Future Perspectives on Pathogenesis of Lupus Nephritis
2016; Elsevier BV; Volume: 186; Issue: 11 Linguagem: Inglês
10.1016/j.ajpath.2016.06.026
ISSN1525-2191
AutoresOle Petter Rekvig, Dhivya Thiyagarajan, Hege Lynum Pedersen, Kjersti Daae Horvei, Natalya Seredkina,
Tópico(s)Atherosclerosis and Cardiovascular Diseases
ResumoDivergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti–double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed. Divergent incommensurable models have been developed to explain the pathogenesis of lupus nephritis. Most contemporary models favor a central role for anti-chromatin antibodies. How they exert their pathogenic effect has, however, endorsed conflicts that at least for now preclude insight into definitive pathogenic pathways. The following paradigms are contemporarily in conflict with each other: i) the impact of anti–double-stranded DNA (dsDNA) antibodies that cross-react with inherent renal antigens, ii) the impact of anti-dsDNA antibodies targeting exposed chromatin in glomeruli, and iii) the impact of relative antibody avidity for dsDNA, chromatin fragments, or cross-reacting antigens. Aside from these three themes, the pathogenic role of T cells in lupus nephritis is not clear. These different models should be tested through a collaboration between scientists belonging to the different paradigms. If it turns out that there are different pathogenic pathways in lupus nephritis, the emerging pathogenic mechanism(s) may be encountered with new individual causal therapy modalities. Today, therapy is still unspecific and far from interfering with the cause(s) of the disorder. This review attempts to describe what we know about processes that may cause lupus nephritis and how such basic processes may be affected if we can specifically interrupt them. Secondary inflammatory mechanisms, cytokine signatures, activation of complement, and other contributors to inflammation will not be discussed herein; rather, the events that trigger these factors will be discussed. Lupus nephritis represents the arrowhead among pathogenic manifestations in systemic lupus erythematosus (SLE),1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 2van Bavel C.C. van der Vlag J. Berden J.H. Glomerular binding of anti-dsDNA autoantibodies: the dispute resolved?.Kidney Int. 2007; 71: 600-601Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 3Weening J.J. D'agati V.D. Schwartz M.M. Seshan S.V. Alpers C.E. Appel G.B. Balow J.E. Bruijn J.A. Cook T. Ferrario F. Fogo A.B. Ginzler E.M. Hebert L. Hill G. Hill P. Jennette J.C. Kong N.C. Lesavre P. Lockshin M. Looi L.M. Makino H. Moura L.A. Nagata M. The classification of glomerulonephritis in systemic lupus erythematosus revisited.J Am Soc Nephrol. 2004; 15: 241-250Crossref PubMed Scopus (1462) Google Scholar, 4Berden J.H. Lupus nephritis.Kidney Int. 1997; 52: 538-558Abstract Full Text PDF PubMed Scopus (199) Google Scholar because it is dangerous, but also because it is scientifically challenging to comprehend its nature.1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 5Lorenz G. Desai J. Anders H.J. Lupus nephritis: update on mechanisms of systemic autoimmunity and kidney immunopathology.Curr Opin Nephrol Hypertens. 2014; 23: 211-217Crossref PubMed Scopus (32) Google Scholar, 6Marion T.N. Postlethwaite A.E. Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus.Semin Immunopathol. 2014; 36: 495-517Crossref PubMed Scopus (38) Google Scholar, 7Goilav B. Putterman C. The role of anti-DNA antibodies in the development of lupus nephritis: an alternative, or complementary, viewpoint?.Semin Nephrol. 2015; 35: 439-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar This situation prevents us from developing therapy strategies that attack the basic pathogenic processes beyond today's therapy regimens.8Anders H.J. Jayne D.R. Rovin B.H. Hurdles to the introduction of new therapies for immune-mediated kidney diseases.Nat Rev Nephrol. 2016; 12: 205-216Crossref PubMed Scopus (38) Google Scholar, 9Mok C.C. Treat-to-target in systemic lupus erythematosus: are we there yet?.Expert Rev Clin Pharmacol. 2016; 9: 675-680Crossref PubMed Scopus (10) Google Scholar, 10Mok C.C. Towards new avenues in the management of lupus glomerulonephritis.Nat Rev Rheumatol. 