Patho-physiological analysis of collagen vascular disease development results from dysfunction of the membrane microdomain, lipid rafts

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The findings that FcgRIIB, a prototypical negative regulatory immune receptor, has a common structural polymorphism associated with systemic lupus erythematodes at the transmembrane stretch, and that this polymorphism results in a reduction-of-function receptor, have for the first time prevailed the pivotal role of the negative regulatory receptor family in the immuno-surveillance in humans as well as previously underestimated functional significance of transmembrane domain in immune receptors. This study has been aimed at the structural elucidation of the transmembrane interface developed after the productive oligomerization of immune receptors with polyvalent antigens, immune complexes and stimulatory antibodies, and at the further knowledge of the initiation mechanisms of immune receptor signaling. During the study interval supported by the grant, we have for the first time unveiled that FcgRIIA, a counterpart of FcgRIIB with positive regulatory functions, specifically self associate with one another at the N terminus (outer surface) of the transmembrane stretch, and that this association is in fact productive event: dimerization of the receptor with the aid of disulfide bond mutageneis located at the N-terminus augments Lyn activation, Btk activation and Phospholipase C gamma activation without further ligation of the receotir. This model experiments clearly show that there is a specific, productive interface in immune receotor transmembrane domain, and suggest that the interface serves as a novel therapeutic target for the medicines dissociating the functional interface.