Natural Antibodies Bridge Innate and Adaptive Immunity Saswati Panda and Jeak L. Ding This information is current as J Immunol 2015; 194:13-20; ; of September 28, 2021. doi: 10.4049/jimmunol.1400844 http://www.jimmunol.org/content/194/1/13 Downloaded from References This article cites 124 articles, 47 of which you can access for free at: http://www.jimmunol.org/content/194/1/13.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • 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 *average by guest on September 28, 2021 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. Th eJournal of Brief Reviews Immunology Natural Antibodies Bridge Innate and Adaptive Immunity Saswati Panda1 and Jeak L. Ding Natural Abs, belonging to isotypes IgM, IgG3, and IgA, present at the mucosal surfaces, such as the gut, respira- IgA, were discovered nearly half a century ago. Despite tory tract, and urogenital tract, plays an essential role in mu- cosal immunity (15–17). In humans, some B cells are known knowledge about the role of the polyreactive natural 2 IgM in pathogen elimination, B cell survival and ho- to generate IgM IgD+ plasmablasts through both T cell–de- meostasis, inflammatory diseases, and autoimmunity, pendent and T cell–independent (TI) pathways in the sec- there is a lack of clarity about the physiological role ondary lymphoid organs of the upper respiratory mucosa upon of natural IgG and natural IgA because they appear Ag exposure. These plasma cells produce IgD that is highly incapable of recognizing Ags on their own and are specific to respiratory commensals and pathogens (18). IgD also was shown to be polyreactive and may play a role in perceived as nonreactive. However, recent research re- Downloaded from vealed exciting functions of natural IgG in innate im- anergy through tolerogenic pathways. However, there are munity. Natural IgG:lectin collaboration swiftly and contradictory reports indicating that IgD may also protect B cells from tolerance (19). Despite these interesting findings, effectively kills invading pathogens. These advances the biological role of IgD is still enigmatic. Further studies are prompt further examination of natural Abs in immune required to provide insights into its role in innate immunity. defense and homeostasis, with the potential for devel- In general, Ag-specific Abs elicit immune defense through the oping novel therapeutics. This review provides new activation of the classical complement system (20–22), http://www.jimmunol.org/ insights into the interaction between natural Abs and pathogen neutralization (23, 24), phagocytosis of apoptotic lectins, with implications on how interactions between cells (25–27), and priming of immune cells (28, 29). molecules of the innate and adaptive immune systems In addition to Ag-specific Abs, there are natural Abs that are bridge these two arms of immunity. The Journal of produced after birth in neonates and in adults prior to an Immunology, 2015, 194: 13–20. infection (30, 31). Extensive studies have been performed in mice to shed light on natural Abs. Natural Abs are reportedly ntibodies belong to the Ig superfamily. Ag-specific produced by B-1 cells (32–34) in both mice (35) and humans Abs are secreted by plasma cells in response to an (36, 37). Although natural Abs have the ability to recognize by guest on September 28, 2021 A Ag (1). During the primary innate immune re- certain self-antigens through their V region, they have been sponse, APCs, such as dendritic cells (2, 3) and macrophages, perceived to lack specificity for any particular foreign Ag. recognize the pathogen through an array of pattern recogni- However, reports indicate that certain natural Abs in mice tion receptors (PRRs; e.g., TLRs) (4, 5) and present the have the ability to recognize foreign Ags. The T(EPC)-15 or processed Ag to B cells. These Ag-stimulated B cells undergo T-15 idiotype natural Ab specifically recognizes phosphor- somatic hypermutation (6, 7) and clonal selection to become ylcholine on the surface of Gram-negative and Gram-positive long-lived plasma cells that produce Ag-specific Abs in the bacteria, protozoa, fungi, and even modified low-density li- secondary adaptive immune response (8). poprotein (38). The T-15 idiotype Ab was shown to confer Five isotypes of Ig exist (IgM, IgG, IgA, IgE, IgD) that differ protection in atherosclerosis, apoptosis, and immunity against based on the H chain C region (9). IgM is the first isotype pathogens (39). Natural IgM broadly and nonspecifically produced prior to class