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Harnessing Their Therapeutic PotentialNatural IgM in Immune Equilibrium and

Srini V. Kaveri, Gregg J. Silverman and Jagadeesh Bayry

http://www.jimmunol.org/content/188/3/939doi: 10.4049/jimmunol.1102107

2012; 188:939-945; ;J Immunol 

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Natural IgM in Immune Equilibrium and Harnessing TheirTherapeutic PotentialSrini V. Kaveri,*,†,‡,x Gregg J. Silverman,{ and Jagadeesh Bayry*,†,‡,x

Natural IgM Abs are the constitutively secreted prod-ucts of B1 cells (CD5+ in mice and CD20+CD27+

CD43+CD702 in humans) that have important anddiverse roles in health and disease. Whereas the roleof natural IgM as the first line of defense for protectionagainst invading microbes has been extensively investi-gated, more recent reports have highlighted their po-tential roles in the maintenance of tissue homeostasisvia clearance of apoptotic and altered cells throughcomplement-dependent mechanisms, inhibition of in-flammation, removal of misfolded proteins, and regu-lation of pathogenic autoreactive IgG Abs and auto-antibody-producing B cells. These observations haveprovided the theoretical underpinnings for efforts thatcurrently seek to harness the untapped therapeutic po-tential of natural IgM either by boosting in vivo natu-ral IgM production or via therapeutic infusions ofmonoclonal and polyclonal IgM preparations. TheJournal of Immunology, 2012, 188: 939–945.

Cooperation between innate and adaptive immunecompartments reinforces host protection from inva-ding pathogens while maintaining an immunologic

tolerance toward self. Igs or Abs, the product of B cells, aresome of the essential components of the immune system andare divided into five isotypes, namely IgG, IgM, IgA, IgE, andIgD. Well established as effector molecules of the adaptivecompartment, Igs also participate as links or organizing factorsfor certain functions of the innate immune system by identifyingand neutralizing the pathogens in part through the triggering ofFcRs and activation of the complement system (1, 2).

Properties of IgM

IgM isotype represents one of the major Ig classes in the body.IgM is also the earliest type of membrane-associated Ig ex-pressed during B cell ontogeny and as secreted Abs duringAg-specific immune responses. Although the molecular massof a monomeric IgM is 190 kDa, circulating IgM exists more

frequently as a pentamer or sometimes even as a hexamer,which can convey increased avidity for the binding of an Ag.Pentameric IgM is generally associated with a J chain to forma macromolecule of ∼970 kDa. In healthy adults, circulatinghuman polyclonal IgM is generally present at ∼1 to 2 mg/mlof blood, with a t1/2 of ∼5 d. Although IgM are often potentactivators of the classical pathway of complement, there aregreat variations in the properties of different IgM-secretingB cell clones, even when they share the same fine bindingspecificity.IgM is known to bind to two receptors: Fca/mR and the

polymeric Ig receptor (3, 4). However, these receptors are notsolely specific for IgM and can also recognize IgA. CD22, aninhibitory coreceptor on B cells, can also act as receptor forthe glycoconjugates on soluble IgM through its sialoprotein-binding domain (5). In addition, TOSO/FAIM3, regulator ofFas-induced apoptosis, was identified as a high-affinity FcRspecific for IgM (6, 7).TOSO is a transmembrane protein of ∼60 kDa expressed

predominantly by lymphocytes, and in contrast to its name,it has no antiapoptotic functions. However, the binding ofIgM, in particular the multimeric form of IgM, to TOSOwould facilitate B and T cell cooperation, complement acti-vation, and enhanced Ab-dependent cell-mediated cytotoxic-ity. TOSO recognizes the Fc portion of pentameric IgM withhigh affinity (∼10 nM). The multimeric form of IgM seemsto be critical for this binding, as higher concentrations(.100-fold) are required for binding of IgM monomers toTOSO (6, 7). Furthermore, TOSO may play a role in im-mune surveillance through internalization of IgM-bound im-mune complexes that contribute to B cell activation. As leu-kemic B cells generally express high levels of TOSO, thisreceptor represents an attractive therapeutic target for the de-livery of IgM-conjugated drugs into these cancer cells (8).

