Since autoantibodies of multiple specificities are a hallmark of SLE, it is natural that the role of B cells and autoantibodies has been a dominant focus of study in SLE in general and in lupus glomerulonephritis in particular. T cells were considered mainly for the provision of help to B cells for the production of autoantibodies. During the past several years, the focus on the role of T cells in lupus glomerulonephritis has been changed to the emphasis of these cells as effectors mediating tissue injury.
Evidence for the importance of T cells as effectors in lupus glomerulonephritis comes from several approaches. The first approach was the finding that renal disease is present in MRL/lpr
mice lacking circulating Ig but with B cells expressing a B cell receptor transgene [19
]. The study showed that MRL/lpr
mice expressing a surface transgenic B cell receptor to 4-hydroxy-3-nitrophenyl develop unique renal disease characterized by glomerular sclerosis and interstitial inflammation despite the absence of circulating Ig. Secondly, NZB/W F1 mice with established chronic glomerulonephritis treated with CTLA4Ig and a suboptimal dose of cyclophosphamide showed a significant delay in mortality without reduction in glomerular immune complex deposits [20
]. Thus, blocking T cell activation by CTLA4Ig could prevent disease progression. This reaffirms the original observation by Wofsy et al.
] that anti-T cell antibody therapy of NZB/WF1 mice reduced glomerular inflammation, severe proteinuria and early mortality. In NZM2328 mice, early immune complex deposits and acute proliferative glomerulonephritis was associated with glomerular and peri-glomerular T cell infiltration [22
]. In addition, MHC II positive, CD11c dendritic cells were seen in the glomeruli. This was accompanied by increased frequency of CD4+ T cell activation in the regional lymph nodes. All these findings suggest a local T cell response in kidney and regional lymph nodes early in the disease process.
Recently, using a transgenic mouse model system, Heymann et al.
] have demonstrated a role for CD4 and CD8 T cells in glomerular injury. Transgenic mice expressing ovalbumin and hen egg lysozyme proteins in glomerular epithelial cells, the podocytes, were generated. Ovalbumin-specific transgenic CD8+ T cells injected into these mice could get activated and expanded in the renal lymph nodes. The T cell activation was prevented by depletion of CD11c dendritic cells. These studies suggest that uptake of podocyte antigens by dendritic cells and cross-presentation to CD8+ T cells occurs in the renal lymph nodes. Transfer of ovalbumin-specific CD4+ T cells did not result in expansion or division. However, repeated co-injection of ovalbumin-specific activated CD4 and naïve CD8 T cells caused renal disease characterized by peri-glomerular inflammation, infiltration of macrophages and dendritic cells, and onset of mild proteinuria. Although this model does not completely mimic the regional CD4+ T cell activation in lupus mice, it is the first direct demonstration for the role of dendritic cells and CD4+ and CD8+ T cells in glomerular injury. Another significant difference of this model from lupus glomerulonephritis is the absence of glomerular immune complex deposits. These differences should be taken into account in its applicability to lupus nephritis.
Careful analysis of the kinetics of inflammatory cell migration and chemokine expression in the NZB/W F1 kidneys collected at different ages show distinct patterns of gene expression with disease progression [24••
]. Cohorts of mice in remission following treatment with cyclophosphamide, CTLA4Ig, and anti-CD154 were also studied. A significant finding of this study was that infiltration of activated macrophages in the renal interstitium corresponded with disease progression. Significantly, remission following treatment was associated with reduced macrophage activation. Thus, macrophage infiltration is a key indicator of disease progression. As discussed earlier, peri-glomerular inflammation caused by glomerular antigen-reactive T cells in the renal cortex leads to increased macrophage infiltration. It is likely that the inflammatory macrophages are attracted to the renal interstitium as a result of the periglomerular T cell infiltrate.
Several recent studies have investigated the pathogenic capacity of different CD4+ T cell subsets. Kidneys of nephritic NZM2328 mice show increased expression of Th1 cytokines (IFN gamma and IL12) [22
]. A recent study [25•
] showed increased mortality in NZM2328 mice deficient in TNF receptor 1 and 2. The TNF receptor deficient mice had accelerated onset of renal disease with activated CD4+ cells showing a Th17 gene profile. Thus, in addition to Th1 T cells, lupus glomerulonephritis can also be mediated by Th17 T cells. Laser microdissection of glomerular, periglomerular and perivascular infiltrates in MRL/lpr mice also showed increased IL17 expression, along with IFN gamma and IL13 [26
]. This is further supported by the study of Crispin et al.
] showing expanded double negative T cells producing IL17 and infiltrating kidneys in patients with SLE. Other studies suggesting a potential role of Th17 cells in SLE have been reviewed by Garrett-Sinha et al.
]. The follicular helper T cell subsets characterized as IL21 producing CD4 + inducible T cell costimulator (ICOS) + cells have been identified in spleens of BXSB-yaa
]. In another study [30•
], MRL/lpr mice lacking ICOS show a significant reduction in IgG autoantibody, but a modest reduction in glomerulonephritis. The role of these subsets in renal disease is unclear.
In summary an increasing number of studies support a role for T cell mediated renal disease in SLE. The next advance in lupus nephritis is the identification of target antigens that activate autoreactive T cells leading to glomerular and interstitial infiltration of inflammatory cells.