Sarcoidosis Associated T-cell Dysregulation Predisposes to Progressive Multifocal Leukoencephalopathy

Sarcoidosis is a systemic granulomatous disease, which is characterized by noncaseating epitheloid granulomas and mainly affects the lung and the lymph nodes. The pathogenesis is still not clear, a disturbed immune response to pathogens or environmental factors and a defect of T-cell function is assumed. Moreover, it has recently been reported that patients with active sarcoidosis have an increased number of regulatory T cells (Tregs) and that Tregs suppress the proliferation of CD4+ T cells. The decrease of CD4+ T cells could predispose to opportunistic diseases. Progressive multifocal leukoencephalopathy (PML) is known as a devastating demyelinating disease caused by an opportunistic infection of oligodendrocytes with JC Virus and is associated with immunosuppressive diseases or drugs. There are some case reports of patients who developed PML and were former diagnosed with sarcoidosis, but most of them received an immunosuppressive therapy before diagnosis. However, whether sarcoidosis associated T-cell dysregulation might cause the development of PML is unknown. Here, we report on three cases with bioptically confirmed PML who had not received previous immunosuppressive medication and primary or secondary immunodeficiencies could be excluded. Notably, all of them were additionally diagnosed with sarcoidosis, one showed already a positive biopsy before development of PML, in the other two patients sarcoidosis was proven after detection of PML. Mechanistically, FACS analysis of the blood of the three PML patients revealed an increase of Tregs and a decrease of CD4+ T cells as low as 101/μl. Also naïve T cells were dramatically reduced. Additionally, we could detect increased frequencies of double positive CD4 + CD8+ T cells, which are claimed to be immature cells and are normally absent, but could also be found in other autoimmune diseases like rheumatoid arthritis. Two patients who developed a progression of the PML improved during the treatment with infliximab, a monoclonal antibody directed against TNF-alpha, which is an established therapy for sarcoidosis. In summary, our data suggest that sarcoidosis leads to a dysfunction of T cells and that this is an underestimated risk factor for the development of PML. If the common reasons for immunosuppression are excluded, diagnosis of sarcoidosis has to be considered and analysis of T cell subsets should be performed.