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Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms
AUTREV-01638; No of Pages 3 Autoimmunity Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms Konstantin N. Konstantinov a,⁎, Constance J. Ulff-Møller b, Antonios H. Tzamaloukas c a
Division of Rheumatology, Department of Internal Medicine, University of New Mexico School of Medicine Health Sciences Center, Mail Stop MSC10-5550, Albuquerque, NM 87131, USA Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, University Hospital, Blegdamsvej 9, DK-2100 Denmark Section of Nephrology, Raymond G. Murphy Veterans Affairs Medical Center and University of New Mexico School of Medicine, Renal Section, VA Medical Center, 1501 San Pedro, SE, Albuquerque, NM 87108, USA
b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 13 October 2014 Accepted 21 October 2014 Available online xxxx
The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infectiontriggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self-antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions. © 2014 Published by Elsevier B.V.
Contents 1. Introduction . . . . . . . . 2. Autoantigen complementarity 3. Molecular mimicry . . . . . 4. Epigenetics . . . . . . . . . 5. NETosis . . . . . . . . . . 6. Toll-like receptors . . . . . . 7. Conclusions . . . . . . . . . Take-home messages . . . . . . References . . . . . . . . . . .
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1. Introduction The association between infections, formation of antineutrophil cytoplasmic antibodies (ANCA) and ANCA-mediated disease has been known for decades [1,2]. Both experimental [3] and epidemiological [4] studies have provided strong supportive evidence to the concept
⁎ Corresponding author. E-mail addresses: [email protected] (K.N. Konstantinov), [email protected] (C.J. Ulff-Møller), [email protected] (A.H. Tzamaloukas).
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that infections may trigger exacerbations of ANCA-mediated disease and may even be the main pathogenetic mechanism of ANCA formation. ANCA formation has been reported during the course of various chronic infections of viral, bacterial, fungal, protozoal, and multicellular parasitic etiology (Table 1). ANCA-mediated disease has been observed in the course of various infections [5]. Research efforts have been directed towards elucidation of the mechanisms by which infection triggers ANCA formation. The purpose of this report is to review recent developments in these mechanisms. We will discuss recently described mechanisms of ANCA formation in infectious episodes, including autoantigen complementarity, molecular mimicry, epigenetics, NETosis, and Toll-like receptors.
http://dx.doi.org/10.1016/j.autrev.2014.10.020 1568-9972/© 2014 Published by Elsevier B.V.
Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020
2
K.N. Konstantinov et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Table 1 Infections associated with ANCA formation. Viruses
Bacteria
Fungi
Protozoa
Multicellular organisms
HIV
Streptococcus
Aspergillus
Hepatitis B virus Hepatitis C virus Parvovirus B-19 Epstein-Barr virus Arbovirus Ross river virus
Staphylococcus Enterococcus Bartonella Gemella
Histoplasma Sporothrix Pneumocystis Paracoccidioides
Entamoeba Echinococcus histolytica Plasmodium Strongyloides Leishmania Toxocara
Propionibacterium Saccharomyces Neisseria Actinobacillus Pseudomonas Escherichia Bacteroides Campylobacter Helicobacter Yersinia Salmonella Proteus Corynebacterium Stenotrophomonas Klebsiella Mycoplasma Chlamydia Ricketsia Treponema Leptospira Mycobacterium
Modified with permission from: Konstantinov KN et al. Glomerular disease in patients with infectious processes developing antineutrophil cytoplasmic antibodies. ISRN Nephrology 2013; Article ID 324315. HIV = human immunodeficiency virus.
