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Receptor 2-Deficient Mice Polysaccharide in C3- and Complement Streptococcal Type III Capsular Impaired Antibody Response To

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Receptor 2-Deficient Mice Polysaccharide in C3- and Complement Streptococcal Type III Capsular Impaired Antibody Response To Impaired Antibody Response to Group B Streptococcal Type III Capsular Polysaccharide in C3- and Complement Receptor 2-Deficient Mice This information is current as of September 24, 2021. Olga Pozdnyakova, Hilde-Kari Guttormsen, Farah N. Lalani, Michael C. Carroll and Dennis L. Kasper J Immunol 2003; 170:84-90; ; doi: 10.4049/jimmunol.170.1.84 http://www.jimmunol.org/content/170/1/84 Downloaded from References This article cites 38 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/170/1/84.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 © 2003 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Impaired Antibody Response to Group B Streptococcal Type III Capsular Polysaccharide in C3- and Complement Receptor 2-Deficient Mice1 Olga Pozdnyakova,2* Hilde-Kari Guttormsen,2‡ Farah N. Lalani,‡ Michael C. Carroll,* and Dennis L. Kasper3†‡ Group B Streptococcus (GBS) is the foremost bacterial cause of serious neonatal infections. Protective immunity to GBS is mediated by specific Abs to the organism’s capsular polysaccharide Ags. To examine the role of complement in the humoral immune response to type III GBS capsular polysaccharide (III-PS), mice deficient in C3 or in CD21/CD35 (i.e., complement receptors 1 and 2; CR1/CR2) were immunized with III-PS. Mice deficient in C3 or Cr2 had an impaired primary immune response to III-PS. The defective response was characterized by low IgM levels and the lack of an isotype switch from IgM to IgG Ab Downloaded from production. Compared with wild-type mice, C3- and Cr2-deficient mice exhibited decreased uptake of III-PS by follicular den- dritic cells within the germinal centers and impaired localization of III-PS to the marginal zone B cells. Complement-dependent uptake of capsular polysaccharide by marginal zone B cells appears necessary for an effective immune response to III-PS. The normal immune response in wild-type mice may require localization of polysaccharide to marginal zone B cells with subsequent transfer of the Ag to follicular dendritic cells. The Journal of Immunology, 2003, 170: 84–90. http://www.jimmunol.org/ espite advances in antimicrobial therapy, infections with the help of T cells, but the presence of T cell factors enhances the extracellular encapsulated bacteria such as Neisseria IgG response. meningitidis, Streptococcus pneumoniae, and group B Despite the clinical significance of bacterial polysaccharides, the D 4 Streptococcus (GBS) remain important clinical problems. GBS is mechanisms underlying immune responses to polysaccharide Ags the most common cause of serious infections in newborns and have not yet been fully elucidated. It has been suggested that the young infants in most of the developed world, with a 5–8% case- cells within the splenic marginal zone (MZ) play an important role fatality ratio in the United States (1). Nine serotypes of GBS have in responses to TI-2 Ags. The MZ is a specialized compartment been identified on the basis of distinct capsular polysaccharides. containing a subpopulation of B lymphocytes, i.e., MZ B cells, by guest on September 24, 2021 Type III is the serotype most frequently associated with meningitis dendritic cells, and MZ macrophages (5). One hypothesis impli- Ͼ and with infant infections of late onset ( 7 days after birth). cates MZ B cells in the induction of humoral responses to TI-2 Ab responses in the spleen play an essential role in host defense Ags. MZ B cells are distinguished from follicular B cells by cell against encapsulated bacteria (2). Accordingly, patients with ana- surface phenotype (e.g., IgMhigh, CD21high, IgDlow, CD23low). tomic or functional asplenia are highly susceptible to infections Lane et al. (6) reported that the immune response of recovering with these organisms (3, 4). Protection against neonatal type III x-irradiated mice to TI-2 Ags correlated with the reappearance of GBS infections is associated with the presence of Abs specific for B cells in the MZ. Furthermore, responsiveness to polysaccharide the type III GBS capsular polysaccharide (III-PS). Pure polysac- Ag develops in children at ϳ2 years of age—a timing that coin- charides are characterized as thymus-independent type 2 (TI-2) cides with the maturation of MZ B cells (7, 8). A recent study with Ags. These Ags can induce a primary