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Natural Bridge Innate and Adaptive 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

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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 elimination, B survival and ho- to generate IgM IgD+ plasmablasts through both –de- meostasis, inflammatory diseases, and , 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 (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 (20–22), http://www.jimmunol.org/ insights into the interaction between natural Abs and pathogen neutralization (23, 24), 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- through their V region, they have been sponse, APCs, such as dendritic cells (2, 3) and , 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 natural Ab specifically recognizes phosphor- (6, 7) and to become ylcholine on the surface of Gram-negative and Gram-positive long-lived plasma cells that produce Ag-specific Abs in the , protozoa, fungi, and even modified low-density li- secondary adaptive (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 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, 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 (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 ; DAMP, danger-associated molecular pattern; MBL, mannose-binding lectin; MZ, ; PRR, pattern Received for publication April 7, 2014. Accepted for publication September 11, 2014. recognition receptor; SLE, systemic 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 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 , 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 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 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. Pentameric natural IgM, exposure to self-antigens, such as dsDNA (49) and nucleo- with 10 potential Ag-binding sites (74), recognizes multiple http://www.jimmunol.org/ somes (50, 51), and TI Ags (52). B-1 cells are generated phylogenetically conserved structures like nucleic acids, predominantly during fetal and neonatal development from phospholipids, and carbohydrates (40). Natural IgM also may precursor cells located in the liver and omentum (32); how- exist in the monomeric form in patients suffering from au- ever, it is unclear whether natural Abs exist before birth. In toimmunity (75) and chronic liver disease (76). A protective adults, the B-1 cell population is maintained at a constant size role for natural IgM was found in numerous viral, bacterial, as a result of its self-renewing capacity, thus sustaining the fungal, and parasitic infections (77). For example, vesicular levels of serum natural Abs (53–56). stomatitis , lymphocytic choriomeningitis virus, influ-

The B-1 Ig genes tend to have preferential usage of the JH- enza virus, Streptococcus pneumoniae, and Cryptococcus neo- by guest on September 28, 2021 proximal VH gene segments during V(D)J recombination, formans (78, 79) are bound, neutralized, and cleared by with fewer N-region insertions (32) and a lower rate of so- natural IgM (80–83). Natural IgM also alerts and primes the matic (57) compared with the B-2 counterpart, against subsequent pathogen attack thus giving rise to a restricted natural Ab repertoire. Like their by directing Ags to the secondary lymphoid organs. Mice murine counterparts, human peripheral blood B-1 cells pro- deficient in natural IgM succumb to infections as a result of duce polyreactive Abs toward a limited range of self-antigens a lack of pathogen clearance, decreased recruit- (57). However, it is unclear to what extent human B-1 cells ment, and elevated proinflammatory serum (84). resemble mouse B-1 cells because of the lack of identifiable The level of natural IgM is unaffected by foreign Ags (45), cell surface markers on human B-1 cells. Interestingly, B-1 ascertaining the innate immune character of natural IgM. cells that produce natural IgM from unmutated or minimally Under the innate immunity arm, natural IgM limits the mutated V(D)J genes can enter the follicular pathway to spread of infection by using strategies like neutralization (80, undergo somatic hypermutation and class switching to pro- 81, 83), complement-mediated formation duce higher-affinity natural IgG or IgA (42), and pathogen elimination by complement activation (83, 85), particularly under autoimmune conditions, such as systemic and recruitment of Ags into secondary lymphoid organs, thus lupus erythematosus (SLE) (58) and priming the subsequent adaptive immune response (81, 86) (59). In addition to B-1 cells, natural Abs are produced by and linking the innate and adaptive immune systems. Natural a subset of B-2 cells, which may include marginal zone (MZ) IgM also plays a role in clearing apoptotic cells (87), main- B cells (60), transitional B cells (61), and/or an unidentified taining B cell homeostasis (88), inflammation (89, 90), ath- population of B cells (62). However, there is a lack of in- erosclerosis (91), and autoimmunity (92, 93). Natural IgM formation on the origin and type of signals that stimulate was proposed to bind strongly to complement factor C1q and natural Ab production by these B-2 cell subsets. B-1 cells to activate the complement cascade (85, 94). Natural IgM respond to certain altered-self components or danger-as- also binds mannose-binding lectin (MBL), which is bound to sociated molecular patterns (DAMPs), such as asialylated apoptotic cells (95, 96), and directs the clearance of immune glycoproteins with exposed terminal galactose residues. The complexes by binding to the putative Fca/mR receptor on human anti-gal a 1-3 gal Ab is one such abundant natural . Conversely, natural IgM bound to apoptotic cells IgG that is a xenoreactive natural Ab (63). Other examples may recruit MBL, and the immune complex may be cleared include natural IgG Abs with specificities toward gal a 1-2 by the phagocytic receptor (89). Fig. 1 summa- gal, gal a 1-4 gal, and gal a 1-6 glc (melibiose), which are not rizes the diverse roles of natural IgM identified through studies xenoreactive (64). Isohemagglutinins, such as anti-A and anti- in mice. The Journal of Immunology 15

Natural IgG is not quiescent: it collaborates with serum lectins in tween natural IgG:ficolin (109) showed that infection–in- frontline immune defense flammation–induced lower pH regulates the intermolecular Despite vast knowledge about natural IgM, the existence and electrostatic interaction. By hydrogen-deuterium exchange physiological function of natural IgG and IgA, which are mass spectrometry, Panda et al. (109) delineated the binding predominant serum and mucosal natural Abs (32), are unclear interfaces of the CH2–CH3 region of natural IgG Fc and the and, hence, have been a subject of interest since their dis- P-subdomain of the ficolin FBG domain. Notably, histidine is covery almost 50 y ago (97). Because of their low affinity, critical for the molecular interaction. Mild acidosis at the site nonspecificity, and low valency, natural IgG and natural IgA of infection–inflammation probably resulted in protonation appeared to be unreactive and were deemed incapable of of histidine side chains that increased the interaction affinity recognizing and eliminating pathogens. overall (109). These studies also imply that the immune Recent studies exploring the untapped potential of these system exploits the prevailing physicochemical changes at the natural Ab isotypes demonstrated that both mice and human infection site for effective immune defense. natural IgG is not nonreactive, rather it plays a proactive The immunomodulatory activities resulting from the pH fundamental role in the systemic innate immune response (98). change ensure a specific immune response rather than a ran- In vitro studies revealed that natural IgG purified from dom PRR:PRR interaction, which could lead to immune uninfected/healthy human serum recognized a range of overactivation that manifests as autoimmune diseases. Inter- Gram-negative and Gram-positive bacteria with the aid of estingly, formation of the natural IgG:ficolin immune com- serum lectin PRRs (e.g., ficolin and MBL), which are known plex is similar in humans and mice. During infection, the Downloaded from bind to sugar residues (e.g., N-acetylglucosamine) on the human and mouse ficolins bind to the pathogen and recruit microbes. The partnership between natural IgG and lectins natural IgG to form an immune complex. Conservation of this (prebound on the microbe) efficiently drove phagocytosis of phenomenon suggests the fundamental significance of natural the bacteria via the FcgR1 receptor on human . IgG:ficolin-mediated innate immune defense. The importance of natural IgG during infection was dem- Natural IgG specifically collaborates with pathogen-

