- Email: [email protected]
IgM in the kidney: a multiple personality disorder
commentary
be translated into new clinical algorithms to halt or reduce fibrosis in renal patients. First, there are currently no specific mTORC2 inhibitors available. Second, the UUO model is an acute renal fibrosis model, while fibrotic processes within the human kidney are mostly chronic.1 Whether mTORC1 and mTORC2 play a role in this chronic fibrotic remodeling remains to be established. Third, mTORC1 inhibition in the kidney unfortunately has a highly ambiguous history: While the mTORC1 inhibitor everolimus did improve renal function as measured by estimated glomerular filtration rate when used instead of a calcineurin inhibitor in recent transplant patients,5 it failed to halt cyst growth and functional decline in patients with autosomal dominant polycystic kidney disease (ADPKD).6 In fact, although not statistically significant, there was even a trend for worse renal function in ADPKD patients treated with everolimus compared with placebo in this study.6 Similarly, while everolimus exerted a beneficial effect in patients with tuberous sclerosis suffering from renal angiomyolipoma, a case series in focal segmental glomerulosclerosis using rapamycin demonstrated nephrotoxicity and functional decline in the treatment group.7 One could argue that these negative studies were all performed with mTORC1 inhibitors, but as already mentioned, long-term exposure to mTORC1-specific compounds will disturb assembly and hence function of mTORC2 as well.3 So, are dual inhibitors acting on the catalytic kinase domain of the mTOR kinase itself a viable option? Up to now, only one proof-of-concept trial in a murine ADPKD model with pp242, one of these new compounds, has been described.8 In this study, cyst growth and functional decline could be effectively reduced to an extent similar to that previously shown for mTORC1 inhibition alone.8 Yet human data are completely lacking. A different pharmacological class of ‘triple’ inhibitors, targeting phosphatidylinositol-3′-kinase (PI3K) as well as both mTOR complexes at once, are currently being evaluated in anticancer trials, but so far no kidney-specific data Kidney International (2015) 88
have been published. Hence, although we already have established inhibitors against mTORC1, dual kinase inhibitors against both mTORC1 and mTORC2, and even ‘triple’ inhibitors targeting both mTORCs as well as PI3K, none of these drugs seem easy to use. This probably is even more true if we consider the potential necessity of long-term administration and keep in mind the side effect profile of these compounds.5,9 Cell-specific delivery modes, similar to the mouse genetic approach of Li et al.,2 would be an elegant way to limit side and off-target effects. Hence, apart from discovering new drug targets to ameliorate renal fibrosis, we have to start thinking about cell-specific drug delivery strategies to enable efficient and safe use of available inhibitors on newly identified targets.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
Work in the author’s laboratory is supported by the German Research Council through CRC 1140 KIDGEM Project A01.
9.
Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010; 21: 1819–1834. Li J, Ren J, Liu X et al. Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis. Kidney Int 2015; 88: 515–527. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274–293. Jiang L, Xu L, Mao J et al. Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. J Am Soc Nephrol 2013; 24: 1114–1126. Budde K, Becker T, Arns W et al. Everolimusbased, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 2011; 377: 837–847. Walz G, Budde K, Mannaa M et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363: 830–840. Cho ME, Hurley JK, Kopp JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis 2007; 49: 310–317. Ravichandran K, Zafar I, Ozkok A et al. An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease. Nephrol Dial Transplant 2015; 30: 45–53. Bissler JJ, Kingswood JC, Radzikowska E et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 2013; 381: 817–824.
