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Published on: August 19, 2020
Intrinsic renal cell expression of CD40 directs Th1 effectors inducing experimental crescentic glomerulonephritis
Amanda-Jane Ruth1, A Richard Kitching, Timothy J Semple
1Centre for Inflammatory Diseases, Monash University, Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
Insights
CD40 signaling drives Th1 immune responses crucial for crescentic glomerulonephritis (GN) development. Blocking CD40 ligand or CD40 on non-immune renal cells protects against GN, highlighting CD40 as a therapeutic target for kidney disease.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Crescentic glomerulonephritis (GN) pathogenesis involves Th1-predominant immunity.
- CD40/CD154 signaling is critical for initiating and directing Th1 responses.
Purpose of the Study:
- To investigate the role of CD40 in the development of experimental anti-glomerular basement membrane GN.
- To assess CD40-CD154 interactions in intrarenal effector responses and kidney injury.
Main Methods:
- Murine model of experimental anti-glomerular basement membrane GN using wild-type (WT) and CD40-/- mice.
- Immune neutralization of CD40 ligand (CD154).
- Chimeric mice (WT-->CD40-/- and WT-->WT) to assess the role of renal cell CD40 expression.
Main Results:
- CD40-/- mice failed to develop significant GN, indicating CD40's necessity.
- Neutralization of CD154 reduced Th1 effectors and injury.
- WT-->CD40-/- chimeras showed reduced chemokine mRNA, minimal immune cell influx, and protection from injury compared to WT-->WT controls.
- Renal CD40 expression by non-immune cells induced Th1 chemokine production.
Conclusions:
- CD40-CD154 interactions are pivotal in initiating injurious Th1 effector responses in GN.
- CD40 expressed by non-immune renal cells plays a significant role in GN pathogenesis.
- Targeting CD40-CD154 interactions presents a potential therapeutic strategy for GN.
Abstract:
Evidence suggests that human and experimental crescentic GN results from Th1-predominant immunity to glomerular antigens. CD40/CD154 signaling plays a key role in initiating Th1 responses and may direct Th1 effector responses. The role of CD40 in the development of GN was assessed in murine experimental anti-glomerular basement membrane GN. In this model, C57BL/6 wild-type (WT) mice sensitized to sheep globulin develop crescentic GN resulting from Th1 effector responses when challenged with sheep globulin planted in glomeruli. CD40-/- mice do not develop immunity in response to sheep globulin and thus fail to develop effector responses or significant GN. CD40 is expressed in nephritic glomeruli, suggesting a potential role for intrarenal CD40-CD154 interactions in injurious effector responses. Immune neutralization of the CD40 ligand (CD154) at the time of challenge significantly reduced accumulation of Th1 effectors and injury. The role of CD40 expression by renal cells was assessed by comparing GN in WT-->CD40-/- chimeras (absent renal but intact bone marrow CD40) and sham chimeric mice (WT-->WT). Both groups developed strong antigen-specific immune responses (antibody and IFN-gamma production). However, WT-->CD40-/- chimeras demonstrated reduced renal monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA levels and minimal T cell and macrophage influx and were protected from renal injury. Sham chimeric mice developed reduced GFR, with prominent renal expression of monocyte chemotactic protein 1 and IFN-inducible protein 10 mRNA and effector cell accumulation. In conclusion, the expression of CD40 by nonimmune renal cells plays a major role in Th1 effector responses by inducing Th1 chemokine production. Therefore, CD40-CD154 interactions are a potential therapeutic target in GN.
