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Malaria Polyclonal B Cell Activator Activation of the Memory Increased B Cell Survival and Preferential Activation of the Memory Compartment by a Malaria Polyclonal B Cell Activator This information is current as Daria Donati, Bobo Mok, Arnaud Chêne, Hong Xu, Mathula of October 2, 2021. Thangarajh, Rickard Glas, Qijun Chen, Mats Wahlgren and Maria Teresa Bejarano J Immunol 2006; 177:3035-3044; ; doi: 10.4049/jimmunol.177.5.3035 http://www.jimmunol.org/content/177/5/3035 Downloaded from References This article cites 35 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/177/5/3035.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 October 2, 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 © 2006 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Increased B Cell Survival and Preferential Activation of the Memory Compartment by a Malaria Polyclonal B Cell Activator1 Daria Donati,2† Bobo Mok,* Arnaud Cheˆne,*† Hong Xu,† Mathula Thangarajh,‡ Rickard Glas,† Qijun Chen,§ Mats Wahlgren,* and Maria Teresa Bejarano*† Chronic malaria infection is characterized by polyclonal B cell activation, hyperglobulinemia, and elevated titers of autoantibod- ies. We have recently identified the cysteine-rich interdomain region 1␣ (CIDR1␣)ofthePlasmodium falciparum erythrocyte membrane protein 1 as a T cell-independent polyclonal B cell activator and Ig binding protein. Here, we show that, although the binding affinity of CIDR1␣ to human IgM and IgG is relatively low, B cell activation still proceeds. CIDR1␣ rescues tonsillar B cells from apoptosis, and increases the proportion of cycling cells. Comparison of the impact on naive and memory B cell compartment indicated that CIDR1␣ preferentially activates memory B lymphocytes. Analysis of the gene expression profiles Downloaded from induced by CIDR1␣ and anti-Ig activation using a cDNA microarray demonstrated a low degree of homology in the signatures imposed by both stimuli. The microarray data correlate with the functional analysis demonstrating that CIDR1␣ activates various immunological pathways and protects B cells from apoptosis. Together, the results provide evidence for a role of malaria in preferentially activating the memory B cell compartment. The polyclonal B cell activation and augmented survival induced by CIDR1␣ is of relevance for understanding the mechanisms behind the increased risk of Burkitt’s lymphoma in malaria endemic areas. The Journal of Immunology, 2006, 177: 3035–3044. http://www.jimmunol.org/ berrant immune activation induced by chronic infections sent ϳ40% of the splenocytes. Thus, IE and their constituent Ags with Plasmodium falciparum leads to polyclonal B cell could interact in the spleen with B cells displaying a variety of A activation characterized by the presence of hyperglobu- surface phenotypes, Ag-binding repertoires and signaling profiles linemia (1), elevated titers of autoantibodies (2, 3), and frequent (7). Among malarial Ags, the P. falciparum erythrocyte membrane occurrence of Burkitt’s lymphoma (4) and splenic lymphoma (5). protein 1 (PfEMP1) family of proteins often display Ig binding The mechanisms that lead to this polyclonal B cell activation are properties (8, 9). The Ig binding activity of the PfEMP1, cloned poorly understood. from two different P. falciparum strains, resides in two different by guest on October 2, 2021 The marked effect of malaria infection on B cells is related both variable domains, the Duffy binding-like domain 2␤ (DBL2␤) and to the biology of the infection, and to the nature of the malarial the cysteine-rich interdomain region 1␣ (CIDR1␣) (8). The latter Ags. P. falciparum-infected erythrocytes (IE)3 have the potential domain has been identified as a polyclonal B cell activator and an to directly interact with B cells in different anatomical sites and to Ig binding protein (IBP) (10) with a binding pattern similar to that induce B cell proliferation and differentiation into Ab-secreting of another microbial IBP, the protein A of Staphylococcus aureus cells. We have shown that a large proportion (83%) of fresh iso- (8, 10, 11). Microbial IBPs are produced by protozoa, viruses, and lates of IE bind nonimmune Igs (6), suggesting that in the periph- bacteria (12), and play important physiological roles (13). During eral blood IE could interact with B cells through their surface Igs. an