Cellular and Molecular Basis for Antigen Transport Across Epithelial Barriers

Marian R. Neutra , Jean-Pierre Kraehenbuhl , in Mucosal Immunology (Third Edition), 2005

Barrier function of stratified squamous epithelia

Stratified squamous epithelia form barriers to antigens in the oral cavity and oral pharynx including the palatine and lingual tonsils, the anal canal, the male foreskin, and the female vagina and ectocervix. These mucosal surfaces are covered by nonkeratinized or parakeratinized epithelia that consist of multilayered cells joined by desmosomes. Although small molecules and proteins can diffuse into the uppermost cell layers, these epithelia provide a permeability barrier to macromolecules by secretion of a glycolipoprotein substance into the narrow intercellular spaces of the lower stratified layers (Farbman 1988). There are many regional variations in the thickness, surface cell phenotypes, and protein expression in stratified squamous epithelia that are determined both by genetic factors and by the local environment. In the vagina and exocervix of some species, for example, fluctuations in hormonal signals over the course of the female cycle have dramatic effects on epithelial thickness, endocytic activity of epithelial cells, and turnover of Langerhans cells (Young and Hosking 1986; Yeaman et al. 1998). Proteins administered to the luminal surface of the vagina in mice can be taken up by stratified epithelial cells, but such epithelia have no mechanism for directional transcytosis. In addition, there is no evidence for vectorial transport across these barriers. It is unlikely that proteins, other macromolecules, or microbes can passively diffuse through stratified epithelia. Thus the immune system obtains samples of intact foreign antigens from these mucosal surfaces through the activities of motile DCs.

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Histologic Definition and Diagnosis of Epithelia in the Esophagus and Proximal Stomach

Parakrama T. Chandrasoma , in GERD, 2018

3.1 Stratified Squamous Epithelium

Stratified squamous epithelium is limited to the esophagus in the human foregut. It does not occur in the stomach. This is not universal to all species; ruminating animals have squamous epithelium in the proximal stomach.

The normal stratified squamous epithelium of the esophagus can be reliably differentiated from columnar epithelium at gross examination of specimens (Figs. 4.3 and 4.4) and endoscopy (Fig. 4.5). Histologically, it has multiple layers of epithelial cells with a flat surface and broad rete pegs in its deep aspect (Fig. 4.6). The rete pegs are separated by short papillae that give the deep aspect of the epithelium an undulating appearance.

Figure 4.4. Esophagectomy specimen showing a long segment of columnar metaplasia involving the thoracic esophagus. The differentiation of squamous from columnar epithelia is easy. The differentiation of different types of columnar epithelium and the distal end of the columnar-lined segment (CLE) is impossible; it requires histology. Note that the distal end of the CLE (i.e., the gastroesophageal junction) is not clearly definable in this specimen.

Figure 4.5. Endoscopic view of the thoracic esophagus shows visible columnar-lined epithelium, its pink color clearly contrasting with the white appearance of the squamous epithelium.

Figure 4.6. Histology of normal squamous epithelium. Note the tight cell junctions with no spaces and the thin basal cell zone.

Stratified squamous epithelium consists of a single basal layer containing stem cells, 2–3 layers of proliferative basaloid cells in the suprabasal region, and larger keratinized cells toward the surface. The esophageal squamous epithelium is nonkeratinizing, i.e., it does not have a stratum corneum.

The overall thickness of the epithelium varies. No normal measured limits exist for squamous epithelial thickness. In the "normal" state, the proliferative basal cell region is less than 30% of the epithelial thickness and the papillary height is less than 60% of the thickness of the epithelium (Fig. 4.6). It is difficult to define "normal" because of the potential frequency of mild unrecognized reflux-induced changes. Squamous epithelial parameters for "normalcy" are adjusted to the upper limit beyond which the epithelium can be recognized as abnormal with high specificity (Fig. 4.7).

Figure 4.7. Reflux esophagitis. This shows basal cell hyperplasia, separation of cell junctions (dilated intercellular spaces), and scattered intraepithelial eosinophils. These findings are not specific for reflux and can be seen in other types of esophageal injury.