see basic research on page 528
IgM in the kidney: a multiple personality disorder Jeffrey L. Platt1,2 and Marilia Cascalho1,2 IgM in the blood of normal individuals consists mainly of ‘natural’ polyreactive antibodies. Natural IgM is thought to provide an initial defense against infection and to promote the healing of wounded cells. Yet, as Panzer and colleagues show, these benefits can be eclipsed when the IgM binds to damaged cells of the glomerulus, activating complement. IgM in glomeruli thus signifies cellular damage and may warn that the pace of that damage exceeds the capacity for repair. Kidney International (2015) 88, 439–441. doi:10.1038/ki.2015.153
1
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA and 2Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA Correspondence: Jeffrey L. Platt, Department of Surgery, University of Michigan, A520B Medical Sciences Research Building I, 1150 W. Medical Center Drive, Ann Arbor, Michigan, 48109-5656, USA. E-mail: [email protected]
There has always been discussion, and sometimes debate, about why all immunologically competent individuals have natural antibodies. Natural antibodies (antibodies produced without a known history of exposure to antigen) against blood groups A and B pose a powerful barrier to the transfusion of 439
commentary
Alternative pathway complex
IgM
Classical pathway complex
Injury Repair Accommodation
Figure 1 | Natural IgM and complement in the injury, and potentially in the repair, of cell surfaces in factor H-deficient mice. In mice lacking complement factor H, the complement system is constitutively activated, and this damages cells in the glomerulus and elsewhere. In some systems, binding of natural antibodies and activation of complement at a low level induced repair and protection against further injury, a condition called accommodation. However, when IgM binds to damaged cells of the glomerulus, complement is further activated via the classical pathway and the rate and/or extent of damage exceeds the capacity for repair or accommodation.
incompatible erythrocytes and to the transplantation of incompatible organs. Other natural antibodies, particularly natural IgM, have been found to protect against infection,1 suppress autoimmunity,2 and facilitate healing.3 But natural IgM may also incite common types of cellular injury.4 Besides the question of why normal individuals have natural antibodies that can promote disease, there is the question of whether some natural IgM antibodies can both protect and harm. We think observations reported in a magnificent paper by Panzer et al.5 (this issue) provide powerful insights and an intriguing step toward answering these questions. We usually teach that IgM is the first immunoglobulin produced in response to infection and that the severe bacterial infections experienced by infants with IgM deficiency affirm its importance for host defense. Because IgM has ten antigen combining sites, it is confined mainly to the blood vessels. These multiple sites can enable even lowaffinity IgM to activate complement via the classical pathway. IgM also serves as the antigen receptor (BCR) of naive B cells. Random recombination of Ig variable-region gene segments in developing B cells generates about 109 different BCRs in each individual and makes the BCR repertoire of each individual, including identical twins, different. Stimulation of BCRs by antigen in conjunction with T-cell help induces ‘hypermutation’ of germline V-region
440
genes and recombination of constantregion exons (isotype switching). Inherited defects in hypermutation and class-switch recombination cause the hyper-IgM syndrome, which (like IgM deficiency, ironically) greatly increases the risk of infection and autoimmune disease. Most B cells with BCRs that bind to self are deleted during development, and this deletion enacts tolerance and averts autoimmunity. Failure of self-censorship allows autoreactive B cells to undergo hypermutation, selection, and isotype switching, which generate pathogenic IgG antibodies (which can leave blood vessels) and cause autoimmune disease. However, the properties of natural antibodies and the B cells that produce them appear to violate some of these first principles. Unlike antibodies produced in response to infection or vaccination, that is, elicited antibodies, natural antibodies can recognize many antigens, each antibody being ‘polyreactive.’ Approximately 50–80% of IgM in blood has this property. Some B cells that produce natural antibodies are censored by self-antigens (a person of blood group A has no B cells capable of secreting anti-A antibodies). But the B cells that produce polyreactive antibodies are not. Each of these B cells can recognize many self-antigens. The polyreactive antibodies are encoded by germline V-region genes, not further diversified by somatic hypermutation. The specificities and even the idiotypes
