Common Variable Immunodeficiency (CVID) and Autoimmunity

Document Type : Review


Department of Immunology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran



Autoimmunity is observed by almost one-third of patients with CVID. Different mechanisms including genetic defects and dysregulation of innate and adaptive immunity leads to autoimmunity in these patients CVID. The clinical phenotypes of autoimmunity in CVID patients comprise fall in a wide spectrum, from organ-specific autoimmunity to systemic complications. The most common autoimmunity is autoimmune cytopenia in CVID patients. In this article, we have provided a collection of the most significant and recent information about prevalence, genetics, pathogenesis and clinical manifestations of autoimmunity in CVID patients, and provided an overview on its management and future perspective.


1. Cunningham-Rundles C, Maglione PJ. Common variable immunodeficiency. J Allergy Clin Immunol. 2012;129(5):1425-6 e3. 2. Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, et al. Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee. J Allergy Clin Immunol. 2007;120(4):776-94. 3. Xiao X, Miao Q, Chang C, Gershwin ME, Ma X. Common variable immunodeficiency and autoimmunity–an inconvenient truth. Autoim-mun Rev. 2014;13(8):858-64. 4. 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. 5. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34-48. 6. Busse PJ, Razvi S, Cunningham-Rundles C. Efficacy of intravenous immunoglobulin in the prevention of pneumonia in patients with common variable immunodeficiency. J Allergy Clin Immunol. 2002;109(6):1001-4. 7. Azizi G, Abolhassani H, Asgardoon MH, Alinia T, Yazdani R, Mohammadi J, et al. Autoimmunity in common variable immunodeficiency: epidemiology, pathophysiology and management. Expert Rev Clin Immunol. 2017;13(2):101-15. 8. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308-16. 9. Chapel H, Lucas M, Lee M, Bjorkander J, Webster D, Grimbacher B, et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood. 2008;112(2):277-86. 10. Boileau J, Mouillot G, Gérard L, Carmagnat M, Rabian C, Oksenhendler E, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun. 2011;36(1):25-32. 11. 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. 12. Ramirez-Vargas N, Arablin-Oropeza SE, Mojica-Martinez D, Yamazaki-Nakashimada MA, de la Luz Garcia-Cruz M, Teran-Juarez LM, et al. Clinical and immunological features of common variable immunodeficiency in Mexican patients. Allergol Immunopathol (Madr). 2014;42(3):235-40. 13. Ho HE, Cunningham-Rundles C. Non-infectious Complications of Common Variable Immunodeficiency: Updated Clinical Spectrum, Sequelae, and Insights to Pathogenesis. Front Immunol. 2020;11:149. 14. Gereige JD, Maglione PJ. Current Understanding and Recent Developments in Common Variable Immunodeficiency Associated Autoimmunity. Front Immunol. 2019;10:2753. 15. Karaj I. Common variable immunodeficiency: epidemiology, pathogenesis, clinical manifestations, diagnosis, classification and management. J Investig Allergol Clin Immunol. 2020;30(1). 16. Warnatz K, Voll RE. Pathogenesis of autoimmunity in common variable immunodeficiency. Front Immunol. 2012;3:210. 17. Farrokhi AS, Aghamohammadi A, Pourhamdi S, Mohammadinejad P, Abolhassani H, Moazzeni SM. Evaluation of class switch recombination in B lymphocytes of patients with common variable immunodeficiency. J Immunol Methods 2013;394(1-2):94-9. 18. Resnick ES, Cunningham-Rundles C. The many faces of the clinical picture of common variable immune deficiency. Curr Opin Allergy Clin Immunol. 2012;12(6):595-601. 19. OMIi M. Online Mendelian Inheritance in Man, OMIM. Baltimore, MD: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University. 2016. 20. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat genet. 2005;37(8):829-34. 