CTLA-4 Deficiency: Pathophysiology, Clinical Manifestations, and Immunological Findings
Abstract
Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) deficiency is a primary immune regulatory disorder caused by heterozygous germline loss-of-function variants in the CTLA4 gene. CTLA-4 is expressed mainly on activated T cells and regulatory T cells that plays a key role in maintaining immune tolerance by limiting T-cell activation. Also, CTLA-4 has recently become a key target in immune checkpoint-based therapeutics, particularly in cancer treatment via the use of monoclonal antibodies against this molecule. Loss of CTLA-4 function leads to uncontrolled T-cell activation and impaired Treg-mediated immune regulation. Consequently, this immune dysregulation underlies the coexistence of autoimmunity and immune deficiency. Hypogammaglobulinemia is one of the most common immunologic findings in CTLA-4 deficiency and may resemble common variable immunodeficiency. However, CTLA-4 deficiency is a multisystem disorder. Clinical manifestations are highly variable and may include recurrent respiratory infections, bronchiectasis, chronic diarrhea, malabsorption, autoimmune cytopenia, lymphadenopathy, splenomegaly, and organ infiltration. Laboratory findings commonly include lymphopenia, reduced naïve CD4⁺ T cells, increased activated T cells, impaired regulatory T-cell function, reduced CD19⁺ B cells, decreased class-switched memory B cells, expanded CD21-low B cells, reduced natural killer cells, and low serum immunoglobulin levels. Recognition of these clinical and laboratory features is essential for early diagnosis, appropriate management, and improved long-term outcomes in patients with CTLA-4 deficiency. This study reviews the pathophysiology, clinical manifestations and laboratory findings in patients with CTLA-4 deficiency.
1. McCusker C, Upton J, Warrington R. Primary immunodeficiency. Allergy Asthma Clin Immunol. 2018;14(Suppl 2):61.
2. Verma N, Burns SO, Walker LSK, Sansom DM. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol. 2017;190(1):1-7.
3. Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A, et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity. 2010;33(3):326-39.
4. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-6.
5. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. Journal of Allergy and Clinical Immunology. 2018;142(6):1932-46.
6. Musabak U, Erdoğan T, Ceylaner S, Özbek E, Suna N, Özdemir BH. Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report. World J Clin Cases. 2023;11(26):6176-82.
7. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-7.
8. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445-80.
9. Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991;173(3):721-30.
10. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993;262(5135):905-7.
11. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11(12):852-63.
12. Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192(2):295-302.
13. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162(10):5813-20.
14. Calvo CR, Amsen D, Kruisbeek AM. Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70. J Exp Med. 1997;186(10):1645-53.
15. Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity. 2000;13(3):313-22.
16. Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282(5397):2263-6.
17. Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565-94.
18. Abrams SI. Role of anti-CTLA-4 therapies in the treatment of cancer. Curr Opin Mol Ther. 2004;6(1):71-7.
19. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712-7.
20. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372-7.
21. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043-53.
22. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005-16.
23. Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008;105(39):14987-92.
24. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-54.
25. Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14(11):1104-11.
26. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24(7):1813-21.
27. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67.
28. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-5.
29. Allard-Chamard H, Hillier K, Ramseier ML, Bertocchi A, Kaneko N, Premo K, et al. Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans. Blood Adv. 2025;9(3):520-32.
30. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932-46.
31. Uzel G, Karanovic D, Su H, Rump A, Agharahimi A, Holland SM, et al. Management of Cytopenias in CTLA4 Haploinsufficiency Using Abatacept and Sirolimus. Blood. 2018;132(Supplement 1):2409-.
32. Egg D, Rump IC, Mitsuiki N, Rojas-Restrepo J, Maccari ME, Schwab C, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149(2):736-46.
33. Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK, et al. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut. 2015;64(12):1889-97.
34. Krone KA, Winant AJ, Vargas SO, Platt CD, Bartnikas LM, Janssen E, et al. Pulmonary manifestations of immune dysregulation in CTLA-4 haploinsufficiency and LRBA deficiency. Pediatr Pulmonol. 2021;56(7):2232-41.
