NDT Advance Access originally published online on October 17, 2006
Nephrology Dialysis Transplantation 2007 22(3):965-966; doi:10.1093/ndt/gfl622
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Chlamydia pneumoniae infection and MPO-ANCA-associated glomerulonephritis
Email: iyoda{at}med.showa-u.ac.jpSir,
The pathogenesis of myeloperoxidase antineutrophil cytoplasmic autoantibody-associated glomerulonephritis (MPO-ANCA-associated GN) is still unknown. Various exogenous factors, such as silica exposure or propylthiouracil, have been suggested to be associated with MPO-ANCA-associated vasculitis [1,2], but little is known about the role of microbial agents. Chlamydia pneumoniae, a cause of respiratory tract infection [3], was recognized as the third Chlamydia species in 1986 [4]. In addition to respiratory diseases, the organism has been linked with atherosclerosis and related clinical manifestations such as coronary heart disease, carotid artery stenosis, aortic aneurysm, claudication and stroke [5,6]. Recent evidence suggests C. pneumoniae organisms can survive and multiply within, not only macrophage, but also polymorphonuclear neutrophils (PMN) [7]. There is a possibility that persistent infection of C. pneumoniae within PMN may lead to autoimmunity, and plays a role in enhancement of the process of ANCA production. In addition, C. pneumoniae infected macrophages adhere to the endothelium and migrate to the subendothelium in atherosclerotic lesion. These processes result in the release of cytokines and growth factor synthesis, which up-regulate endothelial cell adhesion molecules, leading to increased leucocyte adhesion [8]. These components, including macrophage infiltration, cytokine release, up-regulation of adhesion molecules and leucocyte adhesion, are indispensable to the pathogenesis of MPO-ANCA-associated GN [9]. Furthermore, C. pneumoniae produces chlamydial heat shock protein (cHSP) in infected cell macrophages and elicits a hypersensitivity reaction of the host, resulting in severe endothelial injury [10]. It is likely that the focal inflammatory reaction would be strongly enhanced resulting in necrotizing vasculitis in the presence of circulating ANCA, the production of which may be the result of interactions between T cells and B cells activated by microbial superantigens. Thus, we were interested in whether there is a high prevalence of active C. pneumoniae infection in patients with MPO-ANCA-associated GN.
We examined the level of anti-C. pneumoniae IgG-, IgA- and IgM-antibodies (abs), as a marker of an inactive, chronic persistence of active, and active infection, respectively, using ELISA in 15 patients with active idiopathic MPO-ANCA-associated GN (ANCA (active)) (mean ± SD age, 64.80 ± 12.64 years) and 50 controls (65.80 ± 13.45 years). We also studied paired sera from 10 patients in ANCA (active) who were in the remission phase of the disease [ANCA (remission)] (71.30 ± 9.18 years). There was no significant difference in the three groups with respect to seropositivity to anti- C. pneumoniae IgG and IgA abs; whereas seropositivity to anti-C. pneumoniae IgM ab, which was measured in 60% of the patients in ANCA (active), 30% of the patients in ANCA (remission) and 26% of controls, was associated with the risk of active MPO-ANCA-associated GN (P = 0.01) (Table 1). To comprehensively investigate the relative association between C. pneumoniae infection and the development of MPO-ANCA-associated GN, we compared the titres of C. pneumoniae abs in the active and remission phase of the disease in the same patients. The titres of anti-C. pneumoniae IgM and IgA, but not IgG abs in ANCA (remission) group significantly decreased compared with that in ANCA (active) [IgM ab: 1.22 ± 0.47 vs 1.05 ± 0.49 U, P < 0.05; IgA ab: 1.70 ± 1.20 vs 1.29 ± 0.88 U, P < 0.05, ANCA (active) vs ANCA (remission)]. Our study revealed that the presence of positive IgM ab against C. pneumoniae was closely associated with the development of MPO-ANCA-associated GN, while the presence of positive IgG- and IgA ab against C. pneumoniae as a risk factor did not reach statistical significance. In addition, our study confirmed that the increased titres of IgM- and IgA ab against C. pneumoniae in the ANCA (active) group was significantly reduced in the ANCA (active) group. The serological pattern of increased IgM and IgA titres has been suggested to indicate active infection and chronic persistence of active infection, respectively. IgG titres in the absence of IgM or IgA titres may be a serological marker of an older, inactive infection. Thus, active or chronically active rather than inactive C. pneumoniae infection may increase the risk of MPO-ANCA-associated GN. Based on the results, we propose a possibility that C. pneumoniae influences the pathogenesis of MPO-ANCA-associated GN.
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Our experiment indicates for the first time, a significantly higher prevalence of active C. pneumoniae infection in patients with MPO-ANCA-associated GN. The hypothesis that C. pneumoniae is aetiologically involved in MPO-ANCA-associated GN is of particular therapeutic relevance, because this is a potentially eradicable infectious agent. However, the number of patients in our study was small, a large-scale prospective confirmation of these findings is thus required.
Conflict of interest statement. None declared.
Department of Nephrology
Showa University School of Medicine
1-5-8 Hatanodai
Shinagawaku
Tokyo 145-8666
Japan
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