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

Mehmet Cihangir Catak1,2,3, Salim Can1,2,3, Satanay Hubrack4

  • 1Department of Pediatric Allergy and Immunology, Faculty of Medicine, Marmara University, Istanbul, Turkey.

Journal of Human Immunity
|June 11, 2026
PubMed

Insights

The first case of homozygous CTLA-4 deficiency presents with severe autoimmunity and immune cell dysregulation. Abatacept therapy successfully restored immune homeostasis, highlighting CTLA-4

Area of Science:

  • Immunology
  • Genetics
  • Clinical Medicine

Background:

  • Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is a key immune checkpoint regulating self-tolerance and immune activation.
  • Defects in immune checkpoints can lead to severe autoimmune and lymphoproliferative disorders.

Purpose of the Study:

  • To describe the first case of homozygous CTLA-4 deficiency (CTLA4S172P/S172P) and its clinical and immunological manifestations.
  • To investigate the mechanistic impact of the identified CTLA-4 variant on protein function and immune cell behavior.
  • To evaluate the therapeutic efficacy of Abatacept in managing CTLA-4 deficiency.

Main Methods:

  • Clinical case description and immunological profiling of a patient with homozygous CTLA-4 deficiency.
  • Analysis of CTLA-4 protein stability, expression, and function, including CD80 transendocytosis.
  • Assessment of T- and B-cell phenotypes and function.
  • Evaluation of treatment response to Abatacept (CTLA-4-Ig).

Main Results:

  • The patient presented with early-onset autoimmunity, lymphoproliferation, and growth failure due to homozygous CTLA-4 deficiency.
  • Immunological analysis revealed profound T- and B-cell dysregulation, including T-cell hyperproliferation and atypical B-cell expansion.
  • The CTLA4S172P/S172P variant impaired CTLA-4 protein stability, leading to reduced expression and defective CD80 transendocytosis.
  • Abatacept therapy effectively restored immune regulation and controlled disease activity.

Conclusions:

  • Homozygous CTLA-4 deficiency results in severe immune dysregulation and early-onset autoimmunity.
  • Residual CTLA-4 function correlates with disease severity, and targeted modulation with Abatacept is a viable therapeutic strategy.
  • This case expands the understanding of CTLA-4-related disorders and their management.

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