When Do Microbes Stimulate Rheumatoid Factor?

Abstract

A nti-␥ -globulins or rheumatoid factors (RF) were first described in the early 1940s. They are present in Ͼ 70% of patients with rheumatoid arthritis (RA) and high titers are associated with severe disease, but they also appear in a large number of other diseases including viral, bacterial, and parasitic infections (1). In spite of their wide spread occurrence, it is still a puzzle how or why RF are generated.RF come in two varieties. Low affinity RF (K d of ‫ف‬ 10 Ϫ 5 M) are IgM natural antibodies with specificity for IgG-Fc determinants and cross-reactivity with other autoantigens, i.e., polyreactivity. They are produced by CD5 ϩ B cells in normal subjects (2). Frequently they are IgM antibodies and use selected germline V genes for both H and L chains. This is why they share cross-reactive idiotypes, as discovered by Kunkel et al. in the 1970s (3). These antibodies are typically T cell independent. They are similar to the RF produced in response to polyclonal B cell activation by EBV (4) or LPS (5, 6). B cells producing these RF appear to be susceptible to malignant transformation as the RF-associated V genes are frequently expressed in low grade chronic B lymphoproliferative diseases such as chronic lymphocytic leukemia, Waldenstrom's macroglobulinemia, mixed cryoglobulinemia and lymphoma associated with Sjögren's disease. This may be due to constitutive expression of STAT3 in B1 cells (7). The RF-associated V genes are also over-expressed by human fetal B cells (8, 9), perhaps consistent with a role for low affinity RF in neonates that lack a mature humoral immune system. In spite of the low affinity, the multivalency of IgM RF allows excellent agglutination of latex particles or red blood cells, and presumably also microbial organisms, in vivo, that are coated with specific IgG antibodies. The presence of IgM RF can lead to large immune complexes with lattice formation, that are poorly soluble and rapidly removed by the mononuclear phagocyte system (10).High affinity RF (K d of ‫ف‬ 10 Ϫ 7 M) can be IgM, IgG, IgA, or IgE antibodies. RA patients may have high titers of this type of RF. Their production is T cell dependent. These antibodies often do not share the V genes used by the low affinity RF (11). They have undergone affinity maturation, as there are multiple somatic mutations in the V genes, and are therefore produced by antigen driven B cells. These RF bind most avidly to the Ig isotype which stimulated their production. In RA, RF are particularly abundant in the synovium. In some reports the dominant specificity of synovial RF is for IgG3-Fc (12), implying that the

Influenza Virus-Induced Type I Interferon Leads to Polyclonal B-Cell Activation but Does Not Break Down B-Cell Tolerance

“…One is due to chronic exposure of B cells to repetitive epitopes on the viral surface that maintains polyclonal B-cell activation through a T-cell-independent mechanism. The other occurs when the virus epitopes are presented in immune complexes and therefore induce a T-celldependent and antigen-specific RF production (26). In our model, we suppose that this antigen-specific event is missing, probably due to the incapacity of influenza virus to directly activate B cells.…”

A Mouse Herpesvirus Induces Relapse of Experimental Autoimmune Arthritis by Infection of the Inflammatory Target Tissue

“…Previous work showed that acute polyarthritis was observed in association with EBV infection (11), increased Ab titers were found in RA (12)(13)(14), molecular mimicry was entertained (15,16), and CD8 cell clones specific for lytic and latent EBV gene products were clonally expanded in inflamed synovia (17)(18)(19)(20). Staining with MHC class I peptide tetramers showed that EBV-specific CD8 T cells were enriched in RA synovia compared with blood from the same subject (21,22).…”

Immunostimulation in the era of the metagenome

“…While high titers of rheumatoid factor (RF) are associated with severe rheumatoid arthritis, they also appear in a number of other diseases including viral, bacterial and parasitic infections. 23 Maturation of RF can be initiated by chronic infections. 24 For example, patients with subacute bacterial endocarditis, which is frequently tied to the presence of Streptococcus, also often present with high levels of RF.…”