ARTICLE |
Correspondence to: Sunil Badve, Div. of Surgical Pathology, Feinberg Pavilion 7-325, Northwestern Memorial Hospital, 251 East Huron, Chicago, IL 60611. E-mail: s-badve@northwestern.edu
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Summary |
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During the initiation of an immune response, antigen-presenting cells employ MHC class II antigens as key molecules to present small peptides to CD4-positive lymphocytes. The invariant chain (Ii; CD74) plays a critical role in this process by influencing the expression and peptide loading of the MHC class II molecules. Therefore, coordinate expression of these molecules is believed to play an important role in antigen presentation. This study explores the expression of these molecules in fetal tissues. Formalin-fixed, paraffin-embedded multi-organ tissue blocks from aborted fetuses (age range 722 weeks) were immunostained for Ii/CD74 and MHC class II antigens using commercially available monoclonal antibodies for Ii/CD74 (LN2) and MHC class II antigens (LN3), respectively. Coordinate staining for Ii/CD74 and MHC class II antigens was seen in the skin, proximal renal tubules, tips of small intestinal mucosa, and cells of the reticuloendothelial system, including the spleen and thymus. Expression of Ii/CD74, but not of MHC class II antigens, was seen in pulmonary alveolar epithelium in all cases and in testicular Leydig cells (11 of 11 testes examined). The distribution and intensity of staining did not change significantly with age. In conclusion, this study describes distribution of Ii/CD74 and MHC class II antigens in human fetal tissues. Coordinate expression of Ii/CD74 and MHC class II antigens was identified in most fetal tissues, but there were also notable exceptions. In all cases this took the form of expression of Ii/CD74 in the absence of MHC class II expression. Discordance was particularly striking in pulmonary alveolar epithelium and testicular Leydig cells. This suggests that the Ii/CD74 molecule has functional roles in addition to its role in antigen presentation.
(J Histochem Cytochem 50:473482, 2002)
Key Words: fetal tissues, MHC class II, invariant chain, CD74, LN2, LN3, discordance
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Introduction |
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MAJOR HISTOCOMPATIBILITY ANTIGENS (MHCs) fulfill a critical role in the immune system by presenting antigenic peptides to T-lymphocytes. MHC class I antigens present predominantly to CD8-positive T-cells and MHC class II (MHC II) antigens on specialized antigen-presenting cells (APCs), to CD4-positive T-cells (c.f. and ß) that together form a polymorphic antigenic peptide-binding groove (
After synthesis, MHC II proteins undergo folding in the endoplasmic reticulum before transport to the endosomal vesicles, where binding to the antigenic peptides takes place (c.f.
Ii/CD74 is synthesized intracellularly in parallel with MHC class II synthesis, although the genes that encode them are located on different chromosomes. Ii/CD74 contains an unstructured region, the class II-associated Ii peptide (CLIP) that acts as a surrogate peptide and interacts directly with the peptide-binding site of the MHC II molecule (
The complex interdependence of MHC class II molecules and Ii/CD74 antigens throughout processing is further reflected in their concordant regulation and expression in cell lines and in most adult tissues (
In spite of their implications for development of immunological competence, expression of these antigens in human development has not been systematically studied. Results from such studies may add to understanding of the development of the antigen-presentation machinery in fetal tissues and could suggest additional functions for Ii or MHC II proteins by, e.g., revealing discordant expression patterns. Therefore, the concordant expression of the two molecules is a reflection of their underlying interdependent involvement in antigen presentation, whereas discordant expression in some cell types would point to additional independent functions of one or the other of the molecules. We undertook a study of the expression of these two molecules in tissues of fetuses of various ages ranging from 7 to 22 weeks estimated gestational age.
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Materials and Methods |
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Human fetal tissues were obtained, after Institutional Review Board approval, from 23 autopsied fetuses (age range 722 weeks estimated gestational age), with the majority of the cases being from the second trimester. These fetuses were the subjects of surgical pathology review and special care had been taken with the diagnostic tissue blocks to include representative tissues from several organs from each fetus, sampled by a 3-mm-diameter skin punch. Organs sampled included the liver, kidney, pancreas, heart, skeletal muscle, lung, esophagus, stomach, small and large intestines, bone/cartilage, skin, testis, ovary, thymus, spleen, adrenal, and thyroid. The brain and spinal cord from these fetuses had been harvested for another study, and therefore samples from these organs could not be obtained. Multiple tissue samples (1015) from an individual were placed into one cassette and processed according to standard protocol to generate paraffin blocks.
