¹, Smail Hadj-Rabia⁷, Christine Bodemer⁷, Jacinta Bustamante^{1

2

3

4}, Hervé Luche²⁰, Anne Puel^#^{1

2

3}, Gilles Courtois^#²¹, Paul Bastard^#^{1

2

3

30}, Nils Landegren^#^{9

54}, Mark S Anderson^#⁶, Jean-Laurent Casanova^#^{1

2

3

55

56}

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France.
² Imagine Institute, University of Paris Cité , Paris, France.
³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
⁴ Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris, France.
⁵ Clinical Immunology Department, AP-HP, Saint-Louis Hospital, Paris, France.
⁶ Diabetes Center, University of California San Francisco , San Francisco, CA, USA.
⁷ Department of Dermatology, Reference Center for Genodermatosis and Rare Skin Diseases (MAGEC), University of Paris Cité, Necker Hospital for Sick Children, AP-HP, Paris, France.
⁸ Reference Center for Mastocytosis (CEREMAST), Necker Hospital for Sick Children, AP-HP , Paris, France.
⁹ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
¹⁰ Pediatric Radiology Department, Necker Hospital for Sick Children, Imagine Inserm Institute, U1163, AP-HP, Paris, France.
¹¹ Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," IGB-CNR , Naples, Italy.
¹² Clinics of Dermatovenerology, Clinical Center of Serbia , Belgrade, Serbia.
¹³ School of Medicine, University of Belgrade , Belgrade, Serbia.
¹⁴ Section of Dermatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.
¹⁵ Section of Pediatric Dermatology, Hospital da Criança Santo Antônio, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.
¹⁶ Hiroshima University Graduate School of Biomedical and Health Sciences , Hiroshima, Japan.
¹⁷ Unit of Fetal Pathology, Hospital Antoine Béclère, Paris Saclay University , Paris, France.
¹⁸ Department of Immunology, Sidra Medicine, Doha, Qatar.
¹⁹ University of Paris Cité, CNRS, Inserm, Institut Cochin , Paris, France.
²⁰ Immunophenomics Center (CIPHE), Aix Marseille University, Inserm, CNRS , Marseille, France.
²¹ University Grenoble Alpes, CEA, Inserm , BGE UA13, Grenoble, France.
²² Sorbonne University, Inserm, Centre for Immunology and Microbial Infections, CIMI-Paris , Paris, France.
²³ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
²⁴ Center for Immunity, Inflammation and Infectious Diseases, Montréal Clinical Research Institute (IRCM) , Montréal, Canada.
²⁵ Department of Medicine, Montréal University, Montréal, Canada.
²⁶ Center of Research of the Geriatric University Institute of Montréal, University of Montréal , Montréal, Canada.
²⁷ Department of Genetics, André Mignot Hospital, Versailles, France.
²⁸ Department of Obstetrics and Gynecology, André Mignot Hospital, Versailles, France.
²⁹ Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
³⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
³¹ Diabetes Research Institute, IRCCS Ospedale San Raffaele , Milan, Italy.
³² Department of Respiratory Diseases, Foch Hospital, Suresnes, France.
³³ Internal Medicine, Brussels University Hospital, Free University of Brussels, Anderlecht, Belgium.
³⁴ Department of Parasitology Mycology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
³⁵ Department of Pediatrics, Jean Verdier Hospital, AP-HP, Bondy, France.
³⁶ Department of Dermatology, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
³⁷ European Reference Network (ERN) for Rare and Undiagnosed Skin Disorders.
³⁸ Unit of Immunology, Vaccinology, and Rheumatology, Division of General Pediatrics, Department of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
³⁹ Internal Medicine Department, Lariboisière Hospital, AP-HP, University of Paris Cité, Paris, France.
⁴⁰ Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan.
⁴¹ Department of Pediatrics, Hiroshima Prefectural Hospital, Hiroshima, Japan.
⁴² Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴³ Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
⁴⁴ Departments of Pediatric Neurology, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
⁴⁵ Department of Immunology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
⁴⁶ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm U1163, Paris, France.
⁴⁷ Department of Virology, University of Paris Cité and Cochin Hospital, AP-HP, Paris, France.
⁴⁸ MAGEC Reference Center for Rare Skin Diseases, Dijon Bourgogne University Hospital, Dijon, France.
⁴⁹ Institute of Histology and Embryology, School of Medicine, University of Belgrade , Belgrade, Serbia.
⁵⁰ College of Health and Life Sciences, Hamad Bin Khalifa University , Doha, Qatar.
⁵¹ Institute for Genetics, University of Cologne , Cologne, Germany.
⁵² Private Dermatology Practice , Porto Alegre, Brazil.
⁵³ Department of Genomic Medicine, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
⁵⁴ Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
⁵⁵ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
⁵⁶ Howard Hughes Medical Institute , New York, NY, USA.