2 2 http://www.jimmunol.org/ onstrated further in vivo in AID / mice (these mice lack associated lectins to elicit an effective antimicrobial action class switching and produce IgM but not other subclasses of against opportunistic Pseudomonas aeruginosa and Staphylo- 2 2 Abs). The susceptibility of AID / mice to infection was coccus aureus (98). The immune evasiveness of such pathogens overcome by i.v. administration of purified natural IgG, is a significant barrier to their clearance and resolution of the which was shown to collaborate with the serum lectins to infection and inflammation; hence, a continuing effort to elicit effective antimicrobial activity (98). Future studies using devise new and more effective therapies is needed to combat 2 2 ficolin and MBL double knockout mice and FcgR1 / mice such infections. Because natural IgG (specifically IgG3 iso- might provide insight into the collaboration between natural type) interacts with pathogen-associated ficolins through its

IgG and lectins at the crossroad of the innate–adaptive im- conserved CH2–CH3 region in the constant Fc region, it is by guest on September 28, 2021 mune defense. Fig. 2 summarizes the natural IgG–mediated plausible that IgG3 derived from plasma cells in bone marrow bacterial recognition and clearance in collaboration with se- interacts with ficolins in a similar manner once the ficolins rum lectins and highlights the gray areas that warrant further have bound to the pathogen. Further studies are required to exploration. These efforts will pave the way for developing investigate this hypothesis. Nevertheless, new insights into the natural IgG–mediated therapies. mechanism of interaction between the innate and adaptive immune should advance our understanding of how Infection–inflammation condition triggers the interaction between the host might counter the immune evasiveness of these natural IgG:ficolin and enhances the immune response pathogens. Infection or injury causes an influx of inflammatory cells to the site, leading to inflammation (99, 100). Inflammation is Natural IgG bridges innate and adaptive immunity and boosts characterized by a drop in the pH (101–103) and calcium immune response (104–106) levels in the microenvironment of infection/injury. The mechanisms underlying the specificity, signaling In vitro and ex vivo studies with human samples, using pathways, and cellular trafficking of PRR immune complexes a simulated uninfected normal condition (typically, pH 7.4 have been characterized extensively. Interestingly, multiple and 2.5 mM calcium) and an infection-inflammation con- pathogen-associated molecular patterns that simultaneously dition (pH 6.5 and 2 mM calcium) (98, 107) explored var- activate numerous PRRs (4,110)wereshowntoinduce ious PRR:PRR interactions under infection-induced changes PRR:PRR interactions as a prerequisite for effective immune in the microenvironment. The infection–inflammation con- responses. For example, CRP and ficolins, which are ini- dition increases PRR:PRR interaction affinity and boosts the tiators of the classical and lectin complement pathways, re- immune responses. Examples include the C-reactive protein spectively, interact with each other to boost the immune (CRP):ficolin interaction, which synergistically enhances the response against pathogens (107). Second, TLRs in collab- classical and lectin complement pathways (107), and the oration with other PRRs orchestrate both pathogen- and cell natural IgG:ficolin interaction, which facilitates bacterial type–specific host responses to fight infections (111–113). phagocytosis (98, 108). These studies demonstrate how per- Third, interactions between C1q and CRP were observed turbations in the serum that result in mild local acidosis and during the immune response (114). Last, several studies hypocalcaemia change the conformation of PRRs, exposing showed the Ab-like behavior of pentraxins, which bind to novel interaction motifs between them and leading to more FcgRs on macrophages and other immune cells to elicit effective pathogen binding and clearance. The identification immune responses. For example, serum amyloid P, an acute- of the amino acids involved in the molecular interplay be- phase pentraxin, was shown to bind to FcgRIIA (115). 16 BRIEF REVIEWS: NATURAL Abs BRIDGE INNATE AND ADAPTIVE IMMUNITY Downloaded from http://www.jimmunol.org/ by guest on September 28, 2021

FIGURE 1. Diverse roles of natural IgM (nIgM) in immunity. nIgM, produced by B-1 cells in the peritoneum, bone marrow, and splenic MZ B cells, plays a crucial role in many immune processes: (1) direct pathogen neutralization; (2) classical complement activation in collaboration with C1q; (3) Ag recruitment to secondary lymphoid organs and priming of subsequent TI adaptive immunity; (4) Ab-dependent cell-mediated cytotoxicity: nIgM clears target cells through NK cell–mediated release of perforin and granzymes; (5) apoptotic cell phagocytosis in collaboration with C1q and MBL through C1qR and Fca/mR, which reduces inflammation and restores homeostasis [figure adapted with permission from Ehrenstein and Notley (40)]; (6) prevention of autoimmunity by clearance of DAMPs, such as dsDNA; and (7) immune regulation and B cell homeostasis. The Journal of Immunology 17

FIGURE 2. Current and future perspectives on the roles of natural IgG (nIgG) in immune de- fense. nIgG is an understudied, but important, molecule of the natural Ab repertoire. Recent studies on the role of nIgG in pathogen recog- nition and clearance (left) showed that it col- laborates with ficolin and MBL to indirectly recognize the pathogen and clear it via FcgR1- mediated phagocytosis, thus controlling inflam- mation by regulating the production of cytokines

(reducing proinflammatory TNF, IL-6, and IL-8 Downloaded from and increasing anti-inflammatory IL-10). Future research on nIgG would elucidate its unexplored role in health and disease: (i) controlling or ex- acerbating , SLE; (ii) ame- liorating inflammation with applications for rheumatoid arthritis and atherosclerosis, (iii) immune regulation and homeostasis, and (iv) http://www.jimmunol.org/ development of safer and more effective immu- nomodulators and antimicrobial therapies in conjunction with partner proteins (right). by guest on September 28, 2021

