Dorin Bogdan Borza, Ph.D.

Research Summary

Type IV collagen is a major component of basement membranes, evolutionarily conserved in all animal phyla. In mammals, collagen IV family comprises six chains that assemble into three distinct heterotrimeric molecules and networks, with tissue specific distribution and function. The a3a4a5(IV) collagen of the glomerular basement membrane (GBM) is an important constituent of the glomerular filtration barrier. Mutations that impair the normal assembly of a3a4a5(IV) collagen in the GBM are the underlying cause of Alport syndrome, the most common inherited glomerulopathy leading to end-stage renal disease.
The GBM is also the primary site of injury in very aggressive forms of glomerulonephritis mediated by anti-GBM antibodies. Pathogenic antibodies are elicited by autoimmune or alloimmune mechanisms and target specific sites on a3a4a5(IV) collagen. These sites are located within the non-collagenous (NC1) domains, which mediate the specific assembly of collagen IV chains into quaternary structures, forming NC1 hexamers in the native tissues. The fulminant course of anti-GBM nephritis demands prompt therapeutic intervention, but current immunosuppressive treatments are non-specific, toxic, and often unsuccessful. The development of more effective, targeted therapies is hindered by our rudimentary understanding of the mechanisms by which immune self-tolerance to collagen IV is normally established in health, broken in autoimmune anti-GBM disease, or selectively deficient in Alport syndrome.
A major objective of our research is to determine at molecular level how the adaptive immune system is abnormally engaged, initiating anti-GBM nephritis in human disease and mouse models. Our premise is that assembly of collagen IV chains into quaternary structures profoundly affects adaptive immune responses to this antigen in health and disease, because the formation of NC1 hexamers: a) hides cryptic B cell epitopes while creating novel quaternary epitopes; b) affects the processing and presentation of T cell epitopes; and c) shapes immune tolerance by determining which collagen IV chains associate and their native structure in tissues. We focus on anti-GBM antibodies because they play a central role in the disease pathogenesis by coupyling the activation of antigen-specific B and T cells to effector pathways causing tissue damage. The nephritogenicity of anti-GBM antibodies is contingent upon their ability to bind to accessible sites in the GBM and engage inflammatory effectors. We hypothesize that the formation of pathogenic antibodies is determined by both molecular structure of the antigen and the host genetic background (antigen-deficient or -sufficient).
Projects in my lab seek to: a) characterize novel subsets of anti-GBM autoantibodies and alloantibodies from patients; b) establish rodent models of anti-GBM nephritis induced by passive transfer of human auto/alloAbs from patients; c) determine the mechanisms uncoupling adaptive humoral immune responses from glomerulonephritis in patients with anti-GBM auto/alloAbs but normal renal function; d) identify the pathogenic determinants of the inciting alloantigen and of the anti-GBM alloAbs causing post-transplant nephritis in Alport patients; e) characterize the molecular features of the antigen and antibodies determining the development of anti-GBM nephritis in mouse models, and their effector mechanisms; f) establish how the genetic deficiency of collagen IV chains in Alport syndrome is permissive for pathogenic alloimmune responses by identifying abnormal B cell and T cell responses to collagen IV in antigen-knockout mice.
Better knowledge of antigenic determinants and effector mechanisms of pathogenic antibodies will facilitate the development of targeted strategies for prevention, detection, and treatment of human anti-GBM disease.

Research Keywords

Biochemistry, Immunology, Pathology, Protein Structure, Renal biology,