More than one of the following was used to estimate the fetal age: maternal ultrasound, last menstrual date, and fetal measurements such as crownrump length, foot length, and fetal weight.
Monoclonal antibodies to Ii/CD74 (LN2) or MHC class II antigens (LN3) were purchased from Dako (Carpinteria, CA). The immunohistochemical assay used the avidinbiotinperoxidase (ABC) method on serial sections. Briefly, 4-µm-thick paraffin sections, after deparaffinization and blocking of endogenous peroxidase activity, were subjected to microwave antigen retrieval for 10 minutes in a citrate buffer, pH 6.0. After this the sections were incubated with anti-LN2 or anti-LN3 for 12 hr. After subsequent incubations with biotinylated anti-mouse Ig and avidin-labeled peroxidase, reactions were visualized using diaminobenzidine (DAB) as the substrate, followed by counterstaining with hematoxylin. Normal tonsils were used as positive controls. The specificity of staining was ascertained by (a) staining in the absence of primary antibody (negative control) and (b) staining with a number of additional antibodies with different specificity, including anti--1-microglobulin (
Semiquantitative evaluation of staining intensity (0, absent; +, weak; ++, medium; or +++, strong) was performed by independent reading of the slides by all three authors, followed by collective evaluation in a multiheaded microscope.
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Results |
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General Tissue Distribution of LN2 and LN3
In our material overall, staining for LN2 was more widespread than staining for LN3, confined not only to cells of the macrophage lineage but also apparent in epithelial cells. In fetal whole mount (EGA 7 weeks), both LN2 and LN3 staining was present in scattered cells in all the organs examined. Stained cells were either within hematolymphopoietic organs or existed as scattered single cells within the interstitium of organ parenchyma and soft tissue, and persisted throughout the fetal period studied. Representative examples of these tissues, at Week 21 of EGA, are presented in Fig 1 Fig 2 Fig 3. As might be expected, cytoplasmic staining was seen in APCs and in epithelial cells of endodermal and mesodermal origin. The pattern of expression of either antigen did not vary significantly with fetal age in most organs, with a few exceptions, notably in the kidney (Table 1). Staining patterns by organ system are described below.
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Cardiovascular System. Scattered cells positive for LN2 and LN3 were detected within the myocardium. These were judged most likely to be tissue histocytes. There was no significant staining of the cardiac myocytes, endocardium or pericardium, or of the endothelia of small blood vessels or capillaries in the heart.
Respiratory System. The bronchial epithelium showed almost no reactivity to either antibody at 7 weeks of gestation. Expression did occur, however, in fetuses aged 14 weeks and older, and followed a similar pattern to that described for the pulmonary interstitium (see below), with non-epithelial cells reactive for both antibodies. Staining was also detected in some tracheal and laryngeal epithelial cells. These positive-staining epithelial cells were morphologically similar to those that did not express LN2 or LN3. There were greater numbers of cells staining for LN2 than LN3 at all ages. Lung parenchyma was poorly represented in the sections from the 7-week fetus.
Strong staining of the scattered single non-epithelial cells in the pulmonary interstitium with both LN2 and LN3 was seen at all ages (Fig 1B and Fig 1D). These cells, presumed mostly to be tissue macrophages, increased in number with age. Pleural epithelial cells and subpleural fibroblasts did not stain with either antibody, nor did the endothelium of the pulmonary blood vessels show expression of target proteins.
LN2 Reactivity. In older fetuses, the lung acinar (alveolar) epithelium stained for LN2 in part or whole acini by the age of 1214 weeks (Fig 1B). There was no or only minimal staining of the smaller bronchioles/alveolar ducts.
LN3 Reactivity. LN3 reactivity was restricted to the non-epithelial cells in the pulmonary interstitium.
