Immune evasion of tumor cells using membrane-bound complement regulatory proteins

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Immune evasion of tumor cells using membrane-bound complement regulatory proteins Arko Gorter and Seppo Meri Membrane-bound complement regulatory proteins (mCRPs) play an important role in the protection

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n the circulation, the complement one or more of a group of molecules that of cells from complement-mediated system undergoes continuous lowregulate complement activation on the cell injury. It is now apparent that level activation, thereby patrolling surface (CD35, CD46, CD55 and CD59; Fig. for any potential invaders1. Whether 2; Table 1)1,4. malignant tumor cells also express this surveillance function also extends to With the exception of CD35, these regulathese proteins to escape complement tumor cells escaping to blood from their tors are also expressed on the majority of solid original site has not been examined thortumors. CD46 (membrane cofactor protein; attack. Here, Arko Gorter and Seppo oughly, although in principle, the compleMCP) acts as a cofactor for factor I-mediated Meri discuss the implications of ment system has the ability to destroy such cleavage of C3b and C4b, whereas CD55 complement resistance for the nucleated cells2. Activation of the comple(decay-accelerating factor; DAF) binds to C3b ment membrane attack complex (MAC; and C4b, and accelerates the decay of C3 and immunotherapeutic treatment of C5b–9) can lead to direct lysis of target cells C5 convertases. CD59 binds to C8 and C9 solid tumors with monoclonal via complement-dependent cytotoxicity and prevents pore formation by the MAC. In antibodies. (CDC; Fig. 1). This can occur via the classical addition to these mCRPs, soluble complepathway, after binding of antibodies to the ment inhibitors, such as factor H, might limit target cells, or directly, in an antibodythe complement attack against tumors9. The level of CD46, CD55 and CD59 expression in malignant independent manner, via the alternative pathway. Deposition of C3b, inactivated C3b (iC3b) and, in some cases, also of C1q or C4b on tumors is equal to, or sometimes greater than, that seen in the surthe target cell surface can facilitate phagocytosis and other forms of rounding normal tissue10–15. In situ, expression of CD46, CD55 and CD59 has been reported for most tumors originating from, for excomplement-dependent cellular cytotoxicity (CDCC; Fig. 1). As an effector mechanism, CDCC is similar and parallel to anti- ample, the respiratory tract16, alimentary system11,17, kidneys and body-dependent cellular cytotoxicity (ADCC; Fig. 1). Moreover, urinary tract16, endocrine system12, CNS (Ref. 18), eye19, skin20, these processes can be enhanced by the chemotactic and cell-activating breast10,15 and female13,21 and male genital tracts14. However, some anaphylatoxins, such as C5a (Ref. 3). However, despite these power- tumor types do not seem to express one or more of the mCRPs. ful mechanisms, tumor cells often escape elimination. Only recently Small-cell lung carcinomas were reported to have essentially no have we begun to understand the mechanisms underlying comple- staining for any of the mCRPs investigated, and CD55 was unment resistance in malignant cells. Information on resistance mecha- detectable in squamous or adenosquamous lung carcinoma16 in nisms will be extremely important when immunotherapy of solid Paget’s disease20, and a subset of breast carcinomas (grade III tumors with monoclonal antibodies (mAbs) – mAb immunotherapy invasive ductal carcinomas)10. In addition, some renal tumors were – is being considered. For this reason, we will discuss the contribu- reported to lack mCRP expression16. The different levels of extion of membrane-bound complement regulatory proteins (mCRPs) pression of individual mCRPs have been associated with tumor to the protection of tumor cells, the role of the complement system differentiation and mucus production in several tumor in mAb immunotherapy and strategies to exploit the complement types10,11,13,17,20–22. The expression level of CD55 is usually lower than that of CD46 system to improve mAb immunotherapy. or CD59. CD46 is usually expressed evenly on tumor-cell membranes. The expression patterns of the glycophosphatidylinositol Contribution of mCRPs to the protection of tumor (GPI)-anchored CD55 and CD59 molecules are more variable and, in cells most cases, they are found apical/luminal or adjacent to the baseExpression of mCRPs by tumors ment membrane. Loss of this polar expression might be associated Compared with B- and T-cell-based recognition mechanisms, the with tumor differentiation13,17,18. The observed granular membrane complement system has only a limited ability to discriminate be- staining pattern of CD59 might indicate that CD59 molecules are tween foreign invaders and self. Consequently, human cells express clustered on the cell membrane13,18. 0167-5699/99/$ – see front matter © 1999 Elsevier Science Ltd. All rights reserved.