It is likely that acid-damaged squamous epithelium often shows changes that cannot be differentiated from "normal." One of these that have been suggested as a sensitive diagnostic marker of GERD is the presence of "dilated intercellular spaces" at the ultrastructural level. 10 The requirement of electron microscopy to accurately detect this change limits its practical usefulness.

The normal state of the squamous epithelium depends on the dynamics of cell loss and replacement. The cells in the basal proliferative zone continually divide and move upward in the epithelium, becoming terminally differentiated keratinocytes that replace the cells that are continually shed at the surface. The keratinocytes have small nuclei and abundant eosinophilic cytoplasm and flatten out at the surface.

In the normal epithelium, the proliferative zone can be identified by immunoperoxidase staining for Ki67 where it is normally seen as 2–3 layers of basaloid cells above the Ki67 negative basal layer (Fig. 4.8). In normal squamous epithelium, the average time taken for a cell to move from the basal zone to the surface is 7–8   days. 21

Figure 4.8. Immunoperoxidase stain for Ki67 showing positive nuclear staining of a thin proliferative cell zone immediately above the basal layer that contains the stem cells (usually nonproliferative).

Normal stratified squamous epithelium is an excellent barrier that is impervious to luminal molecules. 22 The lack of permeability results from the presence of tight junctions that keep the keratinocytes closely apposed to one another. With reflux-induced damage, intercellular edema results in separation of the squamous cells (Fig. 4.9), increasing permeability of the epithelium to increasingly larger molecules. 22

Figure 4.9. Squamous epithelium in reflux disease showing intercellular edema causing separation of cells (dilated intercellular spaces). This increases permeability of the epithelium, permitting entry of luminal molecules into the epithelium.

Two types of mucous glands are seen normally in the squamous-lined esophagus. There are small mucous glands that resemble minor salivary glands in the mucosal lamina propria between the squamous epithelium and muscularis mucosae (Fig. 4.10). Larger lobulated mucous glands are present in the submucosa deep to the muscularis mucosae (Fig. 4.11). The submucosal glands drain onto the surface by well-formed ducts that traverse the muscularis mucosae, the lamina propria of the mucosa, and the stratified squamous epithelium to open at the surface (Figs. 4.12 and 4.13). The ducts may be lined by columnar epithelium, which can sometimes be ciliated, squamous epithelium, or a mixture of the two. The function of the mucous glands is presumably to secrete mucin that lubricates the surface of the squamous epithelium.

Figure 4.10. Normal esophageal squamous epithelium with a mucous gland in the mucosa above the level of the muscularis mucosae.

Figure 4.11. Resected esophagus, normal area lined by squamous epithelium, showing a submucosal gland between the muscularis mucosae above and the muscularis propria below. Submucosal glands are evidence of esophageal location of this specimen.

Figure 4.12. Squamous-lined gland duct in mucosa lined by metaplastic oxyntocardiac epithelium. The presence of the gland duct is evidence of an esophageal location of this biopsy.

Figure 4.13. Columnar-lined gland duct in mucosa lined by oxyntocardiac epithelium. The columnar cells are focally ciliated. The presence of the gland duct is evidence of esophageal location of this biopsy.

The submucosal glands of the esophagus develop in late fetal life after squamous epithelium has replaced the fetal columnar epithelium of the esophagus. 23 Submucosal glands do not occur in the human stomach where squamous epithelium does not develop. As such, submucosal mucous glands and their gland ducts are specific markers for the anatomic esophagus. 4,7 Submucosal glands are seen only in resection (endoscopic and surgical) specimens. Ducts from the glands are seen in mucosal biopsies. 24 It is important to recognize that only the positive finding has value in localizing location. If a submucosal gland or gland duct is present in this region, the conclusion can be made that the location is the esophagus and not the stomach. Because submucosal glands are distributed variably in number and randomly in distribution in different people, the absence of submucosal glands and ducts is not evidence that the organ is the stomach and not the esophagus.