of the natural antibodies are remarkably shared in the population, suggesting that the B cells are selected for polyreactivity and autoreactivity. Why do healthy individuals have the same autoreactive natural antibodies, including those that worsen cellular injury? Unexpectedly, Panzer and colleagues may have begun to answer this question (Figure 1). The authors previously studied adriamycin nephropathy in mice, observing that depletion of B cells prevents deposition of IgM and C3 in glomeruli and lessens the tempo and severity of disease,6 suggesting that IgM and C3 might be pathogenic and not just markers of nonimmune injury. To explore that possibility, Panzer et al.5 asked whether IgM can add to existing cellular damage, possibly by activating complement via the classical pathway (involving C1q, C4, and C2). The question was addressed with the use of factor H knockout mice. Complement factor H controls, by several mechanisms, the alternative complement pathway, which undergoes continuous activation (unlike the classical pathway, which is mainly activated by bound antibodies). Activation of the alternative pathway fixes C3, leaving C1q, C4, IgM, and IgG unbound. Consistent with that concept, the glomeruli in young, factor H-deficient mice have deposits containing C3, but no IgG. However, when Panzer and colleagues studied these mice over time, they found that besides deposits of C3, the glomeruli had deposits of IgM and C4 (but no IgG). The presence of IgM and C4 might reflect ‘trapping’ in a damaged kidney, or autoimmunity caused by factor H deficiency or binding of natural antibodies to damaged cells. To determine whether IgM and C4 were pathogenic and whether the IgM was autoimmune, the authors examined the kidneys of factor H-deficient mice that had been cross-bred with B celldeficient mice. These mice exhibited only mild mesangial hypercellularity. The glomeruli contained no C4 or C1q, and the disease did not progress. Thus, progression of kidney disease in factor H-deficient mice depended on
Kidney International (2015) 88
commentary
binding of IgM to something in the damaged glomeruli and activation of the classical complement pathway. To confirm this possibility and to provide at least a preliminary glimpse at the nature of the bound antibody, the authors administered IgM isolated from serum of normal mice and a monoclonal natural IgM to the cross-bred factor H-deficient, B cell-deficient mice. The IgM from normal serum (predominantly natural IgM) and the monoclonal polyreactive IgM bound to glomeruli, causing proteinuria. Thus, IgM from normal (not autoimmune) mice and even a monoclonal polyreactive IgM bound to damaged glomeruli, activated complement, and exacerbated underlying injury. Instead of the classical complement pathway recruiting the alternative pathway to amplify injury, as convention holds, in factor H-deficient mice the alternative complement pathway caused IgM to bind, recruiting the classical pathway to amplify injury. These findings certainly advance understanding about how glomerular disease progresses; how widely this understanding can be applied will be seen with time. Yet the implications of the work extend beyond the subject of kidney disease to the questions posed at the outset—why normal individuals have natural IgM autoantibodies and whether the same natural antibodies that defend against microbial inflections and heal damaged cells also cause disease. The most immediate danger infection and tissue injury pose are dissemination of microorganisms and uncontrolled necrosis (releasing C3b, thrombin, and cytokines). Both can trigger the systemic inflammatory response syndrome and multiorgan failure. The cellular elements of innate immunity circumscribe infection and necrosis by recognizing the products of damaged cells, particularly endothelial cells, and provoking endothelial-cell activation, hemostasis, coagulation, vasoconstriction, and so on. The humoral elements of innate immunity, particularly natural antibodies and complement, probably do likewise. And there
Kidney International (2015) 88
is a physiological reason for recognition of damaged cells. Neither inflammatory receptors nor natural antibodies can recognize all of the organisms, toxins, and so on that pose threats, but, as Panzer and colleagues show, natural antibodies can recognize damaged cells and their products, and such selfrecognition may circumscribe damaged tissue, providing the time needed for an elicited immune response to ensue. Natural antibodies might also facilitate healing of damaged cells. The repair of cell membranes wounded by physical injury and pore-forming proteins can require binding of annexins to acidic moieties in the inner membrane and clustering in such a way that surface tension decreases and the wounded membrane is removed.7 Recognition of acidic moieties on damaged cell surfaces by polymeric natural IgM should have the same impact. However, other natural antibodies recognize basic proteins such as annexins and the binding of these natural antibodies to ischemic tissues worsens injury.8 Why then do we have these antibodies that promote and inhibit repair? If these antibodies inhibit the anticoagulant function of annexins, they might help sequester microorganisms and the contents of cells damaged beyond repair, at the expense of local tissue injury. But can natural antibodies with the same specificity incite injury and protection and repair? Panzer and colleagues provide an exciting hint. Panzer et al.5 clearly show that in factor H-deficient mice natural antibodies cause glomerular damage that progresses over 6 months, the proof being drawn from comparison of this course with the milder non-progressive course of glomerular disease in factor H-deficient mice lacking B cells. However, if the course of kidney disease in factor H-deficient mice is more severe in mice that produce natural antibodies, it is strikingly mild when compared with the immediate and devastating course of kidney disease in recipients of ABO-incompatible allografts and xenografts. These differences are yet
