Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency

Romain Lévy; Florian Gothe; Mana Momenilandi; Thomas Magg; Marie Materna; Philipp Peters; Johannes Raedler; Quentin Philippot; Anita Lena Rack-Hoch; David Langlais; Mathieu Bourgey; Anna Lisa Lanz; Masato Ogishi; Jérémie Rosain; Emmanuel Martin; Sylvain Latour; Natasha Vladikine; Marco Distefano; Taushif Khan; Franck Rapaport; Marian S. Schulz; Ursula Holzer; Anders Fasth; Georgios Sogkas; Carsten Speckmann; Arianna Troilo; Venetia Bigley; Anna Roppelt; Yael Dinur-Schejter; Ori Toker; Karen Helene Bronken Martinsen; Roya Sherkat; Ido Somekh; Raz Somech; Dror S. Shouval; Jörn Sven Kühl; Winnie Ip; Elizabeth M. McDermott; Lucy Cliffe; Ahmet Ozen; Safa Baris; Hemalatha G. Rangarajan; Emmanuelle Jouanguy; Anne Puel; Jacinta Bustamante; Marie Alexandra Alyanakian; Mathieu Fusaro; Yi Wang; Xiao Fei Kong; Aurélie Cobat; David Boutboul; Martin Castelle; Claire Aguilar; Olivier Hermine; Morgane Cheminant; Felipe Suarez; Alisan Yildiran; Aziz Bousfiha; Hamoud Al-Mousa; Fahad Alsohime; Deniz Cagdas; Roshini S. Abraham; Alan P. Knutsen; Borre Fevang; Sagar Bhattad; Ayca Kiykim; Baran Erman; Tugba Arikoglu; Ekrem Unal; Ashish Kumar; Christoph B. Geier; Ulrich Baumann; Bénédicte Neven; Meino Rohlfs; Christoph Walz; Laurent Abel; Bernard Malissen; Nico Marr; Christoph Klein; Jean Laurent Casanova; Fabian Hauck; Vivien Béziat; Julie Calas; Elizabeth Feuille; Angela Chan; Gozde Yesil; Justine Nammour; Élise Bandet; Capucine Picard; Ibtihal Benhsaien; Peter Lang; Faranaz Atschekzei; Klaus Warnatz; Sophie Hambleton; Mukesh Desai; Elif Karakoc-Aydiner; Burcu Kolukisa; Saleh Al-Muhsen; Mohammed F. Alosaimi; Funda Cipe; Anas M. Alazami; Gonca Hancioglu; Bilge Can Meydan; Hanne S. Sorte; Asbjørg Stray-Pedersen; Geetha Mammayil; Nazan Tökmeci; Anna Shcherbina; Polina Stepensky; Adeeb Naser Eddin; Claire Rouzaud; Akihiro Hoshino; Oded Shamriz; Oren Ledder; Maria Elena Maccari; Carla N. Castro; Bodo Grimbacher; Reinhold E. Schmidt; Matthew Collin; Victorya Zakharova