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PII: S0167-5699(99)01537-6

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ADCC

CDC

Cytokines C5a

Soluble CD46, CD55 and CD59 Frequently, strong expression of CD55 and, to a lesser degree, of CD59 has been observed on stromal tissue16 and might be the result of shedding of CD55 or CD59 from tumor cells. Alternatively, these GPIanchored proteins might be synthesized by stromal cells. The presence of small amounts of soluble CD46, CD55 or CD59 in serum supports shedding of these molecules23–25. Levels of soluble CD46 have been reported to be raised in the sera of cancer patients23. Solubilization of CD46 necessitates proteolytic cleavage to allow its release from the transmembrane polypeptide, whereas the GPI-anchored CD55 and CD59 molecules can be clipped off by phospholipases. In their soluble forms, CD46 and CD55 can both act as complement inhibitors26. Recently, soluble CD59 was found in the supernatant of cell cultures of melanoma cell lines27. This form had retained its phospholipid tail, and was therefore able to reincorporate into other cell membranes and act as a MAC inhibitor. Thus, shedding of mCRPs might provide tumor cells with an additional mechanism to prevent local complement damage.

CDCC

C1qR FcγR

I

II III Phagocytosis Lysis

CR1 C3 C4

CR3 Phagocytosis Lysis

C1q

C1-9

Ig

IgG

MAC Lysis

C3b iC3b C4b Tumor cell

Initiator

IgG

C3b, C4b, iC3b, C1q

IgG, IgM

Transducer

FcγRI, II, III

CR1, CR3, C1qR

C1q

Effector

Mo, PMN, NK cell

Mo, PMN, NK cell

MAC Immunology Today

Fig. 1. Antibody-induced effector mechanisms mediated by phagocytes, NK cells or the complement system. ADCC and CDCC can occur after binding of IgG or C3b, C4b, iC3b or C1q to their respective receptors, resulting in either cell-mediated lysis or phagocytosis of the tumor cells, depending on the effector cell type. Target-cell-bound IgG and complement components are recognized principally by Fcg-receptors (CD64, CD32 and CD16), and CR1 (CD35), CR3 (CD11b/CD18) or C1qR on the effector cells. CDC of tumor cells occurs after binding of C1q to IgG or IgM, resulting in classical pathway activation and the formation of lytic MAC (C5b–9) on the tumor-cell membrane. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; C1qR, C1q receptor; CDC, complementdependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; CR1, complement receptor type 1; FcgR, Fc receptor for IgG; iC3b, inactivated C3b; MAC, membrane attack complex; Mo, monocyte; NK cell, natural killer cell; PMN, polymorphonuclear leukocyte.

Relationship between deposition of complement and mCRP expression If mCRPs do protect cells against complement-mediated injury, the prediction is that signs of complement activation will occur at sites where there is little or no mCRP expression. Few studies have examined the deposition of C3 and C5b–9 in association with the expression of mCRPs. Yamakawa et al.12 reported that strong CD55 expression in thyroid carcinoma correlated with low levels of C3 deposition, supporting the concept of downregulation of local complement activation by mCRP. Niehans et al.16 observed C3 deposition in blood vessels, but not around tumor nests. Occasionally, C5b–9 deposits have been found within tumors in association with necrotic tumor cells. Because only a few investigators have studied the association between mCRPs and complement deposition in situ, further studies are needed to clarify this point. In addition to providing complement resistance in situ, high expression levels of mCRP might facilitate the survival of metastasizing tumor cells when