Natural IgM

In health, the circulating IgM that arise without knownimmune exposure or vaccination are referred to as natural,

*INSERM Unite 872, Paris, F-75006, France; †Centre de Recherche des Cordeliers,Equipe 16-Immunopathologie et Immunointervention Therapeutique, Universite Pierreet Marie Curie–Paris 6, Unite Mixte de Recherche S 872, Paris F-75006, France;‡Universite Paris Descartes, Unite Mixte de Recherche S 872, Paris F-75006, France;xInternational Associated Laboratory IMPACT (INSERM-France and Indian Council ofMedical Research-India), National Institute of Immunohaematology, Mumbai 400012,India; and {New York University School of Medicine, New York, NY 10016

Received for publication October 14, 2011. Accepted for publication December 7, 2011.

This work was supported by INSERM, Universite Pierre et Marie Curie, Universite ParisDescartes (to S.V.K. and J.B.); Centre National de la Recherche Scientifique (to S.V.K.);a grant from the European Community’s Seventh Framework Programme (FP7-2007-2013)-HEALTH-F2-2010-260338-ALLFUN (to J.B.); National Institutes of Health GrantsR01 AI090118, R01 AI068063, and American Recovery and Reinvestment Act of 2009

supplement R01 AI090118; and the American College of Rheumatology Research Ed-ucation Foundation Within Our Reach campaign, the Alliance for Lupus Research, theArthritis Foundation, and the P. Robert Majumder Charitable Trust (to G.J.S.).

Address correspondence and reprint requests to Dr. Srini V. Kaveri, INSERM Unite872, Centre de Recherche des Cordeliers, 15 Rue de l’Ecole de Medicine, Paris F-75006,France. E-mail address: srini.kaveri@crc.jussieu.fr

Abbreviations used in this article: AC, apoptotic cell; ACM, apoptotic cell membrane;DC, dendritic cell; IVIgM, i.v. IgM; MBL, mannose-binding lectin; MDA, malondial-dehyde; nIgM, natural IgM; OxLDL, oxidized low-density lipoprotein; PAMP,pathogen-associated molecular pattern; PC, phosphorylcholine.

Copyright� 2012 by TheAmerican Association of Immunologists, Inc. 0022-1767/12/$16.00

www.jimmunol.org/cgi/doi/10.4049/jimmunol.1102107

whereas immune IgM are generated in response to definedantigenic stimuli. In the mouse, natural IgM (nIgM) are oftenwithout N-region additions and are germline encoded or withminimal somatic hypermutations, although less is knownabout the human counterparts. nIgM can display polyre-activity, whereas some IgM clones have highly refined Ag-binding specificities. A major set of nIgM has been reportedto recognize self-Ags (9).

B-1 cells

The B-lineage compartment includes at least three distinctmature B cell subsets: B-1 that constitutively produce nIg,which is most often IgM, but can be IgG and IgA isotypes;marginal zone B cells that are responsible for responses toencapsulated organisms and their nonprotein Ags; and B-2cells (also termed follicular B cells) that are recruited intoT cell-dependent germinal centers upon protein Ag exposure(10, 11). In mice, B-1 cells that express CD5 have long beenconsidered as the major source of nIgM (12, 13). Althoughidentification of their human cellular counterpart has beencontroversial, in part because CD5 can be an activationmarker on human B cells, a recent report identified CD20+

CD27+CD43+ memory B cells as the human B-1 cell equiv-alent. These cells are distinct from CD20+CD27+CD432

activated memory B and CD20+CD272CD432 naive B cells,as B-1 cells do not display the activation markers CD69 andCD70 (14). B-1 cells are also characterized by their ability toefficiently present Ags and can provide potent signaling toT cells in the absence of specific antigenic stimulus (14–16).Compared to B-2 cells that are susceptible to BCR-mediatednegative selection due to activation-induced apoptotic death,B-1 cells are resistant to strong BCR-mediated signaling (14,17). B-1 cells also have a special ability for self-renewal, andthere is also constant addition to the peripheral B-1 reper-toire from newly generated cells from the bone marrow thatensures the continuous production of nIgM throughout life(18–21).The functional contributions of B-1 cells are intertwined

in the tight regulation of their trafficking between differentlymphoid compartments. B-1 cells migrate from the bone mar-row and into the peritoneal cavity as they follow gradients ofCXCL13, and CXCL13-deficient mice have reduced levelsof peritoneal B-1 cells (22, 23). Stimulation with certain cy-tokines, or by infectious agent-derived ligands that bear thepathogen-associated molecular patterns (PAMPs), recognizedby innate immune receptors, such as TLRs, can activate peri-toneal B-1 cells. This process can also induce expression of thechemokine receptor CCR7 that can mediate their relocali-zation to other lymphoid organs and differentiation into Ig-producing cells. However, the homing of B1 cells into theperitoneal cavity is not an absolute requirement for mountingT-independent Ab responses, as most of the production ofIgM by murine B-1 cells occurs in the spleen (24).

nIgM in immune equilibrium

nIgM can play diverse roles in health and disease. Whereasextensive studies have documented the contribution of nIgMas a first line of defense from infection, more recent reportshave highlighted their potential roles in the maintenance of im-mune homeostasis, prevention from overexuberant inflamma-tory responses, and development of autoimmune disease.