Gastrointestinal System Intestines. LN2 and LN3 positive cells, predominantly in the lamina propria and submucosa, were present in the intestinal stroma as early as at 7 weeks of gestation. With increasing age there was a marked increase in positive-staining cells in the lamina propria, particularly in the small and large intestines (Fig 2A and Fig 2C). These cells were located immediately beneath the basement membrane of the surface epithelium, giving a wreath-like appearance on cross-section. Rare scattered LN2- and LN3-positive cells were observed within the muscularis propria and in the region of myenteric plexuses.
LN2 Staining. Weak expression of LN2 was seen in the gastric mucosa and focally in small intestinal surface epithelium in the older fetuses. There was no staining of the endothelial cells in most locales with either antibody. Expression of LN2 but not LN3 was noted in the mesenteric and adventitial vessels of the small bowel (Fig 2A and Fig 2C).
LN3 Staining No staining for LN3 of the surface epithelium or glands was noted at any age.
Liver and Pancreas. Staining of Kupffer cells was seen at 7 weeks of gestation by both LN2 and LN3. There was no staining of the hepatocytes or biliary tree at any age. In the pancreas, rare scattered stromal cells that were reactive with LN2 and LN3 were noted from very early stages. The number of these cells increased with age. No staining of the pancreatic duct lining cells was seen. Endothelial reactivity within few of the pancreatic blood vessels was noted in the late second-trimester fetuses with LN2 and in some cases also with LN3.
LN2 Staining At older ages and with the development of biliary radicals, clusters of LN2-positive cells were seen in the portal tracts (Fig 3A). LN2 expression was noted in both islet and parenchymal cells of the fetal pancreas. This took the form of a dot-like supranuclear positivity, with the rest of the cytoplasm being devoid of any staining (Fig 2B). A diffuse cytoplasmic staining of the acinar cells was seen.
LN3 Staining. Although LN3 reactivity was more or less restricted to the scattered stromal cells described above, in an occasional case weak diffuse staining of the islet cells was seen.
Genitourinary System Urinary Tract. At 7 weeks of gestation, scattered cells positive for both LN2 and LN3 were identified in the renal interstitium and in the glomerular mesangium. At all ages, more LN2- than LN3-positive interstitial cells were observed. The number of cells reacting with either antibody increased with age and followed the pattern of Ii/CD74 expression followed by MHC II expression. The ureters and urinary bladder were not represented in the samples examined.
LN2 Reactivity. By 1014 weeks of gestation, additional staining for LN2 was noted predominantly in the proximal convoluted tubules (Fig 1A), small tubules in the deep medulla, and endothelia of small blood vessels. Tissues from some of the older fetuses that included collecting ducts were reactive with LN2 and only infrequently with LN3.
LN3 Reactivity. The medullary tubules did not react with LN3 at any age.
Genital Tract. No significant staining of the ovaries with either antigen was seen. However, the generally poor quality of this material precluded further evaluation of these tissues.
LN2 Reactivity. In the testes, a dual pattern of staining was revealed at all ages. One population of cells stained strongly (3+ intensity), was interstitial in location, and had the morphology of tissue macrophages. The second population consisted of Leydig cells, which stained with variable intensity. In the seminiferous tubules no staining was apparent in either the germ cells or the Sertoli cells. By comparison, the rete testis and the epididymis showed strong expression of LN2 (Fig 1E and Fig 1F).
LN 3 Reactivity. No staining was seen of Leydig cells, rete testis, or epididymis (Fig 1G and Fig 1H). As expected, the interstitial macrophages stained positive for LN3.
Endocrine System. There was no staining of fetal thyroid or parathyroid glands, with the exception of interstitial cells staining with both LN2 and LN3. The adrenal gland showed prominent diffuse cytoplasmic staining (LN2>LN3) of the zona fasciculata and scattered interstitial cells. The medulla showed no significant staining in the cases examined.
Reticuloendothelial System. Staining for both LN2 and LN3 was seen in cells belonging to the macrophage lineage and within the thymus. Intense staining of almost all the cells was noted in the thymic medulla. In the thymic cortex (Fig 3C), positive-staining cells were more scattered and were intermixed with unstained lymphoid cells. High-intensity staining also was seen in the spleen (Fig 3D) and lymphoid tissues.
