T Cell Epitope Mimicry in Antiglomerular Basement Membrane Disease

Abstract

Antiglomerular basement membrane (GBM) disease or Goodpasture’s syndrome is among the earliest recognized human autoimmune diseases. Although collagen 4α3 NC1 (Col4α3NC1) has been identified as the responsible autoantigen, it remains unknown how autoimmunity to this autoantigen is provoked. We have demonstrated in our rat model that a single nephritogenic T cell epitope pCol28–40 of Col4α3NC1 induces glomerulonephritis. We hypothesized that microbial peptides that mimic this T cell epitope could induce the disease. Based on the critical residue motif (xxtTxNPsxx) of pCol28–40, seven peptides derived from human infection-related microbes were chosen through GenBank search and synthesized. All peptides showed cross-reactivity with pCol28–40-specific T cells at various levels. Only four peptides induced transient proteinuria and minor glomerular injury. However, the other three peptides induced severe proteinuria and modest to severe glomerulonephritis in 16–25% of the immunized rats. Unexpectedly, the most nephritogenic peptide, pCB, derived from Clostridium botulinum, also induced modest (25%) to severe (25%) pulmonary hemorrhage, another important feature of anti-GBM disease; this was not correlated with the severity of glomerulonephritis. This finding suggests that subtle variations in T cell epitope specificity may lead to different clinical manifestations of anti-GBM disease. In summary, our study raises the possibility that a single T cell epitope mimicry by microbial Ag may be sufficient to induce the anti-GBM disease.

Identification of a nephritogenic immunodominant B and T cell epitope in experimental autoimmune glomerulonephritis

“…Further evidence supporting the role of T cell-mediated cellular immunity in the pathogenesis of EAG is documented in recent studies, including our own, demonstrating that synthetic peptides derived from a3(IV)NC1 can induce glomerulonephritis in Wistar Kyoto (WKY) rats [28][29][30][31][32][33][34][35]. Luo et al showed that a 24-mer synthetic peptide, pCol , from the N terminus of a3(IV)NC1 was capable of inducing glomerulonephritis, although this was mild and inconsistent [29], while Wu et al showed that a 13-mer peptide, pCol (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), containing a T cell epitope from a3(IV)NC1, induced severe crescentic glomerulonephritis [30].…”

“…In this study we have demonstrated that a 15-mer peptide from the N-terminus of a3(IV)NC1, pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38), is recognized by B and T cells from rats immunized with recombinant a3(IV)NC1, and that the same peptide is capable of inducing crescentic glomerulonephritis. Identification of this immunodominant peptide should be of value in designing new therapeutic strategies for mucosal tolerance in EAG, which may be applicable to patients with glomerulonephritis.…”

“…In order to investigate whether B and T cell responses in EAG are directed towards immunodominant peptides within the same region of rat a3(IV)NC1, we immunized WKY rats with five 15-mer overlapping synthetic peptides spanning the region of the major human B cell epitope within the N-terminus of a3(IV)NC1. Positive control animals immunized with recombinant rat a3(IV)NC1 produced an antibody response directed towards a3(IV)NC1 and the second 15-mer peptide, pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Splenic T cells from these animals proliferated in response to a3(IV)NC1 and pCol (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38).…”

“…5. (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38). Results shown represent the mean Ϯ standard deviation of each group at week 6 after immunization.…”

“…Luo et al showed that a 24-mer synthetic peptide, pCol , from the N terminus of a3(IV)NC1 was capable of inducing glomerulonephritis, although this was mild and inconsistent [29], while Wu et al showed that a 13-mer peptide, pCol (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40), containing a T cell epitope from a3(IV)NC1, induced severe crescentic glomerulonephritis [30]. In further characterization of this T cell epitope, it was shown that autoantibody deposition followed T cell-mediated damage to the kidney [31] and that only three residues within the peptide were critical for disease induction [32].…”