The Contribution of B Cells to Renal Interstitial Inflammation
Abstract
Local B-cell infiltrates play a role in tissue fibrosis, neolymphangiogenesis, and renal allograft survival. We sought to characterize the B-cell infiltrates, factors involved in B-cell recruitment, and lymphangiogenesis in renal interstitial injury (ie, acute and chronic interstitial nephritis and chronic IgA nephropathy). CD20-positive B cells formed a prominent part of the interstitial infiltrating cells. Together with CD3-positive T cells, the CD20-positive B cells formed larger nodular structures. CD10-positive pre-B cells were rare, and the majority were mature CD27-positive B cells. Proliferating B cells were detected within nodular infiltrates. The level of mRNA expression of the chemokine CXCL13 was increased and correlated with CD20 mRNA in the tubulointerstitial space. CXCL13 protein was predominantly found at sites of nodular infiltrates, in association with CXCR5-positive B cells. Furthermore, sites of chronic interstitial inflammation were associated with a high number of lymphatic vessels. B-cell infiltrates form a prominent part of the interstitial infiltrates both in primary interstitial lesions and in IgA nephropathy. CXCR5-positive B cells might be recruited via the chemokine CXCL13 and seem to contribute to the formation of intrarenal lymphoid follicle-like structures. These might represent an intrarenal immune system.
During chronic kidney diseases an inflammatory process occurs within the tubulointerstitium, which finally results in fibrosis.1 The severity of interstitial leukocyte accumulation, monocytes/macrophages, and T lymphocytes, is associated with renal function at the time of biopsy.2–5 Because B cells are considered to be important mostly in lymph nodes, spleen, and in humoral immune responses, little attention has been paid to their potential role as intrarenal infiltrating cells.
Several new aspects of B-cell function have surfaced. These include the release of proinflammatory cytokines and chemokines, antigen presentation, T-cell activation, a role in tissue fibrosis, neolymphangiogenesis (ie, de novo formation of lymphatic vessels), and ectopic lymphogenesis; ie, formation of tertiary lymphatic organs in inflamed tissues.6–8 Furthermore, therapeutic studies targeting B cells via anti-CD20 antibodies have renewed interest in B-cell biology during chronic diseases.
At sites of chronic inflammation, ectopic formation of lymphoid follicle-like aggregates containing B cells has been described, eg, in autoimmune diseases such as thyroiditis and rheumatoid arthritis, as well as during renal allograft rejection.7,9,10 A contribution of B cells to the formation of lymphoid-like structures has been proposed.6,11 The accumulation of B cells could be mediated by chemokines.12,13 CXCR5 is a chemokine receptor expressed by B cells, which binds the chemokine CXCL13.14 CXCR5 and the corresponding ligand CXCL13 play a role in B-cell migration to secondary lymphoid organs, and in lymphoid organogenesis.15,16 Furthermore, high expression of CXCL13 has been demonstrated in synovial tissue with large B-cell aggregates, suggesting a potential role of CXCL13 for B-cell accumulation.17,18
Previously, the relative percentage of B cells in the renal interstitium of chronic kidney diseases was considered to be low.19–22 In contrast, a prominent accumulation of CD20-positive B cells has recently been described in membranous nephropathy.23 Furthermore, in renal allografts a detrimental role for CD20-positive B cells has been postulated because they were associated with increased graft loss.24
Here, we describe that CD20-positive B cells form a prominent part of interstitial infiltrates in both primary interstitial disease as well as in secondary involvement during primary IgA nephropathy. The B-cell infiltrate is associated with increased local expression of the chemokine CXCL13 and the corresponding receptor CXCR5 on B cells. Furthermore, T- and B-cell infiltrates form lymphoid-like nodular structures, which are surrounded by newly formed lymphatic vessels in these chronic diseases. These data invite speculations about a role of these intrarenal B-cell-rich lymphoid follicle-like structures in a local immune response in chronic renal diseases.
m, male; f, female.
Acknowledgments
We thank Hildegard Segerer for the illustration of the triple immunohistochemistry illustrated in Figure 7 and the members of the European Renal cDNA Bank/Kroener-Fresenius biopsy bank (ERCB/KFB) at the time of this study: J.P. Rougier, P. Ronco, Paris; M.P. Rastaldi, G. D’Amico, Milano; F. Mampaso, Madrid; P. Doran, H.R. Brady, Dublin; D. Mönks, C. Wanner, Würzburg; A.J. Rees, Aberdeen; F. Strutz, G. Müller, Göttingen; P. Mertens, J. Floege, Aachen; T. Risler, Tübingen; L. Gesualdo, F.P. Schena, Bari; J. Gerth, U. Ott, G. Wolf, Jena; R. Oberbauer, D. Kerjaschki, Vienna; B. Banas, B. Krämer, Regensburg; W. Samtleben, Munich; H. Peters, H.H. Neumayer, Berlin; K Ivens, B. Grabensee, Düsseldorf; M. Zeier, H.J. Groene, Heidelberg; M. Merta, V. Tesar, Prague; C.D. Cohen, H. Schmid, M. Kretzler, D. Schlöndorff, Munich.
Footnotes
Address reprint requests to Stephan Segerer, M.D., Medizinische Poliklinik-Innenstadt, Klinikum der Universität-München, Pettenkoferstr. 8a, 80336 Munich, Germany. .ed.nehcneum-inu.zrl@rereges.nahpets :liam-E
Supported by the Else Kröner-Fresenius Stiftung, Germany (to S.S. and C.D.C.); the Deutsche Forschungsgemeinschaft (SE 888/4-1 to S.S.); and the European Union Network of Excellence “MAIN” (FP6-502935 to S.S.).