Annexin A1 as a target for managing murine pristane-induced systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a polygenic pathological disorder which involves multiple organs. Self-specific B cells play a main role in the lupus pathogenesis by generating autoantibodies as well as by serving as important autoantigen-presenting cells. Autoreactive T lymphocytes, on the other hand, are responsible for B cell activation and proliferation, and cytokine production. Therefore, both factors promote the idea that a down-modulation of activated self-reactive T and B cells involved in the pathogenic immune response is a reasonable approach for SLE therapy. Annexin A1 (ANX A1) is expressed by many cell types and binds to phospholipids in a Ca dependent manner. Abnormal expression of ANX A1 was found on activated B and T cells in both murine and human autoimmunity, suggesting its potential role as a therapeutic target. While its role on T lymphocytes is through formyl peptide receptor-like molecules (FPRL), and the formed ANX A1/FPRL pathway modulates T cell receptor signalling, there is still no fool-proof data available for the role of ANX A1 in B cells. We employed a lupus model of Balb/c mice with pristane-induced SLE which very closely resembles human lupus. In the present study, we investigated the possibility to modulate the autoimmune response in a pristane-induced mouse model of SLE using an anti- ANX A1 antibody. Administration of this monoclonal antibody resulted in the inhibition of T-cell activation and proliferation, suppression of IgG anti-dsDNA antibody-secreting plasma cells and of proteinuria, decreased disease activity and prolonged survival compared to control group.

Suppression of autoreactive T and B lymphocytes by anti-annexin A1 antibody in a humanized NSG murine model of systemic lupus erythematosus

“…Incubation of PBMCs isolated from SLE patients with anti‐ANX A1 antibody reduced the expression of CD25 + /CD69 + activation markers on activated T cells, suppressed the cell proliferation of dsDNA‐specific IgG antibody‐secreting plasma cells in a dose‐dependent manner, and induced B and T cells apoptosis of activated lymphocytes. Similar results were observed in pristane‐induced murine lupus using the same antibody, suggesting shared mechanisms of T cell activity regulation through the ANX A1–FPR2 signalling pathway . The accumulated data suggest a more complex relation between ANX A1, the monoclonal antibody and apoptosis, respectively, rather than a simple pro‐ or anti‐apoptotic effect .…”

“…Nevertheless, we found that more than 20% of SLE patients' T cells and only 4% of healthy donors' T cells expressed ANX A1 on the outer membrane leaflet. We studied the effect of anti-ANX A1 in the Murphy Roths large/lymphoproliferation (MRL/lpr) and pristane-induced lupus models, and discovered that ANX A1 is also expressed on the surface of murine B cells, reaching significant levels for the BALB/c mice (up to 20% of splenocytes of animals with induced SLE and approximately 10% of healthy animals) [19]. Contrary to our murine experiments, human B cells exhibited low expression of ANX A1 (1-3%) in SLE patients and less than 1% in healthy donors.…”

“…We have already used the same approach (0·2 μg antibody/mouse) and a similar design of treatment (every 6 days) to explore the monoclonal anti-ANX A1 antibody in a pristane-induced mouse model of SLE in BALB/c mice, as well as in a lupus-prone MRL/lpr model. This treatment suppressed disease symptoms and autoantibody production, protected kidney histology and prolonged survival compared to the control groups [19]. Other authors have used even lower concentrations of antibody with the same specificity for the same period [38].…”

Monoclonal antibody therapy that targets phospholipid‐binding protein delays lupus activity in MRL/lpr mice

“…These include glomerulonephritis, vasculitis, splenomegaly, hypergammaglobulinemia and the production of anti-dsDNA antibodies and autoantibodies to other nuclear components. 20,21 Previously, we employed a pristane-induced mouse model of SLE in Balb/c mice and humanized mouse SLE model in order to suppress disease activity by a monoclonal anti-ANX A1 antibody. The treatment of sick animals with this antibody led to downregulation of IgG anti-dsDNA antibody-secreting plasma cells and of proteinuria, improved kidney histology and prolonged survival compared with the control groups.…”

Immuno-moodulin: a new anxiogenic factor produced by autoimmune-prone T cells

“…As with many other multifunctional mediators, AnxA1 plays a homeostatic role in the immune system as it can exert both positive and negative functions depending on the contexts. In the context of T cells, studies have indeed provided contrasting and opposite results showing that it can act as both a positive [18][19][20][21][22][23][24][25][26][27] and a negative modulator of T cell activation [27][28][29][30] . All these studies have been done using either exogenously administered recombinant AnxA1 (and its mimetic) or AnxA1-deficient mice where the protein is absent in every immune cell.…”