^# Contributed equally.

PMID: 39352576
PMCID: PMC11448874
DOI: 10.1084/jem.20231152

Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

Jérémie Rosain et al. J Exp Med. 2024.

. 2024 Nov 4;221(11):e20231152.

doi: 10.1084/jem.20231152. Epub 2024 Oct 1.

Authors

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Inserm U1163, Necker Hospital for Sick Children, Paris, France.
² Imagine Institute, University of Paris Cité , Paris, France.
³ St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA.
⁴ Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, Assistance Publique-Hôpitaux de Paris (AP-HP) , Paris, France.
⁵ Clinical Immunology Department, AP-HP, Saint-Louis Hospital, Paris, France.
⁶ Diabetes Center, University of California San Francisco , San Francisco, CA, USA.
⁷ Department of Dermatology, Reference Center for Genodermatosis and Rare Skin Diseases (MAGEC), University of Paris Cité, Necker Hospital for Sick Children, AP-HP, Paris, France.
⁸ Reference Center for Mastocytosis (CEREMAST), Necker Hospital for Sick Children, AP-HP , Paris, France.
⁹ Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden.
¹⁰ Pediatric Radiology Department, Necker Hospital for Sick Children, Imagine Inserm Institute, U1163, AP-HP, Paris, France.
¹¹ Institute of Genetics and Biophysics "Adriano Buzzati-Traverso," IGB-CNR , Naples, Italy.
¹² Clinics of Dermatovenerology, Clinical Center of Serbia , Belgrade, Serbia.
¹³ School of Medicine, University of Belgrade , Belgrade, Serbia.
¹⁴ Section of Dermatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre, Brazil.
¹⁵ Section of Pediatric Dermatology, Hospital da Criança Santo Antônio, Irmandade da Santa Casa de Misericórdia de Porto Alegre, Porto Alegre, Brazil.
¹⁶ Hiroshima University Graduate School of Biomedical and Health Sciences , Hiroshima, Japan.
¹⁷ Unit of Fetal Pathology, Hospital Antoine Béclère, Paris Saclay University , Paris, France.
¹⁸ Department of Immunology, Sidra Medicine, Doha, Qatar.
¹⁹ University of Paris Cité, CNRS, Inserm, Institut Cochin , Paris, France.
²⁰ Immunophenomics Center (CIPHE), Aix Marseille University, Inserm, CNRS , Marseille, France.
²¹ University Grenoble Alpes, CEA, Inserm , BGE UA13, Grenoble, France.
²² Sorbonne University, Inserm, Centre for Immunology and Microbial Infections, CIMI-Paris , Paris, France.
²³ Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
²⁴ Center for Immunity, Inflammation and Infectious Diseases, Montréal Clinical Research Institute (IRCM) , Montréal, Canada.
²⁵ Department of Medicine, Montréal University, Montréal, Canada.
²⁶ Center of Research of the Geriatric University Institute of Montréal, University of Montréal , Montréal, Canada.
²⁷ Department of Genetics, André Mignot Hospital, Versailles, France.
²⁸ Department of Obstetrics and Gynecology, André Mignot Hospital, Versailles, France.
²⁹ Department of Pediatrics, Columbia University Medical Center, New York, NY, USA.
³⁰ Pediatric Hematology-Immunology and Rheumatology Unit, Necker Hospital for Sick Children, AP-HP, Paris, France.
³¹ Diabetes Research Institute, IRCCS Ospedale San Raffaele , Milan, Italy.
³² Department of Respiratory Diseases, Foch Hospital, Suresnes, France.
³³ Internal Medicine, Brussels University Hospital, Free University of Brussels, Anderlecht, Belgium.
³⁴ Department of Parasitology Mycology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
³⁵ Department of Pediatrics, Jean Verdier Hospital, AP-HP, Bondy, France.
³⁶ Department of Dermatology, Medical Center-University of Freiburg, Freiburg im Breisgau, Germany.
³⁷ European Reference Network (ERN) for Rare and Undiagnosed Skin Disorders.
³⁸ Unit of Immunology, Vaccinology, and Rheumatology, Division of General Pediatrics, Department of Woman, Child, and Adolescent Medicine, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland.
³⁹ Internal Medicine Department, Lariboisière Hospital, AP-HP, University of Paris Cité, Paris, France.
⁴⁰ Department of Pediatrics, Hiroshima University Hospital, Hiroshima, Japan.
⁴¹ Department of Pediatrics, Hiroshima Prefectural Hospital, Hiroshima, Japan.
⁴² Department of Pediatrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
⁴³ Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan.
⁴⁴ Departments of Pediatric Neurology, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
⁴⁵ Department of Immunology, Pitié-Salpêtrière Hospital, AP-HP, Paris, France.
⁴⁶ Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Inserm U1163, Paris, France.
⁴⁷ Department of Virology, University of Paris Cité and Cochin Hospital, AP-HP, Paris, France.
⁴⁸ MAGEC Reference Center for Rare Skin Diseases, Dijon Bourgogne University Hospital, Dijon, France.
⁴⁹ Institute of Histology and Embryology, School of Medicine, University of Belgrade , Belgrade, Serbia.
⁵⁰ College of Health and Life Sciences, Hamad Bin Khalifa University , Doha, Qatar.
⁵¹ Institute for Genetics, University of Cologne , Cologne, Germany.
⁵² Private Dermatology Practice , Porto Alegre, Brazil.
⁵³ Department of Genomic Medicine, Necker Hospital for Sick Children, AP-HP, University of Paris Cité, Paris, France.
⁵⁴ Center for Molecular Medicine, Department of Medicine (Solna), Karolinska Institute, Stockholm, Sweden.
⁵⁵ Department of Pediatrics, Necker Hospital for Sick Children, AP-HP, Paris, France.
⁵⁶ Howard Hughes Medical Institute , New York, NY, USA.