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Bb C9

C6 C7 iC3b

C3b

C3b

C5b C8

CD46 (MCP)

CD35 (CR1)

CD59

CD55 (DAF)

Immunology Today

Fig. 2. Functions of membrane-bound complement regulatory proteins. CD46 (MCP) is a cofactor for factor I-mediated cleavage of C3b and C4b into iC3b and iC4b, respectively. CD55 (DAF) accelerates the decay of C3 convertases (C4b2a and C3bBb) or C5 convertases (C4b2aC3b and C3bBbC3b) by displacing C2a or Bb from the complexes. The figure shows cofactor activity only for C3b and decayaccelerating activity for C3bBb. CD35 (CR1) has both cofactor and decay-accelerating activities. In addition, CR1 promotes further cleavage of iC3b. CD59 inhibits the formation of a functional MAC (C5b–9) by inhibiting the insertion of C9 through the target cell membrane. Abbreviations: CR1, complement receptor type 1; DAF, decay-accelerating factor; I, factor I; iC3b, inactivated C3b; MCP, membrane cofactor protein.

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Table 1. Membrane-bound complement regulatory proteins CD number

Name

Chromosomal location

Molecular weight (kDa)

SCRs (number)

GPIDistribution anchored

First characterized

CD35

CR1

1q32

190–220

30

No

1979 (Ref. 5)

CD46

MCP, Gp45-70 DAF

1q32

48–56, 58–68 70

4

No

4

Yes

20

None

Yes

CD55 CD59

1q32

P18, HRF20, 11p13 MIRL, MACIF, protectin

Erythrocytes, leukocytes, glomerular podocytes Ubiquitous, except erythrocytes Ubiquitous, except NK cells Ubiquitous

1985 (Ref. 6) 1981 (Ref. 7) 1988 (Ref. 8)

Abbreviations: CR, complement receptor; DAF, decay-accelerating factor; GPI, glycophosphatidylinositol; HRF20, homologous restriction factor 20; MACIF, membrane attack complex-inhibiting factor; MCP, membrane cofactor protein; MIRL, membrane inhibitor of reactive lysis; NK, natural killer; SCRs, short consensus repeats.

they enter the circulation, whereas low levels of mCRP might predispose tumor cells to elimination by complement-mediated mechanisms.

Expression and consequences of mCRP expression The expression of mCRPs on tumor-cell lines in vitro has been investigated in many studies by means of flow cytometry13–15,18,19,28,29. When compared with the expression of mCRPs in situ on tumor tissue sections, the in vitro measurements have shown a higher apparent expression of mCRPs on cultured cell lines13,18. Similarly, as with in situ expression on tumors, the expression of mCRPs has varied between cell lines of different origin. In addition, differences in the expression levels have been observed between cell lines derived from the same tissue18,28,29, probably reflecting tumor heterogeneity30. In light of these differences, it is relevant to ask whether increased or decreased expression of mCRP on tumor cells has functional consequences. This has been studied by either removing the GPI-anchored CD55 and CD59 molecules, by means of phosphatidylinositol-specific phospholipase C, or blocking mCRPs with specific mAbs. From these studies it is clear that CD46, CD55 and CD59 can play a role in the prevention of complement-mediated damage of both normal and malignant cells13,14,18,28,29,31,32. In classical pathway complement activation, CD55 (Refs 13, 18, 32) and CD59 (Refs 28, 29) probably play the most prominent role in preventing cell lysis.