35. Lo B, Fritz JM, Su HC, Uzel G, Jordan MB, Lenardo MJ. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood. 2016;128(8):1037-42.
36. García-Chagollán M, Ledezma-Lozano IY, Hernández-Bello J, Sánchez-Hernández PE, Gutiérrez-Ureña SR, Muñoz-Valle JF. Expression patterns of CD28 and CTLA-4 in early, chronic, and untreated rheumatoid arthritis. J Clin Lab Anal. 2020;34(5):e23188.
37. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2008;105(49):19396-401.
38. Minning S, Xiaofan Y, Anqi X, Bingjie G, Dinglei S, Mingshun Z, et al. Imbalance between CD8(+)CD28(+) and CD8(+)CD28(-) T-cell subsets and its clinical significance in patients with systemic lupus erythematosus. Lupus. 2019;28(10):1214-23.
39. Mesquita D, Jr., Cruvinel WM, Araujo JA, Salmazi KC, Kallas EG, Andrade LE. Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus. Braz J Med Biol Res. 2014;47(8):662-9.
40. Mohammadzadeh A, Rad IA, Ahmadi-Salmasi B. CTLA-4, PD-1 and TIM-3 expression predominantly downregulated in MS patients. J Neuroimmunol. 2018;323:105-8.
41. Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sørensen PS. FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. Clin Exp Immunol. 2012;170(2):149-55.
42. Wang CJ, Schmidt EM, Attridge K, Kenefeck R, Wardzinski L, Chamberlain JL, et al. Immune regulation by CTLA-4--relevance to autoimmune diabetes in a transgenic mouse model. Diabetes Metab Res Rev. 2011;27(8):946-50.
43. Sharma R, Di Dalmazi G, Caturegli P. Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase. Thyroid. 2016;26(8):1117-24.
44. Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117.
45. Hayakawa S, Okada S, Tsumura M, Sakata S, Ueno Y, Imai K, et al. A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. J Clin Immunol. 2016;36(1):28-32.
46. Wei J, Yin H, Wang L, Cui L, Wang R. Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management. Neurosurg Rev. 2019;42(2):255-61.
47. Schindler MK, Pittaluga S, Enose-Akahata Y, Su HC, Rao VK, Rump A, et al. Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder. The Journal of clinical investigation. 2020;130(10):5551-61.
48. Gambineri E, Ciullini Mannurita S, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, et al. Clinical, immunological, and molecular heterogeneity of 173 patients with the phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Frontiers in immunology. 2018;9:2411.
49. Hiroshi U, Shuichi K, Kazuharu K, Masako Y, Yasushi K, Toshihiko A, et al. Immune dysregulation syndrome with de novo CTLA4 germline mutation responsive to abatacept therapy. International Journal of Hematology. 2020;111(6):897-902.
50. Ayrignac X, Goulabchand R, Jeziorski E, Rullier P, Carra-Dallière C, Lozano C, et al. Two neurologic facets of CTLA4-related haploinsufficiency. Neurology: Neuroimmunology & Neuroinflammation. 2020;7(4):e751.
51. Coustal C, Goulabchand R, Labauge P, Guilpain P, Carra-Dallière C, Januel E, et al. Clinical, radiologic, and immunologic features of patients with CTLA4 deficiency with neurologic involvement. Neurology. 2023;101(15):e1560-e6.
52. Hoshino A, Toyofuku E, Mitsuiki N, Yamashita M, Okamoto K, Yamamoto M, et al. Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study. Front Immunol. 2021;12:784901.
53. Mahat U, Terzioglu MK, Buhtoiarov I. CTLA4 haploinsufficiency as a predisposition to classical Hodgkin lymphoma. Pediatr Hematol Oncol. 2020;37(2):176-83.
54. Hou TZ, Verma N, Wanders J, Kennedy A, Soskic B, Janman D, et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. 2017;129(11):1458-68.
