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Relevance of Major Histocompatibility Complex Class II Expression as a Hallmark for the Cellular Differentiation in the Human Adrenal Cortex¹

Department of Internal Medicine III (C.M. S.R.B., G.W.W.), University of Leipzig, 04103 Leipzig, Leipzig; Department of Pediatrics (M.P., W.G.S.) Christian-Albrechts-University, Kiel; and Diabetes Forschungsinstitut (W.A.S.), Heinrich-Heine-University, Düsseldorf, Germany

Address all correspondence and requests for reprints to: Stefan R. Bornstein, M.D., NICHD, NIH, Building 10, Room 10N262, Bethesda, Maryland 20892.

	Abstract

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Major histocompatibility complex (MHC) class II antigens are expressed on adrenocortical cells of the zona reticularis and have been shown to be a marker of dignity. This suggests a correlation to the zellular differentiation of the adrenal cortex. Therefore, we immunohistochemically investigated the MHC class II expression in the context of the ontogenesis of the zonal and cellular differentiation in fetal, postnatal, childhood, and adult adrenals. Cell types and cell turnover were studied using specific immune markers (including expression of CD95/Fas), in situ end labeling of apoptosis, and electron microscopy. We show that prenatal (fetal and definitive) steroid cells, as well as postnatal adrenals, reveal no expression of MHC class II. In childhood, these antigens first appear by the fourth year, in parallel with the differentiation of reticularis cells. The expression index in childhood was 7.43% ± 2.78 (mean ± SEM), in adult adrenals 18.63% ± 3.14 (third decade), and 15.15% ± 1.26 (fourth through sixth decade). In conclusion, MHC class II expression and the development of the functional maturation of the adult adrenal cortex occur simultaneously. The expression of MHC class II on steroid cells may thus be involved in potential immune-adrenal interactions.

	Introduction

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THE ADRENAL cortex appears at the 25th day of gestation and consists of a blastema of rapidly dividing, undifferentiated cells. The first evidence of an adrenocortical zonation appears by the 6th–8th week. The innermost cells of the blastema begin to differentiate, as demonstrable by beginning expression of steroidogenic enzymes (1), and build the fetal zone. The outermost cells remain undifferentiated and form the definitive zone. The cells of the fetal zone account for the fetal steroidogenic functions, which differ from those of adults. Between the 9th and 12th week of life, the sinusoidal vascularization of the gland develops, setting the framework for the development of the definitive zonation. After week 28, the definitive cells start to differentiate and slowly replace the fetal zone. A transition zone between definitive and fetal zones is still found at the end of the 1st year post partum. The appearance of reticularis cells means the final step in the development of adrenocortical zonation, which is believed to be completed by the end of the 2nd decennium (2).

A clear concept to integrate different observed patterns of proliferation, migration, functional differentiation, and apoptosis has not emerged, as yet, but there is increasing evidence of a centripetal migration toward the medulla, where the cortical cells are believed to undergo apoptosis. This model has been advanced by localizing the proliferating cells in an intermediate layer, from where the cells can bidirectionally migrate and differentiate into glomerulosa cells producing mineralocorticoids and fasciculata/reticularis cells producing glucocorticoids and androgens (reviewed in 3 . As we have previously shown, this may reflect a differentially regulated apoptosis in the three zones (4).

It has already been observed that, with unknown relevance, steroid-producing cells of the innermost adrenocortical zone (zona reticularis) show the expression of human lymphocyte antigen (HLA) class II antigens (5). These cells produce large amounts of androgens during puberty. The expression of these antigens might reflect these functional changes (6). In fetal adrenals, the expression of major histocompatibility complex (MHC) class II has only been examined in tissues of the 14th–20th week, but the specimens showed no reactivity, except for immune cells (7). It has not yet been established when MHC class II antigens appear for the first time in the adrenal cortex.

Since disturbances in zonal and/or cellular differentiation occur during tumorigenesis of the adrenal cortex, we previously examined the expression of MHC class II in adrenocortical tumors (8). The constitutive expression of MHC class II by steroid cells is found also in the majority of benign adrenocortical tumors but was abrogated in all carcinomas examined.