immune response without Pyk-2-deficient mice lacking MZ B cells showed a reduction in IgM and IgG responses to trinitrophenyl (TNP)-Ficoll (a model TI-2 Ag) as well as abrogated Ag localization to MZ B cells. *Departments of Pathology and Pediatrics, Center for Blood Research, †Department However, studies of CD19-deficient mice, which also have re- of Microbiology and Molecular Genetics, Harvard Medical School, and ‡Channing duced numbers of MZ B cells, have revealed normal-if not ele- Laboratory, Department of Medicine, Brigham and Women’s Hospital, Harvard Med- ical School, Boston, MA 02115 vated-responses to haptenated Ficoll (9, 10). An alternative hy- Received for publication May 24, 2002. Accepted for publication October 23, 2002. pothesis is that MZ macrophages are essential in early uptake of TI-2 Ags. Macrophages within the MZ take-up and retain carbo- 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 hydrate macromolecules such as Ficoll (11). However, the impor- with 18 U.S.C. Section 1734 solely to indicate this fact. tance of macrophage uptake remains unclear because in vivo elim- 1 This work was supported by National Institutes of Health Grants 1R01 AI36389 (to ination of MZ macrophages appears not to alter the response to M.C.C.) and AI23339 (a Merit Award to D.L.K.). TNP-Ficoll (12). 2 O.P. and H.-K.G. contributed equally. Binding of Ficoll by MZ B cells in naive wild-type (WT) mice 3 Address correspondence and reprint requests to Dr. Dennis L. Kasper, Channing has been shown to be dependent on C3 and on CD21/CD35 (com- Laboratory, 181 Longwood Avenue, Boston, MA 02115. E-mail address: [email protected] plement receptors (CR) 1 and 2; CR1/CR2) (13), whereas uptake 4 Abbreviations used in this paper: GBS, group B Streptococcus; III-PS, type III GBS by MZ macrophages takes place independent of C3 (3). Despite capsular polysaccharide; TI-2, thymus-independent type 2; MZ, marginal zone; TNP, this differential complement dependence for Ag uptake by MZ trinitrophenyl; WT, wild type; CR, complement receptor; CVF, cobra venom factor; FDC, follicular dendritic cell; tg, transgenic; HSA, human serum albumin; ASC, cells, a role for complement in the humoral response to TI-2 Ags Ab-secreting cell; GC, germinal center; PNA, peanut lectin agglutinin. remains controversial. Early studies by Pepys (14) showed that Copyright © 2003 by The American Association of Immunologists, Inc. 0022-1767/03/$02.00 The Journal of Immunology 85 complement depletion with cobra venom factor (CVF) had no ef- ELISPOT assay for III-PS-specific Ab-secreting cells (ASCs) fect on the primary response to polyvinylpyrrolidone 360. Studies The frequency of ASCs in spleens was determined by ELISPOT assay. In by Markham et al. (15) demonstrated that complement depletion brief, 24-well plates (Falcon, San Diego, CA) were coated overnight with with CVF abrogated the Ab response to pneumococcal type 14 III-PS conjugated to HSA (III-HSA; 5 ␮g/ml). Wells were blocked with polysaccharide but did not affect the response to the sialic acid- 1% BSA in PBS, splenocytes diluted in DMEM (Life Technologies, Grand ϫ 6 ϫ 6 ϫ 6 containing III-PS. In contrast, studies by Pryjma and Humphrey Island, NY) were added (5 10 ,1 10 ,or0.5 10 cells per well), and preparations were incubated for 12–18hat37°C. Plates were washed (16) identified a reduced immune response to pneumococcal type in 0.1% BSA, then coated for 4 h at room temperature with goat anti-mouse 3 polysaccharide in CVF-treated mice. Moreover, Griffioen et al. IgM or IgG conjugated to alkaline phosphatase (Sigma-Aldrich). Plates (17) documented enhanced Ab responses to pneumococcal poly- were developed with X-phosphate/5-bromo-4-chloro-indolyl-phosphate saccharide upon conjugation to C3d. Humans deficient in comple- (BCIP; Boehringer Mannheim, Indianapolis, IN) in 2-amino-2-methyl-1- propanol (AMP; Sigma-Aldrich) agarose solution. Spots were counted with ment exhibit increased susceptibility to infections by encapsulated a Leica microscope (Deerfield, IL). bacteria, possibly because of impaired humoral immunity and lack of effector function (18). Much of our knowledge about humoral immunity to TI-2 Ags comes from studies conducted with nonphysiological Ags. To in- vestigate the role of complement in humoral immunity to a clini- cally relevant polysaccharide, we immunized mice deficient in C3 or CD21/CD35 with purified III-PS. These mice had impaired IgM and IgG responses to III-PS; the impairment was characterized by Downloaded from a negligible uptake of Ag by follicular dendritic cells (FDCs) and MZ B cells.
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