more striking if one considers that complement regulation is normal in ABO-incompatible transplantation (it is abnormal in xenotransplantation). Various explanations for these differences come to mind, but one we find appealing is that in factor H-deficient mice, antibodies and complement induce ‘accommodation,’9 that is, acquired resistance of the kidneys and other organs to complement-mediated injury. Accommodation is seen archetypically when natural antibodies are depleted before an incompatible transplant is performed and then allowed slowly to return. If the kidneys of factor H-deficient mice are accommodated, as we suspect, the extent of damage inflicted by IgM and complement exceeds the capacity for repair. But in the absence of accommodation things could be far worse. DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Boes M, Prodeus AP, Schmidt T et al. A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J Exp Med 1998; 188: 2381–2386. Gronwall C, Silverman GJ. Natural IgM: beneficial autoantibodies for the control of inflammatory and autoimmune disease. J Clin Immunol 2014; 34(Suppl 1): S12–S21. Wootla B, Watzlawik JO, Denic A et al. The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment. Exp Rev Clin Immunol 2013; 9: 535–549. Weiser MR, Williams JP, Moore FDJ et al. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med 1996; 183: 2343–2348. Panzer SE, Laskowski J, Renner B et al. IgM exacerbates glomerular disease progression in complement-induced glomerulopathy. Kidney Int 2015; 88: 528–537. Strassheim D, Renner B, Panzer S et al. IgM contributes to glomerular injury in FSGS. J Am Soc Nephrol 2013; 24: 393–406. Potez S, Luginbuhl M, Monastyrskaya K et al. Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities. J Biol Chem 2011; 286: 17982–17991. Kulik L, Fleming SD, Moratz C et al. Pathogenic natural antibodies recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury. J Immunol 2009; 182: 5363–5373. Cascalho MI, Chen BJ, Kain M et al. The paradoxical functions of B cells and antibodies in transplantation. J Immunol 2013; 190: 875–879.
441
be translated into new clinical algorithms to halt or reduce fibrosis in renal patients. First, there are currently no specific mTORC2 inhibitors available. Second, the UUO model is an acute renal fibrosis model, while fibrotic processes within the human kidney are mostly chronic.1 Whether mTORC1 and mTORC2 play a role in this chronic fibrotic remodeling remains to be established. Third, mTORC1 inhibition in the kidney unfortunately has a highly ambiguous history: While the mTORC1 inhibitor everolimus did improve renal function as measured by estimated glomerular filtration rate when used instead of a calcineurin inhibitor in recent transplant patients,5 it failed to halt cyst growth and functional decline in patients with autosomal dominant polycystic kidney disease (ADPKD).6 In fact, although not statistically significant, there was even a trend for worse renal function in ADPKD patients treated with everolimus compared with placebo in this study.6 Similarly, while everolimus exerted a beneficial effect in patients with tuberous sclerosis suffering from renal angiomyolipoma, a case series in focal segmental glomerulosclerosis using rapamycin demonstrated nephrotoxicity and functional decline in the treatment group.7 One could argue that these negative studies were all performed with mTORC1 inhibitors, but as already mentioned, long-term exposure to mTORC1-specific compounds will disturb assembly and hence function of mTORC2 as well.3 So, are dual inhibitors acting on the catalytic kinase domain of the mTOR kinase itself a viable option? Up to now, only one proof-of-concept trial in a murine ADPKD model with pp242, one of these new compounds, has been described.8 In this study, cyst growth and functional decline could be effectively reduced to an extent similar to that previously shown for mTORC1 inhibition alone.8 Yet human data are completely lacking. A different pharmacological class of ‘triple’ inhibitors, targeting phosphatidylinositol-3′-kinase (PI3K) as well as both mTOR complexes at once, are currently being evaluated in anticancer trials, but so far no kidney-specific data Kidney International (2015) 88
have been published. Hence, although we already have established inhibitors against mTORC1, dual kinase inhibitors against both mTORC1 and mTORC2, and even ‘triple’ inhibitors targeting both mTORCs as well as PI3K, none of these drugs seem easy to use. This probably is even more true if we consider the potential necessity of long-term administration and keep in mind the side effect profile of these compounds.5,9 Cell-specific delivery modes, similar to the mouse genetic approach of Li et al.,2 would be an elegant way to limit side and off-target effects. Hence, apart from discovering new drug targets to ameliorate renal fibrosis, we have to start thinking about cell-specific drug delivery strategies to enable efficient and safe use of available inhibitors on newly identified targets.
REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
DISCLOSURE
The author declared no competing interests. ACKNOWLEDGMENTS
Work in the author’s laboratory is supported by the German Research Council through CRC 1140 KIDGEM Project A01.