Another pentraxin, PTX3, binds to FcgRIII (116), sug- sion of evasive pathogens, immune overreaction is an Achilles’ gesting its potential role in neutrophil and NK cell activa- heel to autoimmunity and inflammatory diseases if left un- tion. These PRR:PRR interaction–mediated mechanisms induce controlled. stronger and rapid immune responses that prime and shape adaptive immunity. Implications of natural Abs in autoimmunity and inflammatory Natural IgG was recently shown to interact with pathogen- diseases associated lectins, such as ficolin and MBL, and to form Natural IgM was reported to control autoimmunity and in- immune complexes to clear the pathogens (98, 108). Axi- flammatory diseases. Mouse models of SLE have reduced levels omatically, Ag-specific IgG that binds directly to pathogens is of natural IgM (118) with an increase in the B-1 cell subset also expected to interact with other PRRs, such as C1q (117), and an increase in IgG autoantibodies (92, 93). Decreased to activate the classical complement pathway. Notably, both natural IgM apparently makes these mice susceptible to the Ag-specific IgG (117) and natural IgG interact with PRRs numerous infections. Natural IgM with C1q is known to through their H chain C region (109), indicating that the Fc recognize, bind, and clear autoantigens [e.g., oxidized low- is conserved in relaying the host defense information down- density lipoprotein in atherosclerotic plaques (119, 120) stream, irrespective of the origin and specificity of the IgG and phospholipids and dsDNA expressed on apoptotic cells Abs. Identification of the interaction domains involved in the (87)]. Hence, a reduction in natural IgM levels is associated formation of immune complexes between natural IgG:ficolin with ineffective clearance of apoptotic cells, resulting in au- and between Ag-specific IgG:C1q indicated that different toimmune diseases. Conversely, stronger and persistent rec- PRRs (ficolins and C1q, in these instances) interact with ognition of apoptotic cells by natural Abs may lead to unique regions of the IgG Fc (98, 117). These findings evoke overactivation of the immune system and chronic inflamma- curiosity about why such subtle differences exist and how they tion. Further studies on the extent of apoptotic cell uptake, may fine-tune the immune response. The interaction between immunomodulation by infection-induced microenvironmen- natural IgG:lectins corroborates the direct functional link tal changes, and responses by natural Abs in auto- between the two arms of immunity, which boosts antimi- immune patients will provide clarity about the overall con- crobial response. Although this is crucial to prevent subver- tribution of natural Abs in autoimmunity. 18 BRIEF REVIEWS: NATURAL Abs BRIDGE INNATE AND ADAPTIVE IMMUNITY

How do natural Abs control inflammatory diseases? On one calcium conditions in the infection–inflammation microen- hand, natural IgM reduces the inflammatory response by re- vironment to modulate the downstream immune response. moving the apoptotic cells and preventing inflammatory ar- To this end, various questions need to be addressed. What is thritis (121) and atherosclerosis (91). On the other hand, the spectrum of apoptotic cell DAMPs and autoantigens natural IgM enhances inflammation through increasing the recognized by the natural Ab:PRR immune complexes? What precipitation of urate crystals, which recruits and mechanism does natural IgG use to ameliorate inflammation? worsens inflammation (122). Natural IgM is also involved in Is it through the removal of pathogens, apoptotic cell debris, ischemia–reperfusion injury, including myocardial infarction and/or harmful DAMPs? Which immune cell type(s) does and intestinal ischemia–reperfusion injury, wherein it targets natural IgG regulate? What are the dynamics of the cytokine autoantigen-expressing endothelial cells (123, 124). It is likely profile during such a response? How can i.v. Ig, involving that these two opposing and parallel processes of the natural natural IgG and/or lectins, aid in controlling inflammation? IgM–mediated immune response maintain homeostasis. The How do natural IgG Abs regulate ongoing immune processes potential role of natural IgG in controlling inflammation was and specifically control autoimmunity-related inflammation? recently uncovered based on the existence of the natural IgG: Is there a potential feedback/autoregulation of the production hemoglobin complex that is formed under hemolytic con- of natural IgG? Some of these questions may be answered ditions: natural IgG facilitated uptake of the redox active with in vivo studies on IgG-deficient or conditional knockout hemoglobin by immune cells (125), leading to resolution of mice to provide mechanistic insights. inflammation and restoration of homeostasis. Recently, Hess Ig infusions, consisting primarily of IgG, have been used to Downloaded from et al. (126) also reported that Abs produced in a TI manner, treat inflammatory and autoimmune diseases, with limited similar to natural Abs, elicit anti-inflammatory properties. success. Additionally, the finding that differential glycosylation This is suggested to be attributable to differences in their patterns in the Fc region of Abs determines the immune re- glycosylation patterns compared with conventional Abs, sponse (sialylated leading to anti-inflammatory response and which lead to a proinflammatory response. Natural Abs ex- agalactosylated or asialylated leading to proinflammatory re- hibit a sialylated pattern, which confers an anti-inflammatory sponse) (126) could aid in efficient vaccine design and i.v. Ig http://www.jimmunol.org/ . In contrast, Ag-specific Abs are either agalactosylated therapy to treat these inflammatory diseases. There are no or asialylated and exhibit proinflammatory properties. This reports on the use of natural IgG Abs in i.v. Ig therapy for finding has important implications in the immunoregulatory recurrent infections in patients with primary immune defi- nature of Abs during a TI response to self-antigens in auto- ciencies. However, recent findings on the association between immunity or inflammatory diseases initiated by TI Ags. In natural IgG and ficolins (lectins that bind to microbial sugar addition, this information could aid in vaccine design for residues) regulated by perturbations in pH and calcium developing specific Abs with unique glycosylation patterns to conditions in the microenvironment (98) suggest the poten-

