Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21 low B cells
Main Article Content
Keywords
Common variable immunodeficiency, Autoimmunity, Tregs cells, CVID, CD21low B cells, CD4 CD45RO T cells
Abstract
Background: Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies defined by marked reductions in serum IgG, IgA and/or IgM levels and recurrent bacterial infections. Some patients are associated with defects in T cells and regulatory T cells (Tregs), resulting in recurrent viral infections and early-onset autoimmune disease.
Methods: We analyzed whether there is an association between Tregs cells (CD4+CD25+CD127low and CD4+CD25+FoxP3+); memory T cells (CD4+CD45RO+); memory B cells (CD19+CD27-IgD-); and CD21low B cells (CD19+CD38lowCD21low); as well as autoimmune manifestations in 36 patients with CVID (25 women and 11 men, mean age 24 years), all by flow cytometry.
Results: Fourteen patients presented with autoimmune diseases (AI) (39%), including 11 with autoimmune thrombocytopenia (ITP) (31%); two with vitiligo (6%); one with systemic lupus erythematosus (LES) (3%); and one with multiple sclerosis (MS) (3%). CVID patients with AI had a reduced proportion of Tregs (both CD4+CD25+CD127low and FoxP3+ cells) compared with healthy controls. CVID patients with AI had expanded CD21low B cell populations compared with patients who did not have AI. A correlation between increased CD4+CD45RO T cell populations and reduced Tregs was also observed.
Conclusions: Our results showed that 39% of patients with CVID had AI and reduced Tregs populations. Research in this area might provide noteworthy data to better understand immune dysfunction and dysregulation related to CVID.
References
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28. Michel M, Chanet V, Galicier L, Ruivard M, Levy Y, Hermine O, et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine (Baltimore). 2004;83:254-63.
29. Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev. 2006;5:156-9.
30. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, MogicaMartinez D, Garcia-Latorre E, Blancas-Galicia L, et al. Lymphocytes and B cell abnormalities in patients with common variable immunodeficiency (CVID). Allergol Immunopathol (Madr). 2014;42(1):35-43.
31. Ebbo M, Gerard L, Carpentier S, Vely F, Cypowyj S, Farnarier C, et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBioMedicine. 2016;6:222-30.
32. Yu GP, Chiang D, Song SJ, Hoyte EG, Huang J, Vanishsarn C, et al. Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease. Clin Immunol. 2009;131:240-53.
33. 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;322:271-5.
34. 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;20:1410-6.
35. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63.
36. Oraei M, Aghamohammadi A, Rezaei N, Bidad K, Gheflati Z, Amirkhani A, et al. Naive CD4+ T cells and recent thymic emigrants in common variable immunodeficiency. J Invest Allergol Clin Immunol. 2012;22:160-7.
37. Carbone J, Sarmiento E, Micheloud D, Rodriguez-Molina J, Fernandez-Cruz E. Elevated levels of activated CD4 T cells in common variable immunodeficiency: association with clinical findings. Allergol Immunopathol (Madr). 2006;34: 131-5.
38. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77-85.
39. Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol. 2003;23:385-400.
2. Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet. 2016;53:575-90.
3. Agematsu K, Futatani T, Hokibara S, Kobayashi N, Takamoto M, Tsukada S, et al. Absence of memory B cells in patients with common variable immunodeficiency. Clin Immunol. 2002;103:34-42.
4. Giovannetti A, Pierdominici M, Mazzetta F, Marziali M, Renzi C, Mileo AM, et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J Immunol. 2007;178:3932-43.
5. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, SantosArgumedo L, Lopez-Macias C, Isibasi A, et al. Impaired selective cytokine production by CD4(+) T cells in Common Variable Immunodeficiency associated with the absence of memory B cells. Clin Immunol. 2016:166-7.
6. Arandi N, Mirshafiey A, Abolhassani H, Jeddi-Tehrani M, Edalat R, Sadeghi B, et al. Frequency and expression of inhibitory markers of CD4(+) CD25(+) FOXP3(+) regulatory T cells in patients with common variable immunodeficiency. Scand J Immunol. 2013;77:405-12.
7. Fevang B, Yndestad A, Sandberg WJ, Holm AM, Muller F, Aukrust P, et al. Low numbers of regulatory T cells in common variable immunodeficiency: association with chronic inflammation in vivo. Clin Exp Immunol. 2007;147:521-5.
8. Horn J, Manguiat A, Berglund LJ, Knerr V, Tahami F, Grimbacher B, et al. Decrease in phenotypic regulatory T cells in subsets of patients with common variable immunodeficiency. Clin Exp Immunol. 2009;156:446-54.
9. Sakaguchi S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nat Immunol. 2005;6:345-52.
10. Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006;203:1701-11.
11. Gathmann B, Mahlaoui N, Ceredih, Gerard L, Oksenhendler E, Warnatz K, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134:116-26.
12. Notarangelo LD. Primary immunodeficiencies (PIDs) presenting with cytopenias American Society of Hematology Education Program. Hematology. 2009:139-43.
13. Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood. 2014;124:2337-44.
14. Warnatz K, Wehr C, Drager R, Schmidt S, Eibel H, Schlesier M, et al. Expansion of CD19(hi)CD21(lo/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia. Immunobiology. 2002;206:502-13.
