Background/Purpose: Costimulatory molecules which mediate cross-talks between leukocytes, have been identified to play a pathogenetic pivotal role in systemic lupus erythematosus (SLE). Abrogation of the costimulatory CD137-CD137 ligand (CD137L) system has previously been shown to worsen systemic lupus erythematosus and yet improve experimental autoimmune encephalitis in murine models. Here, we aimed to investigate the phenotypic effects in dermatological, renal and cerebral manifestations, and the potential alterations of the immunological mechanisms when CD137L was absent in a murine lupus model.

Methods: B6.CD137L^-/- and lupus-prone C57BL/6.Fas^lpr-/- (B6.lpr) mice were crossed to obtain mice knocked out for the CD137L and Fas genes (DKO mice). The DKO mice were studied and compared with the B6.lpr mice phenotypically regarding survival, dermatitis, glomerulonephritis, cerebral demyelination, microglial activation and hippocampal long-term potentiation (LTP) induced by theta burst stimulation (TBS). Serological studies and the frequency of splenic leukocyte subsets and helper T (Th) cell transcription factors were studied and compared between the DKO and B6.lpr mice (and B6.WT mice where required).

Results: An observation of 22 months involving 226 DKO and 137 B6.lpr mice demonstrated significantly more severe dermatitis (mean±SE unit: 1.03±0.2 vs. 0.37±0.1, p=0.003), more frequent proliferative glomerulonephritis (33.3% vs. 7.9%, p=0.005) and shorter survival (median± SE survival: 44±4.5 versus 74±3.3 weeks, p<0.001) of the DKO mice compared to the B6.lpr mice. Conversely, microglial activation and cerebral demyelination were milder and the synaptic efficacy in terms of hippocampal LTP was superior in the DKO than B6.lpr mice, without affecting the basal synaptic transmission. DKO mice had a significantly higher frequency of splenic Th17 (CD3⁺CD4⁺CD8^–RoRγt⁺) cells than the B6.lpr and B6.WT mice while the frequencies of Th1 and Th2 cells were comparable between the groups. In vitro experiments which involved T-cell stimulation with anti-CD3 did not alter intracellular IL-10 and IL-17 expressions in splenocytes of the DKO and B6.pr mice but a lower proportion of splenic IL-10-producing CD11b⁺ cells were identified in the DKO mice than in the B6.lpr and B6.WT mice. Serological studies revealed lower serum IL-10 levels in the DKO than in the B6.lpr mice (p=0.017).

Conclusion: In the absence of CD137L, higher splenic Th17 and lower IL-10-producing CD11b⁺ frequencies and lower serum IL-10 levels may explain the more severe renal and dermatological pathology of B6.lpr mice, yet this creates an environment in the central nervous system for milder cerebral damage and enhanced long-term synaptic plasticity.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-differential-impact-of-the-abrogation-of-the-costimulatory-molecule-cd137-ligand-on-renal-and-cerebral-manifestations-in-c57bl-6-faslpr-mice/