2. Verma N, Burns SO, Walker LSK, Sansom DM. Immune deficiency and autoimmunity in patients with CTLA-4 (CD152) mutations. Clin Exp Immunol. 2017;190(1):1-7.
3. Yokosuka T, Kobayashi W, Takamatsu M, Sakata-Sogawa K, Zeng H, Hashimoto-Tane A, et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity. 2010;33(3):326-39.
4. Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410-6.
5. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4–insufficient subjects. Journal of Allergy and Clinical Immunology. 2018;142(6):1932-46.
6. Musabak U, Erdoğan T, Ceylaner S, Özbek E, Suna N, Özdemir BH. Efficacy of abatacept treatment in a patient with enteropathy carrying a variant of unsignificance in CTLA4 gene: A case report. World J Clin Cases. 2023;11(26):6176-82.
7. Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science. 2014;345(6204):1623-7.
8. Mueller DL, Jenkins MK, Schwartz RH. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445-80.
9. Linsley PS, Brady W, Grosmaire L, Aruffo A, Damle NK, Ledbetter JA. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991;173(3):721-30.
10. Hathcock KS, Laszlo G, Dickler HB, Bradshaw J, Linsley P, Hodes RJ. Identification of an alternative CTLA-4 ligand costimulatory for T cell activation. Science. 1993;262(5135):905-7.
11. Walker LS, Sansom DM. The emerging role of CTLA4 as a cell-extrinsic regulator of T cell responses. Nat Rev Immunol. 2011;11(12):852-63.
12. Read S, Malmström V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192(2):295-302.
13. Brunner MC, Chambers CA, Chan FK, Hanke J, Winoto A, Allison JP. CTLA-4-Mediated inhibition of early events of T cell proliferation. J Immunol. 1999;162(10):5813-20.
14. Calvo CR, Amsen D, Kruisbeek AM. Cytotoxic T lymphocyte antigen 4 (CTLA-4) interferes with extracellular signal-regulated kinase (ERK) and Jun NH2-terminal kinase (JNK) activation, but does not affect phosphorylation of T cell receptor zeta and ZAP70. J Exp Med. 1997;186(10):1645-53.
15. Chuang E, Fisher TS, Morgan RW, Robbins MD, Duerr JM, Vander Heiden MG, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity. 2000;13(3):313-22.
16. Lee KM, Chuang E, Griffin M, Khattri R, Hong DK, Zhang W, et al. Molecular basis of T cell inactivation by CTLA-4. Science. 1998;282(5397):2263-6.
17. Chambers CA, Kuhns MS, Egen JG, Allison JP. CTLA-4-mediated inhibition in regulation of T cell responses: mechanisms and manipulation in tumor immunotherapy. Annu Rev Immunol. 2001;19:565-94.
18. Abrams SI. Role of anti-CTLA-4 therapies in the treatment of cancer. Curr Opin Mol Ther. 2004;6(1):71-7.
19. Hodi FS, Mihm MC, Soiffer RJ, Haluska FG, Butler M, Seiden MV, et al. Biologic activity of cytotoxic T lymphocyte-associated antigen 4 antibody blockade in previously vaccinated metastatic melanoma and ovarian carcinoma patients. Proc Natl Acad Sci U S A. 2003;100(8):4712-7.
20. Phan GQ, Yang JC, Sherry RM, Hwu P, Topalian SL, Schwartzentruber DJ, et al. Cancer regression and autoimmunity induced by cytotoxic T lymphocyte-associated antigen 4 blockade in patients with metastatic melanoma. Proc Natl Acad Sci U S A. 2003;100(14):8372-7.
21. Attia P, Phan GQ, Maker AV, Robinson MR, Quezado MM, Yang JC, et al. Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol. 2005;23(25):6043-53.
22. Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, et al. Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study. Ann Surg Oncol. 2005;12(12):1005-16.
23. Liakou CI, Kamat A, Tang DN, Chen H, Sun J, Troncoso P, et al. CTLA-4 blockade increases IFNgamma-producing CD4+ICOShi cells to shift the ratio of effector to regulatory T cells in cancer patients. Proc Natl Acad Sci U S A. 2008;105(39):14987-92.