15. Wehr C, Eibel H, Masilamani M, Illges H, Schlesier M, Peter HH, et al. A new CD21low B cell population in the peripheral blood of patients with SLE. Clin Immunol. 2004;113:161-71.
16. Dorner T, Jacobi AM, Lipsky PE. B cells in autoimmunity. Arthrit Res Therapy. 2009;11:247.
17. Mouillot G, Carmagnat M, Gerard L, Garnier JL, Fieschi C, Vince N, et al. B-cell and T-cell phenotypes in CVID patients correlate with the clinical phenotype of the disease. J Clin Immunol. 2010;30:746-55.
18. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:210.
19. Salzer U, Chapel HM, Webster AD, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820-8.
20. Lopez-Herrera G, Tampella G, Pan-Hammarstrom Q, Herholz P, Trujillo-Vargas CM, Phadwal K, et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90:986-1001.
21. Alkhairy OK, Rezaei N, Graham RR, Abolhassani H, Borte S, Hultenby K, et al. RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol. 2015;135:1380-440.
22. 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: 1623-7.
23. Kofod-Olsen E, Jorgensen SE, Nissen SK, Westh L, Moller BK, Ostergaard L, et al. Altered fraction of regulatory B and T cells is correlated with autoimmune phenomena and splenomegaly in patients with CVID. Clin Immunol. 2016;162:49-57.
24. Azizi G, Abolhassani H, Kiaee F, Tavakolinia N, Rafiemanesh H, Yazdani R, et al. Autoimmunity and its association with regulatory T cells and B cell subsets in patients with common variable immunodeficiency. Allergol Immunopathol (Madr). 2018;46:127-35.
25. Conley ME. Diagnostic guidelines -an international consensus document. Clin Immunol. 1999;93:189.
26. George JN, Woolf SH, Raskob GE, Wasser JS, Aledort LM, Ballem PJ, et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996;88:3-40.
27. Warnatz K, Denz A, Drager R, Braun M, Groth C, WolffVorbeck G, et al. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(−)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood. 2002;99:1544-51.
28. Michel M, Chanet V, Galicier L, Ruivard M, Levy Y, Hermine O, et al. Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature. Medicine (Baltimore). 2004;83:254-63.
29. Knight AK, Cunningham-Rundles C. Inflammatory and autoimmune complications of common variable immune deficiency. Autoimmun Rev. 2006;5:156-9.
30. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, MogicaMartinez D, Garcia-Latorre E, Blancas-Galicia L, et al. Lymphocytes and B cell abnormalities in patients with common variable immunodeficiency (CVID). Allergol Immunopathol (Madr). 2014;42(1):35-43.
31. Ebbo M, Gerard L, Carpentier S, Vely F, Cypowyj S, Farnarier C, et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBioMedicine. 2016;6:222-30.
32. Yu GP, Chiang D, Song SJ, Hoyte EG, Huang J, Vanishsarn C, et al. Regulatory T cell dysfunction in subjects with common variable immunodeficiency complicated by autoimmune disease. Clin Immunol. 2009;131:240-53.
33. 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;322:271-5.
34. 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;20:1410-6.
35. Sallusto F, Geginat J, Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol. 2004;22:745-63.
36. Oraei M, Aghamohammadi A, Rezaei N, Bidad K, Gheflati Z, Amirkhani A, et al. Naive CD4+ T cells and recent thymic emigrants in common variable immunodeficiency. J Invest Allergol Clin Immunol. 2012;22:160-7.
37. Carbone J, Sarmiento E, Micheloud D, Rodriguez-Molina J, Fernandez-Cruz E. Elevated levels of activated CD4 T cells in common variable immunodeficiency: association with clinical findings. Allergol Immunopathol (Madr). 2006;34: 131-5.
38. Wehr C, Kivioja T, Schmitt C, Ferry B, Witte T, Eren E, et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood. 2008;111:77-85.
39. Piqueras B, Lavenu-Bombled C, Galicier L, Bergeron-van der Cruyssen F, Mouthon L, Chevret S, et al. Common variable immunodeficiency patient classification based on impaired B cell memory differentiation correlates with clinical aspects. J Clin Immunol. 2003;23:385-400.
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Oct 15, 2019
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López-Herrera, G., Segura-Méndez, N., O’Farril-Romanillos, P., Nunez-Nu-˜ nez, M., Zarate-Hernández, M., Mogica-Martínez, D., Yamazaki-Nakashimada, M., Staines-Boone, A., Santos-Argumedo, L., & Berrón-Ruiz, L. (2019). Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21 low B cells. Allergologia Et Immunopathologia, 47(5), 457-466. https://www.all-imm.com/index.php/aei/article/view/284
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How to Cite
López-Herrera, G., Segura-Méndez, N., O’Farril-Romanillos, P., Nunez-Nu-˜ nez, M., Zarate-Hernández, M., Mogica-Martínez, D., Yamazaki-Nakashimada, M., Staines-Boone, A., Santos-Argumedo, L., & Berrón-Ruiz, L. (2019). Low percentages of regulatory T cells in common variable immunodeficiency (CVID) patients with autoimmune diseases and its association with increased numbers of CD4+CD45RO+ T and CD21 low B cells. Allergologia Et Immunopathologia, 47(5), 457-466. https://www.all-imm.com/index.php/aei/article/view/284