Skin and Musculoskeletal Systems. LN2 and LN3 reactivity was present in scattered cells within the dermis as early as 7 weeks of gestational age (Fig 3B). With maturation of the fetus, stained cells increased in number and in staining intensity. Staining within the epidermis was not detected at 7 weeks. Basally located dendritic cells were detected at around 1012 weeks of age by virtue of their reactivity with both the antibodies. No significant staining was seen in other epidermal cells or in adnexal structures. Scattered LN2- and/or LN3-positive cells were detected in the subcutaneous tissues and muscle at all ages. No staining was apparent in cartilage.
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Discussion |
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LN2 and LN3 are monoclonal antibodies to Ii/CD74 and a non-polymorphic portion of the HLA-DR -chain (human MHC class II antigen), respectively. Using these antibodies and immunohistochemical methods, we characterized the expression of MHC II and Ii/CD74 antigens in fetal tissues from estimated gestational ages of 722 weeks. We found expression of these antigens not only in APCs, but also in fetal epithelial cells. This suggests that induction, either by inflammatory or neoplastic processes, is not necessary for MHC expression in epithelial cells. The expression of MHC II and Ii/CD74 was concordant in most of the tissues studied. However, in some organs (lung, kidney, testis, and pancreas), we noted discordant expression (see Table 2). In these latter tissues, Ii/CD74 was expressed in non-immune cells in the absence of MHC II expression. In some tissues, such as the kidney, more interstitial cells expressed Ii/CD74 than MHC II at all ages.
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On examination of serial sections, it appeared that all cells expressing MHC II also express Ii/CD74 (data not shown). It has been previously suggested that expression of at least one of the human MHC class II isotypes (DR, DP, DQ) might be essential for the full constitutive expression of Ii/CD74.
The pattern of expression of Ii/CD74 within the pulmonary epithelium was also interesting and to our knowledge has not been previously described. Ii/CD74 expression was observed in cells lining the developing pulmonary acini (Fig 1b) but not in the bronchioles and air ducts. This pattern of expression suggests a role for Ii/CD74 in the development and maturation of the alveolar epithelium. Expression of MHC II and Ii/CD74 is seen in normal pulmonary epithelium and in non-small-cell lung carcinomas (
In adult pulmonary epithelium, previous studies by one of us (
Expression of MHC class II was also noted in rare scattered cells of the bronchial epithelium. These cells, akin to those described by
Within the intestines, expression of Ii/CD74 and MHC II was seen predominantly in the APCs in the lamina propria (Fig 2A and Fig 2C). Surface epithelial cells of the small intestines were only weakly reactive for Ii/CD74, and no staining for MHC II was seen in these cells. This is in contrast to the findings of (
In the fetal intestine, staining of the endothelial cells for Ii/CD74 but not for MHC II was noted (Fig 2A and Fig 2C). In contrast,
As for endocrine organs, our findings are similar to those reported by
Our finding of discordant expression of MHC class II and Ii/CD74 in Leydig cells of the testis and in epididymis (Fig 1E1H) has not been previously reported. In the adult,
Expression of Ii/CD74 in the Leydig cells of the testis and in the cells lining the epididymis was an unexpected and previously unreported finding. The only other study that studied expression of Ii/CD74 (
In conclusion, although MHC II antigens and Ii/CD74 are generally concordantly expressed on cells of the monocyte/RES lineage in most tissues in fetal as well as adult life, reflecting their interdependent role in antigen presentation, several examples of tissue demonstrating discordant expression were seen in this study of fetal material. The lack of concordance was particularly prominent in fetal lung epithelium, epididymis, and on testicular Leydig cells, but also was noted on cell types in other tissues, such as renal tubule cells, pancreatic islet cells, bronchial and intestinal surface epithelium, and mesenteric vascular endothelium. This non-concordance always took the form of Ii/CD74 expression in the absence of MHC class II expression. It is unlikely that non-classical MHC class II antigens are playing a role as alternative partners to Ii/CD74 in some early fetal tissues, because it has been shown, at least in the bowel, that HLA-DR are the first of the class II antigens to be expressed (
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Footnotes |
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1 Data were presented in part as a poster at the ASCP meeting, Washington, 1999.
2 These authors contributed equally to the project.
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Acknowledgments |
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We wish to thank Linda Lögdberg for helping with the preparation of the manuscript.
Received for publication March 19, 2001; accepted October 24, 2001.
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