A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation

Mehmet Cihangir Catak; Salim Can; Satanay Hubrack; Feyza Bayram Catak; Asha Elmi; Royala Babayeva; Razin Amirov; Melek Yorgun Altunbas; Sevgi Bilgic Eltan; Deniz Ertem; Baris Yilmaz; Ahmet Koc; Batu Erman; Emine Bozkurtlar; Elif Karakoc-Aydiner; Ahmet Ozen; Bernice Lo; Safa Baris

doi:10.70962/jhi.20250227

A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation

Mehmet Cihangir Catak
, Salim Can
, Satanay Hubrack
, Feyza Bayram Catak
, Asha Elmi
, Royala Babayeva
, Razin Amirov
, Melek Yorgun Altunbas
, Sevgi Bilgic Eltan
, Deniz Ertem
, Baris Yilmaz
, Ahmet Koc
, Batu Erman
, Emine Bozkurtlar
, Elif Karakoc-Aydiner
, Ahmet Ozen
, Bernice Lo^*
, Safa Baris^*

^*Corresponding author for this work

HBKU College of Health & Life Sciences

Marmara University
Istanbul Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
The Isil Berat Barlan Center for Translational Medicine
Sidra Medicine
Division of Translational Medicine
Acibadem Mehmet Ali Aydinlar Universitesi
HBKU College of Health and Life Sciences

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

2 Citations (Scopus)

Abstract

CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4^S172P/S172P), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T-and B-cell dysregulation, characterized by T-cell hyperproliferation, a T_H1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4–related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.

Original language	English
Article number	e20250227
Journal	Journal of Human Immunity
Volume	2
Issue number	5
DOIs	https://doi.org/10.70962/jhi.20250227
Publication status	Published - 7 Sept 2026

Keywords

Autoimmunity
Clinical phenotypes
Diagnostics
Therapeutics

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10.70962/jhi.20250227

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Catak, M. C., Can, S., Hubrack, S., Catak, F. B., Elmi, A., Babayeva, R., Amirov, R., Altunbas, M. Y., Eltan, S. B., Ertem, D., Yilmaz, B., Koc, A., Erman, B., Bozkurtlar, E., Karakoc-Aydiner, E., Ozen, A., Lo, B., & Baris, S. (2026). A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation. Journal of Human Immunity, 2(5), Article e20250227. https://doi.org/10.70962/jhi.20250227

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title = "A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation",

abstract = "CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4S172P/S172P), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T-and B-cell dysregulation, characterized by T-cell hyperproliferation, a TH1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4{\textendash}related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.",

keywords = "Autoimmunity, Clinical phenotypes, Diagnostics, Therapeutics",

author = "Catak, \{Mehmet Cihangir\} and Salim Can and Satanay Hubrack and Catak, \{Feyza Bayram\} and Asha Elmi and Royala Babayeva and Razin Amirov and Altunbas, \{Melek Yorgun\} and Eltan, \{Sevgi Bilgic\} and Deniz Ertem and Baris Yilmaz and Ahmet Koc and Batu Erman and Emine Bozkurtlar and Elif Karakoc-Aydiner and Ahmet Ozen and Bernice Lo and Safa Baris",

note = "Publisher Copyright: {\textcopyright} 2026 Catak et al.",

year = "2026",

month = sep,

day = "7",

doi = "10.70962/jhi.20250227",

language = "English",

volume = "2",

journal = "Journal of Human Immunity",

issn = "3065-8993",

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Catak, MC, Can, S, Hubrack, S, Catak, FB, Elmi, A, Babayeva, R, Amirov, R, Altunbas, MY, Eltan, SB, Ertem, D, Yilmaz, B, Koc, A, Erman, B, Bozkurtlar, E, Karakoc-Aydiner, E, Ozen, A, Lo, B & Baris, S 2026, 'A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation', Journal of Human Immunity, vol. 2, no. 5, e20250227. https://doi.org/10.70962/jhi.20250227

TY - JOUR

T1 - A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation

AU - Catak, Mehmet Cihangir

AU - Can, Salim

AU - Hubrack, Satanay

AU - Catak, Feyza Bayram

AU - Elmi, Asha

AU - Babayeva, Royala

AU - Amirov, Razin

AU - Altunbas, Melek Yorgun

AU - Eltan, Sevgi Bilgic

AU - Ertem, Deniz

AU - Yilmaz, Baris

AU - Koc, Ahmet

AU - Erman, Batu

AU - Bozkurtlar, Emine

AU - Karakoc-Aydiner, Elif

AU - Ozen, Ahmet

AU - Lo, Bernice

AU - Baris, Safa

PY - 2026/9/7

Y1 - 2026/9/7

N2 - CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4S172P/S172P), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T-and B-cell dysregulation, characterized by T-cell hyperproliferation, a TH1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4–related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.

AB - CTLA-4 is a critical immune checkpoint that maintains self-tolerance by regulating immune activation. Here, we describe the first case of homozygous CTLA-4 deficiency (CTLA4S172P/S172P), presenting with early-onset autoimmunity, lymphoproliferation, and growth failure. Immunological profiling revealed profound T-and B-cell dysregulation, characterized by T-cell hyperproliferation, a TH1-skewed helper T-cell phenotype, and expansion of activated and atypical B-cell subsets. The identified variant led to impaired CTLA-4 protein stability and enhanced lysosomal degradation, resulting in significantly reduced but still detectable total and surface expression and defective CD80 transendocytosis. Abatacept (CTLA-4-Ig) therapy effectively restored immune regulation and controlled disease activity. These findings expand the clinical and mechanistic spectrum of CTLA-4–related disorders, linking residual CTLA-4 function with the severity of immune dysregulation and emphasizing the therapeutic potential of targeted CTLA-4 modulation.

KW - Autoimmunity

KW - Clinical phenotypes

KW - Diagnostics

KW - Therapeutics

UR - https://www.scopus.com/pages/publications/105049274828

U2 - 10.70962/jhi.20250227

DO - 10.70962/jhi.20250227

M3 - Article

AN - SCOPUS:105049274828

SN - 3065-8993

VL - 2

JO - Journal of Human Immunity

JF - Journal of Human Immunity

IS - 5

M1 - e20250227

ER -

A homozygous CTLA-4 variant causes CTLA-4 deficiency with severe immune dysregulation

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Keywords

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