doi:10.1084/jem.20220275

Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency

Romain Lévy, Florian Gothe, Mana Momenilandi, Thomas Magg, Marie Materna, Philipp Peters, Johannes Raedler, Quentin Philippot, Anita Lena Rack-Hoch, David Langlais, Mathieu Bourgey, Anna Lisa Lanz, Masato Ogishi, Jérémie Rosain, Emmanuel Martin, Sylvain Latour, Natasha Vladikine, Marco Distefano, Taushif Khan, Franck RapaportMarian S. Schulz, Ursula Holzer, Anders Fasth, Georgios Sogkas, Carsten Speckmann, Arianna Troilo, Venetia Bigley, Anna Roppelt, Yael Dinur-Schejter, Ori Toker, Karen Helene Bronken Martinsen, Roya Sherkat, Ido Somekh, Raz Somech, Dror S. Shouval, Jörn Sven Kühl, Winnie Ip, Elizabeth M. McDermott, Lucy Cliffe, Ahmet Ozen, Safa Baris, Hemalatha G. Rangarajan, Emmanuelle Jouanguy, Anne Puel, Jacinta Bustamante, Marie Alexandra Alyanakian, Mathieu Fusaro, Yi Wang, Xiao Fei Kong, Aurélie Cobat, David Boutboul, Martin Castelle, Claire Aguilar, Olivier Hermine, Morgane Cheminant, Felipe Suarez, Alisan Yildiran, Aziz Bousfiha, Hamoud Al-Mousa, Fahad Alsohime, Deniz Cagdas, Roshini S. Abraham, Alan P. Knutsen, Borre Fevang, Sagar Bhattad, Ayca Kiykim, Baran Erman, Tugba Arikoglu, Ekrem Unal, Ashish Kumar, Christoph B. Geier, Ulrich Baumann, Bénédicte Neven, Meino Rohlfs, Christoph Walz, Laurent Abel, Bernard Malissen, Nico Marr, Christoph Klein, Jean Laurent Casanova, Fabian Hauck, Vivien Béziat, Julie Calas, Elizabeth Feuille, Angela Chan, Gozde Yesil, Justine Nammour, Élise Bandet, Capucine Picard, Ibtihal Benhsaien, Peter Lang, Faranaz Atschekzei, Klaus Warnatz, Sophie Hambleton, Mukesh Desai, Elif Karakoc-Aydiner, Burcu Kolukisa, Saleh Al-Muhsen, Mohammed F. Alosaimi, Funda Cipe, Anas M. Alazami, Gonca Hancioglu, Bilge Can Meydan, Hanne S. Sorte, Asbjørg Stray-Pedersen, Geetha Mammayil, Nazan Tökmeci, Anna Shcherbina, Polina Stepensky, Adeeb Naser Eddin, Claire Rouzaud, Akihiro Hoshino, Oded Shamriz, Oren Ledder, Maria Elena Maccari, Carla N. Castro, Bodo Grimbacher, Reinhold E. Schmidt, Matthew Collin, Victorya Zakharova

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4⁺ and CD8⁺ memory T cells and CD4⁺ T_REGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV⁺ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4⁺ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

Original language	English (US)
Article number	e20220275
Journal	Journal of Experimental Medicine
Volume	220
Issue number	2
DOIs	https://doi.org/10.1084/jem.20220275
State	Published - Feb 6 2023
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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10.1084/jem.20220275

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Lévy, R., Gothe, F., Momenilandi, M., Magg, T., Materna, M., Peters, P., Raedler, J., Philippot, Q., Rack-Hoch, A. L., Langlais, D., Bourgey, M., Lanz, A. L., Ogishi, M., Rosain, J., Martin, E., Latour, S., Vladikine, N., Distefano, M., Khan, T., ... Zakharova, V. (2023). Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency. Journal of Experimental Medicine, 220(2), Article e20220275. https://doi.org/10.1084/jem.20220275

Lévy, R, Gothe, F, Momenilandi, M, Magg, T, Materna, M, Peters, P, Raedler, J, Philippot, Q, Rack-Hoch, AL, Langlais, D, Bourgey, M, Lanz, AL, Ogishi, M, Rosain, J, Martin, E, Latour, S, Vladikine, N, Distefano, M, Khan, T, Rapaport, F, Schulz, MS, Holzer, U, Fasth, A, Sogkas, G, Speckmann, C, Troilo, A, Bigley, V, Roppelt, A, Dinur-Schejter, Y, Toker, O, Martinsen, KHB, Sherkat, R, Somekh, I, Somech, R, Shouval, DS, Kühl, JS, Ip, W, McDermott, EM, Cliffe, L, Ozen, A, Baris, S, Rangarajan, HG, Jouanguy, E, Puel, A, Bustamante, J, Alyanakian, MA, Fusaro, M, Wang, Y, Kong, XF, Cobat, A, Boutboul, D, Castelle, M, Aguilar, C, Hermine, O, Cheminant, M, Suarez, F, Yildiran, A, Bousfiha, A, Al-Mousa, H, Alsohime, F, Cagdas, D, Abraham, RS, Knutsen, AP, Fevang, B, Bhattad, S, Kiykim, A, Erman, B, Arikoglu, T, Unal, E, Kumar, A, Geier, CB, Baumann, U, Neven, B, Rohlfs, M, Walz, C, Abel, L, Malissen, B, Marr, N, Klein, C, Casanova, JL, Hauck, F, Béziat, V, Calas, J, Feuille, E, Chan, A, Yesil, G, Nammour, J, Bandet, É, Picard, C, Benhsaien, I, Lang, P, Atschekzei, F, Warnatz, K, Hambleton, S, Desai, M, Karakoc-Aydiner, E, Kolukisa, B, Al-Muhsen, S, Alosaimi, MF, Cipe, F, Alazami, AM, Hancioglu, G, Meydan, BC, Sorte, HS, Stray-Pedersen, A, Mammayil, G, Tökmeci, N, Shcherbina, A, Stepensky, P, Eddin, AN, Rouzaud, C, Hoshino, A, Shamriz, O, Ledder, O, Maccari, ME, Castro, CN, Grimbacher, B, Schmidt, RE, Collin, M & Zakharova, V 2023, 'Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency', Journal of Experimental Medicine, vol. 220, no. 2, e20220275. https://doi.org/10.1084/jem.20220275

