Carbohydrate binding proteins of the C-type lectin family are involved in the mechanisms by which cell traffic during an inflammatory response, in the processes of immune cell activation and in the recognition of pathogens through the binding of microbial determinants on these microorganisms. Pathogens have co-opted many of these pathways to provide means by which they can evade the immune response and persist despite immune surveillance. One sub-family, DC-SIGN and its murine homologue, SIGN R1, bind to high mannose oligosaccharides, as well as fucose containing glycans, such as the Lewisx trisaccharides. These binding specificities underlie the ability of these molecules to interact with the envelope glycoprotein of HIV and other virus, as well as the surface glycoproteins of bacterial, protozoal and helminthic pathogens. HIV, M. tuberculosis and S. mansoni have co-opted this pathway to evade immune responses by sequestering within DCs and by triggering pathways that suppresses inflammatory, TH1 type responses, including modulating TLR signaling and preventing DC maturation. We recently described a novel binding interaction mediated by SIGN R1 and DC SIGN, involving a glycoform of IgG found in the serum of healthy adults, 12,6sialylFc, that results in an anti-inflammatory response, capable of conferring protection from the pathogenic effects of autoantibodies. The studies described in this proposal will focus on defining this novel, anti-inflammatory response through the following three aims:
Aim 1 will dissect the specificity of the binding interaction between SIGN R1, DC-SIGN and 12,6sialylFc by generating defined mutations in both the ligand and receptors and performing detailed binding studies;
Aim 2 will address the signaling pathways induced by this binding interaction in marginal zone macrophages and human DCs through transcriptome and proteome analysis and Aim 3 will address the biological consequences in vivo of DC-SIGN and SIGN R1 engagement of 12,6sialylFc through the generation and analysis of defined transgenic and knockout strains of mice.
These studies will dissect an endogenous, anti-inflammatory pathway, initiated by 12,6sialylFc, that that will serve as a guide for the development of novel anti- inflammatory therapeutics for the treatment of autoimmune disorders and as a means of overriding immune evasion by pathogens.
|DiLillo, David J; Tan, Gene S; Palese, Peter et al. (2014) Broadly neutralizing hemagglutinin stalk-specific antibodies require Fc?R interactions for protection against influenza virus in vivo. Nat Med 20:143-51|
|Yuan, R; Clynes, R; Oh, J et al. (1998) Antibody-mediated modulation of Cryptococcus neoformans infection is dependent on distinct Fc receptor functions and IgG subclasses. J Exp Med 187:641-8|
|Clynes, R; Takechi, Y; Moroi, Y et al. (1998) Fc receptors are required in passive and active immunity to melanoma. Proc Natl Acad Sci U S A 95:652-6|