When columnar metaplasia of the squamous epithelium of the esophagus occurs in patients with GERD, the other anatomic elements of the esophagus apart from the surface epithelium remain relatively unaltered. The mucosal glands and submucosal mucous glands and their ducts remain and serve as evidence of esophageal location of the columnar epithelium (Fig. 4.14).

Figure 4.14. Esophagogastrectomy specimen showing surface lined by columnar epithelium. A submucosal gland is present, indicating that this is esophageal in location irrespective of whether this is above or below the end of the tubular esophagus.

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Lesions of the Oral Cavity

Lindsay Montague , ... Jerry Elmer Bouquot , in Gnepp's Diagnostic Surgical Pathology of the Head and Neck (Third Edition), 2021

Pathologic Features

Atrophic stratified squamous epithelium is seen, often with marked parakeratin production, and possibly with epithelial dysplasia of the basal and parabasal layers. Rete ridges may be lost. The subepithelial stroma invariably demonstrates an amorphous, acellular, lightly basophilic change (solar elastosis, actinic elastosis) from the ultraviolet light–induced breakdown of collagen fibers ( Fig. 4.68B). Fibrovascular tissues above and below the elastosis are often scattered with lymphocytes.

The lower margin of the elastosis is relatively uniform throughout the lip, but areas of involvement may be separated laterally by less damaged stroma. Chronic folliculitis may be seen but one must in those cases rule out actinic prurigo cheilitis. Melanosis of the basal epithelial layer further suggests the later disease.

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Gynecologic Cytopathology

In Diagnostic Pathology: Cytopathology (Second Edition), 2018

Epithelial Types

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Stratified squamous epithelium

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Thickens and matures under influence of estrogen [peak levels at mid-cycle (day 15)]

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Estrogen gradually diminishes after day 15 and progesterone predominates; both hormones diminish approaching end of cycle

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Healthy, mature cervicovaginal stratified squamous epithelium in women of reproductive age has 3 main zones

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Basal zone (consisting of least mature, basal cells)

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Mid zone (consisting of parabasal cells and intermediate cells)

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Superficial zone (consisting of superficial cells)

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Due to lower estrogen levels during menopause, squamous epithelium is atrophic, maturing up to lower mid zone (i.e., predominantly parabasal cells)

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Progesterone permits squamous epithelial maturation to upper mid zone, thickening intermediate cell layers

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Proliferation &/or maturation of cervicovaginal squamous epithelium may also occur secondary to chronic irritation, inflammation, or infection and may produce hyperkeratosis &/or parakeratosis regardless of patient age

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Simple endocervical epithelium

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Lining glandular invaginations into underlying endocervical stroma

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At birth, junctions of squamous and endocervical epithelia (i.e., squamocolumnar junctions) are located on ectocervix

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Approaching puberty, cervical elongation retracts squamocolumnar junctions inward into endocervical canal

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At puberty, cervical enlargement extends squamocolumnar junctions outward onto ectocervical circumference; exposed area of thin, endocervical epithelium is termed ectopy (ectropion)

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During reproductive age, ectopic, endocervical epithelium is gradually and haphazardly replaced by patchy, de novo squamous metaplastic epithelium

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Cervical area formed between initial, neonatal (native), squamocolumnar junction at 1 end and new squamocolumnar junctions formed between endocervical columnar cells and maturing squamous metaplastic cell islands is termed transformation zone

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Transformation zone area diminishes with age and its margins migrate inward toward endocervical canal mainly due to progressive squamous metaplasia and decreasing cervical size during menopause

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Replacement of endocervical glandular epithelium in transformation zone by squamous epithelium occurs from 2 processes

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Squamous epithelialization (generation and lateral expansion of native squamous epithelium due to basal cell hyperplasia)

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Squamous metaplasia (de novo generation of squamous epithelial cells from undifferentiated, bipotential, endocervical reserve cell hyperplasia)

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Squamous metaplastic epithelium

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Cytomorphology depends on degree of maturity (squamoid differentiation)

