Abstract
SLE pathogenesis is complex, but it is now widely accepted that autoantibodies play a key role in the process by forming excessive immune complexes; their deposits within tissues leading to inflammation and functional damages. A proliferation inducing ligand (APRIL) is a member of the tumor necrosis factor (TNF) superfamily mediating antibody-producing plasma cell (PC)-survival that may be involved in the duration of pathogenic autoantibodies in lupus. We found significant increases of APRIL at the mRNA and protein levels in bone marrow but not spleen cells from NZB/W lupus mice, as compared to control mice. Selective antibody-mediated APRIL blockade delays disease development in this model by preventing proteinuria, kidney lesions, and mortality. Notably, this was achieved by decreasing anti-DNA and anti-chromatin autoantibody levels, without any perturbation of B- and T- cell homeostasis. Thus, anti-APRIL treatment may constitute an alternative therapy in SLE highly specific to PCs compared to other B-cell targeting therapies tested in this disease, and likely to be associated with less adverse effects than any anti-inflammatory and immunosuppressant agents previously used.
Highlights
Systemic Lupus Erythematosus (SLE) is a disorder of systemic autoimmunity characterized by the production of autoantibodies and subsequent development of glomerulonephritis (GN)
BAFF deletion resulted in a profound decrease in the mature B-cell compartment [7], while a proliferation-inducing ligand (APRIL) deletion resulted in a more restricted immune deficiency [8] that could be attributed to plasma cells (PC) [9]
Elevated levels of APRIL in sera or cerebrospinal fluid have been reported in patients with SLE, which correlated with disease activity [16,17,18]
Summary
Systemic Lupus Erythematosus (SLE) is a disorder of systemic autoimmunity characterized by the production of autoantibodies and subsequent development of glomerulonephritis (GN). SLE is usually treated with steroids in combination with cytotoxic compounds that targets cycling cells, such as cyclophosphamide. Important efforts are currently being made to target B cells in this disease (reviewed in [1,2]) Those treatments include the antagonism of two members of the tumor necrosis factor (TNF) superfamily, the B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL). BAFF and APRIL share the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) and the B-cell maturation antigen (BCMA) as common receptors from the TNF-R superfamily [3]. Despite these similarities, BAFF and APRIL are not redundant molecules. BAFF deletion resulted in a profound decrease in the mature B-cell compartment [7], while APRIL deletion resulted in a more restricted immune deficiency [8] that could be attributed to plasma cells (PC) [9]
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