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In Mice with Lupus Cells Oligoclonal Expansion of Anti-Dsdna B Idiotype-Specific Th Cells Support

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In Mice with Lupus Cells Oligoclonal Expansion of Anti-Dsdna B Idiotype-Specific Th Cells Support Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus This information is current as Kristin Aas-Hanssen, Ane Funderud, Keith M. Thompson, of September 30, 2021. Bjarne Bogen and Ludvig A. Munthe J Immunol published online 15 August 2014 http://www.jimmunol.org/content/early/2014/08/15/jimmun ol.1400640 Downloaded from Supplementary http://www.jimmunol.org/content/suppl/2014/08/15/jimmunol.140064 Material 0.DCSupplemental 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 30, 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 © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published August 15, 2014, doi:10.4049/jimmunol.1400640 The Journal of Immunology Idiotype-Specific Th Cells Support Oligoclonal Expansion of Anti-dsDNA B Cells in Mice with Lupus Kristin Aas-Hanssen,* Ane Funderud,* Keith M. Thompson,* Bjarne Bogen,*,† and Ludvig A. Munthe* Systemic lupus erythematosus (SLE) is marked by a Th cell–dependent B cell hyperresponsiveness, with frequent germinal center reactions and hypergammaglobulinemia. The specificity of Th cells in lupus remains unclear, but B cell idiotypes (Ids) have been suggested. A hallmark is the presence of anti-dsDNA, mutated IgG autoantibodies with a preponderance of arginines in CDR3 of the Ig variable H chain (IgVH). B cells can present V region–derived Id peptides on their MHC class II molecules to Id-specific Th cells. We show that Id-specific Th cells support the proliferation of anti-dsDNA Id+ B cells in mice suffering from systemic autoimmune disease with SLE-like features. Mice developed marked clonal expansions of B cells; half of the IgVH sequences were clonally related. Anti- dsDNA B cells made up 40% of B cells in end-stage disease. The B cells expressed mutated IgVH with multiple arginines in CDR3. Hence, Downloaded from Id-driven T cell–B cell collaboration supported the production of classical anti-dsDNA Abs, recapitulating the characteristics of such Abs in SLE. The results support the concept that Id-specific Th cells may trigger the development of SLE and suggest that manipulation of the Id-specific T cell repertoire could play a role in treatment. The Journal of Immunology, 2014, 193: 000–000. ystemic lupus erythematosus (SLE) is a debilitating sys- the positively charged arginine can bind to the phosphodieseter temic autoimmune disease thatisassociated withgeneticand backbone, as well as donate up to five H bonds (9–12). http://www.jimmunol.org/ S environmental influences, with involvement of multiple Autoreactive B cells experience sustained signaling through their organs, such as the skin and kidneys (1, 2). SLE is marked by a Th cell– BCR, become anergic, and eventually undergo apoptosis, as was de- dependent B cell hyperresponsiveness, with frequent germinal center scribed for anti-dsDNA B cells (13). Nevertheless, such cells may reactions, hypergammaglobulinemia, and high levels of highly be rescued, activated, and expanded if provided with Th cell help mutated, affinity-matured IgG autoantibodies (1–6). Anti- dsDNA (13), a feature that also was found for anergic B cell responses of Abs are a serological hallmark of SLE that mediate, at least in part, other autospecificities (14, 15). However, in contrast to B cells, it is the nephritis that marks the course of this disease in both humans unclear what specificity Th cells may have in cognate interactions and mice (1, 2). with dsDNA-specific B cells. Ab idiotypes (Ids) are a plausible In other mouse models of lupus, MRL/lpr and BWF1 mice candidate because both lupus-prone mice (16–19) and SLE patients by guest on September 30, 2021 spontaneously develop anti-dsDNA and nephritis; however, anti- (20–22) have clearly measurable Th cell responses toward patho- dsDNA autoantibodies also can be induced [e.g., by vaccinating genic anti-dsDNA Abs, suggesting that Id determinants play a role non–lupus-prone strains with dsDNA and adjuvants (7, 8)]. In in pathogenesis. In such experiments, APCs, such as dendritic cells, both spontaneous and induced models, the anti-dsDNA Ig variable present somatically mutated V-region determinants (Id peptides) to H chain (IgVH) regions often express basic amino acids like ar- Th cells. Further, anti-Id Th cell responses increased with disease ginine (R) and lysine (K), or asparagine (N), in Ag-binding CDR severity, and disease was aggravated by injection of Id peptide (17). and FR3 regions (9). The presence of several arginines in CDR3 It has been clear for some time that somatically