9.
Zeisberg M, Neilson EG. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol 2010; 21: 1819–1834. Li J, Ren J, Liu X et al. Rictor/mTORC2 signaling mediates TGFβ1-induced fibroblast activation and kidney fibrosis. Kidney Int 2015; 88: 515–527. Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274–293. Jiang L, Xu L, Mao J et al. Rheb/mTORC1 signaling promotes kidney fibroblast activation and fibrosis. J Am Soc Nephrol 2013; 24: 1114–1126. Budde K, Becker T, Arns W et al. Everolimusbased, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 2011; 377: 837–847. Walz G, Budde K, Mannaa M et al. Everolimus in patients with autosomal dominant polycystic kidney disease. N Engl J Med 2010; 363: 830–840. Cho ME, Hurley JK, Kopp JB. Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity. Am J Kidney Dis 2007; 49: 310–317. Ravichandran K, Zafar I, Ozkok A et al. An mTOR kinase inhibitor slows disease progression in a rat model of polycystic kidney disease. Nephrol Dial Transplant 2015; 30: 45–53. Bissler JJ, Kingswood JC, Radzikowska E et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): a multicentre, randomised, double-blind, placebocontrolled trial. Lancet 2013; 381: 817–824.
see basic research on page 528
IgM in the kidney: a multiple personality disorder Jeffrey L. Platt1,2 and Marilia Cascalho1,2 IgM in the blood of normal individuals consists mainly of ‘natural’ polyreactive antibodies. Natural IgM is thought to provide an initial defense against infection and to promote the healing of wounded cells. Yet, as Panzer and colleagues show, these benefits can be eclipsed when the IgM binds to damaged cells of the glomerulus, activating complement. IgM in glomeruli thus signifies cellular damage and may warn that the pace of that damage exceeds the capacity for repair. Kidney International (2015) 88, 439–441. doi:10.1038/ki.2015.153
1
Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA and 2Department of Microbiology and Immunology, University of Michigan, Ann Arbor, Michigan, USA Correspondence: Jeffrey L. Platt, Department of Surgery, University of Michigan, A520B Medical Sciences Research Building I, 1150 W. Medical Center Drive, Ann Arbor, Michigan, 48109-5656, USA. E-mail: [email protected]
There has always been discussion, and sometimes debate, about why all immunologically competent individuals have natural antibodies. Natural antibodies (antibodies produced without a known history of exposure to antigen) against blood groups A and B pose a powerful barrier to the transfusion of 439
commentary
Alternative pathway complex
IgM
Classical pathway complex
Injury Repair Accommodation
Figure 1 | Natural IgM and complement in the injury, and potentially in the repair, of cell surfaces in factor H-deficient mice. In mice lacking complement factor H, the complement system is constitutively activated, and this damages cells in the glomerulus and elsewhere. In some systems, binding of natural antibodies and activation of complement at a low level induced repair and protection against further injury, a condition called accommodation. However, when IgM binds to damaged cells of the glomerulus, complement is further activated via the classical pathway and the rate and/or extent of damage exceeds the capacity for repair or accommodation.