Taken together, these observations have provided the theoreti-cal underpinnings to justify efforts to exploit the untappedtherapeutic potential of IgM.

nIgM mediate protection against infection. The first indication ofthe crucial role of nIgs in controlling infections came fromthe evidence that primary Ig-deficient patients displayhigh susceptibility for recurrent infections from bacteria,virus, fungi, and parasites. Indeed, reconstitution of im-munodeficient animals with nIgM may itself restore thecapacity of these animals to control certain infections. Thismay be explained by virtue of the ability of polyclonalnIgM to directly recognize a wide range of PAMPs thatleads to inhibition of the growth of microbial pathogensthrough their direct neutralization or by activation of theclassical complement pathway and amplification of humoralimmune responses, leading to the enhanced phagocytosis ofthese opsonized pathogens (25–31) (Fig. 1).Indeed, the roles of nIgM in preventing infections likely

extend beyond simple neutralization and opsonization. Im-mediately after the entry of pathogens into the host, inter-actions with nIgM also set the stage for the shaping of thesubsequent immune response. nIgM promote the recognitionof pathogens by professional APCs, such as dendritic cells(DCs), and may guide the ensuing functional polarization ofT cell responses, as well the isotype class-switch recombinationof the induced B cell response and the induction long-termimmune memory (32, 33). For example, following vaccina-tion with Leishmania protein, nIgM can promote IL-4 se-cretion by CD11b+CD11clo phagocytes (29, 34). Theseresults indicate that formation of complexes of antigenicligands with nIgM could be one of the mechanisms respon-sible for the enhanced humoral immune responses induced byaluminum hydroxide adjuvant-containing vaccines (29, 34).

nIgM in immune tolerance and tissue homeostasis. nIgM may havefirst arisen to reinforce fundamental mechanisms for main-taining homeostasis. Apoptosis is an obligatory outcome ofdevelopment, proliferation, and cell differentiation that con-tinues throughout life. Every day, .1011 cells in our body dieby apoptosis, and therefore, apoptotic cell (AC) clearance isessential for tissue homeostasis. The innate immune systemrecognizes ACs when they become spontaneously decoratedwith soluble innate immune molecules, such as complementC1Q and mannose-binding lectin (MBL) that can recognizeligands specifically expressed on the AC membranes (ACMs).In fact, this specialized process of phagocytic clearance ofACs, termed efferocytosis, is one of the most fundamentalfunctions of the innate immune system. In health, ACs donot pose an immediate threat to the host, as there are re-dundant means to ensure rapid and efficient cell corpse clear-ance by macrophages and DCs. To rationalize how defectsin efferocytosis may be linked to autoimmune pathogenesis,Walport and colleagues (35) developed the waste disposalhypothesis. If efficiency of AC clearance is limited, therecan be progression to secondary necrosis and the ensuingrelease of nuclear Ags such as high-mobility group box 1protein, heat shock proteins, and other components ofdying cells (danger-associated molecular patterns), which arebelieved to activate pattern-recognition receptors of innateimmune cells that include TLR, leading to inflammatoryresponses. Necrotic cells can also release autoantigens thatcan select pathogenic B and T cell clones, which together

940 BRIEF REVIEWS: NATURAL IgM

can lead to the development of autoimmune disease inpredisposed individuals.Naive humans and mice have substantial levels of nIgM that

recognize ACMs, whereas even higher levels can be inducedby i.v. infusions of large numbers of ACs (36). The IgM-dependent deposition of C1Q of the classical complementpathway has a major role in determining the efficiency theclearance of ACs by macrophages (37). Furthermore, experi-mental models have shown that suppression of inflammatoryarthritis mediated by ACs may require nIgM that can directlyinhibit macrophage and DC activation (38) and may alsopromote IL-10–secreting B and T cells (39, 40).Despite the complexity of molecules displayed on ACs,

studies in healthy mice have shown that humoral immuneresponses to AC infusions are dominated by Abs to theoxidation-associated phosphorylcholine (PC) and malondial-dehyde (MDA) neodeterminants on ACMs (36). In expla-nation, PC is a phospholipid head group that is animmunodominant epitope on microbial pathogens, such as