21. Salzer U, Chapel H, Webster A, Pan-Hammarström 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(8):820-8. 22. Romberg N, Chamberlain N, Saadoun D, Gentile M, Kinnunen T, Ng YS, et al. CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest. 2013;123(10):4283-93. 23. Zhang Y, Li J, Zhang YM, Zhang XM, Tao J. Effect of TACI signaling on humoral immunity and autoimmune diseases. J Immunol Res. 2015;2015:247426. 24. 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. 25. Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, et al. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436-40. 26. 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(6):986-1001. 27. Serwas NK, Kansu A, Santos-Valente E, Kuloglu Z, Demir A, Yaman A, et al. Atypical manifestation of LRBA deficiency with predominant IBD-like phenotype. Inflamm Bowel Dis. 2015;21(1):40-7. 28. Charbonnier L-M, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, et al. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked– like disorder caused by loss-of-function mutations in LRBA. J Allergy Clin Immunol. 2015;135(1):217-27. e9. 29. 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. 30. Yazdani R, Abolhassani H, Kiaee F, Habibi S, Azizi G, Tavakol M, et al. Comparison of Common Monogenic Defects in a Large Predominantly Antibody Deficiency Cohort. J Allergy Clin Immunol Pract. 2019;7(3):864-78.e9. 31. 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. 32. Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605-35. 33. Preite S, Gomez-Rodriguez J, Cannons JL, Schwartzberg PL. T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity. Immunol Rev. 2019;291(1):154-73. 34. Thauland TJ, Pellerin L, Ohgami RS, Bacchetta R, Butte MJ. Case Study: Mechanism for Increased Follicular Helper T Cell Development in Activated PI3K Delta Syndrome. Front Immunol. 2019;10:753. 35. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606 e4. 36. Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: a blossoming of relevance to human pathobiology. Cell. 2017;168(1-2):37-57. 37. Scott O, Roifman CM. NF-κB pathway and the Goldilocks principle: Lessons from human disorders of immunity and inflammation. J Allergy Clin Immunol. 2019;143(5):1688-701. 38. Tuijnenburg P, Allen HL, Burns SO, Greene D, Jansen MH, Staples E, et al. Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficien-cy in Europeans. J Allergy Clin Immunol. 2018;142(4):1285-96. 39. Fliegauf M, Bryant VL, Frede N, Slade C, Woon S-T, Lehnert K, et al. Haploinsufficiency of the NF-κB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet. 2015;97(3):389-403. 40. Chen K, Coonrod EM, Kumánovics A, Franks ZF, Durtschi JD, Margraf RL, et al. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812-24. 41. Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat immunol. 2003;4(3):261-8. 42. Clemente A, Pons J, Lanio N, Cunill V, Frontera G, Crespi C, et al. Increased STAT3 phosphorylation on CD27(+) B-cells from common variable immunodeficiency disease patients. Clin Immunol. 2015;161(2):77-88. 43. 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. 44. Azizi G, Rezaei N, Kiaee F, Tavakolinia N, Yazdani R, Mirshafiey A, et al. T-Cell Abnormalities in Common Variable Immunodeficiency. J Investig Allergol Clin Immunol. 2016;26(4):233-43. 45. Boileau J, Mouillot G, Gerard L, Carmagnat M, Rabian C, Oksenhendler E, et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J Autoimmun. 2011;36(1):25-32. 46. Al Kindi M, Mundy J, Sullivan T, Smith W, Kette F, Smith A, et al. Utility of peripheral blood B cell subsets analysis in common variable immunodeficiency. Clin Exp Immunol. 2012;167(2):275-81. 47. Ahn S, Cunningham-Rundles C. Role of B cells in common variable immune deficiency. Expert Rev Clin Immunol. 2009;5(5):557-64. 