T cells and dendritic cells in glomerular disease: the new glomerulotubular feedback loop

Abstract

A newly described glomerulotubular feedback loop may explain the relationship between glomerular damage, epitope spreading, tubulointerstitial nephritis, proteinuria as a progression factor, and the importance of the local milieu in kidney damage. It also opens the horizons for exciting innovative approaches to therapy of both acute and chronic kidney diseases.

Figure 1. Cells in GN

Figure 1 represents an aggregate of data derived from animal models. B cells were classically considered to be involved in the pathogenesis of GN by elaboration of immunoglobulin (Ig). Th-17, CD4 ⁺, and CD8 ⁺ cells have a significant role as shown by abrogation of activity leading to amelioration of GN. Macrophages and peripheral blood leukocyte (PBL) are essential in the histological changes of GN. All result in a variable increase in the mesangial matrix, and involvement of the visceral and parietal epithelial cells. T regulatory cells downregulate disease. Experimental autoimmune glomerulonephritis presumably arises secondary to various etiologies, including broken tolerance, a decrease in suppressor/regulatory cells, epitope mimetics, exposure of cryptic antigens, and possibly autoimmunity to complementary peptides.

Figure 2. Processing of tubular proteins by renal dendritic cells

Uptake and presentation of tubular proteins by renal DCs. The figure shows the potential pathways by which tubular antigens are internalized, processed, and presented to CD8 ⁺ and CD4 ⁺ T-cells in the kidney draining lymph nodes. DC subsets in the interstitium internalize antigens in the tubular lumen either directly by inserting pseudopods into the lumen (CD103 ⁺ DCs) or indirectly by internalizing antigen transported and/or processed by transcellular antigen transport through tubular epithelial cells (TECs). The presence of all DC types shown has been published, except for CD103 ⁺ DCs, which have been identified in preliminary studies (Sung SJ). For cross-presentation, antigens can be directly processed in the endosomes and the MHC-I molecules are loaded by the released peptides and presented to CD8 ⁺ T cells. Other possible pathways of exogenous antigen loading—by transit through the cytosol with processing by proteosomes and MHC-I loading in the endoplasmic reticulum, and processing and MHC-I loading in the phagosomes—are not shown. In cross-presentation in the KDLNs, CD4 ⁺ T-cell help is shown. Cross-presentation by CD11b ⁺ DCs has been shown to be much inferior to other DC types and is not shown. The main functions of CD8 ⁺ T cells and CD4 ⁺ helper cells, but not those of Treg cells, are shown.

Figure 3. The glomerulotubular feedback loop

The figure depicts the glomerulotubular feedback loop involving new paradigms as described by Macconi and Heymann. Under normal circumstances the glomerular filtrate contains many peptides, proteins, and other substances that are filtered or shed into the urinary space. These are taken up by dendritic cells directly from the tubular lumen or after processing by tubular epithelial cells (TECs). Normally, cell death is affected by apoptosis with the presentation of these antigens to T cells without inflammatory cytokines, resulting in tolerance and suppression. Even proteinuria in this circumstance, consisting of a large amount of self-antigens, is not associated with damage sans an inflammatory process. On the other hand, damaged kidney, whether by reduced mass or by autoimmune injury, induces cell necrosis rather than apoptosis, with the release of damage-associated molecular patterns (DAMPs), recruitment of exogenous cells, and stimulation of endogenous cells to proliferate and elaborate the matrix and inflammatory cytokines. The ultrafiltrate contains normal constituents, but also now contains constituents released by renal injury. This inductive phase may progress, depending on regulatory feedback. However, when DCs process and present antigen to T cells in this inflammatory milieu, the result is tubulointerstitial nephritis (TIN) and feedback to the glomerulus, either directly or through a periglomerular infiltrate, which somehow communicates with the glomerulus across Bowman’s capsule. Thus, a glomerulotubular feedback loop is established in the setting of inflammation. This leads to further glomerular damage with CD8 ⁺ CTL cross-presentation of previously irrelevant or self-antigens and progression of TIN and glomerulosclerosis.