Molecular Genetics Laboratory

The immune system is the most complex genetic system described to date. Using a number of different approaches, studies originated in the laboratory of Gary Litman, Ph.D. (emeritus) helped redefine our understanding of the phylogeny of immune response genes. Currently led by Larry Dishaw, Ph.D, the molecular genetics laboratory is studying how diverse components of the immune system maintain normal and healthy interactions with microbial communities that colonize various surfaces of the body, i.e., the microbiome. Since mucosal surfaces are key interfaces between host and the environment, simple disruptions can contribute to instabilities such as loss of homeostasis, inflammation, allergy, autoimmune-like conditions, etc.

Over the years, the molecular genetics laboratory has utilized diverse model systems to identify novel families of immune receptors possessing distinct structural and regulatory features. These innate immune molecules, in some cases, also appear to utilize alternative signaling pathways for mediating immune function and as such have enhanced our understanding of integration of regulatory networks that factor into host protection.

A recently utilized model, for example, was the zebrafish, which afforded unique experimental advantages. Zebrafish was found to possess two major (and 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. Various in vitro and in vivo approaches were used to determine how these extraordinarily diverse genes function in innate immunity; efforts revealed lipid binding as a basic mechanism in modulating innate immune function in the CD300/TREM gene families in higher vertebrate models.

Genetics Laboratory

Molecular Genetics Laboratory faculty include:

The marine invertebrate chordate, Ciona robusta (formerly Ciona intestinalis type A), is a model organism that in recent years has been adapted by our laboratory for studies of host-microbe interactions within the gut. Because Ciona is a chordate that relies exclusively on innate immunity yet is able to manage complex microbiota, it can inform us of the critical roles of innate immunity in homeostasis. We have shown that Ciona expresses the products of a unique gene family, variable-region containing chitin-binding proteins (VCBPs), which are comprised of immunoglobulin variable regions and a chitin binding domain (CBD). VCBP-C, which is expressed predominantly in the gut, binds bacteria and influences processes such as phagocytosis and biofilm formation via its immunoglobulin variable domains. We found that Ciona makes endogenous chitin in the form of a chitin-rich mucus that lines the gut epithelium; VCBPs become tethered to this surface via interactions with the CBD, leaving the Ig domains for interactions with bacteria. Gut microbiota comprise diverse communities of microorganisms that effect several host physiological processes and it is likely that VCBPs also interact with chitin-rich organisms, which are common in the marine environment. Thus, a bifunctional property of VCBP-C is unique among immune effectors in that it can recognize diverse microbes on both the N- and C- terminus of the effector protein.

The molecular genetics 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 understanding how primary immunodeficiency disease can better inform us of the complex dialogues involving host immunity and the microbiome.