Evaluation of B Cell and T Cell Phenotypes in CVID Patients and Its Correlation with the Clinical Phenotypes: Study Protocol
,
Abstract
Background: Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immunodeficiency, which manifests a wide range of clinical phenotypes from recurrent infections of the respiratory system to autoimmunity, enteropathy and lymphoproliferative disorders. Some abnormalities in T and B lymphocyte subpopulations may associate with the development of such clinical complications.
Aim of study: The main objective of this case-control study is to investigate the frequency and absolute count of different lymphocyte subsets in CVID patients as well as the cellular proliferation response. Correlation between lymphocyte abnormalities and different clinical phenotypes of the disease such as infection only (IO), autoimmunity (AI), chronic enteropathy (CE) and lymphoproliferative disorders (LP) are determined. We also aim to evaluate the prognosis of CVID for each clinical manifestation based on lymphocyte phenotype.
Methods: A population of genetically unsolved CVID patients after whole exome sequencing (WES) will be subdivided into 4 clinical phenotypes i.e. IO, AI, CE and LP and an equal number of age and sex-matched healthy controls (HC) will be examined for the frequency of distinct subgroups of CD19+ B cells, CD4+ T cells and CD8+ T cells lymphocyte subsets by flow cytometry. The proliferation response of their CD4+ T cells is then evaluated by Carboxyfluorescein diacetate succinimidyl ester (CFSE) test, using stimulation of isolated peripheral blood mononuclear cells with anti-CD3 and anti-CD28 antibodies. Data analysis will be assessed by parametric or nonparametric tests based on normality of data distribution using IBM SPSS Statistics, V.24 and Stata software V.14.
Ethics and dissemination: Ethical approval of this study is received from the Ethics Committee of Tehran University of Medical Sciences (ID number: IR.TUMS.VCR.REC.1396.3380) and all participants will we asked to sign the informed consent statement. Due to the wide range of variables, objectives and questions, the findings of this study are intended to release as multiple publications in peer-reviewed journals and presented at national and international conferences.
1. Hammarström L, Vorechovsky I, Webster D. Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol. 2000;120(2):225-31.
2. Yazdani R, Abolhassani H, Rezaei N, Azizi G, Hammarström L, Aghamohammadi A. Evaluation of known defective signaling-associated molecules in patients who primarily diagnosed as common variable immunodeficiency. Int Rev Immunol. 2016;35(1):7-24.
3. Abolhassani H, Hammarstrom L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135(9):656-67.
4. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
5. Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, Eshghi P, Yazdani R, et al. Clinical, immunologic, molecular analyses and outcomes of iranian patients with LRBA deficiency: a longitudinal study. Pediatr Allergy Immunol. 2017;28(5):478-84.
6. Abbott JK, Gelfand EW. Common Variable Immunodeficiency: Diagnosis, Management, and Treatment. Immunol Allergy Clin North Am. 2015;35(4):637-58.
7. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(1):38-59.
8. Jolles S. The Variable in Common Variable Immunodeficiency: A Disease of Complex Phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545-56.
9. Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults. Front Immunol. 2018;9(694).
10. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-7.
11. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115(2):412-7.
12. Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc Natl Acad Sci. 2009;106(32):13451-6.
13. Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck 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(5):1544-51.
14. 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(1):77-85.
15. Yaz I, Ozbek B, Ng YY, Cetinkaya PG, Halacli SO, Tan C, et al. Lymphocyte Subgroups and KREC Numbers in Common Variable Immunodeficiency: A Single Center Study. J Clin Immunol. 2020:1-9.
16. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45(2):183-92.
17. 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(5):385-400.
18. Vodjgani M, Aghamohammadi A, Samadi M, Moin M, Hadjati J, Mirahmadian M, et al. Analysis of class-switched memory B cells in patients with common variable immunodeficiency and its clinical implications. J Investig Allergol Clin Immunol. 2007;17(5):321-8.
19. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, Mogica-Martinez 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.
20. Romberg N, Le Coz C, Glauzy S, Schickel J-N, Trofa M, Nolan BE, et al. Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses. J Allergy Clin Immunol. 2019;143(1):258-65.
21. Driessen GJ, van Zelm MC, van Hagen PM, Hartwig NG, Trip M, Warris A, et al. B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. Blood. 2011;118(26):6814-23.
22. Uzzan M, Ko HM, Mehandru S, Cunningham-Rundles C. Gastrointestinal disorders associated with common variable immune deficiency (CVID) and chronic granulomatous disease (CGD). Curr Gastroenterol Rep. 2016;18(4):17.
23. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
24. Geier CB, Kraupp S, Bra D, Eibl MM, Farmer JR, Csomos K, et al. Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency. Eur J Immunol. 2017;47(11):1959-69.
25. Le Saos-Patrinos C, Loizon S, Blanco P, Viallard J-F, Duluc D. Functions of Tfh Cells in Common Variable Immunodeficiency. Front Immunol. 2020;11(6).
26. Turpin D, Furudoi A, Parrens M, Blanco P, Viallard J-F, Duluc D. Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications. Clin Immunol. 2018;197:130-8.
27. Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107(8):3045-52.
28. Oraei M, Aghamohammadi A, Rezaei N, Bidad K, Gheflati Z, Amirkhani A, et al. 2 Naive CD4+ T cells and Recent Thymic Emigrants in Common Variable Immunodeficiency. J Investig Allergol Clin Immunol. 2012;22(3):160.
29. 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(6):3932-43.
30. Bateman EA, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, et al. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol. 2012;170(2):202-11.
31. Arumugakani G, Wood PM, Carter CR. Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21 lo B lymphocytes. J Clin Immunol. 2010;30(2):292-300.
32. Melo KM, Carvalho KI, Bruno FR, Ndhlovu LC, Ballan WM, Nixon DF, et al. A decreased frequency of regulatory T cells in patients with common variable immunodeficiency. PloS one. 2009;4(7):e6269.
33. López-Herrera G, Segura-Méndez N, O’Farril-Romanillos P, Nuñez-Nuñez M, Zarate-Hernández M, Mogica-Martínez D, et al. 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 CD21low B cells. Allergol Immunopathol (Madr). 2019;47(5):457-66.
34. Ganjalikhani-Hakemi M, Yazdani R, Sherkat R, Homayouni V, Masjedi M, Hosseini M. Evaluation of the T helper 17 cell specific genes and the innate lymphoid cells counts in the peripheral blood of patients with the common variable immunodeficiency. J Res Med Sci. 2014;19(Suppl 1):S30-5.
35. Carter CR, Aravind G, Smalle NL, Cole JY, Savic S, Wood PM. CVID patients with autoimmunity have elevated T cell expression of granzyme B and HLA-DR and reduced levels of Treg cells. J Clin Pathol. 2013;66(2):146-50.
36. Lanio N, Sarmiento E, Gallego A, Carbone J. Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings? Allergol Immunopathol (Madr). 2009;37(1):14-20.
37. Ogulur I, Kiykim A, Baser D, Karakoc-Aydiner E, Ozen A, Baris S. Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency. Int Arch Allergy Immunol. 2020;181(3):228-37.
38. Aukrust P, Aandahl EM, Skalhegg BS, Nordoy I, Hansson V, Tasken K, et al. Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency. J Immunol. 1999;162(2):1178-85.
39. North M, Webster A, Farrant J. Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C. Clin Exp Immunol. 1991;85(2):198-201.
40. Perreau M, Vigano S, Bellanger F, Pellaton C, Buss G, Comte D, et al. Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders. J Exp Med. 2014;211(10):2033-45.
41. van de Ven AA, van de Corput L, van Tilburg CM, Tesselaar K, van Gent R, Sanders EA, et al. Lymphocyte characteristics in children with common variable immunodeficiency. Clin Immunol. 2010;135(1):63-71.
42. Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis. J Clin Immunol. 2018;38(7):816-32.
43. European Society for Immunodeficiencies. ESID Registry - Working definitions for clinical diagnosis of PID [Available from: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria.
44. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-70.
45. Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375-80.
46. Fang M, Abolhassani H, Lim CK, Zhang J, Hammarström L. Next generation sequencing data analysis in primary immunodeficiency disorders–future directions. J Clin Immunol. 2016;36(1):68-75.
47. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64.
48. Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, et al. Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. J Investig Allergol Clin Immunol. 2020;30(1):14-34.
2. Yazdani R, Abolhassani H, Rezaei N, Azizi G, Hammarström L, Aghamohammadi A. Evaluation of known defective signaling-associated molecules in patients who primarily diagnosed as common variable immunodeficiency. Int Rev Immunol. 2016;35(1):7-24.
3. Abolhassani H, Hammarstrom L, Cunningham-Rundles C. Current genetic landscape in common variable immune deficiency. Blood. 2020;135(9):656-67.
4. Yazdani R, Ganjalikhani-Hakemi M, Esmaeili M, Abolhassani H, Vaeli S, Rezaei A, et al. Impaired Akt phosphorylation in B-cells of patients with common variable immunodeficiency. Clin Immunol. 2017;175:124-32.