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Squamous metaplastic epithelium develops, matures, becoming indistinguishable from native squamous epithelium

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Squamous metaplasia is divided into 3 categories

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Immature squamous metaplasia

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Mature squamous metaplasia

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Florid squamous metaplasia (tissue repair)

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Endometrial epithelial cells

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Endometrial cells may be identified in Pap test cytopreparations due to physiologic exfoliation (normally during first 1/2 of menstrual cycle)

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Diagnostic significance of endometrial cells in Pap tests depends upon age and hormonal/menstrual status of woman and cytomorphology

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Human Papillomavirus Infections

William Bonnez , Gerhard Lindeque , in Tropical Infectious Diseases (Third Edition), 2011

Pathogenesis and Immunity

The stratified squamous epithelia contain basal cells resting on a basement membrane that are the only ones dividing in the epithelium. This division causes one of the two daughter cells to move upward and start differentiating. Different layers correspond to stages of differentiation. Immediately above the stratum basale is the stratum acanthosum (the prickle cell layer), the stratum granulosum, and on the surface the stratum corneum that constantly sheds dead cells. For the epithelium to become infected, the virus must reach a basal cell, likely through microabrasions or microtrauma, mostly during sexual intercourse. Furthermore, a thin and immature epithelium, as in the adolescent female cervix, facilitates that breach.

Entry of the virion involves at least one receptor, probably a syndecan. The basal cell is suspected of being the target of HPV because viral DNA replication needs the cellular replicative enzymes, the virus being devoid of DNA polymerase. 46,47 Replication can be at a low level, the infection remaining latent, or it can be associated with abundant protein expression, causing active infection. The early proteins E1, E2, E5, E6, and E7 are found in the deeper layers of the epithelium, while E4, L1, and L2 are present in the superficial layers, where viral particles are assembled in the cell nucleus. Virions are released with desquamating cells.

These viral changes of active infection are associated with formation of a wart or papilloma by proliferation of the stratum spinosum (acanthosis), stratum granulosum (parakeratosis), and stratum corneum (hyperkeratosis) ( Fig. 80.1A ). 48,49 This proliferation, called papillomatosis, extends upwards, but also downwards with deepening of the normal scalloping of the basal membrane. One feature is quasi-pathognomonic, the presence in the upper stratum spinosum of large cells with a nucleus surrounded by a halo, koilocytes, which in a cytological sample signal the presence of HPV. A high-risk HPV infection may cause intraepithelial neoplasia ( Fig. 80.1B ). 48,49 In that instance, there is proliferation of the basal layer. The cells start acquiring features associated with malignancy, including high nuclear-to-cytoplasmic ratio and greater number of mitoses. The presence of this basaloid proliferation confined to the lower third of the epithelium is grade 1. Grade 2 extends to the lower two-thirds, and grade 3 goes further. Involvement of the full thickness of the epithelium is carcinoma in situ, and breach of the basal membrane by this process defines invasive SCC. Dyskeratosis is also present.

The body sites where squamous epithelium meets glandular epithelium (squamocolumnar junction, SCJ), such as cervix, anus, and pharynx, are particularly susceptible to HPV infections and HPV-induced malignant transformation. In the cervix, under the influence of factors that include hormones and acidification, this SCJ moves from the exocervix to the endocervix from birth to adulthood, thus defining a transformation zone where SCC arises. The glandular epithelium adjoining the CSJ is also susceptible to HPV-induced malignant transformation leading to cervical adenocarcinoma. Because the glandular epithelium is a monolayer, there are no precursor states other than adenocarcinoma in situ (AIS).