protect against infections without provoking excessive proin- tial use of i.v. Ig treatment for patients affected by primary Ab by guest on September 28, 2021 flammatory responses. deficiencies. With a view to using the protective outcome of Uncontrolled/chronic infection may also result in over- natural IgG:ficolin interaction in i.v. Ig therapy, it will be activation of the immune system, leading to autoimmunity particularly interesting to study the levels of natural IgG and (82). Hence, a timely and well-regulated immune response is lectins and the prevailing microenvironmental conditions necessary to resolve infection and restore normalcy. Further during recurrent infections in these patients. It will also be work is required to fully understand the mechanisms of action crucial to take into account the role of other serum factors of natural Abs in autoimmunity and chronic infection/ that may contribute through new and yet-to-be-explored inflammation. Moreover, knowledge of the role of natural compensatory mechanisms under such conditions. Thus, the IgG and IgA in immunoregulation and homeostasis is still in existing and exciting new findings in the field of natural Abs its infancy, and much remains to be explored. provide a better understanding of their role (in collaboration with partner proteins) and extend the possibilities for devel- Conclusions oping effective drugs to effectively counteract these diseases. Extensive research has highlighted the role of natural IgM in health, infection, inflammation, and autoimmune diseases. Disclosures Recent studies revealed the early protective role of natural IgG The authors have no financial conflicts of interest. in infection, demonstrating that natural IgG:lectin interaction led to enhanced pathogen clearance (98). This collaboration References between molecules of the innate and adaptive immune sys- 1. Burton, D. R., and J. M. Woof. 1992. Human effector function. Adv. Immunol. 51: 1–84. tems blurs the boundaries between the seemingly discrete 2. Banchereau, J., and R. M. Steinman. 1998. Dendritic cells and the control of arms of immunity and opens up a vast area to explore fun- immunity. Nature 392: 245–252. 3. Zitvogel, L. 2002. Dendritic and natural killer cells cooperate in the control/switch damental immunology: what lies at and ahead of the cross- of innate immunity. J. Exp. Med. 195: F9–F14. road of these immune pathways? 4. Janeway, C. A., Jr., and R. Medzhitov. 2002. Innate immune recognition. Annu. Elucidation of the precise contact points between natural Rev. Immunol. 20: 197–216. 5. Dempsey, P. W., S. A. Vaidya, and G. Cheng. 2003. The art of war: Innate and IgG and ficolins (109) offers the potential for development of adaptive immune responses. Cell. Mol. Life Sci. 60: 2604–2621. effective immunomodulatory drugs to intercept the immune 6. Jacob, J., G. Kelsoe, K. Rajewsky, and U. Weiss. 1991. Intraclonal generation of antibody mutants in germinal centres. Nature 354: 389–392. complexes of natural IgG and lectins, to ameliorate immune 7. Berek, C., A. Berger, and M. Apel. 1991. Maturation of the immune response in overreaction, and to pre-empt chronic inflammatory diseases, germinal centers. Cell 67: 1121–1129. 8. Tarlinton, D. M., and K. G. Smith. 2000. Dissecting affinity maturation: a model such as rheumatoid arthritis, atherosclerosis, and SLE. Such explaining selection of antibody-forming cells and memory B cells in the germinal therapies could also be tunable to the prevailing pH and centre. Immunol. Today 21: 436–441. The Journal of Immunology 19

9. Stavnezer, J., J. E. Guikema, and C. E. Schrader. 2008. Mechanism and regulation 42. Casali, P., and E. W. Schettino. 1996. Structure and function of natural anti- of class switch recombination. Annu. Rev. Immunol. 26: 261–292. bodies. Curr. Top. Microbiol. Immunol. 210: 167–179. 10. Fellah, J. S., M. V. Wiles, J. Charlemagne, and J. Schwager. 1992. Evolution of 43. Sidman, C. L., L. D. Shultz, R. R. Hardy, K. Hayakawa, and L. A. Herzenberg. IgM: complete amino acid sequence of the constant region of Ambys- 1986. Production of immunoglobulin isotypes by Ly-1+ B cells in viable toma mexicanum mu chain deduced from cDNA sequence. Eur. J. Immunol. 22: motheaten and normal mice. Science 232: 1423–1425. 2595–2601. 44. Bos, N. A., H. Kimura, C. G. Meeuwsen, H. De Visser, M. P. Hazenberg, 11. Boes, M. 2000. Role of natural and immune IgM antibodies in immune responses. B. S. Wostmann, J. R. Pleasants, R. Benner, and D. M. Marcus. 1989. Serum Mol. Immunol. 37: 1141–1149. immunoglobulin levels and naturally occurring antibodies against carbohydrate 12. Revy, P., T. Muto, Y. Levy, F. Geissmann, A. Plebani, O. Sanal, N. Catalan, antigens in germ-free BALB/c mice fed chemically defined ultrafiltered diet. Eur. J. M. Forveille, R. Dufourcq-Labelouse, A. Gennery, et al. 2000. Activation-induced Immunol. 19: 2335–2339. (AID) deficiency causes the autosomal recessive form of the 45. Haury, M., A. Sundblad, A. Grandien, C. Barreau, A. Coutinho, and A. Nobrega. Hyper-IgM syndrome (HIGM2). Cell 102: 565–575. 1997. The repertoire of serum IgM in normal mice is largely independent of ex- 13. Muramatsu, M., K. Kinoshita, S. Fagarasan, S. Yamada, Y. Shinkai, and T. Honjo. ternal antigenic contact. Eur. J. Immunol. 27: 1557–1563. 2000. Class switch recombination and hypermutation require activation-induced 46. Hooijkaas, H., R. Benner, J. R. Pleasants, and B. S. Wostmann. 1984. Isotypes and cytidine deaminase (AID), a potential RNA editing . Cell 102: 553–563. specificities of immunoglobulins produced by germ-free mice fed chemically de- 14. Schur, P. H. 1987. IgG subclasses—a review. Ann. 58: 89–96, 99. fined ultrafiltered “-free” diet. Eur. J. Immunol. 14: 1127–1130. 15. Woof, J. M., and M. A. Kerr. 2006. The function of in im- 47. Okech, B. A., A. Nalunkuma, D. Okello, X. L. Pang, K. Suzue, J. Li, T. Horii, and munity. J. Pathol. 208: 270–282. T. G. Egwang. 2001. Natural human subclass responses to 16. Underdown, B. J., and J. M. Schiff. 1986. Immunoglobulin A: strategic defense serine repeat antigen in Uganda. Am. J. Trop. Med. Hyg. initiative at the mucosal surface. Annu. Rev. Immunol. 4: 389–417. 65: 912–917. 17. Yan, H., M. E. Lamm, E. Bjo¨rling, and Y. T. Huang. 2002. Multiple functions of 48. Berland, R., and H. H. Wortis. 2002. Origins and functions of B-1 cells with notes immunoglobulin A in mucosal defense against : an in vitro virus on the role of CD5. Annu. Rev. Immunol. 20: 253–300. model. J. Virol. 76: 10972–10979. 49. Hirose, S., M. Wakiya, Y. Kawano-Nishi, J. Yi, R. Sanokawa, S. Taki, 18. Chen, K., W. Xu, M. Wilson, B. He, N. W. Miller, E. Bengte´n, E. S. Edholm, T. Shimamura, T. Kishimoto, H. Tsurui, H. Nishimura, et al. 1993. Somatic P. A. Santini, P. Rath, A. Chiu, et al. 2009. enhances immune diversification and affinity maturation of IgM and IgG anti-DNA antibodies in surveillance by activating antimicrobial, proinflammatory and B cell-stimulating murine lupus. Eur. J. Immunol. 23: 2813–2820. Downloaded from programs in . Nat. Immunol. 10: 889–898. 50. Kantor, A. B., A. M. Stall, S. Adams, K. Watanabe, and L. A. Herzenberg. 1995. 19. Chen, K., and A. Cerutti. 2010. New insights into the enigma of immunoglobulin De novo development and self-replenishment of B cells. Int. Immunol. 7: 55–68. D. Immunol. Rev. 237: 160–179. 51. Gioud, M., B. L. Kotzin, R. L. Rubin, F. G. Joslin, and E. M. Tan. 1983. In vivo 20. Carroll, M. C., and M. B. Fischer. 1997. Complement and the immune response. and in vitro production of anti-histone antibodies in NZB/NZW mice. Curr. Opin. Immunol. 9: 64–69. J. Immunol. 131: 269–274. 21. Carroll, M. C. 1998. The role of complement and complement receptors in in- 52. Martin, F., A. M. Oliver, and J. F. Kearney. 2001. Marginal zone and B1 B cells duction and regulation of immunity. Annu. Rev. Immunol. 16: 545–568. unite in the early response against T-independent blood-borne particulate antigens.

