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Experimental Antiglomerular Basement Membrane GN Induced by a Peptide from Actinomyces
Qiu-Hua Gu1,2,3,4, Megan Huynh5, Yue Shi1,2,3,4
1Renal Division, Peking University First Hospital, Beijing, PR China.
Background:
Antiglomerular basement membrane (anti-GBM) disease is associated with HLA-DRB1*1501 (the major predisposing genetic factor in the disease), with α3127-148 as a nephritogenic T and B cell epitope. Although the cause of disease remains unclear, the association of infections with anti-GBM disease has been long suspected.
Methods:
To investigate whether microbes might activate autoreactive T and B lymphocytes via molecular mimicry in anti-GBM disease, we used bioinformatic tools, including BLAST, SYFPEITHI, and ABCpred, for peptide searching and epitope prediction. We used sera from patients with anti-GBM disease to assess peptides recognized by antibodies, and immunized WKY rats and a humanized mouse model (HLA-DR15 transgenic mice) with each of the peptide candidates to assess pathogenicity.
Results:
On the basis of the critical motif, the bioinformatic approach identified 36 microbial peptides that mimic human α3127-148. Circulating antibodies in sera from patients with anti-GBM recognized nine of them. One peptide, B7, derived from Actinomyces species, induced proteinuria, linear IgG deposition on the GBM, and crescent formation when injected into WKY rats. The antibodies to B7 also targeted human and rat α3127-148. B7 induced T cell activation from human α3127-148-immunized rats. T cell responses to B7 were detected in rats immunized by Actinomyces lysate proteins or recombinant proteins. We confirmed B7's pathogenicity in HLA-DR15 transgenic mice that developed kidney injury similar to that observed in α3135-145-immunized mice.
Conclusions:
Sera from patients with anti-GBM disease recognized microbial peptides identified through a bioinformatic approach, and a peptide from Actinomyces induced experimental anti-GBM GN by T and B cell crossreactivity. These studies demonstrate that anti-GBM disease may be initiated by immunization with a microbial peptide.
Insights
Infections may trigger antiglomerular basement membrane (anti-GBM) disease. A microbial peptide from Actinomyces species was found to mimic a human epitope, causing experimental anti-GBM disease in animal models.
Area of Science:
- Immunology
- Nephrology
- Microbiology
Background:
- Antiglomerular basement membrane (anti-GBM) disease is linked to HLA-DRB1*1501, with the α3127-148 epitope being a key nephritogenic factor for T and B cells.
- The precise cause of anti-GBM disease is unknown, but infections have long been suspected as a potential trigger.
Purpose of the Study:
- To investigate the hypothesis that microbial infections can activate autoreactive T and B lymphocytes through molecular mimicry in anti-GBM disease.
- To identify specific microbial peptides that mimic human epitopes involved in anti-GBM disease pathogenesis.
Main Methods:
- Bioinformatic tools (BLAST, SYFPEITHI, ABCpred) were employed for peptide searching and epitope prediction, focusing on microbial peptides mimicking the human α3127-148 epitope.
- Sera from anti-GBM disease patients were used to identify antibodies recognizing specific microbial peptides.
- Candidate peptides were tested for pathogenicity by immunization in WKY rats and HLA-DR15 transgenic mice.
Main Results:
- Thirty-six microbial peptides mimicking the human α3127-148 epitope were identified. Nine of these were recognized by antibodies in patient sera.
- A peptide (B7) from Actinomyces species induced experimental anti-GBM glomerulonephritis (GN), characterized by proteinuria, IgG deposition on the GBM, and crescent formation in rats.
- Antibodies to B7 cross-reacted with human and rat α3127-148 epitopes, and B7 induced T cell activation, confirming its role in T and B cell cross-reactivity and pathogenicity in HLA-DR15 transgenic mice.
Conclusions:
- Microbial peptides, identified via bioinformatic analysis, are recognized by sera from anti-GBM disease patients.
- A specific peptide from Actinomyces species demonstrated pathogenicity, inducing experimental anti-GBM GN through T and B cell cross-reactivity.
- These findings suggest that anti-GBM disease may be initiated by an immune response to a microbial peptide mimicking a self-epitope.
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