2. Autoantigen complementarity Autoantigen complementarity has been suggested as one of the mechanisms that can break tolerance to ANCA antigens [6,7]. According to this hypothesis, the initial immune response in patients with ANCAassociated vasculitis (AAV) is not directed toward the autoantigen but rather to a peptide that is complementary to the autoantigen epitope. Such complementary peptide pairs have structural and chemical characteristics that allow them to bind together [8]. The complementary peptide immunogen, which is a mirror of the original protein, could arise from antisense transcription of the autoantigen gene or exist as microbial exogenous peptide that mimics the complementary antisense peptide. Antibodies to a complementary protein may induce anti-idiotypic antibodies that cross-react with the original protein [9]. Indeed, some patients with PR3-ANCA-associated vasculitis (AAV) have been found to have not only antibodies against PR3 peptides (anti-PR3) but also antibodies against anti-sense peptides that are complementary to the autoantigen epitopes on PR3 (cPR3 peptide). In an attempt to validate the autoantigen complementarity hypothesis, Pendergraft et al. [6] immunized mice with cPR3. These mice indeed developed antibodies to both cPR3 and PR3. Interestingly, several pathogens, known to be associated with PR3-ANCA such as Staphylococcus aureus, Entamoeba histolytica, and Ross River virus, have peptides homologous to cPR3 and infection by these microorganisms may trigger an autoantibody response. [6]. In addition, circulating anti-cPR3 CD4+ Th1 memory T cells were detected in PR3-ANCA positive patients, but not in MPO + -ANCA positive patients [10]. The HLA-DRB1(*)1501 allele found in African Americans with PR3ANCA encodes an MHC class II receptor that binds sense and cPR3 [11]. It has been suggested that complementary peptides to PR3 could be beneficial to pathogens expressing cPR3 by binding to and neutralizing the antimicrobial properties of PR3 and MPO [12]. One example of a specific clinical manifestation caused by autoantigen complementarity is
vascular thrombotic episodes in AAV. It has been shown that the endogenous protein plasminogen is one of the proteins complementary to the middle portion of PR3 and patients with cross-reacting antibodies to cPR3 ANCA and plasminogen have suppressed fibrinolysis and increased risk for thrombosis [13]. 3. Molecular mimicry It has been theorized that similarities between antibodies to pathogens and epitopes of self-antigens may lead to cross-reactivity and mounting an autoimmune response. Such molecular mimicry may also be the primary mechanism in the development of focal necrotizing glomerulonephritis in patients with ANCA directed against human lysosome-associated membrane protein-2 (LAMP-2) during active disease. LAMP-2 is a heavily glycosylated type 1 membrane protein expressed on the membrane of neutrophil intracellular vesicles that contain PR3 and MPO [14]. LAMP-2 can shuttle between cytoplasm and cell surface of resting neutrophils and endothelial cells; while surface LAMP-2 has a role in cell adhesion, the intracellular LAMP-2 is important for antigen presentation and autophagy [15]. The evidence for pathogenicity of anti-LAMP-2 is convincing, as injection of the antibody into rats causes kidney pathology and apoptosis in microvascular endothelium identical to the lesions observed in humans with ANCA-mediated disease [16]. Interestingly, anti-LAMP-2 ANCA cross react with the adhesive bacterial fimbrial protein FimH, which is found in many Gram-negative bacteria such as Escherichia coli, Klebsiella pneumonia, and Proteus mirabilis and mice immunized with FimH develop ANCA anti-LAMP-2 reactivity [16]. Hypothetically, anti-LAMP-2 autoantibodies could result from molecular mimicry following infection with Gram-negative organisms producing FimH [17]. The autonomy of LAMP-2 autoantibody response in AAV is suggested by the observation that LAMP-2 autoantibodies have been detected and correlated with active vasculitis in MPO and PR3 ANCA-negative patients [18]. 4. Epigenetics Epigenetics refers to stable and somatically heritable changes in gene expression that do not alter the DNA sequence but are reversible and may thus be influenced by environmental factors. Previous studies indicate that pathogenic bacteria and infections may induce changes in the epigenetic information of host organisms, such as histone modifications, DNA methylation changes, and miRNA [19]. A recent study in humans with ANCA vasculitis showed depletion of the histone modification H3K27me3 in leucocytes, leading to increased expression of PR3 and MPO, which was directly correlated to disease activity [20]. This finding, which suggests disrupted epigenetic silencing, has not been linked specifically to infections so far. Although the area remains relatively unexplored, it might lend support to the autoantigen complementarity hypothesis if infection-induced epigenetic synthesis induces the production of complementary proteins through dysregulated expression of anti-sense transcripts [21]. However, further research is needed to test this hypothesis. 5. NETosis Neutrophil extracellular traps (NETs) are a recently described mechanism that is important for control of bacterial infections. NETs formation characterizes a unique type of neutrophil-related cell death named NETosis, which leads to production in neutrophils of a meshwork of chromatin fibers associated with citrullinated histone H3 and antimicrobial proteins, including MPO and PR3. This meshwork forms extracellular nets that trap and kill microbial pathogens [22]. NET-inducing factors are dependent on respiratory burst of neutrophils and include, among others, bacteria such as Staphylococcus, Streptococcus, and Enterococcus, M1 protein, and lipopolysaccharides [23].
Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020
K.N. Konstantinov et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
The contact between primed neutrophils and ANCA IgG can also induce formation of NETs that stick to the endothelium and cause tissue damage [24]. PR3 and elastase containing NETs have been detected in affected human glomeruli [24]. Based on these observations, it has been hypothesized that ANCA IgG may perpetuate a vicious circle of NETs production, which breaks down tolerance by maintaining the delivery of protein-chromatin complexes to the immune system, while the propensity of neutrophils to form NETs is further enhanced by bacterial infection, known to induce NETs and linked to relapses during flares [25]. Use of DNase-1 in small vessel vasculitis not only caused inhibition of NET formation, but also prevented vessel inflammation [26]. 6. Toll-like receptors The discovery of the microbial-sensing proteins called Toll-like receptors (TLRs) transformed our understanding of the body's response to infection. Members of this family are pattern recognition receptors (PRR) that can sense highly conserved structural motifs, which are broadly shared by pathogens, and known as pathogen-associated molecular patterns (PAMPs) [27]. Examples of PAMPs include various bacterial cell wall components and bacterial DNA. TLRs are expressed by different cell types including monocytes, B lymphocytes, granulocytes, and epithelial and endothelial cells. Ligation of TLRs with PAMPs results in release of proinflammatory cytokines, type-1 interferon, antimicrobial peptides, and effector cytokines that direct the adaptive immune response. Recent studies on the expression of TLRs in patients with AAV may provide a susceptibility link between infection and AAV. In their study Tadema et al. [28] demonstrated increased expression of TLRs by monocytes and natural killer cells of patients with AAV. The same group also showed that TLR9 might play a pivotal role in the pathology of AAV. They produced evidence that the bacterial DNA hypomethylated motifs, which are ligands for TLR9, can trigger the in vitro production of ANCA autoantibodies from B lymphocytes derived from patients with AAV in remission [29]. In addition, a strong association of TLR9 geno- and haplo-types with AAV was observed, which supports the role of TLR9 and infections in the disease (re)activation [30]. 7. Conclusions The clinical evidence linking infections and ANCA formation is strong. Recent research developments have shed light on various pathogenetic mechanisms of ANCA formation during infectious episodes. However, a great deal of work is needed to identify the critical pathways of ANCA formation in infectious episodes and, particularly, to develop preventive and therapeutic measures based on these pathways. Take-home messages • Infection may induce/perpetuate AAV. • Current theories for induction of the ANCA autoimmune response do not meet criteria for causality but are setting the stage for further investigations. • Understanding the mechanism of infections as a trigger for ANCA may help the design of new diagnostic tests or promising therapy for AAV. References
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[2] Kallenberg CGM, Tadema H. Vasculitis and infections: contribution to the issue of autoimmunity reviews devoted to “autoimmunity and infection”. Autoimmun Rev 2008;8:29–32. [3] Heeringa P, Little MA. In vivo approaches to investigate ANCA-associated vasculitis: lessons and limitations. Arthritis Res Ther 2011;13(1):204. [4] Chen M, Kallenberg CGM. The environment, geoepidemiology and ANCA-associated vasculitides. Autoimmun Rev 2010;9:A293–8. [5] Konstantinov KN, Emil SN, Barry M, Murata GH, Tzamaloukas AH. Glomerular disease in patients with infectious processes developing antineutrophil cytoplasmic antibodies. ISRN Nephrol 2013:18 [Article ID 324315]. [6] Pendergraft III WF, Preston GA, Shah RR, Tropsha A, Carter Jr CW, Jennette JC, et al. Autoimmunity