2016; 12: 221-234Crossref PubMed Scopus (54) Google Scholar In the upcoming sections, contemporary status of the pathogenesis of SLE and lupus nephritis will be reviewed and discussed, and new causal therapy modalities will be suggested. One central element when we discuss pathogenic processes in SLE is antibodies to double-stranded DNA (dsDNA) and chromatin structures. Anti-DNA antibodies were, however, first described in 1938 to 1939 in patients with infections,11Menzel A.E.O. Heidelberger M. Cell protein fractions of bovine and avian tubercle bacillus strains and of the timothy-grass bacillus.J Biol Chem. 1938; 124: 301-307Google Scholar, 12Sevag M.G. Lackman D.B. Smolen J. The isolation of the components of streptococcal nucleoproteins in serologically active form.J Biol Chem. 1938; 124: 425-436Google Scholar, 13Winkenwerder W.L. Buell M.V. Howard J.E. The sensitizing properties of the nucleic acids and their derivatives.Science. 1939; 90: 356Crossref PubMed Scopus (8) Google Scholar, 14Heidelberger M. Scherp H.W. Protein fractions of a strain of Group "A" hemolytic streptococci.J Immunol. 1939; 37: 563-570Google Scholar as reviewed by Rekvig.15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar Approximately two decades later, they were described in the autoimmune syndrome SLE.16Ceppellini R. Polli E. Celada F. A DNA-reacting factor in serum of a patient with lupus erythematosus diffusus.Proc Soc Exp Biol Med. 1957; 96: 572-574Crossref PubMed Scopus (155) Google Scholar, 17Robbins W.C. Holman H.R. Deicher H. Kunkel H.G. Complement fixation with cell nuclei and DNA in lupus erythematosus.Proc Soc Exp Biol Med. 1957; 96: 575-579Crossref PubMed Scopus (159) Google Scholar, 18Miescher P. Strassle R. New serological methods for the detection of the L.E. factor.Vox Sang. 1957; 2: 283-287Crossref PubMed Scopus (67) Google Scholar, 19Seligman M. Serology-evidence in serum from patients with disseminated lupus erythermatosus of a substance determining a precipitation reaction with desoxyribonucleic acid.C R Hebd Seances Acad Sci. 1957; 245: 243-245PubMed Google Scholar Since then, their role in SLE, rather than in infections and malignancies,15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar has been extensively studied in two contexts: diagnostics and pathogenicity.15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar However, the pathogenesis of SLE is still poorly understood,20Rahman A. Isenberg D.A. Systemic lupus erythematosus.N Engl J Med. 2008; 358: 929-939Crossref PubMed Scopus (1449) Google Scholar, 21Rekvig O.P. van der Vlag J. The pathogenesis and diagnosis of systemic lupus erythematosus: still not resolved.Semin Immunopathol. 2014; 36: 301-311Crossref PubMed Scopus (61) Google Scholar and may even remain unclear because SLE, as classified today, is not linked to any unifying origin or pathogenic process. In fact, if we use the 1982 American College of Rheumatology classification criteria,22Tan E.M. Cohen A.S. Fries J.F. Masi A.T. McShane D.J. Rothfield N.F. Schaller J.G. Talal N. Winchester R.J. The 1982 revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1982; 25: 1271-1277Crossref PubMed Scopus (12517) Google Scholar and classify SLE by randomly selecting 4 of these 11 defined American College of Rheumatology criteria (a minimum requirement to classify a disease as SLE, according to Tan et al22Tan E.M. Cohen A.S. Fries J.F. Masi A.T. McShane D.J. Rothfield N.F. Schaller J.G. Talal N. Winchester R.J. The 1982 revised criteria for the classification of systemic lupus erythematosus.Arthritis Rheum. 1982; 25: 1271-1277Crossref PubMed Scopus (12517) Google Scholar), theoretically 330 different clinical phenotypes embrace the term SLE. Does this mean that we, in fact, are dealing with a pile of unrelated disorders and manifestations that today is called SLE—and can we define biomarkers for SLE on this basis? Recently, Pisetsky23Pisetsky D.S. Anti-DNA antibodies: quintessential biomarkers of SLE.Nat Rev Rheumatol. 