48. Alachkar H, Taubenheim N, Haeney MR, Durandy A, Arkwright PD. Memory switched B cell percentage and not serum immunoglobulin concentration is associated with clinical complications in children and adults with specific antibody deficiency and common variable immunodeficiency. Clin Immunol. 2006;120(3):310-8. 49. Sanchez-Ramon S, Radigan L, Yu JE, Bard S, Cunningham-Rundles C. Memory B cells in common variable immunodeficiency: clinical associations and sex differences. Clin Immunol. 2008;128(3):314-21. 50. 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(2):161-71. 51. Terrier B, Joly F, Vazquez T, Benech P, Rosenzwajg M, Carpentier W, et al. Expansion of functionally anergic CD21-/low marginal zone-like B cell clones in hepatitis C virus infection-related autoimmunity. J Immunol. 2011;187(12):6550-63. 52. 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(5):502-13. 53. 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 U S A. 2009;106(32):13451-6. 54. Abolhassani H, Amirkashani D, Parvaneh N,Mohammadinejad P, Gharib B, Shahinpour S, et al. Autoimmune phenotype in patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2013;23(5):323-9. 55. Picchianti Diamanti A, Rosado MM, Scarsella M, Ceccarelli S, Lagana B, D’Amelio R, et al. Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series. Int J Immunopathol Pharmacol. 2015;28(4):547-56. 56. Mackay F, Woodcock SA, Lawton P, Ambrose C, Baetscher M, Schneider P, et al. Mice transgenic for BAFF develop lymphocytic disorders along with autoimmune manifestations. J Exp Med. 1999;190(11):1697-710. 57. Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol. 2002;2(7):465-75. 58. Thien M, Phan TG, Gardam S, Amesbury M, Basten A, Mackay F, et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity. 2004;20(6):785-98. 59. Matsushita T, Hasegawa M, Yanaba K, Kodera M, Takehara K, Sato S. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum. 2006;54(1):192-201. 60. Mackay F, Schneider P. Cracking the BAFF code. Nat Rev Immunol. 2009;9(7):491-502. 61. Knight AK, Radigan L, Marron T, Langs A, Zhang L, Cunningham-Rundles C. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin Immunol. 2007;124(2):182-9. 62. Azizi G, Kiaee F, Hedayat E, Yazdani R, Dolatshahi E, Alinia T, et al. Rheumatologic complications in a cohort of 227 patients with common variable immunodeficiency. Scand J Immunol. 2018;87(5):e12663. 63. 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. 64. Arumugakani G, Wood PM, Carter CR. Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21lo B lymphocytes. J Clin Immunol. 2010;30(2):292-300. 65. Xiao X, Miao Q, Chang C, Gershwin ME, Ma X. Common variable immunodeficiency and autoimmunity--an inconvenient truth. Autoimmun Rev. 2014;13(8):858-64. 66. Genre J, Errante PR, Kokron CM, Toledo-Barros M, Camara NO, Rizzo LV. Reduced frequency of CD4(+)CD25(HIGH)FOXP3(+) cells and diminished FOXP3 expression in patients with Common Variable Immunodeficiency: a link to autoimmunity? Clin Immunol. 2009;132(2):215-21. 67. 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(5):746-55. 68. 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(5):405-12. 69. 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(2):240-53. 70. Crotty S. T Follicular Helper Cell Biology: A Decade of Discovery and Diseases. Immunity. 2019;50(5):1132-48. 71. Sharifi L, Tavakolinia N, Kiaee F, Rezaei N, Mohsenzadegan M, Azizi G, et al. A Review on Defects of Dendritic Cells in Common Variable Immunodeficiency. Endocr Metab Immune Disord Drug Targets. 2017;17(2):100-13. 72. Yong PF, Workman S, Wahid F, Exley A, Webster ADB, Ibrahim MA. Selective deficits in blood dendritic cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia but not specific polysaccharide antibody deficiency. Clin Immunol. 2008;127(1):34-42. 73. Bayry J, Lacroix-Desmazes S, Kazatchkine MD, Galicier L, Lepelletier Y, Webster D, et al. Common variable immunodeficiency is associated with defective functions of dendritic cells. Blood. 