Background/Purpose: Costimulatory molecules, which are expressed on leukocytes that facilitate their cross-talks via stimulatory and inhibitory signalling, play a potentially important role in the inflammatory processes involved in SLE. Disappointment in clinical trials which tested the efficacy and safety of costimulatory molecule manipulation in SLE treatment prompts more in-depth understanding of the mechanistic impact of costimulatory molecules on the pathophysiology of SLE. We aimed to investigate the effect of the lack of CD137-CD137 ligand (CD137L) signalling in the phenotype and immunological profiles in a murine SLE model, based on our understanding that cognate interaction between CD137 expressed on activated T cells and CD137L constitutively present on antigen presenting cells potently drives pro-inflammatory response.

Methods: To generate C57BL/6-MRL.Fas^lpr-/- (B6.lpr) lupus-prone mice devoid of CD137L, B6.lpr mice were crossed with B6.CD137L^-/- mice to generate the B6.lpr^-/-CD137L^-/- double knockout (DKO) mice. The DKO and B6.lpr mice were phenotypically and immunologically compared to each other, and to B6 WT mice which served as a reference. Phenotypes including survival, lupus dermatitis by clinical scoring and glomerulonephritis by semi-quantitative urinalyses and light microscopy were compared between the DKO and B6.lpr mice. Frequencies, activation status and Th polarization of splenic T lymphocytes as studied by flow cytometry, and serum cytokine levels as measured by the multiplex platform were compared between the 3 groups of mice.

Results: After a 22-month observation, DKO mice (n=226) had significantly shorter survival than B6.lpr mice (n=137) (median ± SE: 44±4.5 vs. 74±3.3 weeks [p<0.001]). Significantly more DKO mice had severe cutaneous lesions, microscopic haematuria and proteinuria than their B6.lpr counterparts. Renal histopathological studies revealed that endocapillary proliferation (2.96±1.08 vs. 0.16±0.1, p=0.013) and glomerular proliferative lesions (33.3% vs. 7.9%, p=0.005) were significantly more frequent in the DKO compared to the B6.lpr mice. Furthermore, DKO mice had a significantly higher mean activity index of lupus nephritis (LN) than their B6.lpr counterparts (0.48±0.1 vs. 0.08±0, p=0.002). While significantly higher frequencies of double negative T cells (CD3+CD4-CD8-) and activated T cells (CD3⁺CD69⁺), particularly the CD3⁺CD8⁺CD69⁺ population, were found in the B6.lpr mice as compared to the DKO and B6 WT mice, the frequencies of Th17 cells (CD3⁺CD4⁺RORγt⁺[±Tbet⁺]) were significantly higher in the DKO than the B6.lpr and B6 WT mice. No difference in the frequencies of regulatory T cells (CD3⁺CD4⁺CD25⁺FoxP3⁺) was found amongst the mice. Cytokine analyses demonstrated significantly lower mean serum IL-10 levels in the DKO mice compared to the B6.lpr and B6 WT counterparts (p=0.017).

Conclusion: Abrogation of bidirectional CD137-CD137L signalling which interrupts CD137-CD137L costimulation resulted in more severe dermatitis and LN and reduced survival in the B6.lpr mouse model. More severe SLE phenotype in B6.lpr mice without CD137-CD137L signalling is potentially mediated by Th17 polarization and lower serum anti-inflammatory IL-10 levels.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lack-of-cd137-cd137-ligand-signalling-aggravates-glomerulonephritis-and-reduces-the-survival-of-lupus-prone-b6-mrllpr-mice/