@article{17f31afeded249c7b3e16088fc01243e,

title = "Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency",

abstract = "Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.",

author = "Romain L{\'e}vy and Florian Gothe and Mana Momenilandi and Thomas Magg and Marie Materna and Philipp Peters and Johannes Raedler and Quentin Philippot and Rack-Hoch, {Anita Lena} and David Langlais and Mathieu Bourgey and Lanz, {Anna Lisa} and Masato Ogishi and J{\'e}r{\'e}mie Rosain and Emmanuel Martin and Sylvain Latour and Natasha Vladikine and Marco Distefano and Taushif Khan and Franck Rapaport and Schulz, {Marian S.} and Ursula Holzer and Anders Fasth and Georgios Sogkas and Carsten Speckmann and Arianna Troilo and Venetia Bigley and Anna Roppelt and Yael Dinur-Schejter and Ori Toker and Martinsen, {Karen Helene Bronken} and Roya Sherkat and Ido Somekh and Raz Somech and Shouval, {Dror S.} and K{\"u}hl, {J{\"o}rn Sven} and Winnie Ip and McDermott, {Elizabeth M.} and Lucy Cliffe and Ahmet Ozen and Safa Baris and Rangarajan, {Hemalatha G.} and Emmanuelle Jouanguy and Anne Puel and Jacinta Bustamante and Alyanakian, {Marie Alexandra} and Mathieu Fusaro and Yi Wang and Kong, {Xiao Fei} and Aur{\'e}lie Cobat and David Boutboul and Martin Castelle and Claire Aguilar and Olivier Hermine and Morgane Cheminant and Felipe Suarez and Alisan Yildiran and Aziz Bousfiha and Hamoud Al-Mousa and Fahad Alsohime and Deniz Cagdas and Abraham, {Roshini S.} and Knutsen, {Alan P.} and Borre Fevang and Sagar Bhattad and Ayca Kiykim and Baran Erman and Tugba Arikoglu and Ekrem Unal and Ashish Kumar and Geier, {Christoph B.} and Ulrich Baumann and B{\'e}n{\'e}dicte Neven and Meino Rohlfs and Christoph Walz and Laurent Abel and Bernard Malissen and Nico Marr and Christoph Klein and Casanova, {Jean Laurent} and Fabian Hauck and Vivien B{\'e}ziat and Julie Calas and Elizabeth Feuille and Angela Chan and Gozde Yesil and Justine Nammour and {\'E}lise Bandet and Capucine Picard and Ibtihal Benhsaien and Peter Lang and Faranaz Atschekzei and Klaus Warnatz and Sophie Hambleton and Mukesh Desai and Elif Karakoc-Aydiner and Burcu Kolukisa and Saleh Al-Muhsen and Alosaimi, {Mohammed F.} and Funda Cipe and Alazami, {Anas M.} and Gonca Hancioglu and Meydan, {Bilge Can} and Sorte, {Hanne S.} and Asbj{\o}rg Stray-Pedersen and Geetha Mammayil and Nazan T{\"o}kmeci and Anna Shcherbina and Polina Stepensky and Eddin, {Adeeb Naser} and Claire Rouzaud and Akihiro Hoshino and Oded Shamriz and Oren Ledder and Maccari, {Maria Elena} and Castro, {Carla N.} and Bodo Grimbacher and Schmidt, {Reinhold E.} and Matthew Collin and Victorya Zakharova",

note = "Publisher Copyright: {\textcopyright} 2022 L{\'e}vy et al.",

year = "2023",

month = feb,

day = "6",

doi = "10.1084/jem.20220275",

language = "English (US)",

volume = "220",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

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TY - JOUR

T1 - Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency

AU - Lévy, Romain

AU - Gothe, Florian

AU - Momenilandi, Mana

AU - Magg, Thomas

AU - Materna, Marie

AU - Peters, Philipp

AU - Raedler, Johannes

AU - Philippot, Quentin

AU - Rack-Hoch, Anita Lena

AU - Langlais, David

AU - Bourgey, Mathieu

AU - Lanz, Anna Lisa

AU - Ogishi, Masato

AU - Rosain, Jérémie

AU - Martin, Emmanuel

AU - Latour, Sylvain

AU - Vladikine, Natasha

AU - Distefano, Marco

AU - Khan, Taushif

AU - Rapaport, Franck

AU - Schulz, Marian S.