24. Lynch TJ, Bondarenko I, Luft A, Serwatowski P, Barlesi F, Chacko R, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30(17):2046-54.
25. Calabrò L, Morra A, Fonsatti E, Cutaia O, Amato G, Giannarelli D, et al. Tremelimumab for patients with chemotherapy-resistant advanced malignant mesothelioma: an open-label, single-arm, phase 2 trial. Lancet Oncol. 2013;14(11):1104-11.
26. Slovin SF, Higano CS, Hamid O, Tejwani S, Harzstark A, Alumkal JJ, et al. Ipilimumab alone or in combination with radiotherapy in metastatic castration-resistant prostate cancer: results from an open-label, multicenter phase I/II study. Ann Oncol. 2013;24(7):1813-21.
27. Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131(1):58-67.
28. Wing K, Onishi Y, Prieto-Martin P, Yamaguchi T, Miyara M, Fehervari Z, et al. CTLA-4 control over Foxp3+ regulatory T cell function. Science. 2008;322(5899):271-5.
29. Allard-Chamard H, Hillier K, Ramseier ML, Bertocchi A, Kaneko N, Premo K, et al. Congenital T-cell activation impairs transitional-to-follicular B-cell maturation in humans. Blood Adv. 2025;9(3):520-32.
30. Schwab C, Gabrysch A, Olbrich P, Patiño V, Warnatz K, Wolff D, et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J Allergy Clin Immunol. 2018;142(6):1932-46.
31. Uzel G, Karanovic D, Su H, Rump A, Agharahimi A, Holland SM, et al. Management of Cytopenias in CTLA4 Haploinsufficiency Using Abatacept and Sirolimus. Blood. 2018;132(Supplement 1):2409-.
32. Egg D, Rump IC, Mitsuiki N, Rojas-Restrepo J, Maccari ME, Schwab C, et al. Therapeutic options for CTLA-4 insufficiency. J Allergy Clin Immunol. 2022;149(2):736-46.
33. Zeissig S, Petersen BS, Tomczak M, Melum E, Huc-Claustre E, Dougan SK, et al. Early-onset Crohn's disease and autoimmunity associated with a variant in CTLA-4. Gut. 2015;64(12):1889-97.
34. Krone KA, Winant AJ, Vargas SO, Platt CD, Bartnikas LM, Janssen E, et al. Pulmonary manifestations of immune dysregulation in CTLA-4 haploinsufficiency and LRBA deficiency. Pediatr Pulmonol. 2021;56(7):2232-41.
35. Lo B, Fritz JM, Su HC, Uzel G, Jordan MB, Lenardo MJ. CHAI and LATAIE: new genetic diseases of CTLA-4 checkpoint insufficiency. Blood. 2016;128(8):1037-42.
36. García-Chagollán M, Ledezma-Lozano IY, Hernández-Bello J, Sánchez-Hernández PE, Gutiérrez-Ureña SR, Muñoz-Valle JF. Expression patterns of CD28 and CTLA-4 in early, chronic, and untreated rheumatoid arthritis. J Clin Lab Anal. 2020;34(5):e23188.
37. Flores-Borja F, Jury EC, Mauri C, Ehrenstein MR. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2008;105(49):19396-401.
38. Minning S, Xiaofan Y, Anqi X, Bingjie G, Dinglei S, Mingshun Z, et al. Imbalance between CD8(+)CD28(+) and CD8(+)CD28(-) T-cell subsets and its clinical significance in patients with systemic lupus erythematosus. Lupus. 2019;28(10):1214-23.
39. Mesquita D, Jr., Cruvinel WM, Araujo JA, Salmazi KC, Kallas EG, Andrade LE. Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus. Braz J Med Biol Res. 2014;47(8):662-9.
40. Mohammadzadeh A, Rad IA, Ahmadi-Salmasi B. CTLA-4, PD-1 and TIM-3 expression predominantly downregulated in MS patients. J Neuroimmunol. 2018;323:105-8.
