Elevated B cell-activating factor of the tumour necrosis factor family in coeliac disease

Objective. The B cell-activating factor of the tumour necrosis factor (TNF) family (BAFF) was recently described as a critical survival factor for B cells, and its expression is increased in several autoimmune diseases. Abnormal production of BAFF disturbs immune tolerance allowing the survival of autoreactive B cells and participates in the progression of B-cell lymphomas. Coeliac disease (CD) is a common autoimmune disorder induced by gluten intake in genetically predisposed individuals, associated with autoantibody production and with an increased risk of lymphoma at follow-up. The purpose of this study was to investigate the possible implications of BAFF in CD. Material and methods. Seventy-three patients with small-bowel biopsies and laboratory-proven diagnosis of CD were included in the study. All serum samples were analysed before the start of a gluten-free diet (GFD). In 12 cases, one or more samples were analysed during follow-up of the GFD. Seventy-seven blood donors were taken as controls. Serum BAFF levels and anti-transglutaminase (a-tTG) antibodies were assessed by ELISA and endomysial antibodies by indirect immunofluorescence. Results. Serum BAFF levels appeared to be significantly more elevated in CD patients than in controls (p<0.0001) and, compared with other autoimmune diseases where BAFF is increased, a much larger percentage (80.8%) of CD patients presented BAFF levels above the normal range. In addition, serum BAFF levels were found to correlate with a-tTG antibody levels (p=0.0007) and there was a significant reduction of BAFF after introduction of a GFD. Conclusions. BAFF may represent a possible pathogenic factor in CD. Its implications for the diagnosis, prognosis and treatment of CD should also be assessed.     

BAFF enhances B-cell-mediated immune response and vaccine-protection against a very virulent IBDV in chickens

Infectious bursal disease (IBD) is an acute, highly infectious and immunosuppressive disease caused by IBDV, which specifically targets destruction of B cells in the bursa of Fabricius. B-cell activating factor belonging to the TNF family (BAFF, also called BLyS, TALL-1, THANK, or zTNF4) is an important factor for B-cell proliferation and survival. Here we demonstrate that human soluble BAFF (hsBAFF) may enhance humoral immune response by elevating B lymphocyte activity of secretion of immunoglobulin (Ig) such as IgA, IgM and IgG in chickens immunized or unimmunized with an inactivated IBDV vaccine from a very virulent strain. Of importance, we found that hsBAFF, as a co-immunostimulant for vaccination, may play a vital role in amplifying the specific protective immune response, thereby potently preventing very virulent IBDV challenge. This is supported by serological evidence that hsBAFF may effectively enhance higher specific IgG activity and titre in serum of immunized chickens. The findings strongly suggest that BAFF may be exploited in combination with specific vaccination for prevention of IBD.     

Aberrant expression of BAFF in T cells of systemic lupus erythematosus, which is recapitulated by a human T cell line, Loucy

B cell-activating factor of the tumor necrosis factor (TNF) family, or BAFF, is mainly produced in monocytes and dendritic cells, and indispensable for proliferation, differentiation and survival of B cells. BAFF is a type II membrane-bound protein and the extracellular C-terminal fragment is released from the cells as soluble BAFF (sBAFF), which binds to specific receptors on B cells. Accumulating evidence suggests that BAFF plays an important role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). In this study, we developed a sensitive sandwich ELISA system to quantify the amount of sBAFF using our own mAb. Treatment of peripheral T cells of SLE patients with an anti-CD3 antibody triggered robust expression of BAFF and subsequent release of sBAFF from the cells. On the other hand, the stimulus induced only marginal elevation of sBAFF from normal T cells. These data indicate that BAFF is expressed in T cells upon stimulation at least under pathological conditions. Expression of BAFF was also largely induced in a human T cell line, Loucy (American Type Tissue Collection CRL-2629), in response to several stimuli, while other T cell lines so far examined produced the cytokine almost constitutively. These data suggest that Loucy recapitulates some of the characteristics of SLE T cells. Investigation of molecular and cellular mechanisms of production of BAFF in Loucy demonstrated that expression of BAFF was regulated through a signal transduction pathway which involves c-jun NH2-terminal kinase and p38, and that shedding of BAFF was catalyzed by a membrane-bound protease, furin.     

BAFF Is Increased in Renal Transplant Patients Following Treatment with Alemtuzumab

Alemtuzumab is a monoclonal antibody that depletes T and B cells and is used as induction therapy for renal transplant recipients. Without long-term calcineurin inhibitor (CNI) therapy, alemtuzumab-treated patients have a propensity to develop alloantibody and may undergo antibody-mediated rejection (AMR). In pursuit of a mechanistic explanation, we analyzed peripheral B cells and serum of these patients for BAFF (Blys) and BAFF-R, factors known to be integral for B-cell activation, survival, and homeostasis. Serum BAFF levels of 22/24 alemtuzumab-treated patients were above normal range, with average levels of 1967 pg/mL compared to 775 pg/mL in healthy controls (p = 0.006). BAFF remained elevated 2 years posttransplant in 78% of these patients. BAFF-R on CD19⁺ B cells was significantly downregulated, suggesting ligand/receptor engagement. BAFF mRNA expression was increased 2–7-fold in CD14⁺ cells of depleted patients, possibly linking monocytes to the BAFF dysregulation. Addition of recombinant BAFF to mixed lymphocyte cultures increased B-cell activation to alloantigen, as measured by CD25 and CD69 coexpression on CD19⁺ cells. Of note, addition of sirolimus (SRL) augmented BAFF-enhanced B-cell activation whereas CNIs blocked it. These data suggest associations between BAFF/BAFF-R and AMR in alemtuzumab-treated patients.     

BAFF et al.: novel members of the TNF ligand and receptor families as therapeutic targets

Tumour necrosis factor (TNF) family ligands and their corresponding receptors play important roles in the immune system, where they regulate lymphoid organ development and influence immune cell proliferation, differentiation, activation and death. Several TNF family members, including TNF-α and CD154, have already provided valuable therapeutic targets for the treatment of immune-mediated diseases. Over the past three years, a new subfamily of TNF-related ligands/receptors, which also plays a role in immunity, has been discovered by sequence-homology database searches. This subfamily, which appears to be particularly important in B cell immunity, includes two ligands termed B cell activating factor of the TNF family (BAFF) and a proliferation-inducing ligand (APRIL) and at least three receptors: B cell maturation protein (BCMA) and transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which bind both ligands, and BAFF receptor (BAFF-R), which binds only BAFF. Besides promoting the survival of B cells and regulating their proliferation and differentiation in collaboration with signals from the B cell antigen receptor, BAFF and APRIL may modulate T cell activation and APRIL may also act as an autocrine growth factor for certain tumour cells. There is evidence that overproduction of BAFF in mice results in a B cell-mediated autoimmune syndrome resembling systemic lupus erythematosus (SLE), and that elevated levels of this cytokine are associated with SLE and rheumatoid arthritis in humans. The discovery of this novel ligand/receptor network has provided novel insights into the mechanisms of immunoregulation. Most importantly, it offers the opportunity for developing novel treatment strategies for autoimmune diseases, immunodeficiencies, lymphoma and cancer. The prospect of exploiting this new information for therapeutic purposes has generated a flurry of recent patent applications that are discussed here.