incompatible erythrocytes and to the transplantation of incompatible organs. Other natural antibodies, particularly natural IgM, have been found to protect against infection,1 suppress autoimmunity,2 and facilitate healing.3 But natural IgM may also incite common types of cellular injury.4 Besides the question of why normal individuals have natural antibodies that can promote disease, there is the question of whether some natural IgM antibodies can both protect and harm. We think observations reported in a magnificent paper by Panzer et al.5 (this issue) provide powerful insights and an intriguing step toward answering these questions. We usually teach that IgM is the first immunoglobulin produced in response to infection and that the severe bacterial infections experienced by infants with IgM deficiency affirm its importance for host defense. Because IgM has ten antigen combining sites, it is confined mainly to the blood vessels. These multiple sites can enable even lowaffinity IgM to activate complement via the classical pathway. IgM also serves as the antigen receptor (BCR) of naive B cells. Random recombination of Ig variable-region gene segments in developing B cells generates about 109 different BCRs in each individual and makes the BCR repertoire of each individual, including identical twins, different. Stimulation of BCRs by antigen in conjunction with T-cell help induces ‘hypermutation’ of germline V-region
440
genes and recombination of constantregion exons (isotype switching). Inherited defects in hypermutation and class-switch recombination cause the hyper-IgM syndrome, which (like IgM deficiency, ironically) greatly increases the risk of infection and autoimmune disease. Most B cells with BCRs that bind to self are deleted during development, and this deletion enacts tolerance and averts autoimmunity. Failure of self-censorship allows autoreactive B cells to undergo hypermutation, selection, and isotype switching, which generate pathogenic IgG antibodies (which can leave blood vessels) and cause autoimmune disease. However, the properties of natural antibodies and the B cells that produce them appear to violate some of these first principles. Unlike antibodies produced in response to infection or vaccination, that is, elicited antibodies, natural antibodies can recognize many antigens, each antibody being ‘polyreactive.’ Approximately 50–80% of IgM in blood has this property. Some B cells that produce natural antibodies are censored by self-antigens (a person of blood group A has no B cells capable of secreting anti-A antibodies). But the B cells that produce polyreactive antibodies are not. Each of these B cells can recognize many self-antigens. The polyreactive antibodies are encoded by germline V-region genes, not further diversified by somatic hypermutation. The specificities and even the idiotypes
of the natural antibodies are remarkably shared in the population, suggesting that the B cells are selected for polyreactivity and autoreactivity. Why do healthy individuals have the same autoreactive natural antibodies, including those that worsen cellular injury? Unexpectedly, Panzer and colleagues may have begun to answer this question (Figure 1). The authors previously studied adriamycin nephropathy in mice, observing that depletion of B cells prevents deposition of IgM and C3 in glomeruli and lessens the tempo and severity of disease,6 suggesting that IgM and C3 might be pathogenic and not just markers of nonimmune injury. To explore that possibility, Panzer et al.5 asked whether IgM can add to existing cellular damage, possibly by activating complement via the classical pathway (involving C1q, C4, and C2). The question was addressed with the use of factor H knockout mice. Complement factor H controls, by several mechanisms, the alternative complement pathway, which undergoes continuous activation (unlike the classical pathway, which is mainly activated by bound antibodies). Activation of the alternative pathway fixes C3, leaving C1q, C4, IgM, and IgG unbound. Consistent with that concept, the glomeruli in young, factor H-deficient mice have deposits containing C3, but no IgG. However, when Panzer and colleagues studied these mice over time, they found that besides deposits of C3, the glomeruli had deposits of IgM and C4 (but no IgG). The presence of IgM and C4 might reflect ‘trapping’ in a damaged kidney, or autoimmunity caused by factor H deficiency or binding of natural antibodies to damaged cells. To determine whether IgM and C4 were pathogenic and whether the IgM was autoimmune, the authors examined the kidneys of factor H-deficient mice that had been cross-bred with B celldeficient mice. These mice exhibited only mild mesangial hypercellularity. The glomeruli contained no C4 or C1q, and the disease did not progress. Thus, progression of kidney disease in factor H-deficient mice depended on
Kidney International (2015) 88
commentary
