The hypothalamic-pituitary-adrenal axis and the immune system interact in a bidirectional manner providing the basis for the regulation of the immune response due to a pathogenic stimulus. This ...interplay is commonly believed to be based on the action of hormones or cytokines, respectively. Since it has been detected that adrenocortical cells offer immunological properties such as expression of MHC class II antigens and/or CD95 (Fas antigen) and its ligand, the question has to be raised whether direct intercellular communication between immune cells and 'immunocompetent' endocrine cells contributes to the complexity of immunoregulation. Here we discuss the possible reciprocal relevance of physiological and pathological adrenal changes, as well as T-cell-mediated immune response for immune and/or adrenal pathology during disease.
The migration and proliferation of adrenocortical cells is accompanied by mechanisms of cellular knock-out. We compared the programmed cell death of normal and malignant adrenocortical tissues on the ...basis of apoptotic rates by the nonradioactive in situ end-labelling of DNA-fragments, immunohistochemistry against PCNA, CD95 and ultrastructural analysis. The highest labelling index (LI) was detectable in the outermost zones of the adrenal cortex of normal adrenals. Average LI in normal adrenal cortex was 20% whereas only 2% was detectable in adrenocortical neoplasms. MHC class II, which was previously shown to be involved in programmed cell death in lymphocyte populations (1), was detectable in normal and benign but not in malignant adrenocortical neoplastic cells. In conclusion, the analysis of apoptosis provides new aspects of normal adrenal zonation and allows the differentiation between normal and neoplastic adrenal cortex although the differentiation between malignant and benign neoplasms requires further markers.
Immunologic escape includes the loss of Fas-receptor and the gain of Fas-ligand expression. Normal adrenal glands express the Fas-receptor and MHC class II molecules in inner cortical zones. A ...distinctive feature of adrenocortical tumors is the loss of MHC class II expression.
Here we demonstrate loss of Fas and gain of Fas-ligand expression in the adrenocortical carcinoma cell line NCI-H295 by immunohistochemistry and RT-PCR. In a co-culture system of turnor cells and HLA-matched leukocytes, CD 8-positive or CD 4-positive lymphocytes, we examined the immunologic escape and the ability to induce apoptosis in the immune cells. The direct co-culture with either leukocytes, CD 8-positive or CD 4-positive lymphocytes reduced spontaneous apoptosis in immunecells from 49.9% to 13.0%, 8.6% and 15.3%, respectively, as determined by FACS analysis of Annexin V binding and LDH release in the medium. In co-culture, cortisol secretion increased up to 200%.
Cellular communication does not induce apoptosis in immune cells, but promotes their survival. This may be due to partial HLA class I mismatches contributing to immunologic activity. The viability of the tumor cells was not affected, and these cells were stimulated to secrete cortisol. In summary, immune escape of adrenocortical carcinomas may occur because of altered Fas/Fas-L system expression and loss of MHC class H expression.
