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Immunodeficiency Patients Differentiation of Common Variable Defined Blocks in Terminal Plasma Cell Differentiation of Common Variable Immunodeficiency Patients This information is current as Nadine Taubenheim, Marcus von Hornung, Anne Durandy, of September 24, 2021. Klaus Warnatz, Lynn Corcoran, Hans-Hartmut Peter and Hermann Eibel J Immunol 2005; 175:5498-5503; ; doi: 10.4049/jimmunol.175.8.5498 http://www.jimmunol.org/content/175/8/5498 Downloaded from References This article cites 35 articles, 13 of which you can access for free at: http://www.jimmunol.org/content/175/8/5498.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 24, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2005 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Defined Blocks in Terminal Plasma Cell Differentiation of Common Variable Immunodeficiency Patients1 Nadine Taubenheim,* Marcus von Hornung,* Anne Durandy,† Klaus Warnatz,‡ Lynn Corcoran,§ Hans-Hartmut Peter,‡ and Hermann Eibel2* Common variable immunodeficiency (CVID) is a heterogeneous disorder characterized by defective Ab production and recurrent bacterial infections. The largely unknown causes are likely to comprise a diverse set of genetic or acquired defects. In this study, we investigated terminal B cell differentiation in lymph nodes from CVID patients. Up to the germinal center B cell stage, B cell differentiation was normal but terminal plasma cell development was found to be impaired. Using differential Blimp-1 and Syndecan-1 expression in controls, we defined three different plasma cell subsets that correspond to progressive developmental stages locating to different sites in the lymph node. In the CVID patients, we could only detect one or two of these subsets indicating a defective differentiation. Thus, terminal plasma cell differentiation was found to be impaired despite normal expression of Downloaded from Blimp-1. B cells reaching only the first stage of plasma cell differentiation were further unable to undergo isotype switching and to up-regulate activation markers on B cells stimulated in vitro. The Journal of Immunology, 2005, 175: 5498–5503. ommon variable immunodeficiency (CVID)3 is the sec- hypermutation (SHM) (9), as well as defective formation of mem- ond most frequent primary immunodeficiency in humans ory B cells (10–13). C with a prevalence of ϳ1 in 30,000 (1). The major hall- Class switch recombination (CSR) as well as SHM of the V http://www.jimmunol.org/ mark of CVID is a significant reduction or absence of Abs in the regions take place in germinal centers (GC) of secondary lymphoid serum of the patients leading to recurrent bacterial infections pre- organs and lead to the generation of Ab-secreting plasma cells and dominantly of the respiratory and gastrointestinal tracts. Further- Ag-specific memory cells. The GC reaction is initiated by the ac- more, an increased incidence of granulomatous inflammation, au- tivation of B cells, which up-regulate BCL-6 and migrate into B toimmune disorders, and gastrointestinal malignancies has been cell follicles where they undergo a phase of strong proliferation. At described (2). The syndrome can occur in both sporadic and fa- the same time, the specificity of the BCR is modified by SHM, milial forms and covers a heterogeneous group of disorders of allowing for affinity maturation due to positive selection of B cells which the underlying molecular bases are largely unknown. Re- for BCRs with the highest affinity. cently, a homozygous deletion in the ICOS gene has been identi- BCL-6 is a zinc finger protein that acts as a transcriptional re- by guest on September 24, 2021 fied in a small group of CVID patients (3). However, in the ma- pressor. BCL-6 mRNA can be found in a variety of tissues (14), jority of the patients, the characterization of genetic defects but on the protein level, the expression is mainly restricted to lym- remains elusive. Several functional defects have been described phocytes (14–16), with the highest expression in GC centroblasts affecting proliferation, activation, and cytokine production in T and centrocytes. PRDM1, encoding the transcriptional repressor cells (4, 5). In B cells, early and late differentiation stages may be Blimp-1, represents a central target gene of BCL-6 (17). Blimp-1 affected resulting in defective up-regulation of surface molecules was proposed to be a key regulator of terminal plasma cell