Fibronectin (Fn) is a high molecular weight cell surface and plasma glycoprotein composed of discrete ligand binding domains (collagen, fibrin, heparin, etc) that mediate various biological activities. Fn has also been found associated with cryoglobulins and immune complexes (ICs). Our studies indicate that the major immunoglobulin (Ig) classes of IgG, IgM, and IgA specifically bind to three separate regions of the Fn molecule. To examine the biochemical nature and structure/function relationship of Fn/Ig interaction, we plan to determine the primary structure in both Ig's and Fn, involved in this interaction. This will be accomplished in two ways: 1) by obtaining proteolytic fragments of Fn and Igs, that retain their binding capacity, for amino acid sequencing. 2) by inhibiting the interaction of Fn with Igs in a competitive ELISA using genetically cloned amino acid sequences of Fn (type I repeat modules) and synthetic peptides of Fn and Igs. Because Fn is an opsonin, the significance of Fn/Ig interaction is implicated in accelerated clearance of ICs from the circulation and at sites of deposition. From a pathological consideration, the interaction of Fn with Ig may be involved in the etiology of immune complex disease (ICD), such as observed in many myeloproliferative and autoimmune disorders, where inflammation results from the deposition of ICs in tissues that contain Fn. We plan to compare the binding interaction (affinities) of Fn with normal Igs and cryoglobulins, by ELISA, and determine whether a minimum aggregate size of Ig complex may dispose the binding of ICs to Fn. Fn-containing extracellular matrices (ECM) will be generated (acellular following cell lysis) and used as an in vitro model to test for IC binding; this system should provide an in vivo correlate for IC deposition in tissues. The Ig-binding peptide sequence of Fn, determined by the structural studies, will be use to inhibit ICs from binding to the ECM. Effective inhibition would demonstrate a role for ECM Fn (tissue) in the sequestration of ICs and thereby, implicate the interaction of Fn with Ig in the mechanism of ICD. The study of the interaction of Fn with Ig should provide insight into the etiology of ICDs and elucidate mechanisms involved in normal host immune function.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Pathobiochemistry Study Section (PBC)
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New York University
Schools of Medicine
New York
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Rostagno, Agueda A; Gallo, Gloria; Gold, Leslie I (2002) Binding of polymeric IgG to fibronectin in extracellular matrices: an in vitro paradigm for immune-complex deposition. Mol Immunol 38:1101-11
Rostagno, A; Williams, M; Frangione, B et al. (1996) Biochemical analysis of the interaction of fibronectin with IgG and localization of the respective binding sites. Mol Immunol 33:561-72