2004;104(8):2441-3. 74. Cunningham-Rundles C, Radigan L. Deficient IL-12 and dendritic cell function in common variable immune deficiency. Clin Immunol. 2005;115(2):147-53. 75. Park J, Munagala I, Xu H, Blankenship D, Maffucci P, Chaussabel D, et al. Interferon signature in the blood in inflammatory common variable immune deficiency. PloS one. 2013;8(9). 76. Mahmoudi M, Hedayat M, Aghamohammadi A, Rezaei N. Soluble CD26 and CD30 levels in patients with common variable immunodeficiency. J Investig Allergol Clin Immunol. 2013;23(2):120-4. 77. Cambronero R, Sewell WC, North ME, Webster ADB, Farrant J. Up-regulation of IL-12 in monocytes: a fundamental defect in common variable immunodeficiency. J Immunol. 2000;164(1):488-94. 78. Mullighan CG, Marshall SE, Welsh KI. Mannose binding lectin polymorphisms are associated with early age of disease onset and autoimmunity in common variable immunodeficiency. Scand J Immunol. 2000;51(2):111-22. 79. Cols M, Rahman A, Maglione PJ, Garcia-Carmona Y, Simchoni N, Ko HM, et al. Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency. J Allergy Clin Immunol. 2016;137(4):1206- 15.e6. 80. AUKKUST P, Müller F, Frøland S. Enhanced generation of reactive oxygen species in monocytes from patients with common variable immunodeficiency. Clin Exp Immunol. 1994;97(2):232-8. 81. Sharifi L, Mirshafiey A, Rezaei N, Azizi G, Magaji Hamid K, Amirzargar AA, et al. The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency. Expert Rev Clin Immunol. 2016;12(2):195-207. 82. Isnardi I, Ng Y-S, Srdanovic I, Motaghedi R, Rudchenko S, von Bernuth H, et al. IRAK-4-and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans. Immunity. 2008;29(5):746-57. 83. Blanco P, Palucka AK, Gill M, Pascual V, Banchereau J. Induction of dendritic cell differentiation by IFN-α in systemic lupus erythematosus. Science. 2001;294(5546):1540-3. 84. Abraham RS, Podjasek JC. Autoimmune cytopenias in common variable immunodeficiency. Front Immunol. 2012;3:189. 85. Mantadakis E, Farmaki E, Taparkou A, Chatzimichael A, Speletas M. Common variable immune deficiency with mutated TNFSRF13B gene presenting with autoimmune hematologic manifestations. J Pediatr Hematol Oncol. 2016;1(4):83-5. 86. Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood, Am Soc Hematol. 2012;119(7):1650-7. 87. Odnoletkova I, Kindle G, Quinti I, Grimbacher B, Knerr V, Gathmann B, et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J Rare Dis. 2018;13(1):201. 88. Feuille EJ, Anooshiravani N, Sullivan KE, Fuleihan RL, Cunningham-Rundles C. Auto-immune Cytopenias and Associated Conditions in CVID: a Report From the USIDNET Registry. J Clin Immunol. 2018;38(1):28-34. 89. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Curr Allergy Asthma Rep. 2009;9(5):347-52. 90. Pituch-Noworolska A, Siedlar M, Kowalczyk D, Szaflarska A, BÅ‚aut-Szlósarczyk A, Zwonarz K. Thrombocytopenia in common variable immunodeficiency patients–clinical course, management, and effect of immunoglobulins. Cent Eur J Immunol. 2015;40(1):83. 91. Papageorgiou A, Ziakas P, Tzioufas A, Voulgarelis M. Indications for bone marrow examination in autoimmune disorders with concurrent haematologic alterations. Clin Exp Rheumatol. 2013;31(1):76-83. 92. Jubelirer SJ, Harpold R. The role of the bone marrow examination in the diagnosis of immune thrombocytopenic purpura: case series and literature review. Clin Appl Thromb Hemost. 2002;8(1):73-6. 93. Agarwal S, Cunningham-Rundles C. Autoimmunity in common variable immunodeficiency. Ann Allergy Asthma Immunol. 2019;123(5):454-60. 94. Allenspach E, Torgerson TR. Autoimmunity and Primary Immunodeficiency Disorders. J Clin Immunol. 2016;36 Suppl 1(1):57-67. 95. Lechner K, Jäger U. How I treat autoimmune hemolytic anemias in adults. Blood, Am Soc Hematol. 