22. Boross, P., and J. H. Leusen. 2012. Boosting antibody therapy with complement. Immunity 14: 617–629. http://www.jimmunol.org/ Blood 119: 5945–5947. 53. Lalor, P. A., L. A. Herzenberg, S. Adams, and A. M. Stall. 1989. Feedback reg- 23. Haigwood, N. L., and L. Stamatatos. 2003. Role of neutralizing antibodies in HIV ulation of murine Ly-1 B cell development. Eur. J. Immunol. 19: 507–513. infection. AIDS 17(Suppl. 4): S67–S71. 54. Deenen, G. J., and F. G. Kroese. 1992. Murine peritoneal Ly-1 B cells do not turn 24. Corti, D., and A. Lanzavecchia. 2013. Broadly neutralizing antiviral antibodies. over rapidly. Ann. N. Y. Acad. Sci. 651: 70–71. Annu. Rev. Immunol. 31: 705–742. 55. Duber,€ S., M. Hafner, M. Krey, S. Lienenklaus, B. Roy, E. Hobeika, M. Reth, 25. Sutterwala, F. S., G. J. Noel, P. Salgame, and D. M. Mosser. 1998. Reversal of T. Buch, A. Waisman, K. Kretschmer, and S. Weiss. 2009. Induction of B-cell proinflammatory responses by ligating the Fcgamma receptor type I. development in adult mice reveals the ability of bone marrow to produce B-1a J. Exp. Med. 188: 217–222. cells. Blood 114: 4960–4967. 26. Kurosaka, K., N. Watanabe, and Y. Kobayashi. 2002. Potentiation by human 56. Holodick, N. E., K. Repetny, X. Zhong, and T. L. Rothstein. 2009. Adult BM serum of anti-inflammatory cytokine production by human macrophages in re- generates CD5+ B1 cells containing abundant N-region additions. Eur. J. sponse to apoptotic cells. J. Leukoc. Biol. 71: 950–956. Immunol. 39: 2383–2394.

