Antibodies to Human Cytomegalovirus 65-Kilodalton Fc Binding Protein in Rheumatoid Arthritis: Idiotypic Mimicry Hypothesis of Rheumatoid Factor Production

Abstract

We previously reported that rheumatoid factors (RFs) might bear the internal image of Fc gamma-binding proteins (FcBPs) of herpes family viruses, suggesting the possibility that some RFs may be produced as antiidiotypic antibodies to anti-viral FcBP antibodies. Since human cytomegalovirus (HCMV) has been implicated in the pathogenesis of RA, we made an attempt to detect antibodies to 65 KD major HCMV FcBP in sera and synovial fluid from patients with RA. Western blotting was performed using HCMV-infected MRC-5 cell lysate as the antigen. Eleven of 23 patients with RA possessed strong serum antibodies to HCMV-65 KD protein, whereas such antibodies were found in only 2 of 23 normal controls. In the synovial fluid, 10 of 19 RA patients showed anti-HCMV 65 KD reactivity. Pepsin-digested IgG retained anti-65 KD reactivity, indicating that false-positive reaction due to the presence of IgG Fc portion and/or RF was unlikely. 65 KD protein was shown to be different from human heat shock proteins (hsps) using monoclonal antibodies against human hsps. Patients' IgG F(ab')2 also reacted with the 65 KD protein of purified HCMV virion itself. These results support the possibility that some RFs could be produced as antiidiotypic antibodies to anti-viral FcBP antibodies.

Do Chickens Immunized with Bacterial Immunoglobulin G‐Binding Proteins Produce Rheumatoid Factor‐Like Antibodies?

“…A number of studies have reported generation of RF-like antibodies in animals immunized with bacterial and viral Ig-binding proteins [1][2][3][4][5][6][7][8][9][10][11]. Three possible explanations have been proposed to account for generation of these antibodies and for the finding that the resulting species reactivity profile of the anti-IgGbinding antibody mimics the reactivity profile of the bacterial or viral Fc-binding protein immunogen.…”

“…Bacterial immunoglobulin (Ig)G-binding proteins, such as staphylococcal protein A and streptococcal protein G, have many similarities in their reactivity to a family of autoantibodies against IgG, designated rheumatoid factors (RF), and present in the serum of certain patients with rheumatoid arthritis [1][2][3][4][5][6][7][8][9]. Rheumatoid factors and bacterial IgG-binding proteins bind to a similar site on the Fc region of IgG and also demonstrate similar patterns of species-specific reactivities [1][2][3][4][5][6][7][8][9]. These observations led to the hypothesis that RF antibodies might arise as part of an idiotype network in which the anti-idiotype to an antibody which specifically recognized a bacterial IgG-Fc-binding protein would result in an internal image of the antigen with similar Fc-binding characteristics [10][11][12].…”

Human Cytomegalovirus Reduces Endothelin-1 Expression in Both Endothelial and Vascular Smooth Muscle Cells

“…Endothelin-1 (ET-1), the most abundant protein of the endothelin family (ET-1, ET-2 and ET-3), is a 21-amino-acid long potent vasoconstrictor peptide that plays a pathophysiological role in various cardiovascular diseases including pulmonary arterial hypertension and atherosclerosis, as well as non-cardiovascular inflammatory diseases such as inflammatory bowel disease [39,40], rheumatoid arthritis [41][42][43] and SLE [44]. The endothelin axis is constituted by ET-1 and its receptors (either endothelin A (ETAR) or B (ETBR) receptor) and plays an important modulatory role in development, cell proliferation, apoptosis and immune responses and has been proposed to contribute to the growth and progression of many tumor types (reviewed in [45][46][47][48][49]).…”

Enhancement human cytomegalovirus replication in a human lung fibroblast cell line by interleukin-8

“…Several lines of evidence, however, suggested an association of CMV with RA. A substantial proportion of RA patients possessed antibody against CMV Fc binding protein (28). Electron microscopical and immunofluorescence analyses demonstrated the presence of CMV particles in cultured synovial cells from a patient with long-standing classical RA (11).…”