Inflammatory disease in HLA-B27 transgenic rats.

Area of Science:

• Immunology
• Genetics
• Rheumatology

Background:

• Human leukocyte antigen B27 (HLA-B27) is strongly associated with spondyloarthropathies.
• A rat model expressing HLA-B27 spontaneously develops inflammatory disease resembling human spondyloarthropathies.

Purpose of the Study:

• To investigate the mechanisms underlying HLA-B27-associated spondyloarthropathy using a transgenic rat model.
• To determine the role of specific HLA-B27 residues and peptide binding in disease development.

Main Methods:

• Generation of transgenic rats expressing human HLA-B27 or related alleles.
• Induction and assessment of inflammatory disease features like colitis and arthritis.
• Analysis of immune cell involvement (T cells), microbial factors, and cytokine profiles (interferon-gamma, interleukin-6).

Main Results:

• Transgenic rats expressing HLA-B27 developed spontaneous colitis and arthritis, dependent on T cells, gut bacteria, and B27 expression in bone marrow-derived cells.
• Rats expressing HLA-B7 or HLA-Cw6 did not develop significant disease, highlighting HLA-B27 specificity.
• A mutation at Cys67 of B27 reduced arthritis prevalence but did not abolish disease, while peptide binding specificity influenced arthritis more than colitis.
• Disease severity varied with the rat genetic background, with DA strain being protective.

Conclusions:

• The rat model demonstrates HLA-B27 specificity for spondyloarthropathy, independent of Cys67.
• Arthritis development is sensitive to HLA-B27 peptide-binding specificity, suggesting a role for peptide presentation.
• Genetic background significantly influences disease susceptibility and phenotype, though other mechanisms for HLA-B27's role remain possible.