The pathogenesis of rheumatoid arthritis (RA), similar to development of a majority of inflammatory and autoimmune disorders, is largely due to an inappropriate or inadequate immune response to environmental challenges. Among these challenges, infectious agents are the undisputed leaders. Since the 1870s, an impressive list of microorganisms suspected of provoking RA has formed, and the list is still growing. Although a definite causative link between a specific infectious agent and the disease has not been established, several arguments support such a possibility. First, in the absence of a defined pathogen, the spectrum of triggering agents may include polymicrobial communities or the cumulative effect of several bacterial/viral factors. Second, the range of infectious episodes (i.e., clinical manifestations caused by pathogens) may vary in the process of RA development from preclinical to late-stage disease. Third, infectious agents might not trigger RA in all cases, but trigger it in a certain subset of the cases, or the disease onset may arise from an unfortunate combination of infections along with, for example, psychological stress and/or chronic joint tissue microtrauma. Fourth, genetic differences may have a role in the disease onset. In this review, two aspects of the problem of “microorganisms and RA” are debated. First, is there an acquired immune deficiency and, in turn, susceptibility to infections in RA patients due to the too frequent and too lengthy infections, which at last break the tolerance of self antigens? Or, second, is there a congenital deficiency in tolerance and inflammation control, which may occur even with ordinary infection frequency and duration?

The aim of this work was to study the peripheral blood monocyte functions in patients with advanced RA and their predisposed to RA relatives in comparison with those in women, not hereditary tainted with autoimmune diseases (donors). In groups comprising 24 RA patients, 24 relatives, and 24 donors the following monocyte functions were assessed: engulfment and digestion (radioisotope method); release of lysosomal glucuronidase in response to opsonized zymosan (fluorescent method); reactive oxygen species (ROS) generation (chemiluminescence), and serum levels of proinflammatory cytokines (ELISA). The monocyte specific feature in patients and their relatives is chiefly extracellular digestion due to the delayed engulfment. The digestive activity, probably inhibited in relatives, is increased in advanced RA. ROS generation by the cells and serum levels of TNF-alpha and IL-1-beta are abundant both in the patients and their relatives. High levels of pro-inflammatory cytokines, presumably, of monocyte origin, and increased levels of stimulated ROS generation may be due to the priming and prolonged activation of monocytes in relatives.Conclusion:We show for the first time that the functioning of circulating mononuclear phagocytes in the assumed to be healthy predisposed to RA individuals differs from that in the healthy people not hereditary tainted with autoimmune diseases and in general resembles the functioning of the cells in the patients with advanced RA.

Rheumatoid arthritis (RA) development results from an inadequate immune response to environmental challenges in genetically predisposed patients. The list of viruses associated with RA is still growing, and includes the cytomegalovirus, the Epstein-Barr virus, and the herpes simplex viruses. Several hypotheses support their causative role. Firstly, RA development may result from a polyviral community or the cumulative effect of several microbial/viral factors thus explaining the absence of a single defined pathogen. Secondly, the process of RA development from preclinical to late-stage disease may result from cumulative episodes of viral infections caused by distinct pathogens. Thirdly, viral agents may trigger RA when associated with other factors such as tobacco, ethnic differences, psychological stress, inflammation, or chronic joint tissue micro-trauma. On the other hand, others consider that RA development occurs even with ordinary infection frequency and duration and results from immune hypersensitivity to viral infections which can lead to loss of tolerance to self-antigens.

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Radioisotope study of mononuclear phagocytes from patients with rheumatoid arthritis showed impaired ingestion of bacteria in the presence of pronounced digestive activity. Excessive accumulation methylumbelliferyl phosphate beta-glucuronide (product of hydrolysis catalyzed by glucuronidase released from cells) into the incubation medium was observed. This was probably related to the predominance of extracellular digestion.