27. Hart, S. P., C. Jackson, L. M. Kremmel, M. S. McNeill, H. Jersmann, 57. Griffin, D. O., N. E. Holodick, and T. L. Rothstein. 2011. Human B1 cells in by guest on September 28, 2021 K. M. Alexander, J. A. Ross, and I. Dransfield. 2003. Specific binding of an umbilical cord and adult peripheral blood express the novel phenotype CD20+ antigen-antibody complex to apoptotic human neutrophils. Am. J. Pathol. 162: CD27+ CD43+ CD702. J. Exp. Med. 208: 67–80. 1011–1018. 58. Kasaian, M. T., H. Ikematsu, J. E. Balow, and P. Casali. 1994. Structure of the 28. Mota, G., M. Manciulea, E. Cosma, I. Popescu, M. Hirt, E. Jensen-Jarolim, VH and VL segments of monoreactive and polyreactive IgA autoantibodies to A. Calugaru, C. Galatiuc, T. Regalia, D. Tamandl, et al. 2003. Human NK cells DNA in patients with systemic lupus erythematosus. J. Immunol. 152: 3137–3151. express Fc receptors for IgA which mediate signal transduction and target cell 59. Harindranath, N., I. S. Goldfarb, H. Ikematsu, S. E. Burastero, R. L. Wilder, killing. Eur. J. Immunol. 33: 2197–2205. A. L. Notkins, and P. Casali. 1991. Complete sequence of the genes encoding the 29. Perussia, B. 1998. Fc receptors on natural killer cells. Curr. Top. Microbiol. VH and VL regions of low- and high-affinity monoclonal IgM and IgA1 rheu- Immunol. 230: 63–88. matoid factors produced by CD5+ B cells from a rheumatoid arthritis patient. Int. 30. Avrameas, S. 1991. Natural autoantibodies: from ‘horror autotoxicus’ to ‘gnothi Immunol. 3: 865–875. seauton’. Immunol. Today 12: 154–159. 60. Cerutti, A., M. Cols, and I. Puga. 2013. Marginal zone B cells: virtues of innate- 31. Coutinho, A., M. D. Kazatchkine, and S. Avrameas. 1995. Natural autoantibodies. like antibody-producing . Nat. Rev. Immunol. 13: 118–132. Curr. Opin. Immunol. 7: 812–818. 61. Capolunghi, F., S. Cascioli, E. Giorda, M. M. Rosado, A. Plebani, C. Auriti, 32. Kantor, A. B., and L. A. Herzenberg. 1993. Origin of murine B cell lineages. G. Seganti, R. Zuntini, S. Ferrari, M. Cagliuso, et al. 2008. CpG drives human Annu. Rev. Immunol. 11: 501–538. transitional B cells to terminal differentiation and production of natural antibodies. 33. Hardy, R. R., and K. Hayakawa. 1994. CD5 B cells, a fetal B cell lineage. Adv. J. Immunol. 180: 800–808. Immunol. 55: 297–339. 62. Descatoire, M., J. C. Weill, C. A. Reynaud, and S. Weller. 2011. A human 34. Hardy, R. R., C. E. Carmack, Y. S. Li, and K. Hayakawa. 1994. Distinctive devel- equivalent of mouse B-1 cells? J. Exp. Med. 208: 2563–2564. opmental origins and specificities of murine CD5+ B cells. Immunol. Rev. 137: 91–118. 63. Ohdan, H., K. G. Swenson, H. S. Kruger Gray, Y. G. Yang, Y. Xu, A. D. Thall, 35. Conrad, K., M. P. Bachmann, E. Matsuura, and Y. Shoenfeld. 2005. From animal and M. Sykes. 2000. Mac-1-negative B-1b phenotype of natural antibody- models to human genetics: research on the induction and pathogenicity of auto- producing cells, including those responding to Gal alpha 1,3Gal in al- antibodies. Autoimmun. Rev. 4: 178–187. pha 1,3-galactosyltransferase-deficient mice. J. Immunol. 165: 5518–5529. 36. Harindranath, N., H. Ikematsu, A. L. Notkins, and P. Casali. 1993. Structure of the 64. Parker, W., S. S. Lin, P. B. Yu, A. Sood, Y. C. Nakamura, A. Song, M. L. Everett, VH and VL segments of polyreactive and monoreactive human natural antibodies to and J. L. Platt. 1999. Naturally occurring anti-alpha-galactosyl antibodies: rela- HIV-1 and Escherichia coli beta-galactosidase. Int. Immunol. 5: 1523–1533. tionship to xenoreactive anti-alpha-galactosyl antibodies. Glycobiology 9: 865–873. 37. Schettino, E. W., S. K. Chai, M. T. Kasaian, H. W. Schroeder, Jr., and P. Casali. 65.Parker,W.,K.Lundberg-Swanson,Z.E.Holzknecht,J.Lateef,S.A.Washburn, 1997. VHDJH gene sequences and antigen reactivity of monoclonal antibodies S. J. Braedehoeft, and J. L. Platt. 1996. Isohemagglutinins and xenoreactive antibodies: produced by human B-1 cells: evidence for somatic selection. J. Immunol. 158: members of a distinct family of natural antibodies. Hum. Immunol. 45: 94–104. 2477–2489. 66. Baumgarth, N., J. W. Tung, and L. A. Herzenberg. 2005. Inherent specificities in 38. Kearney, J. F. 2000. Immune recognition of OxLDL in atherosclerosis. J. Clin. natural antibodies: a key to immune defense against pathogen invasion. Springer Invest. 105: 1683–1685. Semin. Immunopathol. 26: 347–362. 39. Shaw, P. X., S. Ho¨rkko¨, M. K. Chang, L. K. Curtiss, W. Palinski, G. J. Silverman, 67. Choi, Y. S., J. A. Dieter, K. Rothaeusler, Z. Luo, and N. Baumgarth. 2012. B-1 cells in and J. L. Witztum. 2000. Natural antibodies with the T15 idiotype may act in the bone marrow are a significant source of natural IgM. Eur. J. Immunol. 42: 120–129. atherosclerosis, apoptotic clearance, and protective immunity. J. Clin. Invest. 105: 68. Martin, F., and J. F. Kearney. 2002. Marginal-zone B cells. Nat. Rev. Immunol. 2: 1731–1740. 323–335. 40. Ehrenstein, M. R., and C. A. Notley. 2010. The importance of natural IgM: 69. Kretschmer, K., A. Jungebloud, J. Stopkowicz, T. Kleinke, R. Hoffmann, and scavenger, protector and regulator. Nat. Rev. Immunol. 10: 778–786. S. Weiss. 2003. The selection of marginal zone B cells differs from that of B-1a 41. Baumgarth, N., O. C. Herman, G. C. Jager, L. Brown, L. A. Herzenberg, and cells. J. Immunol. 171: 6495–6501. L. A. Herzenberg. 1999. Innate and acquired humoral immunities to influenza 70. Carey, J. B., C. S. Moffatt-Blue, L. C. Watson, A. L. Gavin, and A. J. Feeney. virus are mediated by distinct arms of the immune system. Proc. Natl. Acad. Sci. 2008. Repertoire-based selection into the marginal zone compartment during USA 96: 2250–2255. B cell development. J. Exp. Med. 205: 2043–2052. 20 BRIEF REVIEWS: NATURAL Abs BRIDGE INNATE AND ADAPTIVE IMMUNITY