2010;116(11):1831-8. 96. Wang J, Cunningham-Rundles C. Treatment and outcome of autoimmune hematologic disease in common variable immunodeficiency (CVID). J Autoimmun. 2005;25(1):57-62. 97. Scheuerlein P, Pietsch L, Camacho-Ordonez N, Reiser V, Patel S, Burns SO, et al. is it safe to switch From intravenous immunoglobulin to subcutaneous immunoglobulin in Patients With common Variable immunodeficiency and autoimmune Thrombocytopenia? Front Immunol. 2018;9:1656. 98. Gobert D, Bussel JB, Cunningham- Rundles C, Galicier L, Dechartres A, Berezne A, et al. Efficacy and safety of rituximab in common variable immunodeficiency-associated immune cytopenias: a retrospective multicentre study on 33 patients. Br J Haematol. 2011;155(4):498-508. 99. Ghanima W, Godeau B, Cines DB, Bussel JB. How I treat immune thrombocytopenia: the choice between splenectomy or a medical therapy as a second-line treatment. Blood, Am Soc Hematol. 2012;120(5):960-9. 100. Wong GK, Goldacker S, Winterhalter C, Grimbacher B, Chapel H, Lucas M, et al. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients. Clin Exp Immunol. 2013;172(1):63-72. 101. 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. 102. Daniels JA, Lederman HM, Maitra A, Montgomery EA. Gastrointestinal tract pathology in patients with common variable immunodeficiency (CVID): a clinicopathologic study and review. Am J Surg Pathol. 2007;31(12):1800- 12. 103. Jørgensen SF, Reims HM, Frydenlund D, Holm K, Paulsen V, Michelsen AE, et al. A cross-sectional study of the prevalence of gastrointestinal symptoms and pathology in patients with common variable immunodeficiency. Am J Gastroenterol. 2016;111(10):1467-75. 104. Agarwal S, Smereka P, Harpaz N, Cunningham-Rundles C, Mayer L. Characterization of immunologic defects in patients with common variable immunodeficiency (CVID) with intestinal disease. Inflamm Bowel Dis. 2011;17(1):251-9. 105. Mannon PJ, Fuss IJ, Dill S, Friend J, Groden C, Hornung R, et al. Excess IL-12 but not IL-23 accompanies the inflammatory bowel disease associated with common variable immunodeficiency. Gastroenterology. 2006;131(3):748-56. 106. Oksenhendler E, Gerard L, Fieschi C, Malphettes M, Mouillot G, Jaussaud R, et al. Infections in 252 patients with common variable immunodeficiency. Clin Infect Dis. 2008;46(10):1547-54. 107. Elnachef N, McMorris M, Chey WD. Successful treatment of common variable immunodeficiency disorder-associated diarrhea with budesonide: a case report. Am J Gastroenterol. 2007;102(6):1322-5. 108. Agarwal S, Mayer L. Pathogenesis and treatment of gastrointestinal disease in antibody deficiency syndromes. J Allergy Clin Immunol. 2009;124(4):658-64. 109. Sanges M, Spadaro G, Miniero M, Mattera D, Sollazzo R, D’armiento F, et al. Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn’s-like phenotype: report of a case. Eur Rev Med Pharmacol Sci. 2015;19(14):2641-5. 110. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. 1999;92(1):34-48. 111. Agarwal S, Mayer L. Diagnosis and treatment of gastrointestinal disorders in patients with primary immunodeficiency. Clin Gastroenterol Hepatol. 2013;11(9):1050-63. 112. Song J, Lleo A, Yang GX, Zhang W, Bowlus CL, Gershwin ME, et al. Common Variable Immunodeficiency and Liver Involvement. Clin Rev Allergy Immunol. 2018;55(3):340-51. 113. Daniels JA, Torbenson M, Vivekanandan P, Anders RA, Boitnott JK. Hepatitis in common variable immunodeficiency. Hum Pathol. 2009;40(4):484-8. 114. Giannouli S, Anagnostou D, Soliotis F, Voulgarelis M. Autoimmune manifestations in common variable immunodeficiency. Clin Rheumatol. 2004;23(5):449-52. 115. Swierkot J, Lewandowicz-Uszynska A, Chlebicki A, Szmyrka-Kaczmarek M, Polanska B, Jankowski A, et al. Rheumatoid arthritis in a patient with common variable immunodeficiency: difficulty in diagnosis and therapy. Clin Rheumatol. 