NDT Advance Access originally published online on November 30, 2006
Nephrology Dialysis Transplantation 2007 22(2):350-352; doi:10.1093/ndt/gfl679
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Formation of lymphoid-like tissue in the kidney—is there a role for chemokines?
III. Medizinische Klinik, Zentrum für Innere Medizin, Universitätsklinikum Hamburg Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany
Correspondence and offprint requests to: Rolf A. K. Stahl, III. Medizinische Klinik, Zentrum für Innere Medizin, Universitätsklinikum Hamburg Eppendorf, Martinistrasse 52, 20246, Hamburg Germany. Email: rstahl{at}uke.uni-hamburg.de
Leucocyte recruitment is a hallmark of almost every inflammatory reaction. The time course of leucocyte subset infiltration, along with the tissue distribution of lymphocytes, is a highly regulated process. An increasing number of recent studies have shown the existence of dense leucocyte clusters with separated T- and B-cell zones in chronic autoimmune diseases, including inflammatory kidney disease [1–3]. The highly organized structure of these aggregates is reminiscent of lymph follicles in secondary lymphatic organs, hence they are termed ‘tertiary’ lymphoid tissue. Questions arising from this observation concern the mechanisms that underlie the formation of these lymphoid follicles and their functional role in the immune response.
The molecule family of chemokines and their receptors play a central role in leucocyte trafficking. A specific subset, the so-called lymphoid chemokines (Table 1), is responsible for the development and structural integrity of secondary lymphoid organs [4]. These chemokines are therefore primary candidates for leucocyte cluster formation in non-lymphoid organs. Their expression patterns induce and maintain the microarchitecture of lymphoid tissue with compartmentalization in T-cell and B-cell areas. They regulate the homing of circulating immune cells to lymphatic organs, and mediate the complex processes of cross talk between antigen-presenting dendritic cells (DCs), T lymphocytes and B lymphocytes.
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Recently, our group demonstrated the expression of lymphoid chemokines in rejecting renal transplants [5]. Approximately one-third of patients with acute allograft rejection developed dense intragraft B-cell clusters resembling lymphoid tissue. These B cells express the chemokine receptor CXCR5 and co-localize to areas of elevated intrarenal BCA-1/CXCL13 expression, the only chemokine ligand of CXCR5 known to date.
Another lymphoid chemokine described in acute renal transplant rejection by us [5] and by Kerjaschki et al. [6] is SLC/CCL21, which is expressed in lymphatic vessels in renal allografts. The latter study showed that acute transplant rejection with nodular mononuclear infiltrates is accompanied by extensive intrarenal lymphangiogenesis with podoplanin and SLC/CCL21-positive lymphatics. Furthermore, the cognate receptor of SLC/CCL21, CCR7 is expressed on a number of cells in the vicinity of SLC/CCL21-positive vessels in organs undergoing acute rejection. The authors speculated that neo-lymphangiogenesis might on the one hand be an important exit route for the inflammatory infiltrates, but may on the other hand also contribute to the maintenance of an alloreactive immune response and could thus trigger recurrent episodes of rejection [6]. Unlike BCA-1/CXCL13 expression, SLC/CCL21 is not associated with lymph follicle-like clusters, but it is generally found in lymphatics surrounding inflammatory processes in the kidney.
Recent data extend the observation of intrarenal lymphoid chemokine expression to human and murine experimental glomerulonephritis. As in transplant rejection, about one-third of patients with lupus nephritis display dense intrarenal CXCR5-positive B-cell clusters, which are also exclusively localized to areas of BCA-1/CXCL13 expression. SLC/CCL21 is expressed by lymphatic endothelium in inflamed regions of the kidney, with no special association to the follicles [7]. A similar phenomenon is observed in patients with anti neutrophil cytoplasmatic antibody-associated glomerulonephritis as well as in murine lupus nephritis.
This conserved expression profile of lymphoid chemokines in different pathologies and species argues for a specific functional role. Intrarenal expression of BCA-1/CXCL13 probably leads to the influx of B cells, which carry the corresponding receptor CXCR5. This assumption is underlined by a study performed by Luther et al. [8], who demonstrated that ectopic pancreatic expression of BCA-1/CXCL13 in transgenic mice is sufficient to induce lymphoid-like tissue in the pancreas. A significant role for intrarenal B cells in antibody production is quite unlikely. Rather, the absence of immunoglobulins and the merely sporadic presence of plasma cells in B-cell clusters suggest that infiltrating B cells act as antigen presentors [9]. The regular presence of T cells in the direct vicinity of B-cell clusters supports the hypothesis that intrarenal B cells act as potent costimulators and activators of T cells. A pathological shortcut to T-cell activation independent of secondary lymphoid tissue could thus be established (Figure 1). This shortcut probably leads to T-cell activation only, while the mechanisms required for removal of autoreactive cells, which can be found in more complex secondary lymphoid organs, are missing.
