PAD4 Peptide p8 Targeting T Cells for Rheumatoid Arthritis
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Solution Overview
Problem
The development of rheumatoid arthritis (RA) is influenced by HLA-DRB1 genes, but the specific mechanisms, particularly how shared epitope positive HLA-DRB1 alleles contribute to RA, remain unclear, and the identification of target antigens for T cells that help produce anti-citrullinated peptide antibodies (ACPA) has been elusive.
Innovation Solution
A peptide derived from the PAD4 protein, specifically peptide p8, is identified as a target antigen for T cells that help produce ACPA, with a correlation found between HLA-DRB1 genotypes and the likelihood of PAD4 peptides binding to HLA-DR molecules, suggesting PAD4's role in RA pathogenesis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If HLA-DRB1 alleles associated with RA are used to bind and present peptides, then T cell activation occurs, but the specific target antigen for helper T cells that produce ACPA remains unidentified
Solution Approach 1:
The patent segments the search for target antigens by focusing specifically on PAD4 protein peptides rather than screening all possible citrullinated proteins. This segmentation allows systematic identification of PAD4-derived peptides that bind to HLA-DRB1 molecules and stimulate T cells, thereby resolving the contradiction between T cell activation and identification of specific target antigen.
Solution Approach 2:
The patent performs preliminary identification of PAD4 peptides with high binding affinity to HLA-DRB1 alleles before testing their ability to stimulate T cells. This preliminary screening of peptide candidates based on binding characteristics streamlines the process of identifying the specific target antigen, addressing the information loss about RA mechanisms.
2Quantity of substance
If extensive binding data on hundreds of fibrinogen, vimentin, collagen II and Epstein Barr virus peptides is used, then binding information is obtained, but it contradicts the SECIT hypothesis and fails to identify helper T cell targets
Solution Approach 1:
The patent extracts the specific problem from the overwhelming data by focusing exclusively on PAD4-derived peptides rather than continuing to test peptides from multiple protein sources. This extraction of the core issue (PAD4 as the specific target) resolves the contradiction between testing numerous peptides and precisely identifying the T cell target that produces ACPA.
3Reliability
If PAD4 peptides are used to stimulate T cells, then specific T cell responses are obtained, but the correlation between HLA-DRB1 genotypes and PAD4 peptide binding needs to be established
Solution Approach 1:
The patent establishes that PAD4 peptides serve multiple functions: they bind to various HLA-DRB1 alleles with different affinities, stimulate T cells from different patient groups, and correlate with disease risk. This multi-functionality of PAD4 peptides simplifies the correlation analysis system by providing a universal target that works across different HLA-DRB1 genotypes and patient populations.
Data Source
AI summary
The present invention relates to field of treatment of rheumatoid arthritis. The inventors propose that PAD4, one of the enzymes which convert arginine into citrulline, is a target antigen for T cells that help the production of ACPA. They recently demonstrated that PAD immunization triggers anti-citrullinated fibrinogen antibody production in normal mice. Here, they demonstrate that the risk (OR) to develop RA associated with each of 12 HLA-DRB1 genotype correlates with the likelihood for the two HLA-DR molecules encoded by each genotype to bind at least one random peptide from PAD4, but not from citrullinated or native fibrinogen. PBLs from patients with RA, PsA and controls proliferate to PAD4 and they identify, notably, a peptide from PAD4, p8 (SEQ ID NO: 6), that stimulates T cells from RA patients and a few patients with PsA. Proliferative responses to p8 are associated with RA, shared epitope positive HLA-DR alleles and antibodies to PAD4. Thus the present invention relates to a peptide derived from the PAD4 protein and its use in the treatment and prevention of rheumatoid arthritis.