differ- such as CD86 and CD70 (6, 7), impaired signaling (8), and somatic entiation because ectopic expression of the protein was sufficient to drive the differentiation of mature B cells to plasma cells (18). The defective expression of proteins essential for the differen- *Clinical Research Unit for Rheumatology, University Hospital of Freiburg, Freiburg, tiation of B cells to GC B cells or plasma cells, such as BCL-6 or Germany; †Institut National de la Sante´et de la Recherche Me´dicale (INSERM) Unite´ Blimp-1, could be responsible for the phenotypic features observed 429, Hoˆpital Necker-Enfants Malades, Paris, France; ‡Division of Rheumatology and Clinical Immunology, Department of Medicine, University Hospital of Freiburg, in CVID. In this report, we describe for the first time defects in the Freiburg, Germany; §The Walter and Eliza Hall Institute of Medical Research, GC reaction and plasma cell development in lymph nodes (LN) Parkville, Victoria, Australia from CVID patients. We revealed three different stages by which Received for publication April 28, 2005. Accepted for publication July 22, 2005. plasma cell differentiation takes place in the control LN and could The costs of publication of this article were defrayed in part by the payment of page show distinct blocks in this process in the LN from three CVID charges. This article must therefore be hereby marked advertisement in accordance patients. with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by the European Community through Grants QLCT-2001- 01536 and LSHM-CT-2004-005264 to H.E. and the Grants EURO-POLICY-PID PL Materials and Methods 006411, INSERM, the French Rare Disease Program and the Assistance-Publique, Patients Hopitaux de Paris (to A.D.). 2 In this study patients were only included with established diagnosis of Address correspondence and reprint requests to Dr. Hermann Eibel, Clinical Re- ͗ ͘ search Unit for Rheumatology, University Hospital Freiburg, Zentrum Klinische CVID (ESID criteria, www.esid.org ). The patients were regularly fol- Forschung, Breisacher Strasse 66, 79106 Freiburg, Germany. E-mail address: lowed in our outpatient clinic and received monthly i.v. or weekly s.c. [email protected] replacement therapy, respectively. LN biopsies were from patients who developed during their follow-up regional mediastinal and/or LN swellings 3 Abbreviations used in this paper: CVID, common variable immunodeficiency; CSR, class switch recombination; CT, circle transcript; AICDA, activation-induced cytidine to exclude malignant lymphoma. None of the biopsies of the three CVID deaminase; EGFP, enhanced GFP; GC, germinal center; GLT, germline transcript; patients described here showed malignant lymphomas. Control tissues HD, healthy donor; LN, lymph node; MFI, mean fluorescence intensity; SHM, so- were obtained from patients undergoing LN dissection within the scope of matic hypermutation. lung cancer treatment. Copyright © 2005 by The American Association of Immunologists, Inc. 0022-1767/05/$02.00 The Journal of Immunology 5499 Table I summarizes the clinical and immunological features of the pa- endogenous peroxidases. Immunohistochemical stainings were then per- tients. Informed consent was obtained from all patients and controls using formed according to the procedures specified in Elite Vectastain kits, using biopsy material and peripheral blood for scientific purposes according to a the Nova Red, Vector SG, and Vector AP substrates (Vector Laboratories). local ethics committee approved research protocol (no. 239/1999). Reagents Flow cytometry Primary Abs used for immunohistochemistry: anti-IgD-AP (Southern Bio- PBMC and single cell suspensions of the LN were stained with fluores- technology Associates), anti-Syndecan-1 (Serotec), anti-Ki67 (BD Pharm- cence-conjugated Abs. Cells were acquired using a FACSCalibur analyzer, ingen), anti-BCL 6 and anti-CD23 (DakoCytomation), anti-BOB-1 and anti- and data were analyzed using CellQuest software (BD Biosciences). Dead OCT-2 (Santa Cruz Biotechnology) and anti-Blimp-1 (19). Abs and cells were excluded by gating on propidium iodide-negative cells and on reagents used for flow cytometry: anti-CD19 allophycocyanin and anti- viable lymphocytes according to their forward and side scatters. CD38 FITC (Caltag Laboratories), anti-IgM-bio (Sigma-Aldrich), anti- CD19 PC5 (IO-Test), SA-allophycocyanin, anti-CD27 PE, anti-CD69 FITC
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