{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T18:13:13Z","timestamp":1772820793199,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,7]],"date-time":"2020-04-07T00:00:00Z","timestamp":1586217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"RS","award":["DZIF TTU 07.801"],"award-info":[{"award-number":["DZIF TTU 07.801"]}]},{"name":"RS","award":["01GM1910E"],"award-info":[{"award-number":["01GM1910E"]}]},{"name":"RS","award":["RESIST (EXC 2155)"],"award-info":[{"award-number":["RESIST (EXC 2155)"]}]},{"DOI":"10.13039\/100011444","name":"GS","doi-asserted-by":"publisher","award":["n.a."],"award-info":[{"award-number":["n.a."]}],"id":[{"id":"10.13039\/100011444","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>The phenotype of primary immunodeficiency disorders (PID), and especially common variable immunodeficiency (CVID), may be dominated by symptoms of autoimmune disorders. Furthermore, autoimmunity may be the first manifestation of PID, frequently preceding infections and the diagnosis of hypogammaglobulinemia, which occurs later on. In this case, distinguishing PID from hypogammaglobulinemia secondary to anti-inflammatory treatment of autoimmunity may become challenging. The aim of this study was to evaluate the diagnostic accuracy of peripheral blood lymphocyte phenotyping in resolving the diagnostic dilemma between primary and secondary hypogammaglobulinemia. Comparison of B and T cell subsets from patients with PID and patients with rheumatic disease, who developed hypogammaglobulinemia as a consequence of anti-inflammatory regimes, revealed significant differences in proportion of na\u00efve B cells, class-switched memory B cells and CD21low B cells among B cells as well as in CD4+ memory T cells and CD4+ T follicular cells among CD4+ T cells. Identified differences in B cell and T cell subsets, and especially in the proportion of class-switched memory B cells and CD4+ T follicular cells, display a considerable diagnostic efficacy in distinguishing PID from secondary hypogammaglobulinemia due to anti-inflammatory regimens for rheumatic disease.<\/jats:p>","DOI":"10.3390\/jcm9041049","type":"journal-article","created":{"date-parts":[[2020,4,8]],"date-time":"2020-04-08T05:59:47Z","timestamp":1586325587000},"page":"1049","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Peripheral Blood Lymphocyte Phenotype Differentiates Secondary Antibody Deficiency in Rheumatic Disease from Primary Antibody Deficiency"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7129-100X","authenticated-orcid":false,"given":"Alexandra","family":"Jablonka","sequence":"first","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haress","family":"Etemadi","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ignatius Ryan","family":"Adriawan","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Diana","family":"Ernst","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2942-7924","authenticated-orcid":false,"given":"Roland","family":"Jacobs","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Buyny","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Torsten","family":"Witte","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhold Ernst","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Faranaz","family":"Atschekzei","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0855-2945","authenticated-orcid":false,"given":"Georgios","family":"Sogkas","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Immunology, Hannover Medical School, 30625 Hannover, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1111\/cei.12915","article-title":"When to initiate immunoglobulin replacement therapy (IGRT) in antibody deficiency: A practical approach","volume":"188","author":"Jolles","year":"2017","journal-title":"Clin. Exp. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"33","DOI":"10.3389\/fimmu.2019.00033","article-title":"The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management","volume":"10","author":"Patel","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1016\/j.jaip.2019.02.004","article-title":"The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity","volume":"7","author":"Seidel","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Ameratunga, R., and Woon, S.T. (2019). Perspective: Evolving Concepts in the Diagnosis and Understanding of Common Variable Immunodeficiency Disorders (CVID). Clin. Rev. Allergy Immunol.","DOI":"10.1007\/s12016-019-08765-6"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1272","DOI":"10.3389\/fimmu.2019.01272","article-title":"The German National Registry of Primary Immunodeficiencies (2012-2017)","volume":"10","author":"Biegner","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1182\/blood-2007-11-124545","article-title":"Common variable immunodeficiency disorders: Division into distinct clinical phenotypes","volume":"112","author":"Chapel","year":"2008","journal-title":"Blood"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1016\/j.semarthrit.2006.09.005","article-title":"Common variable immunodeficiency in systemic lupus erythematosus","volume":"36","author":"Citores","year":"2007","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1007\/s10875-016-0330-1","article-title":"Autoimmune and Inflammatory Manifestations in 247 Patients with Primary Immunodeficiency-a Report from the Slovenian National Registry","volume":"36","author":"Blazina","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.semarthrit.2018.02.013","article-title":"Phenotypic characterization of patients with rheumatologic manifestations of common variable immunodeficiency","volume":"48","author":"Gutierrez","year":"2018","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1007\/s10875-019-00708-2","article-title":"Interstitial Lung Disease Frequently Precedes CVID Diagnosis","volume":"39","author":"Hanitsch","year":"2019","journal-title":"J. Clin. