Shaping of the secondary antibody repertoire is generated by means of class- switch recombination (CSR), which replaces IgM with other isotypes, and somatic hypermutation (SHM), which allows production of high-affinity antibodies. Both CSR and SHM are triggered by deamination of cytidine residues (to yield uracil) within the immunoglobulin locus. Deamination is catalyzed by the cytidine deaminase AID, which is thought to bind and deaminate ssDNA exposed on the transcribed immunoglobulin gene, generating U:G mismatches that are resolved via the action of Uracil-N- glycosylase (UNG) to generate either point mutations or switch recombination. Defects in CSR or SHM are directly associated with primary immunodeficiencies, characterized either by a lack of switched isotype production (hyperIgM syndrome) or associated with abnormal somatic hypermutation (Common Variable Immune Deficiency or CVID, and other idiopathic humoral immunodeficiencies). A subset of the molecular defects that give rise to hyperIgM disease have been characterized. Prominently, hyperIgM has been linked with AID deficiency caused by recessive mutations of the aicda gene as well as with defects in UNG function. It has also been linked with defects in the signaling pathway that culminate in, amongst other things, AID production (such as CD40 and CD40 ligand defects). However, a number of hyperIgM patients have been described in the literature, with no defects in these loci. Clearly, mutations of as yet unknown genes can result in hyperIgM syndrome. Genetic experiments with AID mutants has led to a current understanding in the field, that a number of these unknown genes will encode proteins which interact with AID. Herein we describe a novel screen which aims to identify AID co-factors, which we then propose to characterize in vivo. Our experiments have the potential to directly uncover the molecular basis of hyperIgM syndromes for which the cause is unknown, hence offering the opportunity not only to better define the clinical spectrum of this primary immunodeficiency but also, in certain cases, to prompt better diagnostic and therapeutic approaches. PUBLIC HEALTH RELEVANCE: The experiments proposed here are important for determining how our immune system controls the beneficial mutation process upon which it depends to generate antibody specificities against foreign substances. This mutational process is a central component of the immune system and as such its absence has been directly implicated in immune deficiencies. Its deregulation has also been a cause of autoimmune diseases, and furthermore, it has been directly linked to the generation of B cell lymphomas. Therefore understanding the components involved in regulating this process will not only uncover the molecular defects underlying immune deficiencies (such as hyper-IgM syndrome) but will also help us gain better knowledge of the genetic and environmental causes of autoimmune diseases as well as B cell lymphomagenesis.