5. Azizi G, Abolhassani H, Mahdaviani SA, Chavoshzadeh Z, Eshghi P, Yazdani R, et al. Clinical, immunologic, molecular analyses and outcomes of iranian patients with LRBA deficiency: a longitudinal study. Pediatr Allergy Immunol. 2017;28(5):478-84.
6. Abbott JK, Gelfand EW. Common Variable Immunodeficiency: Diagnosis, Management, and Treatment. Immunol Allergy Clin North Am. 2015;35(4):637-58.
7. Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT, et al. International Consensus Document (ICON): Common Variable Immunodeficiency Disorders. J Allergy Clin Immunol Pract. 2016;4(1):38-59.
8. Jolles S. The Variable in Common Variable Immunodeficiency: A Disease of Complex Phenotypes. J Allergy Clin Immunol Pract. 2013;1(6):545-56.
9. Slade CA, Bosco JJ, Binh Giang T, Kruse E, Stirling RG, Cameron PU, et al. Delayed Diagnosis and Complications of Predominantly Antibody Deficiencies in a Cohort of Australian Adults. Front Immunol. 2018;9(694).
10. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-7.
11. Carsetti R, Rosado MM, Donnanno S, Guazzi V, Soresina A, Meini A, et al. The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency. J Allergy Clin Immunol. 2005;115(2):412-7.
12. Rakhmanov M, Keller B, Gutenberger S, Foerster C, Hoenig M, Driessen G, et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc Natl Acad Sci. 2009;106(32):13451-6.
13. Warnatz K, Denz A, Drager R, Braun M, Groth C, Wolff-Vorbeck 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(5):1544-51.
14. 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(1):77-85.
15. Yaz I, Ozbek B, Ng YY, Cetinkaya PG, Halacli SO, Tan C, et al. Lymphocyte Subgroups and KREC Numbers in Common Variable Immunodeficiency: A Single Center Study. J Clin Immunol. 2020:1-9.
16. Yazdani R, Seify R, Ganjalikhani-Hakemi M, Abolhassani H, Eskandari N, Golsaz-Shirazi F, et al. Comparison of various classifications for patients with common variable immunodeficiency (CVID) using measurement of B-cell subsets. Allergol Immunopathol (Madr). 2017;45(2):183-92.
17. 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(5):385-400.
18. Vodjgani M, Aghamohammadi A, Samadi M, Moin M, Hadjati J, Mirahmadian M, et al. Analysis of class-switched memory B cells in patients with common variable immunodeficiency and its clinical implications. J Investig Allergol Clin Immunol. 2007;17(5):321-8.
19. Berron-Ruiz L, Lopez-Herrera G, Vargas-Hernandez A, Mogica-Martinez 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.
20. Romberg N, Le Coz C, Glauzy S, Schickel J-N, Trofa M, Nolan BE, et al. Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses. J Allergy Clin Immunol. 2019;143(1):258-65.
21. Driessen GJ, van Zelm MC, van Hagen PM, Hartwig NG, Trip M, Warris A, et al. B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. Blood. 2011;118(26):6814-23.
22. Uzzan M, Ko HM, Mehandru S, Cunningham-Rundles C. Gastrointestinal disorders associated with common variable immune deficiency (CVID) and chronic granulomatous disease (CGD). Curr Gastroenterol Rep. 2016;18(4):17.
23. Warnatz K, Schlesier M. Flowcytometric phenotyping of common variable immunodeficiency. Cytometry B Clin Cytom. 2008;74(5):261-71.
24. Geier CB, Kraupp S, Bra D, Eibl MM, Farmer JR, Csomos K, et al. Reduced numbers of circulating group 2 innate lymphoid cells in patients with common variable immunodeficiency. Eur J Immunol. 2017;47(11):1959-69.
25. Le Saos-Patrinos C, Loizon S, Blanco P, Viallard J-F, Duluc D. Functions of Tfh Cells in Common Variable Immunodeficiency. Front Immunol. 2020;11(6).
26. Turpin D, Furudoi A, Parrens M, Blanco P, Viallard J-F, Duluc D. Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications. Clin Immunol. 2018;197:130-8.
27. Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107(8):3045-52.
28. Oraei M, Aghamohammadi A, Rezaei N, Bidad K, Gheflati Z, Amirkhani A, et al. 2 Naive CD4+ T cells and Recent Thymic Emigrants in Common Variable Immunodeficiency. J Investig Allergol Clin Immunol. 2012;22(3):160.