Additional resistance of tumor cells to complement-mediated injury In some cases, despite the presence of similar amounts of mAbs bound to the tumor-cell surface and similar expression levels of CD46, CD55 and CD59, complement-dependent lysis can occur in one tumor-cell line when another tumor-cell line derived from the same site of origin is resistant18. Therefore, other less-well characterized membrane proteins might limit complement activation at the tumor-cell surface. These might include the proteases p41 and p69, which have been reported to control C3 deposition33,34, or the putative homologous restriction factor (HRF), which was reported to prevent pore formation35. In addition, tumor cells might express yet

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unknown mCRPs or secrete soluble CRPs. Other resistance mechanisms might also play important roles in the protection of tumor cells against complement-mediated injury36. These might include: (1) shedding of surface molecules with covalently linked C3b or C4b; (2) the formation of MAC-containing membrane vesicles37; (3) growth arrest38; (4) distinct cell membrane lipid composition; and (5) compensatory metabolic activity or turnover of lipids and proteins.

The role of the complement system in mAb immunotherapy Experimental animal models mAb tumor immunotherapy has yielded encouraging results in experimental animal models39–42. For this purpose, the most efficient IgG subclasses have been mouse IgG2a and IgG3, as well as human IgG1 and IgG3 (Ref. 43). These IgG subclasses are activators of the complement system and efficient mediators of ADCC. However, it should be noted that, regardless of its subclass, each mAb is individual in its ability to activate complement44. Nude mice are usually used in mAb immunotherapy studies. The absence of T cells in nude mice leaves the task of tumor cell elimination to CDC, CDCC and ADCC (Fig. 1). It has been reported that of these three processes, ADCC is most important, although little attention has been paid to CDCC (Ref. 45). It is evident from studies on the in vivo antitumor effect of the R24 mAb, specific for the ganglioside GD3 (Refs 40, 41), that the complement system plays a role in eradicating tumor cells in experimental animals (mice and rats). The protective effect of R24 was reversed by pretreatment of the animals with the complement-depleting agent, cobra venom factor (CVF). In addition, the antitumor activity in nude mice of a panel of R24 mAb variants correlated with the complement-activating capacity of the mAbs, rather than their capacity to induce ADCC (Refs 40, 41). Nakamura et al.39 showed that an antiGD2 IgM mAb could suppress the expansion of human small-cell lung carcinoma in nude mice. In addition, human natural IgM inhibited the growth of neuroblastoma cells in a tumor model in nude rats46. The absence of receptors for IgM on phagocytes and natural killer (NK) cells makes it likely that complement activation either induced CDC or that C3b deposition enabled CDCC of tumor cells. In

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Box 1. Main reasons limiting mAb-mediated complement attack on tumor cells Properties of the antibody or the antigen • A complement non-activating mAb is used. • Low antigen density or the antigen epitope is not located close enough to the cell membrane. • Insufficient amount of mAb is used or the mAbs are unable to reach the tumor cells. • Low-affinity mAbs used. • Shedding or internalization of the antigen (antigen modulation). • Antigen-negative sublines might arise.

Restriction of complement activation • Tumor cells are recognized as nonactivators by the complement system (for example, sialic acid, glycosaminoglycans). • Expression of mCRPs. • Presence of soluble complement inhibitors. • Membrane proteases that inactivate complement components. • Shedding of surface molecules with covalently bound C3b or C4b, internalization or exocytosis of MAC. • Other properties (for example, growth arrest, membrane composition or metabolic properties). Abbreviations: mAbs, monoclonal antibodies; MAC, membrane attack complex of complement; mCRPs, membrane-bound complement regulatory proteins.

the latter study, CDCC by neutrophils was thought to be the effector mechanism. These examples illustrate that the complement system can play a role in the elimination of tumor cells in experimental animals.