2016; 12: 102-110Crossref PubMed Scopus (159) Google Scholar characterized anti-dsDNA antibodies as quintessential biomarkers for SLE. In light of the heterogenic image of SLE, and also because anti-dsDNA antibodies occur at various frequencies in different forms of cancers24Bei R. Masuelli L. Palumbo C. Modesti M. Modesti A. A common repertoire of autoantibodies is shared by cancer and autoimmune disease patients: inflammation in their induction and impact on tumor growth.Cancer Lett. 2009; 281: 8-23Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar, 25Cao Q. Xu W. Wen Z. Xu L. Li K. Chu Y. Xiong S. An anti-double-stranded DNA monoclonal antibody induced by tumor cell-derived DNA inhibits the growth of tumor in vitro and in vivo via triggering apoptosis.DNA Cell Biol. 2008; 27: 91-100Crossref PubMed Scopus (9) Google Scholar and infections,15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar the statement that anti-dsDNA antibodies serve as a quintessential biomarker for SLE is difficult to comprehend. In fact, the first successful experiments that resulted in induction of anti-mammalian B helical (dsDNA) were performed by immunizing mice with dsDNA/chromatin fragments in complex with a peptide from Trypanosoma cruzii (Fus 126Desai D.D. Krishnan M.R. Swindle J.T. Marion T.N. Antigen-specific induction of antibodies against native mammalian DNA in nonautoimmune mice.J Immunol. 1993; 151: 1614-1626PubMed Google Scholar), or with a complex of polyomavirus T antigen and dsDNA/chromatin fragments (Figure 1A). The experimental details for this model have been described previously.27Moens U. Seternes O.M. Hey A.W. Silsand Y. Traavik T. Johansen B. Rekvig O.P. In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones.Proc Natl Acad Sci U S A. 1995; 92: 12393-12397Crossref PubMed Scopus (95) Google Scholar, 28Rekvig O.P. Moens U. Sundsfjord A. Bredholt G. Osei A. Haaheim H. Traavik T. Arnesen E. Haga H.J. Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen: a molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.J Clin Invest. 1997; 99: 2045-2054Crossref PubMed Scopus (104) Google Scholar In this experimental context, it is worthwhile to remember that the first discovery of anti-dsDNA antibodies in a natural context was achieved in sera from patients with bacterial infections six decades before the successful immunization experiments with complexes of mammalian chromatin and infectious-derived peptides,11Menzel A.E.O. Heidelberger M. Cell protein fractions of bovine and avian tubercle bacillus strains and of the timothy-grass bacillus.J Biol Chem. 1938; 124: 301-307Google Scholar, 12Sevag M.G. Lackman D.B. Smolen J. The isolation of the components of streptococcal nucleoproteins in serologically active form.J Biol Chem. 1938; 124: 425-436Google Scholar, 13Winkenwerder W.L. Buell M.V. Howard J.E. The sensitizing properties of the nucleic acids and their derivatives.Science. 1939; 90: 356Crossref PubMed Scopus (8) Google Scholar, 14Heidelberger M. Scherp H.W. Protein fractions of a strain of Group "A" hemolytic streptococci.J Immunol. 1939; 37: 563-570Google Scholar and also two decades before their discovery in SLE.15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar Later, data demonstrating that pure chromatin fragments by themselves have the potential to induce diverse antibodies to chromatin have been demonstrated. These may represent antibodies to dsDNA, histones, non-histones, and complex determinants. The cellular processes responsible for these responses are, however, still poorly understood,15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar although they are assumed to be based on a T-cell–dependent immune response, as indicated in Figure 1B. The recent Systemic Lupus International Collaborating Clinics criteria did not solve this problem.29Petri M. Orbai A.M. Alarcon G.S. Gordon C. Merrill J.T. Fortin P.R. et al.Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.Arthritis Rheum. 2012; 64: 2677-2686Crossref PubMed Scopus (1) Google Scholar Experts on SLE implemented clinical and laboratory parameters based on their individual insight, experience, clinical data, and intuition.29Petri M. Orbai A.M. Alarcon G.S. Gordon C. Merrill J.T. Fortin P.R. et al.Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus.Arthritis Rheum. 