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The recruitment of T cells and monocytes to B-cell rich regions in the inflamed kidney is (in contrast to B-cell trafficking) mediated by inflammatory chemokines. Several subgroups of inflammatory chemokines exist that act predominantly on a defined subset of leucocyte species. RANTES/CCL5 for example, binds to the CCR5 which is expressed on monocytes/macrophages and also on Th1 cells. Several experimental and human studies have shown the important role of this chemokine in renal T-cell and monocyte recruitment (reviewed in [10]). MCP-1/CCL2 acts mainly on monocytes/macrophages by activation of its cognate receptor CCR2 and is probably the best characterized chemokine in renal inflammatory disease (reviewed in [11]).
CXCR3 is a chemokine receptor that is highly expressed on Th1 polarized T cells. CXCR3 is activated by any of the three related chemokines IP-10/CXCL10, Mig/CXCL9 and I-TAC/CXCL11. In a variety of human renal inflammatory diseases, including glomerulonephritis [12] and acute transplant rejection [13,14] the enhanced expression of CXCR3 chemokine ligands is followed by the recruitment of CXCR3 positive T cells, supporting an important role of this chemokine receptor in T-cell recruitment. This complex network of chemokine/chemokine-receptor interactions finally leads, in our opinion, to the formation of the aforementioned intrarenal lymphoid clusters, and thereby enables efficient cross talk between different leucocyte subpopulations.
SLC/CCL21 seems to play a different role. Via interaction with its receptor CCR7, SLC/CCL21 expression in high endothelial venules (HEVs) promotes the influx of naïve and central memory T and B cells into secondary lymphatic tissue and expression in afferent lymphatic vessels regulates the influx of mature DCs. SLC/CCL21 has to act in concert with the second CCR7 ligand ELC/CCL19 to mediate these processes. Recently, it has been recognized that expression of SLC/CCL21 in lymphatic endothelial cells outside secondary lymphoid organs is critical for the efflux of mature dendritic cells to draining lymph nodes. In inflammatory kidney diseases, CCR7-bearing mature dendritic cells may leave the renal tissue via SLC/CCL21-positive lymphatic endothelial cells to present their antigen in secondary lymphatic organs. Furthermore, trafficking of CCR7-positive T cells out of the kidney is another likely function of SLC/CCL21 expression observed in intrarenal lymphatic endothelium (Figure 1).
However, many questions remain to be answered. It is, for example, important to characterize the cascade of events triggering BCA-1/CXCL13 expression in the kidney and initiating B-cell follicle formation. Furthermore, the cellular origin of BCA-1/CXCL13 production and the mechanisms that lead to the persistence of B-cell clusters need to be identified. In secondary lymphatic organs, follicular dendritic cells (fDCs), a specific subgroup of DCs, are the main producers of BCA-1/CXCL13. In response to stimulation with BCA-1/CXCL13 via the CXCR5 receptor, B cells in secondary lymphatic organs secrete lymphotoxin alpha, which in turn stimulates fDCs to produce even more BCA-1/CXCL13. Thus, a positive feedback loop between fDCs and B cells is created. The mechanisms in the kidney, however, could be different. So far, no intrarenal expression of lymphotoxin alpha has been detected. In addition, in B-cell follicles in non-renal tissues, BCA-1/CXCL13 production is localized to monocytic cells rather than fDCs [15]. The presence of fDCs within B-cell clusters in the kidney remains to be investigated.
Another very important topic is the identification of developmental changes that clusters might undergo over time. So far only relatively homogeneous clusters lacking the complicated compartmentalization of secondary lymphoid follicles have been observed. It will be interesting to see whether germinal centres are formed and whether HEVs for potential influx of naïve T cells can be detected. Furthermore, it is unknown whether depletion of circulating B cells by Rituximab, which is evaluated as a promising new therapeutic option for inflammatory renal diseases, has any effect on the number of B cells in the kidney [16].
In summary, we conclude that the expression of lymphoid chemokines in inflammatory kidney diseases opens roads that, in the case of SLC/CCL21, facilitate direct trafficking to secondary lymphoid organs and roads that serve as immunological shortcuts for inflammatory-cell activation by the formation of B-cell clusters, organized by the expression of BCA-1/CXCL13. Accumulating evidence shows that these processes are substantially involved in the initiation and perpetuation of immunologically mediated renal disease and therefore represent promising therapeutic targets.
Conflict of interest statement. None declared.
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Accepted in revised form: 19.10.06
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