Clinical trials In humans the success of mAb tumor immunotherapy has been limited. In clinical trials, the most promising (humanized) mAbs directed against solid tumors have been: ch14.18 (directed against the ganglioside GD2)47, R24 (directed against the ganglioside GD3)48, 17-1A [directed against the 17-1A antigen/epithelial cell adhesion molecule (Ep-CAM)]49 and rhuMab HER2 (directed against the p185HER2 growth factor receptor)50. Furthermore, for hematological malignancies, promising results have been reported with CAMPATH-1H (directed against CD52)51 and IDEC-C2B8 (directed against CD20)52. Notably, a Phase II trial with the complementactivating IDEC-C2B8 mAb resulted in a 46% response rate (including three complete remissions) in 37 patients with relapsed low-grade non-Hodgkin’s lymphoma52. Complement activation has been observed in serum in vivo after infusion of the 14.G2a mAb in patients with neuroblastoma53. Treatment of melanoma patients with R24 (Ref. 54) and colorectal cancer patients with 17-1A mAbs (Ref. 55) resulted in C3 and C9 deposition on tumor cells. In addition, the presence of C3 has been reported on breast56 and thyroid57 carcinomas in the absence of mAb treatment. Although complement activation might play a role in the eradication of tumor cells, multiple factors could have contributed to a lack of

complement-mediated killing of tumor cells in mAb immunotherapy (Box 1). Among these mCRPs play a central role. Several explanations can be given for the difference in success rates between mAb immunotherapy in experimental animals and humans. In contrast to fast tumor growth in experimental animals, in humans, tumors usually develop over a period of many years. During this period, selection enforced by the microenvironment and the immune system might lead to the expansion of the most adapted (malignant) tumor clones. In addition, mCRPs have been shown to act in a species-selective manner58,59. This is an important factor: in experimental tumor models in animals, xenogeneic (for example, human) tumor cells are frequently used39–42. Because human mCRPs are often less effective against a non-homologous complement system, mAb immunotherapy will result in a more effective killing of xenogeneic tumor cells. Thus, in syngeneic combinations of host and tumor, as in the case of human tumors, the effect of mAb immunotherapy would be expected to be less pronounced.

Strategies to exploit the complement system to improve mAb immunotherapy It is surprising to note how little attention has been paid to both the analysis of the complement resistance of tumor cells and how to overcome this phenomenon. To exploit the biological ‘power’ of the complement system for the eradication of tumor cells, it is important to understand that tumor cells not only express a panel of mCRPs, but probably also are capable of repairing damage to their membranes (Box 1). There are several possible approaches that might improve the efficacy of complement activation by mAb immunotherapy (Fig. 3). First, the number of complement fragments deposited on the tumor cells is dependent on the number of mAbs bound to the tumor cells. Thus, increased CDC against tumor cells was observed either by using multiple mAbs against different antigens60 or by using multiple mAbs against non-competing epitopes on one antigen61. In addition, high-affinity mAbs have been shown in vitro to be more efficient in mediating CDC and ADCC (Ref. 62). In vivo, the high affinity of any single mAb might restrict its penetration deeper into the tumors. Second, the complement-activating properties of mAbs can be enhanced by isotype switching, genetic engineering (for example, humanization) or various conjugation procedures. Juhl et al.63 have demonstrated that in vitro F(ab9)2–CVF conjugates were effective in the killing of neuroblastoma cells. CVF activates the complement system by forming a stable CVF–Bb enzyme complex, which acts as a C3/C5 convertase. Combinations of mAb–CVF and F(ab9)2–CVF conjugates, directed against different tumor antigens, had an additive effect on CDC (Ref. 64). In nude rats, this type of treatment with mAb–CVF conjugates increased the number of both macrophages and NK cells, which suggested that mAb–CVF conjugates can enhance the inflammatory reaction65. In addition, Reiter and Fishelson66 have used heteroconjugates of mAbs and C3b. Conjugated C3b activated the alternative pathway and thereby increased lysis of tumor cells. A third possibility is to generate heteroconjugates of antibodies directed against a tumor-associated antigen and mAbs directed

