Polyreactivity of Human IgG Fc-binding Phage Antibodies Constructed from Synovial Fluid CD38+ B Cells of Patients with Rheumatoid Arthritis

• Published in: Journal of autoimmunity Vol. 19; no. 4; pp. 241 - 250
• Main Authors: van Esch, W.J.E., Reparon-Schuijt, C.C., Hamstra, H.J., van Kooten, C., Logtenberg, T., Breedveld, F.C., Verweij, C.L.
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 01.12.2002; Elsevier
• Subjects: ADP-ribosyl Cyclase - immunology; ADP-ribosyl Cyclase 1; Antigens, CD - immunology; Arthritis, Rheumatoid - immunology; B-Lymphocytes - immunology; Bacteriophages - immunology; Biological and medical sciences; Chymotrypsinogen - immunology; Complementarity Determining Regions - immunology; Diseases of the osteoarticular system; Humans; Immunoglobulin G - immunology; Inflammatory joint diseases; Medical sciences; Membrane Glycoproteins; Peptide Library; phage display, polyreactivity, rheumatoid arthritis, rheumatoid factor activity, synovial fluid plasma cells; Receptors, Fc - immunology; Rheumatoid Factor - immunology; Synovial Fluid - immunology; phage display, polyreactivity, rheumatoid arthritis, rheumatoid factor activity, synovial fluid plasma cells; Human; Immunopathology; Antigenic determinant; Diseases of the osteoarticular system; IgG; Autoimmune disease; Inflammatory joint disease; B-Lymphocyte; Rheumatoid factor; Synovial fluid; Chronic; Phage display; Reactivity; Immunological investigation; Rheumatoid arthritis
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1006/jaut.2002.0621

Recent data indicate that rheumatoid factors (RFs) that occur in patients with rheumatoid arthritis (RA) are derived from Ig-producing terminally differentiated CD20−, CD38+ plasma cells present in synovial fluids (SFs). Phage antibody display libraries were constructed using CD38+ plasma cells isolated from SFs of two RF-seropositive RA patients. The libraries were enriched for phage antibodies (Phabs) binding to human IgG (HuIgG) Fc fragments and the sequences of their V genes were analysed. These data provided further evidence for an Ag-driven immune response in patients with RA, including expansion of clonally related B cells, selection and isotype switching, all hallmarks of a germinal center reaction. In the present study, the functional characteristics of these HuIgG Fc-binding monoclonal (mo) Phabs were further analysed in order to provide more insight into the specificity of HuIgG Fc-binding Phabs. Remarkably, all HuIgG Fc-binding moPhabs tested (n=48; derived from four different libraries) displayed polyreactivity. Structural analysis of the CDR3 regions revealed characteristic features of polyreactive Igs. Most H chain CDR3 regions harboured tryptophan/tyrosine-rich parts and approximately 60% of the L chain CDR3 regions of both RA patients displayed an identical stretch of amino acids (W/Y-D-S-S). Supportive for a dominant role of VH in specificity, exchange of VL regions with a single VH region yielded moPhabs with similar specificities. All together, the data suggest the presence of an Ag-driven process in the joints of patients with RA, including somatic mutation and clonal selection entailing isotype switching, resulting in the differentiation of B cells into polyreactive RF-secreting plasma cells.