Traditionally, the study of antibody specificity following a physiological immune response to vaccination or in autoimmunity has being focused to the study of circulating antibodies. However, this approach provides littler information of the specificity of circulating B cells. One of the major limitations to study the specificity of circulating B cells is their inability to secret antibodies in the quantities required for their characterisation. A number of culture conditions and cell stimulants i.e. Pokeweed mitogen (PWM), anti-Igs, CpGB etc, have been reported, aimed to overcome this limitation. In order to improve the efficiency of the culture conditions we have design a culture system incorporating a combination of molecules known to play a central role in B cell expansion and differentiation such as CD40 ligand (CD154) BAFF and IL-21. We found that regardless the culture system used, the amount of antibodies (IgA, IgG and IgM) secreted by B cells in vitro varies among the individuals, however, we consistently found that the amount of antibodies secreted increased up to 100 times when culture in the conditions we here describe. The addition of CpGB and/or PWM alone or in combination to our cultured conditions did not result in increased antibody production. The high efficiency of the system will facilitate the study not only of the global circulating B cell antigen recognition repertoire but also those of B cells subpopulations..