Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associate d with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies , also called the "anti-Hu syndrome," is believed to result from an immune response triggered by turner antigens and misdirected to the neurons. To fu rther assess the issue of cell-mediated immunity in this disease, the perip heral blood lymphocyte surface phenotype was studied in 15 patients sufferi ng from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein w as used to stimulate in vitro peripheral blood mononuclear cells of 10 sero positive patients and of 10 patients from each control group. Phenotypic an alysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO(+)CD4(+)) T cells in the seropositive group in comparison with the two control groups, Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [H-3]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells rev ealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant incr ease of the interferon-gamma/interleukin-4 ratio was found in culture super natants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protei n is an antigenic target for autoreactive CD4(+) T cells, presumably of the Thl subtype, which could therefore be directly involved in cell-mediated i njury of the nervous system as well as in antitumoral immunity.