We therefore hypothesized that MHC class II expression is correlated to high cellular differentiation and designed this study to determine the appearance of MHC class II antigens during different stages of life, by examining fetal, postnatal, infantile, and adult, completely differentiated adrenals. The zonal and cellular differentiation of the adrenal was characterized by a panel of specific antibodies against steroid-producing cells, endothelia, immune cells, and chromaffin cells, as well as electron microscopy. Apoptotic cells were identified by in situ DNA fragment labeling and expression of CD95.

	Materials and Methods

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Tissues

Prenatal adrenal glands (15th, 19th, 25th, 32nd, and 41st gestational weeks; three females, two males) were obtained from fetal intrauterine deaths, still birth, or abortus. Postnatal adrenal glands (1, 5, 8, 10, 12 months; two females, four males) were obtained from patients who died from cardio-circulatory collapse. Childhood adrenal glands (2, 4, 6, 12, 13, 15, 16, and 18 yr; four females, four males) were obtained from autopsy cases resulting from cardio-circulatory or central nervous regulation collapse. Adult adrenal glands (aged between 21 and 58 yr) investigated in this study were obtained from human subjects undergoing nephrectomy caused by nonpapillous carcinoma of the kidney. This was approved by the Ethical Committee of the University of Leipzig.

Immunohistochemistry

Table 1 shows all mouse antihuman monoclonal antibodies applied in this study. To determine the expression of MHC class II antigens, we used monoclonal antibodies directed against polyvalent MHC class II determinants. Before use, sections were deparaffinized in xylene and hydrated in a descending ethanol row. Culture slides were fixed in 100% acetone for 15 min and dried. The endogenous peroxidase was quenched by 1.5% H₂O₂, 10% methanol in phosphate-buffered saline for 10 min. Staining was carried out using the avidin-biotin method, immunohistochemistry detection system, oncogene science. Because some antibodies were not sufficient for routine use in paraffin sections, we used the more sensitive LSAB+ streptavidin-biotin system or the catalyzed signal amplification system CSA (Dako, Hamburg, Germany), according to the manufacturer’s instructions (Table 1).

Staining of apoptotic nuclei was carried out by a nonradioactive in situ end-labeling method. Free 3‘-ends of DNA were elongated (independent of template) with TdT enzyme using digoxigenin-marked dUTP, and digoxigenin was subsequently immunodetected with anti-DIG-horseradish peroxidase conjugate using 3‘3-diaminobenzidine (Sigma, München, Germany) as a substrate. Slices were pretreated as described above, followed by a triton X-100 incubation, 0.5% in phosphate-buffered saline for 5 min. In situ end-labeling was carried out according to the supplier’s instructions that were provided for the ApopTag-Kit (Amersham, UK). For control, the incubation with TdT-enzyme solution was omitted.

Electron microscopy

For the ultrastructural investigations, small pieces of adrenal tissue were fixed in 4% paraformaldehyde, 1% glutaraldehyde in 0.1 mol/L phosphate buffer (pH 7.3) for 3 h, postfixed for 90 min in 2% OsO₄ in 0.1 mol/L cacodylate (pH 7.3), dehydrated in ethanol, and embedded in epoxy resin. Ultrathin sections (70 nm) were stained with uranyl acetate and lead citrate and examined at 80 kilovolts under a Phillips electron microscope 301.

	Results

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Fetal adrenals.

Morphological examination of the fetal adrenals of the 15th and 19th week showed a subcapsular zone of small definitive cells, whereas the innermost fetal zone showed large eosinophilic cells. We could not detect any MHC class II positive steroid cells in either fetal or definitive zone, but occasionally, macrophages showed positive staining. Staining of fetal adrenals of the 25th, 32nd, and 41st weeks revealed the same result.

Postnatal adrenals.

The postnatal adrenals, 1–24 months old, showed an enlarging definitive zone. The fetal zone showed signs of degeneration. In these tissues, no zona reticularis (confirmed by abrogated expression of 17-hydroxylase) and, hence, no expression of MHC class II were detectable, except occasionally on mononuclear cells and macrophages.