is triggered bycPR-3(105-201), a protein complementary to the autoantigen proteinase 3. Nat Med 2004;10:72–9. [7] Preston GA, Pendergraft 3rd WF, Falk RJ. New insights that link microbes that link microbes with the generation of antineutrophil cytoplasmic autoantibodies: the theory of autoantigen complementarity. Curr Opin Nephrol Hypertens 2005;14: 217–22. [8] Heal JR, Roberts GW, Raynes JG, Bhakoo A, Miller AD. Specific interactions between sense and complementary peptides: the basis for the proteomic code. Chembiochem 2002;3:136–51. [9] Jennette JC, Falk RJ. Pathogenesis of antineutrophil cytoplasmic autoantibodymediated disease. Nat Rev Rheumatol 2014;10:463–73. [10] Yang J, Bautz DJ, Lionaki S, Hogan SL, Chin H, Tisch RM, et al. ANCA patients have T cells responsive to complementary PR-3 antigen. Kidney Int 2008;74:1159–69. [11] Cao Y, Schmitz JL, Yang J, Hogan SL, Bunch D, Hu Y, et al. DRB1*15 allele is a risk factor for PR3-ANCA disease in African Americans. J Am Soc Nephrol 2011;22: 1161–7. [12] Jeannette JC, Falk RJ, Hu P, Xiao H. Pathogenesis of antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Annu Rev Pathol 2013;8:139–60. [13] Bautz DJ, Preston GA, Lionaki S, Hewins P, Wolberg AS, Yang JJ, et al. Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. J Am Soc Nephrol 2008;19:2421–9. [14] Saftig P, Klumperman J. Lysosome biogenesis and lysosomal membrane proteins: trafficking meets function. Nat Rev Mol Cell Biol 2009;10:623–35. [15] Bosch X, Mirapeix E. LAMP-2 illuminates pathogenesis of ANCA glomerulonephritis. Nat Rev Nephrol 2009;5:247–9. [16] Kain R, Exner M, Brandes R, Ziebermayr R, Cunningham D, Alderson CA, et al. Molecular mimicry in pauci-immune focal necrotizing glomerulonephritis. Nat Med 2008; 14:1088–96. [17] Kain R, Rees AJ. What is the evidence for antibodies to LAMP-2 in the pathogenesis of ANCA associated small vessel vasculitis? Curr Opin Rheumatol 2013;25:26–34. [18] Peschel A, Basu N, Benharkou A, Brandes A, Brown M, Diekmann R, Rees AJ, Kain R. Autoantibodies to hLAMP-2 in ANCA-negative pauci-immune focal necrotizing GN. J Am Soc Nephrol 2014;25:455–63. [19] Bierne H, Hamon M, Cossart P. Epigenetics and bacterial infections. Cold Spring Harb Perspect Med 2012;2:a010272. [20] Ciavatta DJ, Yang J, Preston GA, Badhwar AK, Xiao H, Hewins P, et al. Epigenetic basis for aberrant upregulation of autoantigen genes in humans with ANCA vasculitis. J Clin Invest 2010;120:3209–19. [21] Ciavatta D, Falk RJ. Epigenetics and complementary proteins. Clin Exp Immunol 2011;164(Suppl. 1):17–9. [22] Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, et al. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–5. [23] Yipp BG, Petri B, Salina D, Jenne CN, Scott BN, Zbutnuik LD, et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012;18:1386–93. [24] Kessenbrock K, Krumbholz M, Schonermarck U, Back W, Gross WL, Werb Z, et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009;15: 623–5. [25] Bosch X. LAMPs and NETs in the pathogenesis of ANCA vasculitis. J Am Soc Nephrol 2009;20:1654–6. [26] Sangaletti S, Tripodo Chiodoni C, Guarnotta C, Cappetti B, Casalini P, Piconese S, et al. Neutrophil extracellular traps mediate transfer of cytoplasmic neutrophil antigens to myeloid dendritic cells toward ANCA induction and associated autoimmunity. Blood 2012;120:3007–18. [27] Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010;11:373–84. [28] Tadema H, Abdulahad WH, Stegeman CA, Kallenberg CG, Heeringa P. Increased expression of Toll-like receptors by monocytes and natural killer cells in ANCAassociated vasculitis. PLoS One 2011;6(9):e24315 [2011]. [29] Tadema H, Abdulahad WH, Lepse N, Stegeman CA, Kallengebrg CG, Heeringa P. Bacterial DNA motifs trigger ANCA production in ANCA-associated vasculitis in remission. Rheumatology (Oxford) 2011;50:689–96. [30] Husmann CA, Holle JU, Moosig F, Mueller S, Wilde B, Cohen Tervaert JW, et al. Genetics of toll like receptor 9 in ANCA associated vasculitides. Ann Rheum Dis 2014;73: 890–6.