2012; 64: 2677-2686Crossref PubMed Scopus (1) Google Scholar These criteria therefore represent empirical, rather than scientific, approaches to understand SLE. From this, we cannot deduce the pathogenesis of lupus nephritis from the indistinct and poorly described pathogenesis of SLE per se. If lupus nephritis is one distinct disorder or not is presently unclear, and is discussed below. Theoretically, the approach to study the basic disease pathogenesis of lupus nephritis has a greater probability to succeed than to perform similar studies on the syndrome SLE. However, there is currently no obvious reason to be optimistic because incommensurable models and contradicting data yet preclude international consensus. It is imperative to initiate new collaborations across the different models and paradigms to prepare consensus study protocols to solve the problem whether lupus nephritis is one disease entity with a dominant pathogenesis, or whether different pathogeneses are based on different incommensurable hypotheses, as indicated in Figure 2. The contemporary models of lupus nephritis are dependent on scientific interpretations of experimental data that emerge from different hypotheses. For each hypothesis, study protocols are selected and tailored to optimally analyze the validity of hypotheses. A theoretical model of these conflicting hypotheses and data sets is shown in Figure 2. The emerging concepts and models developed from divergent hypotheses are clearly visible in the conflicting interpretations of the pathogenesis, as described by one set of researchers6Marion T.N. Postlethwaite A.E. Chance, genetics, and the heterogeneity of disease and pathogenesis in systemic lupus erythematosus.Semin Immunopathol. 2014; 36: 495-517Crossref PubMed Scopus (38) Google Scholar, 7Goilav B. Putterman C. The role of anti-DNA antibodies in the development of lupus nephritis: an alternative, or complementary, viewpoint?.Semin Nephrol. 2015; 35: 439-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar versus another set of researchers.1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 2van Bavel C.C. van der Vlag J. Berden J.H. Glomerular binding of anti-dsDNA autoantibodies: the dispute resolved?.Kidney Int. 2007; 71: 600-601Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar, 30van Bavel C.C. Fenton K.A. Rekvig O.P. van der Vlag J. Berden J.H. Glomerular targets of nephritogenic autoantibodies in systemic lupus erythematosus.Arthritis Rheum. 2008; 58: 1892-1899Crossref PubMed Scopus (67) Google Scholar The following discussion has one perspective: to define lupus nephritis pathogenesis and key points for specific, causal therapy strategies. There are no unifying concepts available to explain lupus nephritis as it appears in murine models or in humans with SLE. Some recently reviewed concepts1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 7Goilav B. Putterman C. The role of anti-DNA antibodies in the development of lupus nephritis: an alternative, or complementary, viewpoint?.Semin Nephrol. 2015; 35: 439-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar claim that anti-dsDNA antibodies are pathogenic because they recognize exposed chromatin in the mesangium or in glomerular basement membrane (Figure 3A). Others indicate that antibodies target cross-reacting antigens that appear as normal constituents in glomeruli1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar (Figure 3B), or that chromatin-IgG complexes derive from circulation.31Adu D. Dobson J. Williams D.G. DNA-anti-DNA circulating complexes in the nephritis of systemic lupus erythematosus.Clin Exp Immunol. 1981; 43: 605-614PubMed Google Scholar, 32Fenton K.A. Tommeras B. Marion T.N. Rekvig O.P. Pure anti-dsDNA mAbs need chromatin structures to promote glomerular mesangial deposits in BALB/c mice.Autoimmunity. 2010; 43: 179-188Crossref PubMed Scopus (37) Google Scholar, 33Ehrenstein M.R. Katz D.R. Griffiths M.H. Papadaki L. Winkler T.H. Kalden J.R. Isenberg D.A. Human IgG anti-DNA antibodies deposit in kidneys and induce proteinuria in SCID mice.Kidney Int. 1995; 48: 705-711Abstract Full Text PDF PubMed Scopus (179) Google Scholar These models may be valid irrespective of whether the antibodies are induced by chromatin fragments (Figure 3, A and B) or by a cross-reactive antigen (Figure 3C). In the first model, we need to know the role of the dominant renal endonuclease DNase I in lupus nephritis because renal DNase I is almost completely lost during disease progression.1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 34Fenton K. Fismen S. Hedberg A. Seredkina N. Fenton C. Mortensen E.S. Rekvig O.P. Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice.PLoS One. 2009; 4: e8474Crossref PubMed Scopus (86) Google Scholar, 35Seredkina N. Rekvig O.P. Acquired loss of renal nuclease activity is restricted to DNaseI and is an organ-selective feature in murine lupus nephritis.Am J Pathol. 