mutated Id pep- is relatively rare (10, 11) but is important for DNA binding; tides can serve as cognate Ags for Th cells (23, 24) and that this re- sponsiveness is restricted by tolerance to germline V regions (25, 26). *Centre for Immune Regulation, Department of Immunology, Institute of Clinical Moreover, it was shown that individual B cells can present endoge- Medicine, Oslo University Hospital, University of Oslo, 0424 Oslo, Norway; and nous Id peptide on MHC class II molecules to Th cells and that such † K.G. Jebsen Centre for Influenza Vaccine Research, Department of Immunology, Id+ B cells can collaborate with Id-specific Th cells (27–30). In this Oslo University Hospital, University of Oslo, 0424 Oslo, Norway interaction, B cells can undergo the germinal center reaction, pro- Received for publication March 25, 2014. Accepted for publication July 21, 2014. vided that ligands bind the BCR (31). Such Id-driven Th cell–B cell This work was supported by The Research Council of Norway, Functional Genomics (FUGE), Project 17538, the University of Oslo, and UNIFOR (grants from the Vivi collaboration can also cause expansion of autoreactive B cells, se- Irene Hansen Foundation, the Gertrude and Jack Nelson Foundation, the Signe and cretion of autoantibodies (26, 31), and autoimmune disease (32, 33). Albert Bergsmarken Foundation, and the Henrik Homan Foundation). In the latter studies, mice were double transgenic (DTG): B cells Address correspondence and reprint requests to Dr. Kristin Aas-Hanssen, Prof. Bjarne expressed a transgenic (TG) l2 L chain (Id+), and T cells ex- Bogen, and Prof. Ludvig A. Munthe, Centre for Immune Regulation, Department of d Immunology, Institute of Clinical Medicine, University of Oslo and Rikshospitalet, P.O. pressed an MHC class II (I-E ), Id peptide–restricted TCR trans- Box 4950, Nydalen, 0424 Oslo, Norway. E-mail addresses: kristin.aas-hanssen@medisin. gene.Inthesemice,weobservedamarked,butincomplete,negative uio.no (K.A.-H.), [email protected] (B.B.), and [email protected] (L.A.M.). selection of Id-specific thymocytes, a progressive expansion of low- The online version of this article contains supplemental material. frequency Id-specific T cells, an ongoing collaboration between Id- specific Th cells and Id+ B cells, hypergammaglobulinemia, and Abbreviations used in this article: ANA, anti-nuclear Ab; DTG, double transgenic; Id, idiotype; IgVH, Ig variable H chain; IMGT, International ImMunoGeneTics; autoantibodies, including high titers of anti-nuclear Abs (ANAs). In NCBI, National Center for Biotechnology Information; SLE, systemic lupus erythe- this study, we show clonal expansion of anti-dsDNA B cells in such matosus; TG, transgenic. mice, finding a marked oligoclonality, with clonal expansions of Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 B cells with mutated VH regions and arginine-rich CDR3 regions. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400640 2 Id-DRIVEN ANTI-dsDNA AUTOANTIBODIES Materials and Methods T7 promoter of the pGEM-T Easy vector (GATC Biotech). At least four Mice colonies were sequenced for each sample. Mice were TG for both the l2315 Ig L-chain derived from the MOPC315 IgVH sequence processing and analysis myeloma, as well as an ab TCR transgene specific for the Id(l2315) d The following control data sets were downloaded from the National Center peptide presented on I-E MHC class II molecules (32, 33). The TCR for Biotechnology Information (NCBI) Web site (http://www.ncbi.nlm.nih. l 315 specificity is toward the 2 CDR3 motif that includes three replacement gov/nuccore/): control VH sequences from BALB/c mice, retrieved with mutations (CALWFRNHFVFGG) (23, 24). the search term “V region immunoglobulin heavy chain Balb”; sequences 3 + DTG F1 mice were from TCR transgenic (homozygous females) Id derived from splenic L2-TG mice IgG+ B cells, as deposited (35); anti- transgenic (homozygous males); all offspring are DTG. Alternatively, to DNA hybridomas from BWF1 mice, as deposited (36); and neonatal liver generate littermate controls (Fig. 1), offspring from TCR transgenic B cell IgVH sequences, as deposited (37). 3 + (hemizygous females) Id transgenic (hemizygous males) were ana- Sequences were analyzed with the International ImMunoGeneTics . lyzed. Both TG strains are on a BALB/c background ( 20 backcrosses). (IMGT)/HighV-QUEST version 1.1.2 or IMGT/HighV-QUEST version The Norwegian Animal Research Authority approved the experiments. 3.2.30 tools (http://imgt.cines.fr) and compared with the IMGT/V-QUEST reference directory release: 201310-4 (March 14, 2013) (38). IgVH region Autoantibody analysis family identification and clonality analysis were performed using the statistics module of IMGT/HighV-QUEST.
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