Streptococcus pneumoniae, but the PC head group is alsoa component of neutral phospholipids (e.g., phosphatidylcholine) in the outer leaflet of cell membranes. In healthycells, PC is sequestered and not available for immune recog-nition. Yet, during apoptotic death, the PC head groupbecomes exposed due to oxidative damage to the polyunsat-urated fatty acid side chains of phospholipids to generate re-active aldehydes such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (reviewed in Ref. 41). Thereby,damaged cells are flagged via Ab recognition of PC neo-epitopes. A second major set of anti-ACM IgM recognizesMDA, which is an important degradation product of unsat-urated lipids reacting with reactive oxidation species (42).nIgM recognition of ACs via the oxidation-associated phos-pholipid determinants PC and MDA enables the discrimi-nation of ACs from healthy cells (36, 38, 40, 43–47) (Fig. 1).PC and MDA are also dominant phospholipid-related

epitopes on oxidatively modified (but not native) low-density lipoproteins (OxLDL) in atherosclerosis. The devel-

FIGURE 1. Natural IgM in immune equilibrium. nIgM can maintain immune equilibrium by regulating the tissue homeostasis and acting as a first line of

defense against invading microbes and shaping the subsequent immune response. The role of nIgM in tissue homeostasis implicates activation of compliment

pathways and helps to prevent inflammation, autoimmunity, and malignancy. These functions include recognition of apoptotic cell membranes and promoting

the clearance of apoptotic cells by phagocytic cells such as DCs and macrophage (MQ), clearance of altered or malignant cells or misfolded proteins, and

regulation of the disease-associated IgG and B cell clones. Further, nIgM can confer protection against invading pathogens through direct neutralization of

pathogens, activation of classical complement pathways, opsonization of pathogens and phagocytosis by DC and MQ, and transportation of Ags to lymphoid

organs for initiating the immune responses by innate immune cells. In addition, nIgM can also regulate the immune response to pathogens by influencing the

T cell polarization and B cell class-switch. B, B cell; C1Q, complement C1Q (classical complement pathway); T, T cell.

The Journal of Immunology 941

opment of atherosclerosis is also associated with B cell acti-vation, particularly manifested by enhanced production ofnatural anti-OxLDL IgM and IgG autoantibodies (42). Levelsof circulating anti-OxLDL IgM Abs have been linked withreduced vascular risk in humans (48). Yet anti-OxLDL IgGAbs show variable association with vascular risk (49). In fact,in earlier studies, it was shown that bacterial vaccine thatinduced high levels of IgM anti-PC Abs arrested the pro-gression of atherosclerosis in atherosclerosis-prone mice withcholesterol levels .1000 mg/dl (43). However, the underly-ing mechanisms were undefined, as infusions of such Abs didnot affect the in vivo clearance of OxLDL (50).It was nonetheless postulated that the balance of inflam-

mation and accumulation of ACs in atherosclerosis is a directreflection of the potential influences of specific types ofatherosclerosis-associated autoantibodies. In an earlier report,it was shown that anti-PC IgM Abs blocked phagocyticclearance of ACs (44). However, as described below, subse-quent studies showed that this T15 clonotypic PC-specificIgM enhances AC clearance in vivo and in vitro, in a com-plement-dependent fashion (36, 38) that may suggest thatthere was an insufficient level of early complement factors,such as C1q and MBL, in the assays described in this earlier invitro report (44).Recent studies in murine models demonstrated that anti-

ACM IgM directed against PC and MDA can have twomajor regulatory functions: 1) enhance clearance of ACs byphagocytes (termed efferocytosis) (36, 38); and 2) direct sup-pression of proinflammatory responses induced by agonistsfor TLR3, TLR4, TLR7, and TLR9 and likely many otherinnate pathways (38). However, it is not clear whether thesetwo immunomodulatory functions are mediated through thesame signaling pathway, as inhibition of AC phagocytosisdoes not necessarily inhibit the anti-inflammatory influencesof AC interactions with DCs (51). Investigations of the in-hibitory properties of the prototypic anti-PC IgM T15, whichalso recognizes ACs, did not decrease TLR transcript ex-pression or induce TGF-b or IL-10 in DCs (38).In well-characterized inducible murine models of inflam-