Childhood adrenals.

In childhood adrenals, 4–18 yr old, expression of MHC class II antigens was detectable on steroid cells focally in the zona fasciculata or close to the adrenal medulla (Fig. 1, panels 1 and 2). The staining index was 7.43% ± 2.78. Staining for 17-hydroxylase revealed the presence of reticularis cells and correlated with the expression of MHC class II proteins, although not all reticularis cells were stainable for MHC class II. In two tissues, 4 and 13 yr old, the expression was markedly increased in areas revealing focal infiltrations of lymphoid cells.

View larger version (171K): [in this window] [in a new window]   Figure 1. Appearance of MHC class II expression in infantile adrenals. Surprisingly, clusters of positive cells occur within the zona fasciculata (fourth year; panel 1). Expression of MHC class II within the transitory zone of cortex and medulla (13th year; panel 2). Centripetally increasing staining for 17-hydroxylase occurs in adult adrenals with mature zonation (panel 3, arrow). These tissues reveal strong MHC class II expression in the zona reticularis (panels 4 and 5 arrows). In some tissues, strong staining for CD95/Fas occurs in the inner cortical zone (panel 6). This could be related to the appearance of CD45+ leukocytes in the zona reticularis (panel 7, arrow). Electron microscopy shows evidence for a close apposition of sinusoidal leukocytes and reticularis cells (panel 8). c, cortex; m, medulla; zg, zona glomerulosa; zf, zona fasciculata; zr, zona reticularis; ly, lymphocyte; ret, reticularis cell.

The mature zonation in adult adrenals could be shown by staining for specific antigens occurring in the distinct zones, as well as histological and ultrastructural investigation. By staining against the steroid enzyme P450 17-hydroxylase, we found that only the inner parts of the zona fasciculata and the entire zona reticularis showed reactivity, increasing towards the medulla (Fig. 1, panel 3). The characterization of adrenal cells with the in situ end-labeling of DNA strand breaks, as a characteristic sign of apoptosis, showed positive signals throughout all zones, albeit with varying intensity (not shown).

MHC class II expression in third-decennium adult adrenals was 18.63% ± 3.14, in adrenals between fourth and sixth decennium 15.15% ± 1.26. The staining was restricted to the inner cortex (zona reticularis) and occasionally to fasciculata cells at the fasciculo-reticular transition zone (Fig. 1, panels 4 and 5). The expression pattern was similar to that of 17-hydroxylase. Occasionally, singular leucocytes and macrophages exhibited reactivity for MHC class II antigens, but these populations could be separated morphologically and by staining against leukocyte common antigen CD45 (Fig. 1, panel 6) and against CD68. The highest occurrence of these cells was seen within the zona reticularis.

Endothelial cells were detected throughout the entire adrenal by staining against CD31. They appeared in centripetal direction in the cortex and formed a network of sinusoids in the zona reticularis (not shown). Screening for CD95 antigens revealed a heterogenous distribution pattern. In different tissues, CD95-positive clusters of steroid cells could be observed in all cortical zones. Within two tissues, the main expression was detected in the zona reticularis (Fig. 1, panel 7) and was similar to the expression of MHC class II antigens.

The typical morphological differentiation of zona reticularis cells was confirmed by ultrastructural investigation. Occasionally, a close apposition of immune cells and reticularis cells was observed (Fig. 1, panel 8).

	Discussion

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The expression of MHC class II antigens has been documented in human adrenals during various life stages. In the prenatal ontogenic development of the adrenal cortex, MHC class II antigens could not be detected on steroid cells of either the fetal or definitive zone in either the prenatal or postnatal period. Thus, the fetal zone does not express MHC class II, despite its ability to synthesize androgens in large amounts (9). The expression of MHC class II should be considered as part of a complex system formed by cells of the mature adrenal zones. This was demonstrated by the zonal expression of specific markers. Thereby, the steroid cells of the cortex share a common origin but are differentiated into distinct cell types with different functions. They are morphologically and functionally in close contact to sympathoadrenal cells of the medulla and immunocompetent cells (stained for CD45 and CD68), which belong to ontogenetically or functionally different systems. The interconnection of these tissues may form the basis for coordinating various important metabolic and immunoregulatory functions (10).

