Anti-CD80 monoclonal antibody, clone 48822

Costimulatory molecules facilitate cross-talks among leukocytes via mutual stimulatory and inhibitory signalling, contributing to diverse immunological outcomes in normal physiological responses and pathological conditions. Systemic lupus erythematosus (SLE) is a complex multi-systemic autoimmune condition in which cellular communication through the involvement of costimulatory molecules is crucial in driving proinflammatory responses from the stage of autoantigen presentation to the subsequent process of pathogenic autoantibody production. While the physiology of the costimulatory systems including OX40-OX40L, CD28/CTLA-4-CD80/86, ICOS-B7RP1 and CD70-CD27 has been relatively well studied in SLE, recent data on the immunopathology of the CD137-CD137 ligand (CD137L) system in murine lupus models and patients with SLE highlight the critical role of this costimulatory system in initiating and perpetuating the diverse clinical and serological phenotypes of SLE. CD137, a membrane-bound receptor which belongs to the tumour necrosis factor receptor superfamily, is mainly expressed on activated T cells. Activation of the CD137 receptor via its interaction with CD137L which is expressed on antigen present cells (APC) including B cells, triggers bi-directional signalling; that is, signalling through CD137 as well as signalling through CD137L (reverse signalling), which further activates T cells and polarizes them to the Th1/Tc1 pathway. Further, via reverse CD137L signalling it enhances differentiation and maturation of the APC, particularly of dendritic cells, which subsequently drive proinflammatory cytokine production. In this review, recent data including our experience in the manipulation of CD137L signalling pertaining to the pathophysiology of SLE will be critically reviewed. More in-depth understanding of the biology of the CD137-CD137L co-stimulation system opens an opportunity to identify new prognostic biomarkers and the design of novel therapeutic approaches for advancing the management of SLE.

Leishmaniasis is a vector-borne disease caused by Leishmania parasites. Macrophages are considered the primary parasite host cell, but dendritic cells (DCs) play a critical role in initiating adaptive immunity and controlling Leishmania infection. Accordingly, our previous study in CD11c(cre)IL-4R alpha(-/lox) mice, which have impaired IL-4 receptor alpha (IL-4R alpha) expression on CD11c(+) cells including DCs, confirmed a protective role for IL-4/IL-13-responsive DCs in replication and dissemination of parasites during cutaneous leishmaniasis. However, it was unclear which DC subset/s was executing this function. To investigate this, we infected CD11c(cre)IL-4R alpha(-/lox) and control mice with L. major GFP(+) parasites and identified subsets of infected DCs by flow cytometry. Three days after infection, CD11b(+) DCs and CD103(+) DCs were the main infected DC subsets in the footpad and draining lymph node, respectively and by 4 weeks post-infection, Ly6C(+) and Ly6C(-) CD11b(+) DCs were the main infected DC populations in both the lymph nodes and footpads. Interestingly, Ly6C(+)CD11b(+) inflammatory monocyte-derived DCs but not Ly6C(-)CD11b(+) DCs hosted parasites in the spleen. Importantly, intracellular parasitism was significantly higher in IL-4R alpha-deficient DCs. In terms of DC effector function, we found no change in the expression of pattern-recognition receptors (TLR4 and TLR9) nor in expression of the co-stimulatory marker, CD80, but MHCII expression was lower in CD11c(cre)IL-4R alpha(-/lox) mice at later time-points compared to the controls. Interestingly, in CD11c(cre)IL-4R alpha(-/lox) mice, which have reduced Th1 responses, CD11b(+) DCs had impaired iNOS production, suggesting that DC IL-4R alpha expression and NO production is important for controlling parasite numbers and preventing dissemination. Expression of the alternative activation marker arginase was unchanged in CD11b(+) DCs in CD11(cre)IL-4R alpha(-/lox) mice compared to littermate controls, but RELM-alpha was upregulated, suggesting IL-4R alpha-independent alternative activation. In summary, L. major parasites may use Ly6C(+)CD11b(+) inflammatory DCs derived from monocytes recruited to infection as "Trojan horses" to migrate to secondary lymphoid organs and peripheral sites, and DC IL-4R alpha expression is important for controlling infection.