^# Contributed equally.

PMID: 39352576
PMCID: PMC11448874
DOI: 10.1084/jem.20231152

Abstract

Human inborn errors of thymic T cell tolerance underlie the production of autoantibodies (auto-Abs) neutralizing type I IFNs, which predispose to severe viral diseases. We analyze 131 female patients with X-linked dominant incontinentia pigmenti (IP), heterozygous for loss-of-function (LOF) NEMO variants, from 99 kindreds in 10 countries. Forty-seven of these patients (36%) have auto-Abs neutralizing IFN-α and/or IFN-ω, a proportion 23 times higher than that for age-matched female controls. This proportion remains stable from the age of 6 years onward. On imaging, female patients with IP have a small, abnormally structured thymus. Auto-Abs against type I IFNs confer a predisposition to life-threatening viral diseases. By contrast, patients with IP lacking auto-Abs against type I IFNs are at no particular risk of viral disease. These results suggest that IP accelerates thymic involution, thereby underlying the production of auto-Abs neutralizing type I IFNs in at least a third of female patients with IP, predisposing them to life-threatening viral diseases.

PubMed Disclaimer

Conflict of interest statement

Disclosures: A.V. Parent reported personal fees from Thymmune Therapeutics outside the submitted work; in addition, A.V. Parent had a patent to generate thymic epithelial progenitor cells in vitro licensed (Thymmune Therapeutics). J.D. Milner reported personal fees from Blueprint Pharmaceuticals and grants from Pharming outside the submitted work. M.S. Anderson reported other from Merck, Inc. and Medtronic, Inc. outside the submitted work. No other disclosures were reported.