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1 mAb

CDC ADCC CDCC

Cytokines Ischemia 4

2 Tumor cell

CDC ADCC CDCC

C3b/CVF Conjugated mAb Tumor antigen

Bispecific mAb

Complement regulator

3

Immunology Today

Fig. 3. Potential ways to improve the efficiency of mAb immunotherapy. (1) Increasing the amount or affinity of mAbs bound to the tumor cells. (2) Improving the complement-activating properties of the mAbs (isotype switch, humanization, conjugation of mAbs to CVF or C3b). (3) Tumor-cell binding and inactivation of a complement-regulatory protein by bispecific mAbs. (4) Downregulation of complement-regulatory proteins either by cytokines or inducing ischemia in tumors. Abbreviations: ADCC, antibodydependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; CVF, cobra venom factor; mAb, monoclonal antibody. against mCRPs. Junnikkala et al.67 have reported targeted neutralization of CD59 on melanoma cells using avidin to crosslink biotinylated R24 and anti-CD59 mAbs. This approach increased lysis of tumor cells without substantial toxicity to innocent bystander cells. An alternative approach was followed by Harris et al.68 and Blok et al.69, who made bispecific mAbs directed against CD38*CD59 or G250*CD55 pairs, respectively. These bispecific mAbs were shown to improve target cell lysis. In addition, the G250*CD55 mAb increased C3b deposition. In these latter approaches, tumor-specific binding of the bispecific mAbs might be improved by choosing a high-affinity mAb against tumor-associated antigens and a lowaffinity mAb against mCRPs, which would limit binding to normal cells expressing mCRPs. Another foreseeable problem in using neutralizing bispecific anti-mCRP mAbs is the appearance of soluble CRPs. Soluble CD46, CD55 and CD59 might block binding of the anti-CRP arm to mCRPs on the target cells. In the case of CD59, this problem is expected to be relatively small because soluble CD59, as a result of its small size and absent lipid tail, is rapidly secreted into urine and CD59, with an intact phospholipid tail, binds readily to nearby surfaces70. A fourth possibility is to reduce the expression of mCRPs on cancer cells (or systemically) before mAb treatment; however, to date, it has been difficult to find effective reagents in this regard. A number of studies have reported the effects of cytokines on mCRP expression on non-hematopoietic tumor cells71–74. Several studies have reported

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upregulation of mCRP expression by interleukin 1b (IL-1b), IL-4 or tumor necrosis factor a on colon adenocarcinoma cell lines71–73. However, in renal cell carcinoma cell lines, IL-1b reduced the expression of CD46 and CD59 (V.T. Blok et al., unpublished). In these latter cell lines, transforming growth factor b1 was reported to reduce the expression of CD46 and CD55. In general, the reported effects of cytokines on mCRP expression are variable and seem to depend on the cell line used. Of the pharmacological agents tested, levamisole was found to downregulate CD59 expression75, whereas nitrosourea (CCNU) (Ref. 76) and 5-azacytidine (Ref. 77) upregulated CD55 and CD59. In most studies the resulting level of mCRP expression correlated with the resistance of tumor-cell lines to complement-mediated lysis. In addition to cytokine treatment, ischemia was shown to reduce the expression of mCRPs (Ref. 78). This latter approach might also be exploited to increase the sensitivity of tumor cells to mAb immunotherapy.

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Concluding remarks Utilization of the complement system offers potential for the elimination of tumor cells in mAb immunotherapy. Activation of the complement system causes tumor-cell destruction both by inducing complement lysis and promoting cell-mediated killing. In addition, complement can induce a strong inflammatory response, which might potentiate other antitumor effector mechanisms. An important obstacle to mAb immunotherapy, however, is mCRPs, which have been shown to be expressed on most tumor cells in vivo and in vitro. Blocking or downregulation of these inhibitors could be an important step in the advancement of mAb immunotherapy.

Studies in the authors’ laboratories are supported by the Dutch Kidney Foundation, the Dutch Cancer Society, the Academy of Finland, the University and University Central Hospital of Helsinki and the Sigrid Jusélius Foundation.