infectious process, IBPs may act as an evasion mechanism to Moreover, bloodborne Ags (and thus malarial Ags related to the divert specific Ab responses (14, 15). CIDR1␣ binds to and acti- erythrocytic phase) are trapped in the spleen where B cells repre- vates purified B lymphocytes in vitro, an interaction partially me- diated through the binding to surface Ig (10). To further understand the impact of CIDR1␣ on the immune *Microbiology and Tumorbiology Center, Karolinska Institutet, †Center for Infec- system, we analyzed its effect on the dynamics of the B cell com- tious Medicine, Department of Medicine, ‡Division of Neurology R54, Karolinska § partment and compared the gene expression profiles during acti- Institutet, Karolinska University Hospital Huddinge, and Swedish Institute for In- ␣ fection Disease Control, Stockholm, Sweden vation induced by CIDR1 and the triggering of the BCR via ␣ Received for publication May 24, 2005. Accepted for publication May 25, 2006. anti-Ig. The data show that CIDR1 preferentially induces the ac- tivation of the memory B cell compartment and that this activation The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance seems to be different from the one imposed by anti-Ig treatment. with 18 U.S.C. Section 1734 solely to indicate this fact. 1 This work was supported by grants from the Swedish International Development Cooperation Agency, Barncancerfonden, the Swedish Research Council, the Swedish Materials and Methods Foundation for Strategic Research, and the Karolinska Institutet. Production of recombinant Ags 2 Address correspondence and reprint requests to Dr. Daria Donati, Center for Infec- ␣ tious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, F59, CIDR1 , of the cloned strain FCR3S1.2var1, was cloned in the pGEX-4T SE-141 86 Stockholm, Sweden. E-mail address: [email protected] plasmid (Amersham Biosciences) and expressed in Escherichia coli 3 (BL21) as previously described (8). The CIDR1␣-GST fusion-protein, re- Abbreviations used in this paper: IE, infected erythrocyte; PfEMP1, Plasmodium ␣ falciparum erythrocyte membrane protein 1; IBP, Ig binding protein; CIDR1␣, cys- ferred to as CIDR1 , was expressed and purified according to the instruc- teine-rich interdomain region 1␣; PI, propidium iodide; XIAP, X-linked inhibitor of tions of the manufacturer. GST produced by the empty vector was used as apoptosis; APRIL, a proliferation-inducing ligand; GC, germinal center; CT, cycle control. Henceforth, this is referred to as GST. The purity was determined threshold. by SDS-PAGE and Western blot as described (16) (data not shown). Copyright © 2006 by The American Association of Immunologists, Inc. 0022-1767/06/$02.00 3036 MALARIA AND POLYCLONAL B CELL ACTIVATION B cells and cell culture tions. Real-time PCR was performed using predesigned assays (Applied Biosystems) for bcl-xL and X-linked inhibitor of apoptosis (XIAP) and a Buffy coats from blood of healthy individuals, never exposed to malaria, custom-designed assay for a proliferation-inducing ligand (APRIL). The were obtained from the blood bank of the Karolinska Hospital. Mononu- GAPDH gene was used as an endogenous control. Gene-specific PCR clear cells were isolated by centrifugation over Lymphoprep (Nycomed ϩ products were measured using an ABI PRISM 7700 (Applied Biosystems) Pharma). CD19 B cells were isolated by positive selection using the sequence detection system and analyzed with ABI PRISM 7000 SDS soft- MACS cell separation system (Miltenyi Biotec) according to the manu- ware. With the help of a standard curve, cycle threshold (CT) values were facturer’s instructions; the B cell purity varied between 94 and 99%. used to determine the corresponding mRNA quantities in each sample. Tonsils were obtained from patients undergoing routine tonsillectomy at Ն Samples with a CT 35 were excluded from the analysis. Results were the Karolinska University Hospital. Lymphocyte suspensions were pre- normalized for GADPH gene expression and therefore expressed as rela- pared by mincing the tissues and suspending the cells in complete RPMI tive mRNA expression. 1640. Isolated mononuclear cells were depleted of T cells by two rounds of rosette formation with amino ethyl isothiouronium bromide-treated SRBC DNA microarray analysis on ice. Rosettes were removed by centrifugation over Lymphoprep (17).
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