[1] Pinching AJ, Rees AJ, Russel BA, Lockwood CM, Mitchison RS, Peters DK. Relapses in Wegener's granulomatosis: the role of infection. Br Med J 1980;281:836–8.
Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020
Contents lists available at ScienceDirect
Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev
Review
Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms Konstantin N. Konstantinov a,⁎, Constance J. Ulff-Møller b, Antonios H. Tzamaloukas c a
Division of Rheumatology, Department of Internal Medicine, University of New Mexico School of Medicine Health Sciences Center, Mail Stop MSC10-5550, Albuquerque, NM 87131, USA Department of Infectious Diseases and Rheumatology, Rigshospitalet, Copenhagen, University Hospital, Blegdamsvej 9, DK-2100 Denmark Section of Nephrology, Raymond G. Murphy Veterans Affairs Medical Center and University of New Mexico School of Medicine, Renal Section, VA Medical Center, 1501 San Pedro, SE, Albuquerque, NM 87108, USA
b c
a r t i c l e
i n f o
a b s t r a c t
Article history: Received 13 October 2014 Accepted 21 October 2014 Available online xxxx
The precise cause of the antineutrophil cytoplasmic antibodies (ANCA) autoimmunity is not known and is likely to be multifactorial. Infections may trigger formation of ANCA and a fraction of the patients with infectiontriggered ANCA develop ANCA-associated vasculitis. Here we discuss some of the proposed mechanisms of ANCA formation during the course of infection. They include initiation of autoimmune response by microbial peptides that are complementary to autoantigens; epigenetic silencing and antigen complementarity leading to upregulation of autoantigen genes; molecular mimicry between bacterial and self-antigens; formation of neutrophil extracellular traps that stimulate immune processes including production of ANCA; and interaction of bacterial components with Toll-like receptors, which leads to formation of mediators affecting the immune responses to infections and can trigger ANCA production. Further work is needed to clarify these mechanisms and develop preventive measures and therapeutic interventions. © 2014 Published by Elsevier B.V.
Contents 1. Introduction . . . . . . . . 2. Autoantigen complementarity 3. Molecular mimicry . . . . . 4. Epigenetics . . . . . . . . . 5. NETosis . . . . . . . . . . 6. Toll-like receptors . . . . . . 7. Conclusions . . . . . . . . . Take-home messages . . . . . . References . . . . . . . . . . .
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1. Introduction The association between infections, formation of antineutrophil cytoplasmic antibodies (ANCA) and ANCA-mediated disease has been known for decades [1,2]. Both experimental [3] and epidemiological [4] studies have provided strong supportive evidence to the concept
⁎ Corresponding author. E-mail addresses: [email protected] (K.N. Konstantinov), [email protected] (C.J. Ulff-Møller), [email protected] (A.H. Tzamaloukas).
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that infections may trigger exacerbations of ANCA-mediated disease and may even be the main pathogenetic mechanism of ANCA formation. ANCA formation has been reported during the course of various chronic infections of viral, bacterial, fungal, protozoal, and multicellular parasitic etiology (Table 1). ANCA-mediated disease has been observed in the course of various infections [5]. Research efforts have been directed towards elucidation of the mechanisms by which infection triggers ANCA formation. The purpose of this report is to review recent developments in these mechanisms. We will discuss recently described mechanisms of ANCA formation in infectious episodes, including autoantigen complementarity, molecular mimicry, epigenetics, NETosis, and Toll-like receptors.
http://dx.doi.org/10.1016/j.autrev.2014.10.020 1568-9972/© 2014 Published by Elsevier B.V.
Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020
2
K.N. Konstantinov et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
Table 1 Infections associated with ANCA formation. Viruses
Bacteria
Fungi
Protozoa
Multicellular organisms
HIV
Streptococcus
Aspergillus
Hepatitis B virus Hepatitis C virus Parvovirus B-19 Epstein-Barr virus Arbovirus Ross river virus
Staphylococcus Enterococcus Bartonella Gemella
Histoplasma Sporothrix Pneumocystis Paracoccidioides
Entamoeba Echinococcus histolytica Plasmodium Strongyloides Leishmania Toxocara
Propionibacterium Saccharomyces Neisseria Actinobacillus Pseudomonas Escherichia Bacteroides Campylobacter Helicobacter Yersinia Salmonella Proteus Corynebacterium Stenotrophomonas Klebsiella Mycoplasma Chlamydia Ricketsia Treponema Leptospira Mycobacterium
Modified with permission from: Konstantinov KN et al. Glomerular disease in patients with infectious processes developing antineutrophil cytoplasmic antibodies. ISRN Nephrology 2013; Article ID 324315. HIV = human immunodeficiency virus.