matory autoimmune diseases, collagen-induced arthritis andautoantibody-mediated arthritis, anti-ACM nIgM infusions(i.e., T15 IgM), but not isotype control or saline, protectedfrom inflammatory arthritis (38). Also, recent observations inpatients with the autoimmune disease systemic lupus eryth-ematosus highlight the association of nIgM levels in protec-tion against autoimmunity (52–54). For example, decreasedlevels of anti-PC IgM Abs are characteristic features of activelupus compared with disease in remission (52, 53). Thesestudies suggest that some nIgM may serve as regulators of theinnate immune system to help maintain homeostasis and, incertain cases, suppress the development of inflammatory andautoimmune diseases.Another important role of nIgM in tissue homeostasis

implicates clearance of altered or malignant cells viacomplement-dependent cell lysis and induction of apoptosis(55, 56). Many tumor-related epitopes are carbohydrate innature and by themselves are poorly immunogenic, therebyrendering the formulation of effective active immunizationapproach a daunting task. Owing to their capacity in somecases to recognize the repetitive motifs of some carbohydrateAgs and with an increased avidity due to their polymeric

structure, nIgM may provide an endogenous therapeutic toolfor enhancing certain types of immune responses (57, 58).Deficiency in serum IgM may predispose to the develop-

ment of IgG autoantibodies, suggesting that nIgM contributeto the suppression of disease-associated IgG autoantibodyproduction (59) (Fig. 1). It has also been argued that theprotective effect of IgM may at times involve anti-idiotypic(i.e., targeting of the Ag receptors of some clonally re-lated lymphocytes) downregulation of some autoimmune re-sponses or result from the induction by some IgM anti-id-iotypic Abs of apoptotic death of pathogenic B cell clones orthe selection of other protective B cell subsets (60–62). Themaintenance of tissue homeostasis by nIgM may also involvethe enhanced clearance of misfolded proteins, which couldhave clinical implications for conditions like Alzheimer’sdisease in which pathogenesis results from the deposition ofmisfolded proteins such as b-amyloid plaques in the brain.Relevant to this hypothesis, IgM Abs have been shown torecognize and hydrolyze b-amyloid proteins (63).

How can we boost natural IgM in vivo?

In recent reports, several strategies have been described forboosting of nIgM levels. Following splenectomy or thermalinjury, patients often develop a selective loss of circulating IgMand display an associated heightened susceptibility to certaintypes of infections. While in health, nIgM is constitutivelyproduced; there is extensive evidence that levels can be en-hanced by a number of interventions. Experimental modelssuggest that exogenous administration of IL-18 can restorenIgM production and also strengthen the host defenses toinfection (64, 65) (Fig. 2). Additional strategies to inducenIgM include: 1) parenteral administration of CpG, anunmethylated, oligodeoxynucleotide PAMP that activatesB cells via TLR9; 2) use of mimetic peptides derived fromrandom in silico screening of peptides that mimic poorlyimmunogenic nonprotein Ags; 3) immunization with PC-containing Ags that are also a dominant type of phospho-lipid-related neodeterminant on ACMs and OxLDL; 4)pneumococcal vaccination that exploits the molecular mim-icry among the PC moieties of microbial cell-wall polysac-charide, unfractionated OxLDL, and ACs; and 5) injection ofinternal-image bearing anti-idiotypic Abs (43, 66–70). In-deed, idiotypic vaccination strategies that boost IgM and IgG

FIGURE 2. Means to harness therapeutic potential of natural IgM.

942 BRIEF REVIEWS: NATURAL IgM

levels against NeuGcGM3 ganglioside Ags have also shownpromising results in early clinical trials (71, 72).

Harnessing therapeutic potential of natural IgM

Use of IgM-enriched therapeutic preparations. As normal humanplasma contains a substantial amount of nIgM, it may bepractical and economically viable to harness therapeutic po-tential of these IgM through the generation of therapeuticpreparations in a manner analogous to i.v. Ig that is nowextensively used for the treatment of a wide range of patho-logical conditions (73, 74) (Fig. 2). Indeed, an IgM-enrichedIg preparation, pentaglobin, contains 12% IgM, and this hasbeen successfully used for treating infections associated withsepsis in patients, as well as transplant rejection, and forcertain inflammatory conditions in experimental models(75–78). Such preparations may also provide benefits tocombat infections that arise in patients with autoimmunedisease (79). This preparation likely benefits from enrich-ment for a common type of VH4-34–encoded nIgM Abthat has specific high binding capacity for microbial LPS(80), a factor implicated in infection-induced cardiovascularcollapse.Similarly, a pilot preparation of pooled polyreactive normal