2011; 179: 1120-1128Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar This seems to reduce clearance of chromatin from dead cells, and to promote harmful accumulation of undigested chromatin in glomeruli, which are targeted by chromatin-reactive IgG antibodies, either in situ or in circulation.1Seredkina N. van der Vlag J. Berden J. Mortensen E. Rekvig O.P. Lupus nephritis: enigmas, conflicting models and an emerging concept.Mol Med. 2013; 19: 161-169Crossref PubMed Scopus (44) Google Scholar, 34Fenton K. Fismen S. Hedberg A. Seredkina N. Fenton C. Mortensen E.S. Rekvig O.P. Anti-dsDNA antibodies promote initiation, and acquired loss of renal Dnase1 promotes progression of lupus nephritis in autoimmune (NZBxNZW)F1 mice.PLoS One. 2009; 4: e8474Crossref PubMed Scopus (86) Google Scholar, 35Seredkina N. Rekvig O.P. Acquired loss of renal nuclease activity is restricted to DNaseI and is an organ-selective feature in murine lupus nephritis.Am J Pathol. 2011; 179: 1120-1128Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar In the second model, we need not to worry about extracellular chromatin and renal chromatin metabolism, because the antibodies are claimed to bind inherent renal structures. In several studies,7Goilav B. Putterman C. The role of anti-DNA antibodies in the development of lupus nephritis: an alternative, or complementary, viewpoint?.Semin Nephrol. 2015; 35: 439-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 36Sabbaga J. Pankewycz O.G. Lufft V. Schwartz R.S. Madaio M.P. Cross-reactivity distinguishes serum and nephritogenic anti-DNA antibodies in human lupus from their natural counterparts in normal serum.J Autoimmun. 1990; 3: 215-235Crossref PubMed Scopus (63) Google Scholar, 37Xie C. Liang Z. Chang S. Mohan C. Use of a novel elution regimen reveals the dominance of polyreactive antinuclear autoantibodies in lupus kidneys.Arthritis Rheum. 2003; 48: 2343-2352Crossref PubMed Scopus (54) Google Scholar, 38Kalaaji M. Sturfelt G. Mjelle J.E. Nossent H. Rekvig O.P. Critical comparative analyses of anti-alpha-actinin and glomerulus-bound antibodies in human and murine lupus nephritis.Arthritis Rheum. 2006; 54: 914-926Crossref PubMed Scopus (81) Google Scholar antibodies have been eluted from nephritic kidneys, and the relative amount of anti-dsDNA antibodies has been calculated to comprise up to 20% of the total eluted IgG.39Mannik M. Merrill C.E. Stamps L.D. Wener M.H. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus.J Rheumatol. 2003; 30: 1495-1504PubMed Google Scholar This may indicate that dominant amounts of IgG bind non-dsDNA antigens, like inherent renal antigens, or antigens released from resident cells.7Goilav B. Putterman C. The role of anti-DNA antibodies in the development of lupus nephritis: an alternative, or complementary, viewpoint?.Semin Nephrol. 2015; 35: 439-443Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 38Kalaaji M. Sturfelt G. Mjelle J.E. Nossent H. Rekvig O.P. Critical comparative analyses of anti-alpha-actinin and glomerulus-bound antibodies in human and murine lupus nephritis.Arthritis Rheum. 2006; 54: 914-926Crossref PubMed Scopus (81) Google Scholar, 39Mannik M. Merrill C.E. Stamps L.D. Wener M.H. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus.J Rheumatol. 2003; 30: 1495-1504PubMed Google Scholar, 40Krishnan M.R. Wang C. Marion T.N. Anti-DNA autoantibodies initiate experimental lupus nephritis by binding directly to the glomerular basement membrane in mice.Kidney Int. 2012; 82: 184-192Abstract Full Text Full Text PDF PubMed Scopus (101) Google Scholar A sound basis to discuss these assumptions and observations derives from an article published by Craft and Hardin41Craft J.E. Hardin J.A. Linked sets of antinuclear antibodies: what do they mean?.J Rheumatol Suppl. 1987; 14 Suppl 13: 106-109PubMed Google Scholar in 1987: "Linked sets of antinuclear antibodies: what do they mean?" The meaning could be that complex structures, like chromatin, simultaneously stimulate B cells specific for individual components or complex structures presented by chromatin fragments. This would explain linked production of potentially large arrays of anti-chromatin antibodies other than those uniquely specific for dsDNA15Rekvig O.P. The anti-DNA antibody: origin and impact, dogmas and controversies.Nat Rev Rheumatol. 