The Goodpasture antigen is expressed in the human thymus

Abstract

The results demonstrate that alpha3(IV)NC1 is expressed in the human thymus, and therefore should be available for induction of alpha3(IV)NC1-specific tolerance. This observation has the important implication that patients' alpha3(IV)NC1-specific, autoreactive T cells are more likely to recognize cryptic epitopes that are not adequately presented by thymic antigen-presenting cells (APC) than the major antigen-derived epitopes generally identified by conventional approaches.

The HLA-DRB1*15

“…11 DRB1*15:01 Tg mice were immunized with a1(IV)NC1, a3(IV)NC1, or the E A chimera (containing ha3 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] or the E B chimera (containing ha3 127-141 overlapping the restricted T cell epitope), and lymphocytes were then re-stimulated with either murine a3 9-28 or a3 129-148 . Mice immunized with a1(IV)NC1 or the E A chimera responded to neither peptide ( Figure 4A), whereas mice immunized with the E B chimera or full-length a3(IV)NC1 responded to a3 129-148 but not a3 [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] .…”

“…Autoantibodies bind to the conformational a3(IV) NC1 epitopes "E A " a3 [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31] and "E B " a3 127-141 (all amino acid numbering, including other cited epitopes, follows Netzer et al). 11 Studies examining T cell epitopes in human anti-GBM disease are less common, although an important study showed reactivity to two peptides, a3 68-89 and a3 [129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145][146][147][148] (close to the E B autoantibody epitope), in all six patients studied.…”

Goodpasture Autoantibodies Unmask Cryptic Epitopes by Selectively Dissociating Autoantigen Complexes Lacking Structural Reinforcement

“…Although ␣3(IV) collagen is present in the thymus and available for induction of T cell tolerance (26), autoreactive T cells still escape elimination and circulate (27). The crypticity of the GP epitopes in tissue basement membranes makes it unlikely, however, that autoreactive T cells in the peripheral immune system will expand without an external precipitating event.…”

Mammalian collagen IV

“…Genetic factors have been reported indicating that patients with certain allelic variations (HLA-DRB1*1501 and DRB1*1502) have increased susceptibility to develop the disease, whereas other alleles (HLA-DR7 and DR1) are protective (Phelps and Rees, 1999). The role of autoreactive CD4+ Tcells in mediating the disease has been reported, clearly indicating the importance of cell-mediated autoimmunity in the pathogenesis (Salama et al, 2001;Wong et al, 2001). …”