71. Dorshkind, K., and E. Montecino-Rodriguez. 2007. Fetal B-cell 98. Panda, S., J. Zhang, N. S. Tan, B. Ho, and J. L. Ding. 2013. Natural IgG antibodies and the emergence of B-1-cell potential. Nat. Rev. Immunol. 7: 213–219. provide innate protection against ficolin-opsonized bacteria. EMBO J. 32: 2905–2919. 72. Montecino-Rodriguez, E., H. Leathers, and K. Dorshkind. 2006. Identification of 99. Craig, A., J. Mai, S. Cai, and S. Jeyaseelan. 2009. Neutrophil recruitment to the a B-1 B cell-specified progenitor. Nat. Immunol. 7: 293–301. lungs during bacterial pneumonia. Infect. Immun. 77: 568–575. 73. Montecino-Rodriguez, E., and K. Dorshkind. 2012. B-1 B cell development in the 100. Zhou, J., S. A. Stohlman, D. R. Hinton, and N. W. Marten. 2003. Neutrophils fetus and adult. Immunity 36: 13–21. promote mononuclear cell infiltration during viral-induced encephalitis. 74. Czajkowsky, D. M., and Z. Shao. 2009. The human IgM pentamer is a mushroom- J. Immunol. 170: 3331–3336. shaped molecule with a flexural bias. Proc. Natl. Acad. Sci. USA 106: 14960–14965. 101. Baranov, D., and P. Neligan. 2007. Trauma and aggressive homeostasis man- 75. Bonagura, V. R., L. Mendez, N. Agostino, and B. Pernis. 1987. Monomeric (7S) agement. Anesthesiol. Clin. 25: 49–63, viii. IgM found in the serum of rheumatoid arthritis patients share with 102. Simmen, H. P., H. Battaglia, P. Giovanoli, and J. Blaser. 1994. Analysis of pH, pO2 pentameric (19S) monoclonal rheumatoid factors. J. Clin. Invest. 79: 813–818. and pCO2 in drainage fluid allows for rapid detection of infectious complications 76. Fakunle, Y. M., F. Aranguibel, D. de Villiers, H. C. Thomas, and S. Sherlock. 1979. during the follow-up period after abdominal surgery. Infection 22: 386–389. Monomeric (7S) IgM in chronic liver disease. Clin. Exp. Immunol. 38: 204–210. 103. Bessman, A. N., J. Page, and L. J. Thomas. 1989. In vivo pH of induced soft-tissue 77. Zhou, Z. H., Y. Zhang, Y. F. Hu, L. M. Wahl, J. O. Cisar, and A. L. Notkins. abscesses in diabetic and nondiabetic mice. Diabetes 38: 659–662. 2007. The broad antibacterial activity of the natural antibody repertoire is due to 104. TranVan Nhieu, G., C. Clair, G. Grompone, and P. Sansonetti. 2004. Calcium polyreactive antibodies. Cell Host Microbe 1: 51–61. signalling during cell interactions with bacterial pathogens. Biol. Cell 96: 93–101. 78. Briles, D. E., M. Nahm, K. Schroer, J. Davie, P. Baker, J. Kearney, and 105. Prince, A. S., J. P. Mizgerd, J. Wiener-Kronish, and J. Bhattacharya. 2006. Cell R. Barletta. 1981. Antiphosphocholine antibodies found in normal mouse serum signaling underlying the pathophysiology of pneumonia. Am. J. Physiol. Lung Cell. are protective against intravenous infection with type 3 Streptococcus pneumoniae. Mol. Physiol. 291: L297–L300. J. Exp. Med. 153: 694–705. 106. Eichstaedt, S., K. Ga¨bler, S. Below, C. Muller,€ C. Kohler, S. Engelmann, 79. Subramaniam, K. S., K. Datta, E. Quintero, C. Manix, M. S. Marks, and P. Hildebrandt, U. Vo¨lker, M. Hecker, and J. P. Hildebrandt. 2009. Effects of L. A. Pirofski. 2010. The absence of serum IgM enhances the susceptibility of mice to -hemolysin A on calcium signalling in immortalized human pulmonary challenge with Cryptococcus neoformans. J. Immunol. 184: 5755–5767. airway epithelial cells. Cell Calcium 45: 165–176. 80. Ochsenbein, A. F., T. Fehr, C. Lutz, M. Suter, F. Brombacher, H. Hengartner, 107. Zhang, J., J. Koh, J. Lu, S. Thiel, B. S. Leong, S. Sethi, C. Y. He, B. Ho, and and R. M. Zinkernagel. 1999. Control of early viral and bacterial distribution and J. L. Ding. 2009. Local inflammation induces complement crosstalk which disease by natural antibodies. Science 286: 2156–2159. amplifies the antimicrobial response. PLoS Pathog. 5: e1000282. Downloaded from 81. Baumgarth, N., O. C. Herman, G. C. Jager, L. E. Brown, L. A. Herzenberg, and 108. Puga, I., and A. Cerutti. 2013. Protection by natural IgG: a sweet partnership with J. Chen. 2000. B-1 and B-2 cell-derived antibodies are soluble lectins does the trick! EMBO J. 32: 2897–2899. nonredundant components of the protective response to influenza virus infection. 109. Panda, S., J. Zhang, L. Yang, G. S. Anand, and J. L. Ding. 2014. Molecular in- J. Exp. Med. 192: 271–280. teraction between natural IgG and ficolin–mechanistic insights on adaptive-innate 82. Choi, Y. S., and N. Baumgarth. 2008. Dual role for B-1a cells in immunity to immune crosstalk. Sci. Rep. 4: 3675. influenza virus infection. J. Exp. Med. 205: 3053–3064. 110. Medzhitov, R., and C. A. Janeway, Jr. 2002. Decoding the patterns of self and 83. Jayasekera, J. P., E. A. Moseman, and M. C. Carroll. 2007. Natural antibody and nonself by the . Science 296: 298–300.

complement mediate neutralization of influenza virus in the absence of prior 111. Beutler, B., Z. Jiang, P. Georgel, K. Crozat, B. Croker, S. Rutschmann, X. Du, http://www.jimmunol.org/ immunity. J. Virol. 81: 3487–3494. and K. Hoebe. 2006. Genetic analysis of host resistance: Toll-like receptor sig- 84. Boes, M., A. P. Prodeus, T. Schmidt, M. C. Carroll, and J. Chen. 1998. A critical naling and immunity at large. Annu. Rev. Immunol. 24: 353–389. role of natural immunoglobulin M in immediate defense against systemic bacterial 112. Brown, G. D. 2006. Dectin-1: a signalling non-TLR pattern-recognition receptor. infection. J. Exp. Med. 188: 2381–2386. Nat. Rev. Immunol. 6: 33–43. 85. Ogden, C. A., R. Kowalewski, Y. Peng, V. Montenegro, and K. B. Elkon. 2005. 113. Hoebe, K., P. Georgel, S. Rutschmann, X. Du, S. Mudd, K. Crozat, S. Sovath, IGM is required for efficient complement mediated phagocytosis of apoptotic cells L. Shamel, T. Hartung, U. Za¨hringer, and B. Beutler. 2005. CD36 is a sensor of in vivo. Autoimmunity 38: 259–264. diacylglycerides. Nature 433: 523–527. 86. Boes, M., C. Esau, M. B. Fischer, T. Schmidt, M. Carroll, and J. Chen. 1998. 114. McGrath, F. D., M. C. Brouwer, G. J. Arlaud, M. R. Daha, C. E. Hack, and Enhanced B-1 cell development, but impaired IgG antibody responses in mice A. Roos. 2006. Evidence that complement protein C1q interacts with C-reactive deficient in secreted IgM. J. Immunol. 160: 4776–4787. protein through its globular head region. J. Immunol. 176: 2950–2957. 87. Chen, Y., Y. B. Park, E. Patel, and G. J. Silverman. 2009. IgM antibodies to 115. Lu, J., K. D. Marjon, C. Mold, T. W. Du Clos, and P. D. Sun. 2012. Pentraxins