AU - Holzer, Ursula

AU - Fasth, Anders

AU - Sogkas, Georgios

AU - Speckmann, Carsten

AU - Troilo, Arianna

AU - Bigley, Venetia

AU - Roppelt, Anna

AU - Dinur-Schejter, Yael

AU - Toker, Ori

AU - Martinsen, Karen Helene Bronken

AU - Sherkat, Roya

AU - Somekh, Ido

AU - Somech, Raz

AU - Shouval, Dror S.

AU - Kühl, Jörn Sven

AU - Ip, Winnie

AU - McDermott, Elizabeth M.

AU - Cliffe, Lucy

AU - Ozen, Ahmet

AU - Baris, Safa

AU - Rangarajan, Hemalatha G.

AU - Jouanguy, Emmanuelle

AU - Puel, Anne

AU - Bustamante, Jacinta

AU - Alyanakian, Marie Alexandra

AU - Fusaro, Mathieu

AU - Wang, Yi

AU - Kong, Xiao Fei

AU - Cobat, Aurélie

AU - Boutboul, David

AU - Castelle, Martin

AU - Aguilar, Claire

AU - Hermine, Olivier

AU - Cheminant, Morgane

AU - Suarez, Felipe

AU - Yildiran, Alisan

AU - Bousfiha, Aziz

AU - Al-Mousa, Hamoud

AU - Alsohime, Fahad

AU - Cagdas, Deniz

AU - Abraham, Roshini S.

AU - Knutsen, Alan P.

AU - Fevang, Borre

AU - Bhattad, Sagar

AU - Kiykim, Ayca

AU - Erman, Baran

AU - Arikoglu, Tugba

AU - Unal, Ekrem

AU - Kumar, Ashish

AU - Geier, Christoph B.

AU - Baumann, Ulrich

AU - Neven, Bénédicte

AU - Rohlfs, Meino

AU - Walz, Christoph

AU - Abel, Laurent

AU - Malissen, Bernard

AU - Marr, Nico

AU - Klein, Christoph

AU - Casanova, Jean Laurent

AU - Hauck, Fabian

AU - Béziat, Vivien

AU - Calas, Julie

AU - Feuille, Elizabeth

AU - Chan, Angela

AU - Yesil, Gozde

AU - Nammour, Justine

AU - Bandet, Élise

AU - Picard, Capucine

AU - Benhsaien, Ibtihal

AU - Lang, Peter

AU - Atschekzei, Faranaz

AU - Warnatz, Klaus

AU - Hambleton, Sophie

AU - Desai, Mukesh

AU - Karakoc-Aydiner, Elif

AU - Kolukisa, Burcu

AU - Al-Muhsen, Saleh

AU - Alosaimi, Mohammed F.

AU - Cipe, Funda

AU - Alazami, Anas M.

AU - Hancioglu, Gonca

AU - Meydan, Bilge Can

AU - Sorte, Hanne S.

AU - Stray-Pedersen, Asbjørg

AU - Mammayil, Geetha

AU - Tökmeci, Nazan

AU - Shcherbina, Anna

AU - Stepensky, Polina

AU - Eddin, Adeeb Naser

AU - Rouzaud, Claire

AU - Hoshino, Akihiro

AU - Shamriz, Oded

AU - Ledder, Oren

AU - Maccari, Maria Elena

AU - Castro, Carla N.

AU - Grimbacher, Bodo

AU - Schmidt, Reinhold E.

AU - Collin, Matthew

AU - Zakharova, Victorya

PY - 2023/2/6

Y1 - 2023/2/6

N2 - Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

AB - Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

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U2 - 10.1084/jem.20220275

DO - 10.1084/jem.20220275

M3 - Article

C2 - 36515678

AN - SCOPUS:85152482775

SN - 0022-1007

VL - 220

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 2

M1 - e20220275

ER -

Human carmil2 deficiency underlies a broader immunological and clinical phenotype than cd28 deficiency

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