switching (10); it effectively recognizes recognizes diverse microbial determinants and autoantigens. and eliminates pathogens in the early stage of immune de- The significance of natural Abs is becoming increasingly ap- fense (11). Upon Ag stimulation, the B cells undergo class parent through decades of research on the function of natural switching (12, 13) and convert into plasma cells that produce IgM, which have shed light on its involvement in multiple high-affinity IgG, IgA, IgE, and IgD. IgG is the major serum biological processes, including infection, B cell homeostasis, isotype and consists of four subtypes (IgG1, IgG2, IgG3, and inflammation, atherosclerosis, and autoimmunity (40). IgG4), with further differences in the hinge region of the H In this review, we first discuss the findings on natural Abs, chain constant fragment. IgG is the only isotype that can cross focusing on the role of natural IgM. This is followed by an the placental barrier to provide immunity to the fetus (14). exposition of the recent findings on natural IgG, which Department of Biological Sciences, National University of Singapore, Singapore 117543 Address correspondence and reprint requests to Dr. Jeak L. Ding, Department of Bio- logical Sciences, National University of Singapore, 14 Science Drive 4, Singapore 1Current address: Program in Molecular Pathogenesis, Department of Medicine, Skir- 117543. E-mail address: [email protected] ball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY. Abbreviations used in this article: CRP, C-reactive protein; DAMP, danger-associated molecular pattern; MBL, mannose-binding lectin; MZ, marginal zone; PRR, pattern Received for publication April 7, 2014. Accepted for publication September 11, 2014. recognition receptor; SLE, systemic lupus erythematosus; TI, T cell–independent. This work was supported by the Ministry of Education, Singapore (Grants Tier 1, R-154-000-584-112, and MOE2013-T2-2-007). Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400844 14 BRIEF REVIEWS: NATURAL Abs BRIDGE INNATE AND ADAPTIVE IMMUNITY collaborates with serum lectins, and how this immune B blood group Abs, are well-known examples of natural IgM complex links innate immunity to adaptive immunity. We Abs. These Abs play a critical role in blood transfusion, discuss how the prevailing microenvironmental changes in- transplantation, and graft rejection through complement ac- duced by infection–inflammation conditions might regulate tivation (65). the antimicrobial action elicited by the natural IgG in hu- Although earlier studies suggested that peritoneal B-1 cells mans, although these results are restricted to in vitro and ex are the main source of natural Abs (66), B-1 cells in the bone vivo studies using human serum and are supported by in vivo marrow (67) and splenic MZ B cells (52, 68–70) also were mice studies. Last, we provide a current opinion on the im- shown to produce natural Abs. The bone marrow B cell pending questions that lie ahead in this field and suggest fu- precursors, which are generally considered to be the progen- ture work that is needed to explore and exploit the role of itors of conventional (B-2) B cells, also produce B-1 cells both natural Abs in health and disease. in the fetus (71, 72) and adult (56). Extensive research efforts have shed light on the developmental origin of B-1 cells. It is Natural Abs: B cell subsets and their contribution now increasingly evident that B-1 cells arise at different times In addition to Ag-specific Abs that are produced by B-2 cells of development from a distinct population of progenitor cells during the adaptive immune response (41), a pool of spon- according to the layered immune system model (reviewed in taneously occurring Abs is present in human cord blood (33), Ref. 73). Further studies in this area should provide more in normal healthy individuals (30, 31, 42), and in germ-free/ insight into understanding B cell immunity and related Ag-free mice (43–46) that belongs to the IgM, IgG, and IgA pathological issues. Downloaded from isotypes. In mice, natural IgG typically belongs to the IgG3 subclass. Although a study suggested that humans also pro- Functions of natural IgM in mice: hints on linkage between innate and duce IgG3 subclass-specific natural IgG Abs (47), the subclass adaptive immunity specification of human natural IgG has not been confirmed. The contribution of natural Abs to immunity has been brought Mouse B-1 cells produce natural Abs in a TI pathway (48) on into focus by studies on natural IgM.