Arko Gorter ([email protected]) is at the Leiden University Medical Center, Dept of Pathology, Building 1, L1Q, PO Box 9600, 2300 RC Leiden, The Netherlands; Seppo Meri is at the Dept of Bacteriology and Immunology, PO Box 21, Haartman Institute, FIN-00014 University of Helsinki, Helsinki, Finland. References 1 Liszewski, M.K., Farries, T.C., Lublin, D.M., Rooney, I.A. and Atkinson, J.P. (1996) Adv. Immunol. 61, 201–283 2 Koski, C.L., Ramm, L.E., Hammer, C.H., Mayer, M.M. and Shin, M.L. (1983) Proc. Natl. Acad. Sci. U. S. A. 80, 3816–3820 3 Gerard, C. and Gerard, N.P. (1994) Annu. Rev. Immunol. 12, 775–808 4 Morgan, B.P. and Harris, C.L. (1999) Complement Regulatory Proteins, Academic Press 5 Fearon, D.T. (1979) Proc. Natl. Acad. Sci. U. S. A. 76, 5867–5871 6 Cole, J.L., Housley, G.A., Jr, Dykman, T.R., MacDermott, R.P. and Atkinson, J.P. (1985) Proc. Natl. Acad. Sci. U. S. A. 82, 859–863 7 Nicholson Weller, A., Burge, J. and Austen, K.F. (1981) J. Immunol. 127, 2035–2039

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The contribution of ER quality control to the biologic functions of secretory IgM Padmalatha S. Reddy and Ronald B. Corley Secretory IgM provides a first line of defense against pathogens and is uniquely capable of enhancing the

mmunoglobulin M (IgM) is the first stimulate the survival of CD51 B1 B cells, primary humoral immune response. antibody that is produced in the which are believed to produce a significant immune system and plays an imfraction of natural IgM to pathogens3. This Complement activation is especially suggests the existence of a positive feedback portant role in primary and adapimportant for these activities. Here, loop that maintains the levels of natural IgM tive humoral immune responses (Table 1). Padmalatha Reddy and Ronald antibodies of various specificities. Finally, IgM comprises a significant fraction of IgM can participate in mucosal immunity, ‘natural’ antibodies, many of which are Corley discuss how the ‘quality as joining (J)-chain-containing polymers can multireactive and bind determinants found control’ mechanisms that regulate be transcytosed across epithelial surfaces on the membranes of bacterial and viral IgM assembly and secretion play by virtue of their interaction with the polypathogens1,2. IgM provides a crucial first line of defense for the immune system, and its immunoglobulin receptor6. important roles in the The central role of secretory IgM in the ability to agglutinate pathogens enhances developmental progression of B cells immune response is supported by studies of phagocytosis and clearance. IgM also effiand in B-cell function. IgM-deficient mice. Mice with mutations in ciently activates complement, especially when the Bruton’s tyrosine kinase (Btk2/2) have bound to cellular antigens, and this further very low levels of IgM and exhibit selective facilitates pathogen opsonization. Complement components are important mediators that link the innate and immunodeficiencies in immune responses to polysaccharides and various pathogens7. IgM2/2 mice that lack both membrane and seadaptive immune systems3. IgM also plays important roles in adaptive humoral immune re- cretory IgM are more susceptible to pathogens than their wild-type sponses. IgM has the unique capacity to enhance immune responses counterparts, owing, at least in part, to the delayed production of specifically against particulate antigens4. The efficiency with which neutralizing antibodies8. Studies of mice that lack only secretory IgM IgM activates complement is crucial for its enhancing activity5. Com- show that they do not respond well to T-dependent antigens, and plement components, especially C3d, increase the deposition of im- that they are not as competent as IgM sufficient mice to respond to mune complexes on complement-receptor positive cells, including B certain pathogens9–11. This deficit can be attributed to diminished cells and follicular dendritic cells (FDC), and this serves to amplify antigen trapping on FDC and impaired germinal center formation. the immune response3. Complement-containing complexes can also Overall, secretory IgM carries out unique and important roles that

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