2. Autoantigen complementarity Autoantigen complementarity has been suggested as one of the mechanisms that can break tolerance to ANCA antigens [6,7]. According to this hypothesis, the initial immune response in patients with ANCAassociated vasculitis (AAV) is not directed toward the autoantigen but rather to a peptide that is complementary to the autoantigen epitope. Such complementary peptide pairs have structural and chemical characteristics that allow them to bind together [8]. The complementary peptide immunogen, which is a mirror of the original protein, could arise from antisense transcription of the autoantigen gene or exist as microbial exogenous peptide that mimics the complementary antisense peptide. Antibodies to a complementary protein may induce anti-idiotypic antibodies that cross-react with the original protein [9]. Indeed, some patients with PR3-ANCA-associated vasculitis (AAV) have been found to have not only antibodies against PR3 peptides (anti-PR3) but also antibodies against anti-sense peptides that are complementary to the autoantigen epitopes on PR3 (cPR3 peptide). In an attempt to validate the autoantigen complementarity hypothesis, Pendergraft et al. [6] immunized mice with cPR3. These mice indeed developed antibodies to both cPR3 and PR3. Interestingly, several pathogens, known to be associated with PR3-ANCA such as Staphylococcus aureus, Entamoeba histolytica, and Ross River virus, have peptides homologous to cPR3 and infection by these microorganisms may trigger an autoantibody response. [6]. In addition, circulating anti-cPR3 CD4+ Th1 memory T cells were detected in PR3-ANCA positive patients, but not in MPO + -ANCA positive patients [10]. The HLA-DRB1(*)1501 allele found in African Americans with PR3ANCA encodes an MHC class II receptor that binds sense and cPR3 [11]. It has been suggested that complementary peptides to PR3 could be beneficial to pathogens expressing cPR3 by binding to and neutralizing the antimicrobial properties of PR3 and MPO [12]. One example of a specific clinical manifestation caused by autoantigen complementarity is
vascular thrombotic episodes in AAV. It has been shown that the endogenous protein plasminogen is one of the proteins complementary to the middle portion of PR3 and patients with cross-reacting antibodies to cPR3 ANCA and plasminogen have suppressed fibrinolysis and increased risk for thrombosis [13]. 3. Molecular mimicry It has been theorized that similarities between antibodies to pathogens and epitopes of self-antigens may lead to cross-reactivity and mounting an autoimmune response. Such molecular mimicry may also be the primary mechanism in the development of focal necrotizing glomerulonephritis in patients with ANCA directed against human lysosome-associated membrane protein-2 (LAMP-2) during active disease. LAMP-2 is a heavily glycosylated type 1 membrane protein expressed on the membrane of neutrophil intracellular vesicles that contain PR3 and MPO [14]. LAMP-2 can shuttle between cytoplasm and cell surface of resting neutrophils and endothelial cells; while surface LAMP-2 has a role in cell adhesion, the intracellular LAMP-2 is important for antigen presentation and autophagy [15]. The evidence for pathogenicity of anti-LAMP-2 is convincing, as injection of the antibody into rats causes kidney pathology and apoptosis in microvascular endothelium identical to the lesions observed in humans with ANCA-mediated disease [16]. Interestingly, anti-LAMP-2 ANCA cross react with the adhesive bacterial fimbrial protein FimH, which is found in many Gram-negative bacteria such as Escherichia coli, Klebsiella pneumonia, and Proteus mirabilis and mice immunized with FimH develop ANCA anti-LAMP-2 reactivity [16]. Hypothetically, anti-LAMP-2 autoantibodies could result from molecular mimicry following infection with Gram-negative organisms producing FimH [17]. The autonomy of LAMP-2 autoantibody response in AAV is suggested by the observation that LAMP-2 autoantibodies have been detected and correlated with active vasculitis in MPO and PR3 ANCA-negative patients [18]. 4. Epigenetics Epigenetics refers to stable and somatically heritable changes in gene expression that do not alter the DNA sequence but are reversible and may thus be influenced by environmental factors. Previous studies indicate that pathogenic bacteria and infections may induce changes in the epigenetic information of host organisms, such as histone modifications, DNA methylation changes, and miRNA [19]. A recent study in humans with ANCA vasculitis showed depletion of the histone modification H3K27me3 in leucocytes, leading to increased expression of PR3 and MPO, which was directly correlated to disease activity [20]. This finding, which suggests disrupted epigenetic silencing, has not been linked specifically to infections so far. Although the area remains relatively unexplored, it might lend support to the autoantigen complementarity hypothesis if infection-induced epigenetic synthesis induces the production of complementary proteins through dysregulated expression of anti-sense transcripts [21]. However, further research is needed to test this hypothesis. 