Humoral and cellular autoimmune responses

Newly diagnosed patients with Addisons disease have a variety of circulating autoantibodies to adrenal antigens. Autoantibodies directed against organ-specific antigens localized in the cytoplasm of the adrenocortical cells are present in the circulation of approximately 70% of Addisons disease patients. These antibodies can be detected by indirect immunofluorescence, radioimmunoassay and ELISA, are usually of low titer, belong to the IgG class and react with one or more organ-specific antigens localized in the adrenal cortex. In most cases, immunofluorescence shows that all three layers of the cortex react with adrenal autoantibodies (Figure 2). However, different patterns of staining can be observed: sera from some patients stain all three zones of the cortex, whereas others react with the zona fasciculata and zona reticularis alone. A few sera react with the zona glomerulosa alone. The clinical significance of these findings is unknown, but suggests an immunologic heterogeneity of Addisons disease, with preferential involvement of different adrenal antigens. Complement fixing adrenal autoantibodies have also been observed by immunofluorescence. Autoantibodies to organ-specific surface antigens of adrenal cells are present in the sera of 86% of patients with Addisons disease who have circulating antibodies to adrenal cytoplasmic autoanti-gens. The adrenal-specific surface antigens appear by immunofluorescence as a continuous rim, but separate granules are visible on focusing over the plasma

Figure 2 (A) Antibodies to adrenocortical antigens (indirect immunofluorescence with serum from a patient with Addison's disease on cryostat section of monkey adrenal). (B) Higher magnification of similar field. (With permission from American Society of Clinical Pathologists, Chicago, USA.)

Figure 2 (A) Antibodies to adrenocortical antigens (indirect immunofluorescence with serum from a patient with Addison's disease on cryostat section of monkey adrenal). (B) Higher magnification of similar field. (With permission from American Society of Clinical Pathologists, Chicago, USA.)

membrane. Antibodies to steroid-producing cells of other tissues have also been detected in the circulation of patients with Addisons disease. These autoantibodies react with theca interna cells, interstitial cells and corpus luteum cells of the ovary as well as interstitial cells of the testis and placental trophob-lasts.

Recent studies using molecular cloning and western blotting have shown that different steroidogenic enzymes of the cytochromc P450 family may be the target autoantigens of autoimmune Addisons disease. Purification of native human adrenal proteins, comparative western blotting using patients' sera and rabbit antibodies against recombinant 21-hydroxylase as well as antibody absorption studies, have demonstrated that steroid 21-hydroxylase P450, an enzyme involved in both the glucocorticoid-synthesizing pathway and the mineralocorticoid pathway, is the major target of adrenal autoantibodies found in patients with isolated Addisons dis ease or polyendocrine autoimmune syndrome type 2 (Table 1). On the other hand, patients with polyendocrine autoimmune syndrome type 1 (characterized by adrenal insufficiency, hypoparathyroidism and hypogonadism) have antibodies that react with P450 SCC (cholesterol side-chain cleavage) or, as reported by other authors, another enzyme, the microsomal steroid 17a-hydroxylase (Table 1). It is still uncertain whether these autoantigens are expressed on the surface of adrenal cells or are otherwise accessible to adrenal antibodies in vivo. Finally, IgG preparations from patients with Addisons disease have been reported to cause a dose-dependent decrease of in vitro Cortisol production and/or DNA synthesis induced by ACTH in guinea pig adrenal segments maintained in organ culture. The blocking effects occurred irrespective of the presence or absence of adrenal cytoplasmic autoantibodies and were attributed to the production of antibodies against the receptor for ACTH. This hypothesis has not been confirmed by recent studies that suggest an inhibitory effect of non-IgG components.

Studies of cellular immunity to adrenal antigens have been based on classical (but now rather outdated) methods to detect delayed hypersensitivity reactions and lymphokine production. In these procedures, peripheral blood lymphocytes from patients were incubated in vitro with the putative antigens, often used as a rather crude suspension. Thus, it has been shown that most patients with Addisons disease have cell-mediated immune reactions to adrenal antigens as determined by the leukocyte migration test. There was no correlation with onset of disease, its duration and the presence of adrenal antibodies. The antigen preparations that have been utilized in leukocyte migration studies were organ-specific, but not species-specific, since monkey and porcine adrenals were used with the same success as human adrenals. In some studies the antigenic activity was localized in the mitochondrial but not the microsomal fraction, whereas in other experiments leukocyte migration inhibition was observed after incubation with both components. More modern investigations of cellular immunity (e.g. with steroid 21-hydroxylase P450) are still lacking.

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