Construction And Functional Analysis Of Immune Inhibitors Of Human BAFF

B cell activating factor belonging to the TNF family (BAFF), also known as THANK, BLyS, TALL-1 or zTNF4, is a 285 amino acid member of the tumor necrosis factor (TNF) ligand superfamily. BAFF is a type II transmembrane protein, which can be expressed as a surface-membrane bound molecule or be proteolytically cleaved into a soluble cytokine (134-285 amino acids, sBAFF). The membrance-anchored form and soluble form of BAFF have similar functions. BAFF, under physiologic conditions, circulates in trimeric form and can regulate proliferation and functions of T and B lymphocytes by binding to three different receptors, BAFF-R, TACI, and BCMA. Lack of BAFF in mice can lead to immunodeficiency, whereas overexpression of BAFF in mice results in severe autoimmune lupus-like characteristics with high levels of rheumatoid factors, proteinuria, anti-DNA autoantibodies, and increased numbers of B and effector T cells. Treatment of bona fide systemic lupus erythematosus (SLE) mice with BAFF antagonists ameliorates disease progression and enhances survival. BAFF overexpression is common in human SLE, rheumatoid arthritis (RA) and sjogren's syndrome (SS). Furthermore, serum sBAFF levels correlate with its associated disease severity. These data suggest that BAFF may be an attractive therapeutic target for human BAFF-associated autoimmune diseases.In recent years, a novel vaccination approach for generating long-term antibody responses against disease-related self proteins such as TNF-a has been developed. The autoantibodies are achieved by injecting foreign T-helper cell (Th) epitope-modified recombinant self-protein mutants. This approach has been proven to be safe and very effective, and the principle of raising antibodies that are cross-reactive with pathogenic self proteins can also be applied to other diseases. In this study, we firstly constructed several soluble BAFF cDNA mutants (msBAFF) by one step opposite direction PCR. Then the DNA sequences encoding foreign immunodominant T-helper epitopes were coupled to the 5'-end or 3'-end of msBAFF DNA respectively. After being sequenced, the recombinant...