Infectious Agents

Infectious agents have been associated with the development of malignancies in patients with RA [66], Patients with RA have an increased risk of infection. Sepsis, bacterial and viral infections are common in patients with RA and are among the leading causes of death for patients with RA [8], Furthermore, patients with RA may develop chronic viral infections. This increased risk of infection is related to the immuno-

suppressive therapy and possibly to the immunological alteration that occur as a result of the disease itself.

Chronic infection with Epstein-Barr Virus (EBV) has been associated with the development of lymphomas in patients with RA and patients receiving immunosuppressive therapy for organ transplantation [71]. EBV genome was detected in the malignant cells of RA patients who developed large cell lymphoma. Infected cells from those patients expressed the full complement of EBV encoded proteins and nuclear RNAs essential for latent infection [72].

Natkunam et al. [73] reported 10 cases of patients with RA or dermatomyositis who developed EBV-related lymphomas. In 8 of these cases, the predominant type of EBV was type A. This frequency of infection with type A is similar to that seen in patients with post-solid organ transplantation immunosuppression associated lymphomas [73].

In three patients, a deletion at the 3' end of the latent membrane protein 1 (LMP-1) was seen. The LMP-1 is EBV-encoded membrane protein known to be oncogenic and mutation at the LMP-1 gene is known to increase the tumorigenic effect. In vitro studies have shown that LMP-1 has the ability to transform fibroblasts and induce malignancy in mice, and to inhibit apoptosis of the B cell. Mutation of the LMP-1 gene is associated with aggressive forms of lymphoproliferative diseases [73].

The data suggest that the development of lymphoma in patients with RA is similar to that seen in patients treated with immunosuppressive therapy for solid organ transplantation and infection with EBV plays a central role for the development of lymphoproliferative disorders in those patients.

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