Harnessing antibody variability and specificity
At the heart of antibody production is variable, diverse and joining (VDJ) recombination. This process achieves the seemingly limitless numbers of antibodies needed to deal with the varied onslaught of the immune system in a lifetime. At the same time, an antibody will only ever be able to deal with one specific type of invader. The EU-funded 'Allelic exclusion of antibody gene expression' (KAPPA FLEX MOUSE) project is investigating VDJ as well as the phenomenon of antibody specificity. Due to allelic exclusion, only one allele in the B cell genome can be transcribed. To investigate VDJ and monospecificity, KAPPA FLEX MOUSE scientists engineered a novel gene-targeted mouse, kFlex, which expresses a diverse but allelically-included antibody repertoire. To investigate recombination and allelic exclusion, the scientists looked at distal and proximal gene promoters in the mouse. The scientists found that one distal promoter has an influence on recombination but not a proximal promoter in the same study. Moreover, moving the distal gene closer did not disturb VJ recombination. Unexpectedly, innate immune signals that activate the proximal promoter in mature B cells were identified. Illegal recombination within the Ig gene segments can induce lymphoid cancers and the project team is going to continue to investigate this phenomenon in the next period of the project. Furthermore, infringement of allelic exclusion with regard to Ig genes is linked to autoreactive B lymphocytes leading to autoimmune diseases. The importance of KAPPA FLEX MOUSE research is multi-stranded. The kFlex mouse is a potentially important model for immunotherapy work. The project is being conducted through a collaboration between European and United States partners and stands to support mutually beneficial long-term cooperation.
