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Selection and charcterisation of high affinity antibodies recognising misfolded HLA-B27 heavy chain complexes for the diagnosis and treatment of Ankylosing Spondylitis

English title Selection and charcterisation of high affinity antibodies recognising misfolded HLA-B27 heavy chain complexes for the diagnosis and treatment of Ankylosing Spondylitis
Applicant Renner Christoph
Number 120024
Funding scheme Project funding (Div. I-III)
Research institution Klinik für Onkologie Bereich Innere Medizin-Onkologie Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Immunology, Immunopathology
Start/End 01.06.2008 - 29.02.2012
Approved amount 360'000.00
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Keywords (3)

spondylitis ankylosans; HLA-B27; MHC antibodies

Lay Summary (English)

Lead
Lay summary
Inflammatory diseases of the joints are very common and can be divided into different categories. The expression of the immune-receptor HLA-B27 (B27) is strongly associated with development of the spondyloarthritides, a group of common diseases including reactive arthritis (ReA) and ankylosing spondylitis (AS), where 94% of patients express B27. The role of HLA-B27 in disease remains unclear. ReA usually follows infection with gram-negative intracellular bacteria including Salmonella sp. suggesting a causal link between infection and pathogenesis. The classical function of immune-receptors such as B27 is to present antigenic peptides as a heterotrimeric complex with beta 2-microglobulin (ß2m) for T cell receptor (TCR) recognition by CD8+ cytotoxic T cells. The “arthritogenic“ peptide hypothesis proposes that disease results from the ability of HLA-B27 to form complexes with pathogen-derived antigenic peptides that resemble heterotrimeric complexes with self peptide. Alternatively, HLA class I and/or II complexes with B27-derived peptides could resemble complexes with foreign peptides. HLA-B27 can be expressed in two conformations at the cell surface: as cell surface beta2-microglobulin (beta2m)-free homodimers (B272) and multimers. We hypothesize that B272 is upregulated in spondyloarthritis and that differential interaction of beta2m-associated HLA-B27 and B272 with immune receptors is involved in the pathogenesis of B27-associated spondyloarthritis. B272 and beta2m-associated MHC class I bind differently to receptors expressed by immune cells such as NK and T cells. Our working program includes the selection of antibodies that specifically bind to B272 and not to HLA-B27. These antibodies will be further characterized for their binding profile to recombinant B27 molecules and their ability to recognise B272 dimers on transfected cell lines and leukocyte samples from patients with active disease. With the help of these antibodies we try to define the proportion of B272 dimers on leucocytes from diseased patients, the percentage of positive cells at various stage of disease activity and the potential role of B272 dimers for disease initiation and progression.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Inhibiting HLA-B27 homodimer-driven immune cell inflammation in spondylarthritis.
Payeli SK1 Kollnberger S Marroquin Belaunzaran O (2012), Inhibiting HLA-B27 homodimer-driven immune cell inflammation in spondylarthritis., in Arthritis Rheum., 64(10), 3139-3149.

Collaboration

Group / person Country
Types of collaboration
MRC Oxford Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel

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