ITP has elevated BAFF expression

Cells require precise survival signals to rescue them from default death mechanisms. This is particularly important for lymphocytes. BAFF enhances B-cell survival; overexpression of BAFF results in severe autoimmune disorders in mice and elevated levels of BAFF are present in patients with various autoimmune diseases. This increased BAFF phenotype has now been shown in patients with ITP and suggests that new therapeutic options that target BAFF may be developed for ITP.

B-cell activating factor (BAFF) was reported in 1999 by several groups, belongs to the tumor necrosis factor family, and is thought to be critical for maintenance of normal B-cell development.^1-5  BAFF is produced by macrophages, monocytes, and dendritic cells, and interferon-γ (IFN-γ) stimulates the expression of BAFF by these cells.^1-5  BAFF is the natural ligand of 3 unusual tumor necrosis factor receptors termed BAFF-R, TACI, and BCMA, all of which have differing binding affinities for it.^1-5  Signaling through BAFF-R and BCMA stimulates B lymphocytes to undergo proliferation and to counter their self-destruction by apoptosis, and there are several lines of evidence to suggest that BAFF may play an important role in autoimmune pathogenesis.^1-5  BAFF-transgenic mice suffer from B-cell hyperplasia, splenomegaly, autoantibody production, and severe autoimmunity.¹  In humans, autoreactive B cells have an increased dependence on BAFF for survival, and elevated BAFF plasma levels have been observed in various autoimmune conditions such as rheumatoid arthritis, systemic lupus erythematosus, Sjögren syndrome, and multiple sclerosis.¹  It is now thought that inhibition of BAFF signaling is a potential therapeutic option for the treatment of B cell–mediated autoimmune conditions. For example, belimumab (Benlysta) is a human monoclonal antibody that specifically recognizes and inhibits the biologic activity of BAFF and is currently being used in clinical trials to treat patients with systemic lupus erythematosus.⁶  Alternatively, animal studies and clinical trials have suggested that blockade of BAFF by blocking reagents such as TACI-Ig, BAFF-R-Ig, or BR3-Fc may be an effective therapeutic approach for autoimmune diseases.¹ 

Immune thrombocytopenia (ITP) is an autoimmune disorder in which antiplatelet autoantibodies bind to platelets and cause their premature destruction by Fc-mediated phagocytosis within the spleen.⁷  The autoantibodies are usually of the IgG class with specificity for platelet GPIIb/IIIa and/or GPIb/IX.⁷  ITP is also associated with several abnormalities of T cells such as enhanced IFN-γ production and a deficiency of T regulatory cells that are responsible for loss of tolerance and the production of the platelet autoantibodies.⁷  The nature of these immune abnormalities and the important role that BAFF plays in autoimmunity led Zhu et al⁸  to examine BAFF in patients with ITP.

The authors measured levels of BAFF in 45 patients with chronic ITP. They found that patients with active disease had higher levels of plasma BAFF and BAFF mRNA than patients in remission and controls. Using in vitro assays, they found that addition of recombinant human BAFF to the culture not only promoted the survival of CD19⁺ B cells and CD8⁺ T cells but increased the apoptosis of platelets and the secretion of IFN-γ. They then examined how an inhibitory BAFF-receptor-Fc fusion protein (BR3-Fc) affected the above responses and found that BR3-Fc successfully corrected the above effects of recombinant human BAFF. These findings suggest that not only does BAFF play a pathogenic role in ITP by promoting the survival of both B and T cells, but blockade of BAFF signaling by BR3-Fc might be a promising therapeutic approach for ITP.