Figures

**Figure 1.**
**Auto-Abs** **against type I IFNs in female patients with** IP. (A) Neutralization of 100 pg/ml IFN-α2a, 100 pg/ml IFN-ω, and 10 ng/ml IFN-β by a 1:10 dilution of plasma from the indicated individuals or patients. All patients with a neutralizing ratio below 3 were assessed two or three times independently. **(B)** Neutralization of 1 ng/ml of 15 type I IFNs by plasma diluted 1:10. **(C)** The proportion of individuals with plasma-neutralizing type I IFNs by age, for female patients with IP and the general female population. **(D)** Anti-human IgG fluorescence signal intensities with positive fold-change in 15 IP patients with serum neutralizing type I IFNs and 10 IP patients without auto-Abs neutralizing type I IFNs, relative to 20 healthy donors. Each dot corresponds to the protein spot with the highest signal intensity among the duplicate spots for the protein concerned. Data displayed are merged from two independent experiments.

**Figure 2.**
**Viral diseases in female patients with** IP. (A) Thorax-computed tomography scan for P1 who had critical COVID-19 pneumonia. **(B)** Severity of COVID-19 before vaccination as a function of negativity or positivity for auto-Abs against type I IFNs (Aab−, and Aab+, respectively), and age. One of the patients (P9) was excluded from this figure because she received early treatment with recombinant IFN-β (Bastard et al., 2021b).

**Figure S2.**
**Exposure to viruses and bacteria in females with incontinentia pigmenti**. Related to Fig. 2. Antiviral antibody responses to species for which at least one sample tested seropositive by PhIP-Seq, based on in-house stringent cutoff values, color-coded as indicated.

**Figure 3.**
**Demographic, genetic, and familial features of female patients with** IP by **auto-Abs** **status. (A)** Age distribution of IP patients negative (Aab−) or positive (Aab+) for auto-Abs against type I IFNs. **(B–D)** Distribution of (B) underlying *NEMO* variants, (C) sporadic versus familial forms, and (D) X-chromosome inactivation skewing in female patients with IP negative (Aab−) or positive (Aab+) for auto-Abs against type I IFNs. **(E)** Auto-Ab status for IFN-α2a and IFN-ω in multiplex IP kindreds. Statistical analysis was performed with Student’s t tests. **P < 0.01.

**Figure S3.**
**Level of circulating IFN-α2a in females with incontinentia pigmenti (IP) and pathological study of the thymus from a male fetus with IP.** Fig. 4. **(A)** Determination of IFN-α2a levels with the Simoa platform for plasma from healthy donors (n = 10), patients with systemic lupus erythematosus (SLE, n = 10), and female patients with IP positive (n = 6) or negative (n = 12) for auto-Abs against type I IFNs. **(B)** Keratin 10 (K10), *Ulex europaeus* agglutinin 1 lectin (UEA-1), and pankeratin (PanKrt) staining of the thymus of a human male fetus with IP; comparison with an aged-matched control. Both thymi were obtained from fetuses at 19 wk of gestation with a similar estimated maceration time. Scale bar = 50 μm.

**Figure 4.**
**Thymi of** IP female patients and a male fetus. (A) Thymus volume, assessed by MRI or computed tomography scan; n = 20 aged-matched controls and n = 6 IP patients. More details regarding controls and patients are provided in Table S6. **(B)** MRI images of thymi from IP patients and aged-matched controls of the indicated ages. **(C)** Quantification of TRECs in DNA extracted from the whole blood of healthy donors or patients with IP. Data were merged from three independent experiments. **(D)** Absolute counts of CD25^hiCD127^low regulatory CD4⁺ T cells; naïve (CD45RA⁺CCR7⁺) γδ⁺, CD4⁺, or CD8⁺ T cells; and recent thymic emigrants (CD31⁺CD45RA⁺CCR7⁺) CD4⁺ or CD8⁺ T cells determined by mass cytometry on fresh whole blood from n = 24 female healthy donors and n = 23 IP patients. Experiments were performed independently and data were merged. **(E)** DAPI, keratin 5 (K5), and keratin 8 staining of formalin-fixed paraffin-embedded (FFPE) tissues from the thymus of a single male fetus with IP at 19 wk of gestation and of an aged-matched control. Scale bar = 200 μm.

