Molecular Genetics Laboratory

The immune system is the most complex genetic system described to date. Using a number of different approaches, studies conducted in our laboratory have identified key aspects of the development of the lymphoid system and are shedding light on the origins of mechanisms that create immune receptor diversity as well as the nature of those features of the genome that promote genetic recombination, a major factor in both immune diversity and cancer. Over the past several years, we have defined several extensively diversified families of putative immune receptors possessing distinct structural and regulatory features. In the process, we have identified alternative mechanisms for creating immune diversity, different forms of recognition that may function in innate immunity in humans and alternative pathways of receptor diversification. Novel innate immune molecules have been identified that potentially utilize alternative signaling pathways for mediating immune function and as such have enhanced our understanding of integration of regulatory networks that factor in host protection.

Current efforts focus on two model systems, zebrafish and Ciona, that afford distinct experimental advantages. Zebrafish have been shown by us to possess two major novel families of immune receptor genes that encode variable region domains in addition to those that function in the mammalian-like adaptive immune system of this species. Although one of the gene families, novel immune-type receptors (NITRs), appears to encode natural killer (NK) receptors, the role of the other multigene family, diverse immunoglobulin domain-containing proteins (DICPs), presently is not understood. DICPs bind lipid ligands and lack a homolog outside of bony fish. Different transgenic approaches are being used to determine how these extraordinarily diverse genes function in innate immunity. The role of repetitive DNA in genome stability is being investigated in a zebrafish read-out model and efforts are being made to understand lipid binding as a basic mechanism in modulating innate immune function in the CD300/TREM gene families in higher vertebrate models.

Ciona, a marine urochordate, is being developed as a model to study general features of gut immunity and serves as a gnotobiotic system that can be used to study microbial influences on inflammatory gut pathology in the absence of influences from the adaptive immune system which is not found outside of vertebrates. We have shown that the variable region-containing chitin-binding proteins (VCBPs) in Ciona function in phagocytosis and that these molecules may represent a determining factor in shaping the microbial communities of the gut. The immune phenotype of the dysbiotic gut and the Ciona colitis model are being investigated. Gene silencing approaches (including dietary introduction of dsRNA) are being evaluated as tools to dissect the role of various innate immune receptors in gut-mediated immune dynamics.

Our laboratory has a longstanding interest in the molecular basis for primary immunodeficiency disease and has characterized genotype-phenotype relationships in X-linked agammaglobulinemia as well as the basis for antibody diversity in DiGeorge Syndrome. More recent efforts are focused on the role of gene conversion in the pathogenesis of selected B cell immunodeficiencies.