binding of IgM to something in the damaged glomeruli and activation of the classical complement pathway. To confirm this possibility and to provide at least a preliminary glimpse at the nature of the bound antibody, the authors administered IgM isolated from serum of normal mice and a monoclonal natural IgM to the cross-bred factor H-deficient, B cell-deficient mice. The IgM from normal serum (predominantly natural IgM) and the monoclonal polyreactive IgM bound to glomeruli, causing proteinuria. Thus, IgM from normal (not autoimmune) mice and even a monoclonal polyreactive IgM bound to damaged glomeruli, activated complement, and exacerbated underlying injury. Instead of the classical complement pathway recruiting the alternative pathway to amplify injury, as convention holds, in factor H-deficient mice the alternative complement pathway caused IgM to bind, recruiting the classical pathway to amplify injury. These findings certainly advance understanding about how glomerular disease progresses; how widely this understanding can be applied will be seen with time. Yet the implications of the work extend beyond the subject of kidney disease to the questions posed at the outset—why normal individuals have natural IgM autoantibodies and whether the same natural antibodies that defend against microbial inflections and heal damaged cells also cause disease. The most immediate danger infection and tissue injury pose are dissemination of microorganisms and uncontrolled necrosis (releasing C3b, thrombin, and cytokines). Both can trigger the systemic inflammatory response syndrome and multiorgan failure. The cellular elements of innate immunity circumscribe infection and necrosis by recognizing the products of damaged cells, particularly endothelial cells, and provoking endothelial-cell activation, hemostasis, coagulation, vasoconstriction, and so on. The humoral elements of innate immunity, particularly natural antibodies and complement, probably do likewise. And there
Kidney International (2015) 88
is a physiological reason for recognition of damaged cells. Neither inflammatory receptors nor natural antibodies can recognize all of the organisms, toxins, and so on that pose threats, but, as Panzer and colleagues show, natural antibodies can recognize damaged cells and their products, and such selfrecognition may circumscribe damaged tissue, providing the time needed for an elicited immune response to ensue. Natural antibodies might also facilitate healing of damaged cells. The repair of cell membranes wounded by physical injury and pore-forming proteins can require binding of annexins to acidic moieties in the inner membrane and clustering in such a way that surface tension decreases and the wounded membrane is removed.7 Recognition of acidic moieties on damaged cell surfaces by polymeric natural IgM should have the same impact. However, other natural antibodies recognize basic proteins such as annexins and the binding of these natural antibodies to ischemic tissues worsens injury.8 Why then do we have these antibodies that promote and inhibit repair? If these antibodies inhibit the anticoagulant function of annexins, they might help sequester microorganisms and the contents of cells damaged beyond repair, at the expense of local tissue injury. But can natural antibodies with the same specificity incite injury and protection and repair? Panzer and colleagues provide an exciting hint. Panzer et al.5 clearly show that in factor H-deficient mice natural antibodies cause glomerular damage that progresses over 6 months, the proof being drawn from comparison of this course with the milder non-progressive course of glomerular disease in factor H-deficient mice lacking B cells. However, if the course of kidney disease in factor H-deficient mice is more severe in mice that produce natural antibodies, it is strikingly mild when compared with the immediate and devastating course of kidney disease in recipients of ABO-incompatible allografts and xenografts. These differences are yet
more striking if one considers that complement regulation is normal in ABO-incompatible transplantation (it is abnormal in xenotransplantation). Various explanations for these differences come to mind, but one we find appealing is that in factor H-deficient mice, antibodies and complement induce ‘accommodation,’9 that is, acquired resistance of the kidneys and other organs to complement-mediated injury. Accommodation is seen archetypically when natural antibodies are depleted before an incompatible transplant is performed and then allowed slowly to return. If the kidneys of factor H-deficient mice are accommodated, as we suspect, the extent of damage inflicted by IgM and complement exceeds the capacity for repair. But in the absence of accommodation things could be far worse. DISCLOSURE
The authors declared no competing interests. REFERENCES 1.
2.
3.
4.
5.
6.
7.
8.
9.
Boes M, Prodeus AP, Schmidt T et al. A critical role of natural immunoglobulin M in immediate defense against systemic bacterial infection. J Exp Med 1998; 188: 2381–2386. Gronwall C, Silverman GJ. Natural IgM: beneficial autoantibodies for the control of inflammatory and autoimmune disease. J Clin Immunol 2014; 34(Suppl 1): S12–S21. Wootla B, Watzlawik JO, Denic A et al. The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment. Exp Rev Clin Immunol 2013; 9: 535–549. Weiser MR, Williams JP, Moore FDJ et al. Reperfusion injury of ischemic skeletal muscle is mediated by natural antibody and complement. J Exp Med 1996; 183: 2343–2348. Panzer SE, Laskowski J, Renner B et al. IgM exacerbates glomerular disease progression in complement-induced glomerulopathy. Kidney Int 2015; 88: 528–537. Strassheim D, Renner B, Panzer S et al. IgM contributes to glomerular injury in FSGS. J Am Soc Nephrol 2013; 24: 393–406. Potez S, Luginbuhl M, Monastyrskaya K et al. Tailored protection against plasmalemmal injury by annexins with different Ca2+ sensitivities. J Biol Chem 2011; 286: 17982–17991. Kulik L, Fleming SD, Moratz C et al. Pathogenic natural antibodies recognizing annexin IV are required to develop intestinal ischemia-reperfusion injury. J Immunol 2009; 182: 5363–5373. Cascalho MI, Chen BJ, Kain M et al. The paradoxical functions of B cells and antibodies in transplantation. J Immunol 2013; 190: 875–879.
441