The list of organ-specific autoimmune diseases (AID) is expanding. This is particularly true for T-cell-mediated AID, the pathophysiology of which has largely been ignored until recently. The best arguments for T-cell involvement in AID, although indirect, are the presence of a local T-cell infiltrate and the dramatic sensitivity of the disease to T-cell-selective immunosuppressive agents (e.g. cyclosporin A) as in the case of insulin-dependent (type I) diabetes mellitus (IDDM) and psoriasis. This paper will review current questions concerning the etiology and pathogenesis of organ-specific AID.
The ovine and caprine lentiviruses infect monocytes, and the viral DNA is integrated into the cellular DNA. The provirus remains silent until the monocyte matures into a macrophage. Intrinsic to this maturation is the induction of a class of immediate early genes in the monocyte that includes the transcription factors JUN and FOS. These transcription factors are thought to couple short-term signals in the cell to long-term cellular differentiation by regulation of specific cellular genes. Thus, JUN and FOS bind to the AP-1 site in the promoters of cellular genes and activate their transcription, resulting in maturation of the monocyte into a macrophage. In addition, these cellular factors activate the same AP-1 sequence in the visna virus LTR, leading to transcriptional activation, full viral gene expression, and production of progeny virus. The expression of viral antigens in the context of MHC class II on the macrophage leads to the production of cytokines and a lymphoproliferative response that causes the lesions in specific target organs in an infected animal. We still understand only the framework of these events. The specific mechanisms by which viral genes alter macrophage gene expression and the molecular basis of different viral tropism for specific tissue macrophages, i.e. microglia, remain to be determined.
One of the most important problems in tumor immunology studies is the in vivo role of natural killer (NK) cells and, as a consequence, the regulation of NK cell development and activity. It has been demonstrated that cells and soluble factors, including cytokines and hormones, are able to modulate NK activity by regulating both the reactivity of mature effector cells and the growth and differentiation of their precursors. One of the most interesting aspects of the in vitro generation of NK cells was the study of the role of different soluble factors, possibly involved in this process. In fact, while interleukin (IL)-2 was necessary for NK cell generation it is clear that other factors are involved in the first phase of differentiation and acquisition of IL-2-responsiveness. This suggests that, as in the rat, differentiation of mouse NK cells in addition to IL-2 needs other factors which are present in the CM.
The usual functional inhibition of medium-cultured monocytes by Lymphokine-activated killer (LAK) cells was reversed when the monocytes were cultured in IFN-g. Thus, the opposing effect of granulocyte macrophage-colony stimulating factor (GM-CSF) and IFN-g on monocyte functional susceptibility was similar to that found earlier on monocyte lysis by LAK cells. Antigen presentation is a sentinel process in the immune system. Monocytes take up antigen, process it and display an immunogenic fragment to lymphocytes, thereby delivering an activation signal to T cells. IFN-g protected monocytes from LAK suppression of antigen presentation. The opposing effects of GM-CSF and IFN-g on monocyte functional susceptibility, as measured by antigen presentation, were equivalent to those seen on monocyte antifungal activity. IFN-g protected monocytes from LAK suppression of antigen presentation. Monocytes are important accessory cells in the activation of T cells for specific antigen recognition and for control of microbial invasion.
