Volume 5 Supplement 3
The physiological immunosuppressive network and its putative role in the pathogenesis of autoimmunity: inhibition through signaling, cellular contact, anergy, apoptosis
© The Author(s) 2003
Published: 12 September 2003
A complex cellular system like the human immune system only functions in a tightly regulated balance between activation and inhibition. We therefore hypothesise that defects in immunosuppression might contribute to the pathogenesis of autoimmunity in man. In our work we established a broad basis for testing the function of various immunosuppressive mechanisms in health and autoimmune disease. Signals through certain CD45 epitopes are strongly immunosuppressive in vitro. We therefore hypothesised that we will be able to induce anergy in CD45-treated lymphocytes. As control we used a human leukocyte antigen DR (HLA DR) antibody with equal inhibitory capacities on cell proliferation. We found that HLA DR signals, but not CD45 signals, could induce lymphocytic anergy, which was monocyte dependent. Moreover, these anergic lymphocytes were extremely sensitive for protein kinase C-mediated apoptosis, indicating that immunosuppressive mechanisms are inter-related. We are currently studying the exact prerequisites for this new mode of anergy and apoptosis in cells from normal donors and autoimmune patients. This is especially interesting as we have shown in our previous work that regulation of apoptosis might be disturbed, especially in systemic lupus erythematosus. Shedding of activating surface molecules represents another physiological way to prevent hyperactivation. We have recently identified a family with a mutation close to the protease docking site of tumor necrosis factor alpha converting enzyme in the tumor necrosis factor receptor p55 molecule, leading to a periodic fever syndrome with autoimmune phenomena. Based on our working hypothesis, we postulated that chronically activated lymphocytes need to acquire modulated signaling complexes with proinhibitory capacities. To test this hypothesis we purified lipid microdomains of chronically superantigen-activated lymphocytes. First data seem to confirm this as we have found altered protein composition of raft-associated proteins with inhibitory capacity. Depletion of CD4+CD25+ regulatory T cells (Treg) in mice leads to a polyglandular autoimmune syndrome (PGAIS). We have tested the function of Treg in normal donors, and in patients with PGAIS or only type I diabetes mellitus. The data suggest that the function of Treg might be compromised in patients with PGAIS. This is currently being further analysed in more detail. In conclusion, these data clearly provide evidence that a disturbance of physiological immunosuppressive mechanisms might contribute to the pathogenesis of autoimmune diseases.