2015; 11: 530-540Crossref PubMed Scopus (56) Google Scholar (Figure 1). This idea was tested in our laboratory by injecting plasmids expressing the chromatin-binding polyomavirus BK large T antigen.27Moens U. Seternes O.M. Hey A.W. Silsand Y. Traavik T. Johansen B. Rekvig O.P. In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones.Proc Natl Acad Sci U S A. 1995; 92: 12393-12397Crossref PubMed Scopus (95) Google Scholar, 28Rekvig O.P. Moens U. Sundsfjord A. Bredholt G. Osei A. Haaheim H. Traavik T. Arnesen E. Haga H.J. Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen: a molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.J Clin Invest. 1997; 99: 2045-2054Crossref PubMed Scopus (104) Google Scholar Our prediction was that expressed T antigen bound host cell chromatin, and that chromatin–T antigen complexes were released from dying cells. Subsequently, they could stimulate a large repertoire of chromatin-specific B cells, and T-antigen peptide-specific T helper cells.27Moens U. Seternes O.M. Hey A.W. Silsand Y. Traavik T. Johansen B. Rekvig O.P. In vivo expression of a single viral DNA-binding protein generates systemic lupus erythematosus-related autoimmunity to double-stranded DNA and histones.Proc Natl Acad Sci U S A. 1995; 92: 12393-12397Crossref PubMed Scopus (95) Google Scholar, 28Rekvig O.P. Moens U. Sundsfjord A. Bredholt G. Osei A. Haaheim H. Traavik T. Arnesen E. Haga H.J. Experimental expression in mice and spontaneous expression in human SLE of polyomavirus T-antigen: a molecular basis for induction of antibodies to DNA and eukaryotic transcription factors.J Clin Invest. 1997; 99: 2045-2054Crossref PubMed Scopus (104) Google Scholar The prediction was correct, as plasmid-injected mice simultaneously produced various antibodies to DNA, histones, and transcription factors in addition to T antigen in a timely linked manner (Figure 1A). This model is not fully dependent on non–self-proteins to activate non-tolerant T helper cell. As indicated in Figure 1B, true autoimmune T helper cells (herein specific for histone peptides in the context of human leukocyte antigen II molecules) provide the same effect as T-antigen–specific T helper cells described above, which again may explain a simultaneous production of various anti-chromatin antibodies. This indicates that among the IgG eluted from nephritic kidneys, some bind dsDNA39Mannik M. Merrill C.E. Stamps L.D. Wener M.H. Multiple autoantibodies form the glomerular immune deposits in patients with systemic lupus erythematosus.J Rheumatol. 2003; 30: 1495-1504PubMed Google Scholar but also that an (yet undetermined) amount of eluted IgG may bind other components of chromatin that are not tested for in the referred studies (Figure 3). Therefore, low proportions of eluted anti-dsDNA antibodies can theoretically not represent an argument for a dominant presence of non–chromatin-specific cross-reactive IgG antibodies. However, if some of these antibodies really are cross-reacting, this does not inform about the potential target antigens that really bound the antibodies in vivo (see below for further discussion of this problem). Two models have been developed that might explain the nephritogenic effect of anti-dsDNA antibodies. These are discussed in detail below. Clearance capacity of apoptotic cells is claimed to be reduced in SLE.42Biermann M.H. Veissi S. Maueroder C. Chaurio R. Berens C. Herrmann M. Munoz L.E. The role of dead cell clearance in the etiology and pathogenesis of systemic lupus erythematosus: dendritic cells as potential targets.Expert Rev Clin Immunol. 2014; 10: 1151-1164Crossref PubMed Scopus (61) Google Scholar, 43Gaipl U.S. Voll R.E. Sheriff A. Franz S. Kalden J.R. Herrmann M. Impaired clearance of dying cells in systemic lupus erythematosus.Autoimmun Rev. 2005; 4: 189-194Crossref PubMed Scopus (179) Google Scholar, 44Licht R. Dieker J.W. Jacobs C.W. Tax W.J. Berden J.H. Decreased phagocytosis of apoptotic cells in diseased SLE mice.J Autoimmun. 2004; 22: 139-145Crossref PubMed Scopus (100) Google Scholar This is assumed to be harmful because chromatin is not cleared, but instead chromatin fragments, consisting of the basic nucleosome structure and a vast amount of non-histone proteins and RNA molecules,45van Steensel B. Chromatin: constructing the big picture.EMB
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