5. NETosis Neutrophil extracellular traps (NETs) are a recently described mechanism that is important for control of bacterial infections. NETs formation characterizes a unique type of neutrophil-related cell death named NETosis, which leads to production in neutrophils of a meshwork of chromatin fibers associated with citrullinated histone H3 and antimicrobial proteins, including MPO and PR3. This meshwork forms extracellular nets that trap and kill microbial pathogens [22]. NET-inducing factors are dependent on respiratory burst of neutrophils and include, among others, bacteria such as Staphylococcus, Streptococcus, and Enterococcus, M1 protein, and lipopolysaccharides [23].
Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020
K.N. Konstantinov et al. / Autoimmunity Reviews xxx (2014) xxx–xxx
The contact between primed neutrophils and ANCA IgG can also induce formation of NETs that stick to the endothelium and cause tissue damage [24]. PR3 and elastase containing NETs have been detected in affected human glomeruli [24]. Based on these observations, it has been hypothesized that ANCA IgG may perpetuate a vicious circle of NETs production, which breaks down tolerance by maintaining the delivery of protein-chromatin complexes to the immune system, while the propensity of neutrophils to form NETs is further enhanced by bacterial infection, known to induce NETs and linked to relapses during flares [25]. Use of DNase-1 in small vessel vasculitis not only caused inhibition of NET formation, but also prevented vessel inflammation [26]. 6. Toll-like receptors The discovery of the microbial-sensing proteins called Toll-like receptors (TLRs) transformed our understanding of the body's response to infection. Members of this family are pattern recognition receptors (PRR) that can sense highly conserved structural motifs, which are broadly shared by pathogens, and known as pathogen-associated molecular patterns (PAMPs) [27]. Examples of PAMPs include various bacterial cell wall components and bacterial DNA. TLRs are expressed by different cell types including monocytes, B lymphocytes, granulocytes, and epithelial and endothelial cells. Ligation of TLRs with PAMPs results in release of proinflammatory cytokines, type-1 interferon, antimicrobial peptides, and effector cytokines that direct the adaptive immune response. Recent studies on the expression of TLRs in patients with AAV may provide a susceptibility link between infection and AAV. In their study Tadema et al. [28] demonstrated increased expression of TLRs by monocytes and natural killer cells of patients with AAV. The same group also showed that TLR9 might play a pivotal role in the pathology of AAV. They produced evidence that the bacterial DNA hypomethylated motifs, which are ligands for TLR9, can trigger the in vitro production of ANCA autoantibodies from B lymphocytes derived from patients with AAV in remission [29]. In addition, a strong association of TLR9 geno- and haplo-types with AAV was observed, which supports the role of TLR9 and infections in the disease (re)activation [30]. 7. Conclusions The clinical evidence linking infections and ANCA formation is strong. Recent research developments have shed light on various pathogenetic mechanisms of ANCA formation during infectious episodes. However, a great deal of work is needed to identify the critical pathways of ANCA formation in infectious episodes and, particularly, to develop preventive and therapeutic measures based on these pathways. Take-home messages • Infection may induce/perpetuate AAV. • Current theories for induction of the ANCA autoimmune response do not meet criteria for causality but are setting the stage for further investigations. • Understanding the mechanism of infections as a trigger for ANCA may help the design of new diagnostic tests or promising therapy for AAV. References
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Please cite this article as: Konstantinov KN, et al, Infections and antineutrophil cytoplasmic antibodies: Triggering mechanisms, Autoimmun Rev (2014), http://dx.doi.org/10.1016/j.autrev.2014.10.020