29. 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(6):3932-43.
30. Bateman EA, Ayers L, Sadler R, Lucas M, Roberts C, Woods A, et al. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin Exp Immunol. 2012;170(2):202-11.
31. Arumugakani G, Wood PM, Carter CR. Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21 lo B lymphocytes. J Clin Immunol. 2010;30(2):292-300.
32. Melo KM, Carvalho KI, Bruno FR, Ndhlovu LC, Ballan WM, Nixon DF, et al. A decreased frequency of regulatory T cells in patients with common variable immunodeficiency. PloS one. 2009;4(7):e6269.
33. López-Herrera G, Segura-Méndez N, O’Farril-Romanillos P, Nuñez-Nuñez M, Zarate-Hernández M, Mogica-Martínez D, et al. 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 CD21low B cells. Allergol Immunopathol (Madr). 2019;47(5):457-66.
34. Ganjalikhani-Hakemi M, Yazdani R, Sherkat R, Homayouni V, Masjedi M, Hosseini M. Evaluation of the T helper 17 cell specific genes and the innate lymphoid cells counts in the peripheral blood of patients with the common variable immunodeficiency. J Res Med Sci. 2014;19(Suppl 1):S30-5.
35. Carter CR, Aravind G, Smalle NL, Cole JY, Savic S, Wood PM. CVID patients with autoimmunity have elevated T cell expression of granzyme B and HLA-DR and reduced levels of Treg cells. J Clin Pathol. 2013;66(2):146-50.
36. Lanio N, Sarmiento E, Gallego A, Carbone J. Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings? Allergol Immunopathol (Madr). 2009;37(1):14-20.
37. Ogulur I, Kiykim A, Baser D, Karakoc-Aydiner E, Ozen A, Baris S. Lymphocyte Subset Abnormalities in Pediatric-Onset Common Variable Immunodeficiency. Int Arch Allergy Immunol. 2020;181(3):228-37.
38. Aukrust P, Aandahl EM, Skalhegg BS, Nordoy I, Hansson V, Tasken K, et al. Increased activation of protein kinase A type I contributes to the T cell deficiency in common variable immunodeficiency. J Immunol. 1999;162(2):1178-85.
39. North M, Webster A, Farrant J. Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C. Clin Exp Immunol. 1991;85(2):198-201.
40. Perreau M, Vigano S, Bellanger F, Pellaton C, Buss G, Comte D, et al. Exhaustion of bacteria-specific CD4 T cells and microbial translocation in common variable immunodeficiency disorders. J Exp Med. 2014;211(10):2033-45.
41. van de Ven AA, van de Corput L, van Tilburg CM, Tesselaar K, van Gent R, Sanders EA, et al. Lymphocyte characteristics in children with common variable immunodeficiency. Clin Immunol. 2010;135(1):63-71.
42. Abolhassani H, Kiaee F, Tavakol M, Chavoshzadeh Z, Mahdaviani SA, Momen T, et al. Fourth Update on the Iranian National Registry of Primary Immunodeficiencies: Integration of Molecular Diagnosis. J Clin Immunol. 2018;38(7):816-32.
43. European Society for Immunodeficiencies. ESID Registry - Working definitions for clinical diagnosis of PID [Available from: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria.
44. Seidel MG, Kindle G, Gathmann B, Quinti I, Buckland M, van Montfrans J, et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract. 2019;7(6):1763-70.
45. Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375-80.
46. Fang M, Abolhassani H, Lim CK, Zhang J, Hammarström L. Next generation sequencing data analysis in primary immunodeficiency disorders–future directions. J Clin Immunol. 2016;36(1):68-75.
47. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24-64.
48. Yazdani R, Habibi S, Sharifi L, Azizi G, Abolhassani H, Olbrich P, et al. Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. J Investig Allergol Clin Immunol. 2020;30(1):14-34.
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| Issue | Vol 3, No 4 (2020) | |
| Section | Original Article | |
| DOI | https://doi.org/10.18502/igj.v3i4.7464 | |
| Keywords | ||
| Primary Immunodeficiency Common Variable Immunodeficiency Immunologic Profile Clinical Phenotypes Proliferation Response | ||
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How to Cite
1.
Tofighi Zavareh F, Bagheri Y, Keshtkar AA. Evaluation of B Cell and T Cell Phenotypes in CVID Patients and Its Correlation with the Clinical Phenotypes: Study Protocol. Immunol Genet J. 2020;3(4):228-235.