**Figure 5.**
**Thymi of 7.5-day-old (P7.5) mice with** IP. (A and B) Weight of (A) the body and of (B) thymi from n = 9 WT mice and n = 9 IP mice. Results are expressed as a percentage of the mean for the WT in the same experiment. Data from two independent experiments are displayed. **(C)** Measurement of the area of the thymic cortex. **(D)** Measurement of the ghost area in thymi from WT and IP mice. **(E)** Representative confocal images of K8 (red), K5 (green), and DAPI (blue) staining of the thymus for WT and IP mice. Scale bar = 200 μm, n = 3–4 mice. Representative confocal images of K5/K8 (red), and CD4 (green) staining in WT and IP mice. Scale bar of left panel = 200 μm, Scale bar of other panel = 50 μm. n = 3–4 mice. **(F)** Representative images of K5/K8 (red) staining of thymi from WT mice (n = 4), *Nemo*^+/− female mice (IP, n = 3), and *Tnfr-1*^−/−/*Nemo*^+/− female mice (IP/TNFR1 KO, n = 2). ns = not significant, P > 0.05; **P < 0.01; ****P < 0.0001. All experiments were performed at least two or three times independently.

**Figure S4.**
**Thymi of 7.5-day-old (P7.5) mice with IP**. Related to Fig. 5. **(A)** Images of the thymi, hearts, and spleens of a WT mouse and an IP mouse. **(B)** Representative images of K5/K8 (red) staining of thymi from WT mice (n = 4), *Nemo*^+/− female mice (IP, n = 3), *Tnfr-1*^−/−/*Nemo*^+/+ female mice (TNFR1 KO, n = 1), and *Tnfr-1*^−/−/*Nemo*^+/− female mice (IP/TNFR1 KO, n = 2). Scale bar = 200 μm. **(C)** Representative confocal images of K5 (red), AIRE (green), and DAPI (blue) staining in WT and IP mice. Scale bar = 20 μm, n = 3–4 mice. **(D)** Percentages for the thymocyte subsets extracted from the thymi of n = 14 WT mice or n = 13 IP mice. DN = double-negative (CD4⁻CD8⁻); TN = triple-negative (CD3⁻CD4⁻CD8⁻), DP = double-positive (CD4⁺CD8⁺); ISP = immature single-positive; IE = immediate early. Statistical analysis was performed with Student’s t test. ns = not significant, P > 0.05; *P < 0.05; **P < 0.01. All experiments in mice were performed at least two or three times independently.

**Figure S5.**
**Keratin 5 and 10 staining in thymi from newborn mice**. Related to Fig. 5. Keratin 5 (K5, green), keratin 10 (K10, red), and nuclear (DAPI, blue) staining of thymic sections from WT mice, IP mice, or IP/TNFR1 KO mice. Scale bar = 50 µm. Data representative from two independent experiments are displayed.

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References

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1. Acosta-Ampudia, Y., Monsalve D.M., Rojas M., Rodríguez Y., Gallo J.E., Salazar-Uribe J.C., Santander M.J., Cala M.P., Zapata W., Zapata M.I., et al. . 2021. COVID-19 convalescent plasma composition and immunological effects in severe patients. J. Autoimmun. 118:102598. 10.1016/j.jaut.2021.102598 - DOI - PMC - PubMed
1. Akbil, B., Meyer T., Stubbemann P., Thibeault C., Staudacher O., Niemeyer D., Jansen J., Mühlemann B., Doehn J., Tabeling C., et al. . 2022. Early and rapid identification of COVID-19 patients with neutralizing type I interferon auto-antibodies. J. Clin. Immunol. 42:1111–1129. 10.1007/s10875-022-01252-2 - DOI - PMC - PubMed
1. Allen, R.C., Zoghbi H.Y., Moseley A.B., Rosenblatt H.M., and Belmont J.W.. 1992. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51:1229–1239. - PMC - PubMed
1. Alotaibi, F., Alharbi N.K., Rosen L.B., Asiri A.Y., Assiri A.M., Balkhy H.H., Al Jeraisy M., Mandourah Y., AlJohani S., Al Harbi S., et al. . 2023. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial. Influenza Other Respir. Viruses. 17:e13116. 10.1111/irv.13116 - DOI - PMC - PubMed

