Altered Immune Responses in Patients with Chuvash Polycythemia

Chuvash polycythemia results from a homozygous 598 C>T mutation in exon 3 of the von Hippel-Lindau (VHL) gene. This disrupts the normoxia pathway for degrading hypoxia inducible factor (HIF)-1a and HIF-2a causing altered expression of HIF-1 and HIF-2 regulated genes. As hypoxia induces expression of pro-inflammatory cytokines, we hypothesized that there might be an elevation of Th1 cytokines in the setting of Chuvash polycythemia. Concentrations of Th1 (interleukins-2 and 12, interferon-g, GM-CSF, tumor necrosis factor-a) and Th2 cytokines (interleukins-4, 5, 10 and 13) were measured in plasma using the Bio-Plex multiplex suspension array system. Concentrations of all of these cytokines were elevated in patients with Chuvash polycythemia 598C>T homozygous compared to the control wild type participants. In parallel, peripheral blood concentrations of CD3 positive T-helper cells and CD-4 positive T-helper cells were lower in patients with Chuvash polycythemia compared to controls. The ratios of interferon-g and tumor necrosis factor-a to interleukin-10 did not differ by genotype. Thus, although the upregulated hypoxic response in Chuvash polycythemia is associated with increased plasma products of the Th1 and Th2 pathways, the peripheral blood concentrations of T-helper cells are reduced, perhaps as part of a feed-back mechanism, and the balance between the two pathways may be preserved. Such countervailing responses to unregulated hypoxia sensing may explain why patients with Chuvash polycythemia do not present clinically with immunologic disorders.