IgM that contains .90% i.v. IgM (IVIgM) was generatedfrom plasma of .2500 healthy donors. Such IVIgM alsocontains anti-idiotypic Abs that recognize disease-associatedIgG-autoantibodies from patients with a diverse range of au-toimmune diseases, and this IVIgM can inhibit in vitro theactivities of these IgG-autoantibodies (81). Furthermore, thein vivo therapeutic efficacy of IVIgM was confirmed incomplement-dependent inflammatory conditions and in ex-perimental models of uveitis, myasthenia gravis, and multiplesclerosis (77, 81–84). While exploring the mechanisms forsuch protection, it was found that IVIgM can induce theapoptosis of mononuclear cells, suppress the functions ofT cells and also prevent the activation of the complementcascade under inflammatory conditions (77, 85, 86).

Use of monoclonal IgM Abs. Promising results obtained withpolyclonal nIgM prompted the identification and use ofmonoclonal nIgM Abs in experimental autoimmune diseasesin mice (Fig. 2). Two such mAbs (either derived from serumor generated by recombinant approach), IgM22 and IgM46,have provided protection against Theiler’s murine encepha-lomyelitis virus-induced chronic progressive demyelinatingdisease and lysolecithin-induced demyelination in mice bypromoting remyelination (83, 84, 87, 88) and are potentialcandidates for therapeutic trials.

ConclusionsAlthough the therapeutic opportunities of nIgM appear vast,so far the promise of clinical utility has been evaluated inonly a small range of diseases. Several different approaches tonIgM-based therapy are being considered for suitability forclinical trials. A natural human mAb, IgM22, that binds tooligodendrocytes and promotes their remyelination will sooncomplete primate toxicology testing prior to submission forFood and Drug Administration approval (M. Rodriguez,personal communication). Interestingly, anti-idiotype–basedapproaches that boost IgM Ab directed against NeuGcGM3ganglioside in vivo have also recently reached phase III clinicaltrials for the treatment of metastatic breast cancer (71).

One of the main reasons for the slow progress in translatingthe basic research findings on nIgM to clinical application isthe issue inherent to the nature of the molecules themselves.The existence of IgM in either monomeric or pentameric formspresents a dilemma regarding the identification of the form ofthe therapeutic molecule that will achieve the most attractiveprofiles for efficacy, tolerability, and safety. The pentamericform poses further potential challenges regarding the stabilityof such manufactured IgM-based therapeutics. Similar to IgG,the glycosylation pattern of IgM can also play a critical role inits effector functions, and m C region-associated high mannoseglycoconjugates can mediate the recruitment of MBL, whichcan enhance the clearance of ACs (36), whereas in othersettings, this may instead trigger downstream complementactivation and associated undesirable complications. Hence,the specialized effector functions of IgM can provide clinicalopportunities but also pose challenges for the purification ofwell-characterized homogeneous preparations that are re-quired for therapeutic applications.As for monoclonal IgM, identification of the most relevant

and specific molecular targets and then optimizing productionat an industrial scale are all likely to be technically challengingand time-consuming. Further, depending on the moleculartargets, each particular monoclonal IgM may have a limitedrange of clinical indications. For these reasons, pooled poly-specific IgM may present clear advantages, as the plasmafractionation industry is well suited for these manufacturingchallenges. In fact, an Ig preparation containing 12% pooledIgM is currently used for the treatment of patients with sepsis(75, 76). Early results from pilot IVIgM preparations con-taining ∼90% IgM have also shown immunomodulatorypotential in experimental models of autoimmune and in-flammatory diseases (77, 81–84). In the future, data fromplanned investigations should provide insights into the idealconcentration of IgM in the Ig preparations that strikes theoptimal balance between therapeutic efficacy and minimaladverse reactions. IgM-containing Ig preparations may also beused as supplemental therapy for patients who are treated withagents that induce B cell and Ig depletion or other immu-nosuppressive regimens that can be associated with increasedsusceptibility to infection.

AcknowledgmentsWe thank Peter Spaeth for critical comments. We were limited in the number

of references we could cite, but acknowledge that numerous other key contri-

butions were not included due to space limitations.

DisclosuresThe authors have no financial conflicts of interest.

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