apoptosis-associated determinants recruit C1q and enhance phago- and Fc receptors. Immunol. Rev. 250: 230–238. by guest on September 28, 2021 cytosis of apoptotic cells. J. Immunol. 182: 6031–6043. 116. Mantovani, A., S. Valentino, S. Gentile, A. Inforzato, B. Bottazzi, and 88. Notley, C. A., N. Baker, and M. R. Ehrenstein. 2010. Secreted IgM enhances C. Garlanda. 2013. The long pentraxin PTX3: a paradigm for humoral pattern B cell receptor signaling and promotes splenic but impairs peritoneal B cell sur- recognition molecules. Ann. N. Y. Acad. Sci. 1285: 1–14. vival. J. Immunol. 184: 3386–3393. 117. Duncan, A. R., and G. Winter. 1988. The binding site for C1q on IgG. Nature 89. Chen, Y., S. Khanna, C. S. Goodyear, Y. B. Park, E. Raz, S. Thiel, C. Gro¨nwall, 332: 738–740. J. Vas, D. L. Boyle, M. Corr, et al. 2009. Regulation of dendritic cells and 118. Senaldi, G., R. Ireland, A. J. Bellingham, D. Vergani, K. Veerapan, and F. Wang. macrophages by an anti-apoptotic cell natural antibody that suppresses TLR 1988. IgM reduction in systemic lupus erythematosus. Arthritis Rheum. 31: 1213. responses and inhibits inflammatory arthritis. J. Immunol. 183: 1346–1359. 119. Shaw, P. X., C. S. Goodyear, M. K. Chang, J. L. Witztum, and G. J. Silverman. 90. Fabrizio, K., A. Groner, M. Boes, and L. A. Pirofski. 2007. A human monoclonal 2003. The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis- immunoglobulin M reduces bacteremia and inflammation in a mouse model of associated neo-antigens and apoptotic cells. J. Immunol. 170: 6151–6157. systemic . Clin. Vaccine Immunol. 14: 382–390. 120. Tuominen, A., Y. I. Miller, L. F. Hansen, Y. A. Kesa¨niemi, J. L. Witztum, and 91. Lewis, M. J., T. H. Malik, M. R. Ehrenstein, J. J. Boyle, M. Botto, and D. O. Haskard. S. Ho¨rkko¨. 2006. A natural antibody to oxidized cardiolipin binds to oxidized low- 2009. Immunoglobulin M is required for protection against atherosclerosis in low- density lipoprotein, apoptotic cells, and atherosclerotic lesions. Arterioscler. density lipoprotein receptor-deficient mice. Circulation 120: 417–426. Thromb. Vasc. Biol. 26: 2096–2102. 92. Boes, M., T. Schmidt, K. Linkemann, B. C. Beaudette, A. Marshak-Rothstein, and 121. Gray, M., K. Miles, D. Salter, D. Gray, and J. Savill. 2007. Apoptotic cells protect J. Chen. 2000. Accelerated development of IgG autoantibodies and autoimmune mice from autoimmune inflammation by the induction of regulatory B cells. Proc. disease in the absence of secreted IgM. Proc. Natl. Acad. Sci. USA 97: 1184–1189. Natl. Acad. Sci. USA 104: 14080–14085. 93. Ehrenstein, M. R., H. T. Cook, and M. S. Neuberger. 2000. Deficiency in serum 122. Kanevets, U., K. Sharma, K. Dresser, and Y. Shi. 2009. A role of IgM antibodies in immunoglobulin (Ig)M predisposes to development of IgG autoantibodies. J. Exp. monosodium urate crystal formation and associated adjuvanticity. J. Immunol. Med. 191: 1253–1258. 182: 1912–1918. 94. Quartier, P., P. K. Potter, M. R. Ehrenstein, M. J. Walport, and M. Botto. 2005. 123. Kulik, L., S. D. Fleming, C. Moratz, J. W. Reuter, A. Novikov, K. Chen, Predominant role of IgM-dependent activation of the classical pathway in the K. A. Andrews, A. Markaryan, R. J. Quigg, G. J. Silverman, et al. 2009. Patho- clearance of dying cells by murine bone marrow-derived macrophages in vitro. Eur. genic natural antibodies recognizing annexin IV are required to develop intestinal J. Immunol. 35: 252–260. ischemia-reperfusion injury. J. Immunol. 182: 5363–5373. 95. Nauta, A. J., N. Raaschou-Jensen, A. Roos, M. R. Daha, H. O. Madsen, 124. Haas, M. S., E. M. Alicot, F. Schuerpf, I. Chiu, J. Li, F. D. Moore, and M. C. Borrias-Essers, L. P. Ryder, C. Koch, and P. Garred. 2003. Mannose- M. C. Carroll. 2010. Blockade of self-reactive IgM significantly reduces injury in binding lectin engagement with late apoptotic and necrotic cells. Eur. J. Immu- a murine model of acute myocardial infarction. Cardiovasc. Res. 87: 618–627. nol. 33: 2853–2863. 125. Subramanian, K., R. Du, N. S. Tan, B. Ho, and J. L. Ding. 2013. CD163 and IgG 96. Arnold, J. N., M. R. Wormald, D. M. Suter, C. M. Radcliffe, D. J. Harvey, codefend against cytotoxic hemoglobin via autocrine and paracrine mechanisms. R. A. Dwek, P. M. Rudd, and R. B. Sim. 2005. Human serum IgM glycosylation: J. Immunol. 190: 5267–5278. identification of glycoforms that can bind to mannan-binding lectin. J. Biol. Chem. 126. Hess, C., A. Winkler, A. K. Lorenz, V. Holecska, V. Blanchard, S. Eiglmeier, 280: 29080–29087. A. L. Schoen, J. Bitterling, A. D. Stoehr, D. Petzold, et al. 2013. T cell- 97. Boyden, S. V. 1966. Natural antibodies and the immune response. Adv. Immunol. 5: independent B cell activation induces immunosuppressive sialylated IgG anti- 1–28. bodies. J. Clin. Invest. 123: 3788–3796.