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[1] Abers, M.S., Rosen L.B., Delmonte O.M., Shaw E., Bastard P., Imberti L., Quaresima V., Biondi A., Bonfanti P., Castagnoli R., et al. . 2021. Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19. Immunol. Cell Biol. 99:917–921. 10.1111/imcb.12495 - DOI - PMC - PubMed

[2] Abers, M.S., Rosen L.B., Delmonte O.M., Shaw E., Bastard P., Imberti L., Quaresima V., Biondi A., Bonfanti P., Castagnoli R., et al. . 2021. Neutralizing type-I interferon autoantibodies are associated with delayed viral clearance and intensive care unit admission in patients with COVID-19. Immunol. Cell Biol. 99:917–921. 10.1111/imcb.12495 - DOI - PMC - PubMed

[3] Acosta-Ampudia, Y., Monsalve D.M., Rojas M., Rodríguez Y., Gallo J.E., Salazar-Uribe J.C., Santander M.J., Cala M.P., Zapata W., Zapata M.I., et al. . 2021. COVID-19 convalescent plasma composition and immunological effects in severe patients. J. Autoimmun. 118:102598. 10.1016/j.jaut.2021.102598 - DOI - PMC - PubMed

[4] Acosta-Ampudia, Y., Monsalve D.M., Rojas M., Rodríguez Y., Gallo J.E., Salazar-Uribe J.C., Santander M.J., Cala M.P., Zapata W., Zapata M.I., et al. . 2021. COVID-19 convalescent plasma composition and immunological effects in severe patients. J. Autoimmun. 118:102598. 10.1016/j.jaut.2021.102598 - DOI - PMC - PubMed

[5] Akbil, B., Meyer T., Stubbemann P., Thibeault C., Staudacher O., Niemeyer D., Jansen J., Mühlemann B., Doehn J., Tabeling C., et al. . 2022. Early and rapid identification of COVID-19 patients with neutralizing type I interferon auto-antibodies. J. Clin. Immunol. 42:1111–1129. 10.1007/s10875-022-01252-2 - DOI - PMC - PubMed

[6] Akbil, B., Meyer T., Stubbemann P., Thibeault C., Staudacher O., Niemeyer D., Jansen J., Mühlemann B., Doehn J., Tabeling C., et al. . 2022. Early and rapid identification of COVID-19 patients with neutralizing type I interferon auto-antibodies. J. Clin. Immunol. 42:1111–1129. 10.1007/s10875-022-01252-2 - DOI - PMC - PubMed

[7] Allen, R.C., Zoghbi H.Y., Moseley A.B., Rosenblatt H.M., and Belmont J.W.. 1992. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51:1229–1239. - PMC - PubMed

[8] Allen, R.C., Zoghbi H.Y., Moseley A.B., Rosenblatt H.M., and Belmont J.W.. 1992. Methylation of HpaII and HhaI sites near the polymorphic CAG repeat in the human androgen-receptor gene correlates with X chromosome inactivation. Am. J. Hum. Genet. 51:1229–1239. - PMC - PubMed

[9] Alotaibi, F., Alharbi N.K., Rosen L.B., Asiri A.Y., Assiri A.M., Balkhy H.H., Al Jeraisy M., Mandourah Y., AlJohani S., Al Harbi S., et al. . 2023. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial. Influenza Other Respir. Viruses. 17:e13116. 10.1111/irv.13116 - DOI - PMC - PubMed

[10] Alotaibi, F., Alharbi N.K., Rosen L.B., Asiri A.Y., Assiri A.M., Balkhy H.H., Al Jeraisy M., Mandourah Y., AlJohani S., Al Harbi S., et al. . 2023. Type I interferon autoantibodies in hospitalized patients with Middle East respiratory syndrome and association with outcomes and treatment effect of interferon beta-1b in MIRACLE clinical trial. Influenza Other Respir. Viruses. 17:e13116. 10.1111/irv.13116 - DOI - PMC - PubMed

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Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

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Incontinentia pigmenti underlies thymic dysplasia, autoantibodies to type I IFNs, and viral diseases

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