2006;25(1):92-4. 116. Gutierrez MJ, Sullivan KE, Fuleihan R, Consortium U, Bingham CO, 3rd. Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency. Semin Arthritis Rheum. 2018;48(2):318-26. 117. Maglione PJ. Autoimmune and Lymphoproliferative Complications of Common Variable Immunodeficiency. Curr Allergy Asthma Rep. 2016;16(3):19. 118. Sordet C, Cantagrel A, Schaeverbeke T, Sibilia J. Bone and joint disease associated with primary immune deficiencies. Joint Bone Spine. 2005;72(6):503-14. 119. Lopes-da-Silva S, Rizzo LV. Autoimmunity in common variable immunodeficiency. J Clin Immunol. 2008;28 Suppl 1:S46-55. 120. Popa V, Nagy SM, Jr. Immediate hypersensitivity in adults with IgG deficiency and recurrent respiratory infections. Ann Allergy Asthma Immunol. 1999;82(6):567-73. 121. Thickett KM, Kumararatne DS, Banerjee AK, Dudley R, Stableforth DE. Common variable immune deficiency: respiratory manifestations, pulmonary function and high-resolution CT scan findings. QJM. 2002;95(10):655-62. 122. Yazdani R, Heydari A, Azizi G, Abolhassani H, Aghamohammadi A. Asthma and Allergic Diseases in a Selected Group of Patients With Common Variable Immunodeficiency. J Investig Allergol Clin Immunol. 2016;26(3):209- 11. 123. Fekrvand S, Abolhassani H, Delavari S, Yazdani R, Aghamohammadi A. Are asthma and allergic diseases phenotypic markers for patients with common variable immuno-deficiency? Ann Allergy Asthma Immunol. 2020;124(6):636. 124. Pandit C, Hsu P, van Asperen P, Mehr S. Respiratory manifestations and management in children with Common Variable Immunodeficiency. Paediatr Respir Rev. 2016;19:56-61. 125. Cha SI, Fessler MB, Cool CD, Schwarz MI, Brown KK. Lymphoid interstitial pneumonia: clinical features, associations and prognosis. Eur Respir J. 2006;28(2):364-9. 126. Liebow AA, Carrington CB. Diffuse pulmonary lymphoreticular infiltrations associated with dysproteinemia. Med Clin North Am. 1973;57(3):809-43. 127. Fernandez Perez ER. Granulomatous lymphocytic interstitial lung disease. Immunol Allergy Clin North Am. 2012;32(4):621-32. 128. Park JH, Levinson AI. Granulomatous-lymphocytic interstitial lung disease (GLILD) in common variable immunodeficiency (CVID). Clin Immunol. 2010;134(2):97-103. 129. Chase NM, Verbsky JW, Hintermeyer MK, Waukau JK, Tomita-Mitchell A, Casper JT, et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol. 2013;33(1):30-9. 130. Kohler PF, Cook RD, Brown WR, Manguso RL. Common variable hypogammaglobulinemia with T-cell nodular lymphoid interstitial pneumonitis and B-cell nodular lymphoid hyperplasia: different lymphocyte populations with a similar response to prednisone therapy. J Allergy Clin Immunol. 1982;70(4):299-305. 131. Bates CA, Ellison MC, Lynch DA, Cool CD, Brown KK, Routes JM. Granulomatous-lymphocytic lung disease shortens survival in common variable immunodeficiency. J Allergy Clin Immunol. 2004;114(2):415-21. 132. Megna M, Pecoraro A, Balato N, Villani A, Crescenzi L, Balato A, et al. Psoriasis in a cohort of patients with common variable immunodeficiency. Br J Dermatol. 2019;180(4):935- 6. 133. Gualdi G, Lougaris V, Baronio M, Vitali M, Tampella G, Moratto D, et al. Burden of Skin Disease in Selective IgA Deficiency and Common Variable Immunodeficiency. J Investig Allergol Clin Immunol. 2015;25(5):369-71. 134. Paquin-Proulx D, Sandberg JK. Persistent Immune Activation in CVID and the Role of IVIg in Its Suppression. Front Immunol. 2014;5:637. 135. Jindal AK, Rawat A, Sharma A, Dogra S, Suri D, Singh S. Psoriasis: An Unusual Autoimmune Manifestation in a Boy with Common Variable Immunodeficiency. Indian Dermatol Online J. 2017;8(4):292-4. 136. Plana Pla A, Bassas-Vila J, Roure S, Ferrandiz C. Necrotizing and sarcoidal granulomas in the skin and synovial membrane, associated with common variable immunodeficiency. Clin Exp Dermatol. 2015;40(4):379-82.