According to the migration theory, the centripetally streaming cells are finally converted to androgen-producing reticularis cells, implying that these cells undergo programmed cell death, giving subsequent cells the opportunity to grow in their place. It was already proposed that reticularis cells acquire the ability to express MHC class II (6). According to this model, it can be assumed that the final reticularis cells, expressing MHC class II antigens, are the cells with the highest degree of differentiation.

Bidirectional interactions of the endocrine and immune systems play an important role in both physiology and pathophysiology (11). The function of MHC class II expression in the zona reticularis is still unclear. The production of DHEA-S is linked to 17-hydroxylase expressing steroid cells and thus believed to occur in the inner cortex. The function of this rather weak androgen (12), which is synthesized in high doses during puberty (13), is still subject to discussion. The eventual role of the adrenarche also is still unknown (12). It has been proposed that the increase in androgen and, secondarily, in estrogen might play a role in the introduction of puberty (14). This is questionable, because findings have shown that puberty is not delayed in children with Addison’s disease (15).

We show here that 17-hydroxylase expressing cells appear around the fourth year of life and that these cells subsequently begin to express MHC class II antigens. This also involved cells within the zona fasciculata, possibly indicating a process of differentiation towards reticularis cells.

It is important that the function of the immune system peaks at around puberty and declines with increasing age (16). This involves mainly T cell immunity and relates to postpubertal thymic atrophy, which is experimentally inducible by corticosteroids but antagonized by DHEA produced by the adrenal (17). T cells expressing CD3 and CD4 have been localized in the adrenal cortex, and the number of focal infiltrations is increased in the elderly (18). The high vascularization, as observed by electron microscopy and staining for CD31, may provide the basis for a close apposition and potential interactions between steroid cells and leucocytes.

The demonstration of CD95/Fas, thought to play an important role in the induction of apoptosis and the homeostatic regulation of immune responses (19), on reticularis cells seems to be of interest, because recent reports have told of a functional link between HLA class II complex, CD95, and apoptosis: ligation of the MHC class II complex leads to increased sensitivity of lymphocyte cell lines to Fas-mediated apoptosis (20). Additionally, there is evidence of MHC class II mediated programmed cell death (21). Fas-mediated apoptosis is supposed to prevent autoimmunity because it plays an important role in the elimination of activated autoreactive Fas-ligand bearing T cell clones having survived thymic selection (19). It has long been proposed that inappropriate MHC class II expression plays a role in the pathogenesis of autoimmunity (22). In adrenals with autoimmune Addison’s disease, almost all residual cells, correlated with mononuclear infiltration, show strong expression of these antigens (23).

The cumulation of local adrenal immune functions might point out a role of the adrenarche in the pubertal maturation of the immune system. It is still speculative, whether MHC class II (and/or CD95) expressing steroid cells and corresponding T cells may share the ability of (auto)antigen expression and/or reciprocal induction of apoptosis. Considering the unique morphology and physiology of the adrenal cortex and increasing knowledge of pathophysiological mechanisms leading to autoimmune diseases, further research in this field should be of interest.

Summary

The present study points out: 1) MHC class II expression develops with the maturation of complete zonation during adrenarche and is highly correlated with the cellular differentiation of the adrenal cortex; 2) it is tempting to speculate that the cumulation of adrenal immune functions may indicate a novel role for the adrenarche because the functional peak of the immune system occurs in the second decade of life.

	Acknowledgments

 
We are grateful to Prof. Harms (Kiel), for generously providing tissue specimens. We appreciate the great support of H. Willenberg and S. Brauer and our adrenal research team.

	Footnotes

 
¹ This work was supported by The Deutsche Forschungsgemeinschaft (DFG Bo 1141/2–3) and a Heisenberg Grant (to S.R.B.).

Received February 12, 1997.

Revised April 23, 1997.

Accepted May 19, 1997.

	References

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