41. Sellebjerg F, Krakauer M, Khademi M, Olsson T, Sørensen PS. FOXP3, CBLB and ITCH gene expression and cytotoxic T lymphocyte antigen 4 expression on CD4(+) CD25(high) T cells in multiple sclerosis. Clin Exp Immunol. 2012;170(2):149-55.
42. Wang CJ, Schmidt EM, Attridge K, Kenefeck R, Wardzinski L, Chamberlain JL, et al. Immune regulation by CTLA-4--relevance to autoimmune diabetes in a transgenic mouse model. Diabetes Metab Res Rev. 2011;27(8):946-50.
43. Sharma R, Di Dalmazi G, Caturegli P. Exacerbation of Autoimmune Thyroiditis by CTLA-4 Blockade: A Role for IFNγ-Induced Indoleamine 2, 3-Dioxygenase. Thyroid. 2016;26(8):1117-24.
44. Danikowski KM, Jayaraman S, Prabhakar BS. Regulatory T cells in multiple sclerosis and myasthenia gravis. J Neuroinflammation. 2017;14(1):117.
45. Hayakawa S, Okada S, Tsumura M, Sakata S, Ueno Y, Imai K, et al. A Patient with CTLA-4 Haploinsufficiency Presenting Gastric Cancer. J Clin Immunol. 2016;36(1):28-32.
46. Wei J, Yin H, Wang L, Cui L, Wang R. Systemic autoimmune diseases complicated with hydrocephalus: pathogenesis and management. Neurosurg Rev. 2019;42(2):255-61.
47. Schindler MK, Pittaluga S, Enose-Akahata Y, Su HC, Rao VK, Rump A, et al. Haploinsufficiency of immune checkpoint receptor CTLA4 induces a distinct neuroinflammatory disorder. The Journal of clinical investigation. 2020;130(10):5551-61.
48. Gambineri E, Ciullini Mannurita S, Hagin D, Vignoli M, Anover-Sombke S, DeBoer S, et al. Clinical, immunological, and molecular heterogeneity of 173 patients with the phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Frontiers in immunology. 2018;9:2411.
49. Hiroshi U, Shuichi K, Kazuharu K, Masako Y, Yasushi K, Toshihiko A, et al. Immune dysregulation syndrome with de novo CTLA4 germline mutation responsive to abatacept therapy. International Journal of Hematology. 2020;111(6):897-902.
50. Ayrignac X, Goulabchand R, Jeziorski E, Rullier P, Carra-Dallière C, Lozano C, et al. Two neurologic facets of CTLA4-related haploinsufficiency. Neurology: Neuroimmunology & Neuroinflammation. 2020;7(4):e751.
51. Coustal C, Goulabchand R, Labauge P, Guilpain P, Carra-Dallière C, Januel E, et al. Clinical, radiologic, and immunologic features of patients with CTLA4 deficiency with neurologic involvement. Neurology. 2023;101(15):e1560-e6.
52. Hoshino A, Toyofuku E, Mitsuiki N, Yamashita M, Okamoto K, Yamamoto M, et al. Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study. Front Immunol. 2021;12:784901.
53. Mahat U, Terzioglu MK, Buhtoiarov I. CTLA4 haploinsufficiency as a predisposition to classical Hodgkin lymphoma. Pediatr Hematol Oncol. 2020;37(2):176-83.
54. Hou TZ, Verma N, Wanders J, Kennedy A, Soskic B, Janman D, et al. Identifying functional defects in patients with immune dysregulation due to LRBA and CTLA-4 mutations. Blood. 2017;129(11):1458-68.
| Issue | Vol 9, No 2 (2026); In press | |
| Section | Review Article | |
| Keywords | ||
| Autoimmunity CTLA 4 Deficiency Hypogammaglobulinemia Immune Dysregulation Lymphoproliferation | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Firouzabadi A, Ebrahimi S. CTLA-4 Deficiency: Pathophysiology, Clinical Manifestations, and Immunological Findings. Immunol Genet J. 2026;9(2).