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1650","DOI":"10.1016\/j.jaci.2018.06.039","article-title":"Primary immunodeficiency disorder caused by phosphoinositide 3-kinase \u03b4 deficiency","volume":"142","author":"Sogkas","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2618","DOI":"10.3389\/fimmu.2019.02618","article-title":"Late-Onset Antibody Deficiency Due to Monoallelic Alterations in NFKB1","volume":"10","author":"Sogkas","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1932","DOI":"10.1016\/j.jaci.2018.02.055","article-title":"Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects","volume":"142","author":"Schwab","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1016\/j.ajhg.2015.07.008","article-title":"Haploinsufficiency of the NF-\u03baB1 Subunit p50 in Common Variable Immunodeficiency","volume":"97","author":"Fliegauf","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2303","DOI":"10.1016\/j.jaci.2018.02.007","article-title":"Prevalence and clinical challenges among adults with primary immunodeficiency and recombination-activating gene deficiency","volume":"141","author":"Lawless","year":"2018","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1958","DOI":"10.1016\/j.jaip.2019.02.018","article-title":"Clinical Aspects of STAT3 Gain-of-Function Germline Mutations: A Systematic Review","volume":"7","author":"Fabre","year":"2019","journal-title":"J. Allergy Clin. Immunol. Pract."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1111\/j.1365-2249.2012.04643.x","article-title":"T cell phenotypes in patients with common variable immunodeficiency disorders: Associations with clinical phenotypes in comparison with other groups with recurrent infections","volume":"170","author":"Bateman","year":"2012","journal-title":"Clin. Exp. Immunol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"4112","DOI":"10.4049\/jimmunol.178.7.4112","article-title":"Four functionally distinct populations of human effector-memory CD8+ T lymphocytes","volume":"178","author":"Romero","year":"2007","journal-title":"J. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3270","DOI":"10.1002\/eji.200636976","article-title":"Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children","volume":"37","author":"Junge","year":"2007","journal-title":"Eur. J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1016\/j.immuni.2009.03.003","article-title":"Follicular helper T cells: Lineage and location","volume":"30","author":"Fazilleau","year":"2009","journal-title":"Immunity"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"546","DOI":"10.3389\/fimmu.2016.00546","article-title":"Transitional B Cells in Early Human B Cell Development\u2014Time to Revisit the Paradigm?","volume":"7","author":"Martin","year":"2016","journal-title":"Front. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3389\/fimmu.2011.00081","article-title":"The relationship between CD27 negative and positive B cell populations in human peripheral blood","volume":"2","author":"Wu","year":"2011","journal-title":"Front. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13451","DOI":"10.1073\/pnas.0901984106","article-title":"Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells","volume":"106","author":"Rakhmanov","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1078\/0171-2985-00198","article-title":"Expansion of CD19(hi)CD21(lo\/neg) B cells in common variable immunodeficiency (CVID) patients with autoimmune cytopenia","volume":"206","author":"Warnatz","year":"2002","journal-title":"Immunobiology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1182\/blood-2007-06-091744","article-title":"The EUROclass trial: Defining subgroups in common variable immunodeficiency","volume":"111","author":"Wehr","year":"2008","journal-title":"Blood"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1007\/s10875-016-0264-7","article-title":"Secondary Antibody Deficiency in Glucocorticoid Therapy Clearly Differs from Primary Antibody Deficiency","volume":"36","author":"Wirsum","year":"2016","journal-title":"J. Clin. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1182\/blood.V99.5.1544","article-title":"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","volume":"99","author":"Warnatz","year":"2002","journal-title":"Blood"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"6431","DOI":"10.4049\/jimmunol.0903876","article-title":"Characterization of lymphocyte subsets in patients with common variable immunodeficiency reveals subsets of naive human B cells marked by CD24 expression","volume":"185","author":"Janda","year":"2010","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4951587","DOI":"10.1155\/2016\/4951587","article-title":"Common Variable Immunodeficiency and Circulating TFH","volume":"2016","author":"Coraglia","year":"2016","journal-title":"J. Immunol. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3389\/fimmu.2014.00626","article-title":"Immunoglobulin replacement therapy in secondary hypogammaglobulinemia","volume":"5","author":"Compagno","year":"2014","journal-title":"Front. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/acr.23720","article-title":"Clinical Remission and Low Disease Activity Outcomes Over 10 Years in Systemic Lupus Erythematosus","volume":"71","author":"Tselios","year":"2019","journal-title":"Arthritis Care Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1007\/s10067-013-2468-z","article-title":"Revising DAS28 scores for remission in rheumatoid arthritis","volume":"33","author":"Sheehy","year":"2014","journal-title":"Clin. Rheumatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"108269","DOI":"10.1016\/j.clim.2019.108269","article-title":"A novel NFKBIA variant substituting serine 36 of I\u03baB\u03b1 causes immunodeficiency with warts, bronchiectasis and juvenile rheumatoid arthritis in the absence of ectodermal dysplasia","volume":"210","author":"Sogkas","year":"2020","journal-title":"Clin. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Robin, X., Turck, N., Hainard, A., Tiberti, N., Lisacek, F., Sanchez, J.C., and M\u00fcller, M. (2011). pROC: An open-source package for R and S+ to analyze and compare ROC curves. BMC Bioinform., 12.","DOI":"10.1186\/1471-2105-12-77"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sepriano, A., Kerschbaumer, A., Smolen, J.S., van der Heijde, D., Dougados, M., van Vollenhoven, R., McInnes, I.B., Bijlsma, J.W., Burmester, G.R., and de Wit, M. (2020). Safety of synthetic and biological DMARDs: A systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis. Ann. Rheum. Dis.","DOI":"10.1136\/annrheumdis-2019-216653"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Gr\u00f8n, K.L., Glintborg, B., N\u00f8rgaard, M., Mehnert, F., \u00d8stergaard, M., Dreyer, L., Krogh, N.S., and Hetland, M.L. (2019). Overall infection risk in rheumatoid arthritis during treatment with abatacept, rituximab and tocilizumab; an observational cohort study. Rheumatology.","DOI":"10.1136\/annrheumdis-2019-eular.1478"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1007\/s00296-014-2945-y","article-title":"Serious infections in patients with rheumatoid arthritis and other immune-mediated connective tissue diseases exposed to anti-TNF or rituximab: Data from the Spanish registry BIOBADASER 2.0","volume":"34","author":"Descalzo","year":"2014","journal-title":"Rheumatol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1541","DOI":"10.3389\/fimmu.2019.01541","article-title":"The Natural History of Untreated Primary Hypogammaglobulinemia in Adults: Implications for the Diagnosis and Treatment of Common Variable Immunodeficiency Disorders (CVID)","volume":"10","author":"Ameratunga","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.clim.2018.09.006","article-title":"Increase of follicular helper T cells skewed toward a Th1 profile in CVID patients with non-infectious clinical complications","volume":"197","author":"Turpin","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.1016\/j.semarthrit.2019.04.007","article-title":"Lymphocyte phenotype and its application to precision medicine in systemic autoimmune diseases","volume":"48","author":"Tanaka","year":"2019","journal-title":"Semin. Arthritis Rheum."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.mce.2010.04.005","article-title":"The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights","volume":"335","author":"Coutinho","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1177\/153537020222700907","article-title":"Glucocorticoid-induced apoptosis in early B cells from human bone marrow","volume":"227","author":"Schwartz","year":"2002","journal-title":"Exp. Biol. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1002\/art.38736","article-title":"Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis","volume":"66","author":"Glaesener","year":"2014","journal-title":"Arthritis Rheumatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.rdc.2009.12.002","article-title":"B-cell biology and related therapies in systemic lupus erythematosus","volume":"36","author":"Ahmed","year":"2010","journal-title":"Rheum. Dis. Clin. N. Am."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1002\/art.38107","article-title":"Rituximab-induced T cell depletion in patients with rheumatoid arthritis: Association with clinical response","volume":"65","author":"Mulleman","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Brokstad, K.A., Fredriksen, M., Zhou, F., Bergum, B., Brun, J.G., Cox, R.J., and Skarstein, K. (2018). T follicular-like helper cells in the peripheral blood of patients with primary Sj\u00f6gren\u2019s syndrome. Scand. J. Immunol., e12679.","DOI":"10.1111\/sji.12679"},{"key":"ref_47","first-page":"4578","article-title":"High frequency of circulating follicular helper T cells is correlated with B cell subtypes in patients with ankylosing spondylitis","volume":"15","author":"Long","year":"2018","journal-title":"Exp. Ther. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.clim.2017.10.008","article-title":"Increased proportion of a CD38highIgD+ B cell subset in peripheral blood is associated with clinical and immunological features in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"187","author":"Yoshimoto","year":"2018","journal-title":"Clin. Immunol."},{"key":"ref_49","first-page":"76","article-title":"A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sj\u00f6gren\u2019s syndrome and systemic lupus erythematosus","volume":"183","author":"Papp","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"e12792","DOI":"10.1111\/sji.12792","article-title":"CD21-\/low B cells associate with joint damage in rheumatoid arthritis patients","volume":"90","author":"Thorarinsdottir","year":"2019","journal-title":"Scand. J. Immunol."},{"key":"ref_51","first-page":"1","article-title":"Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: A case-control study","volume":"5","author":"Shimizu","year":"2020","journal-title":"Mod. Rheumatol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/4\/1049\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:16:21Z","timestamp":1760174181000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/9\/4\/1049"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,4,7]]},"references-count":51,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["jcm9041049"],"URL":"https:\/\/doi.org\/10.3390\/jcm9041049","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,4,7]]}}}