Among the many molecular events leading to malignant transformation, at least two appear essential because they are directly linked to the virus. 48,50 They are degradation of the p53 protein by E6 and inactivation of the retinoblastoma protein (Rb) by E7. p53 and Rb are key tumor suppressor proteins that regulate the cell cycle and prevent its acceleration. In addition, E6 inhibits cellular apoptosis, preventing abnormal cells from dying. Before the tissue evolves into an invasive cancer, there is an opportunity for the lesion to regress spontaneously. For example, the chances of regression for CIN grades 1, 2, and 3 are 60%, 40%, and 30%, respectively, while for the same lesions the chances of progression to invasive cancer are 1%, 5%, and greater than 12%, respectively. 51 Progression involves additional events such as hypermethylation of viral and cellular DNA, telomerase activation, and development of chromosomal instability and deletions. In addition, the viral genome tends to become integrated as intraepithelial neoplasia progresses. This integration disrupts E2, which changes the viral expression pattern with overexpression of E6 and E7. E5, E6, and E7 appear to contribute in different ways to inhibition of the immune response. 52,53 Regressing warts are notable for the presence of a lymphomononuclear epidermal infiltrate.

The humoral and cellular immune response that develops after HPV infection is neither uniform nor predictive of the severity or behavior of the infection or associated diseases. 54 E6, E7, and L1 are the more potent antigens. The presence of antibodies to L1 is a good marker of past or present infections that can be used for seroepidemiologic surveys. The cellular immune response after vaccination to peptides derived from E6 and E7 of HPV-16 seems capable of inducing regression of HPV-16-associated vulvar intraepithelial neoplasias. 55

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Connective Tissue Lesions

J. PHILIP SAPP DDS, MS , ... GEORGE P. WYSOCKI DDS, PHD , in Contemporary Oral and Maxillofacial Pathology (Second Edition), 2004

HISTOPATHOLOGY

The surface stratified squamous epithelium is frequently hyperplastic, demonstrating acanthosis with elongated rete ridges. Occasionally, zones of ulceration are encountered and the ulcerated areas are occupied by fibrin with entrapped leukocytes. The bulk of the tissue is composed of mature, fibrous connective tissue that is hypocellular. Spindle-shaped fibroblasts are interposed between dense collagen fibers in a scarlike pattern ( Figure 9-10). When the fibrous hyperplasia extends into the lip and buccal mucosa, minor salivary gland lobules may be identified and will usually show acinar degeneration and ductal dilatation with inflammatory cell infiltration (chronic sclerosing sialadenitis).

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Vulva, vagina and cervix

Tanya Levine , Winifred Gray , in Diagnostic Cytopathology (Third Edition), 2010

Progesterone

Once the stratified squamous epithelium has matured under the influence of oestrogen, progesterone causes rapid desquamation of the topmost layers. The intermediate cells develop curled edges giving a folded appearance, and the cytoplasm often contains glycogen, staining yellow at the centre of the cell. Exfoliation occurs in compact clusters of cells in which the margins of individual cells are indistinct.

Many Döderlein's bacilli (lactobacilli) and leucocytes appear in the smear. They bring about cytolysis of the intermediate cells, causing dissolution of the cell cytoplasm (Fig. 21.43). As a result, numerous naked vesicular nuclei are present and the smear may appear hypocellular. Further progesterone induces the appearance of boat-shaped navicular cells (Fig. 21.44).

When there is mild oestrogen deficiency, as may be encountered at the time of the menopause, the cytological pattern is difficult to distinguish from that of progesterone or androgen stimulation. The clusters are, however, usually slightly smaller, often containing no more than 10 cells.

If progesterone is administered to patients with an atrophic mucosa, maturation of the squamous epithelium including the superficial layers is the initial result. Administration of progesterone to patients with pre-existing mature epithelium leads to disappearance of the superficial layer and no superficial cells are found in the smear.

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Nose, Sinus, Pharynx, and Larynx

Jack R. Harkema , ... Denny Liggitt , in Comparative Anatomy and Histology (Second Edition), 2018

Transitional Epithelium

Between the stratified SE and the ciliated RE is a narrow zone of poorly or nonciliated, microvilli-covered cuboidal/columnar surface epithelium, which has been referred to as nasal nonciliated or scantly ciliated RE, or nasal TE (Figs. 6.3 and 6.4). Common, distinctive features of TE in rodents and primates include (1) an anatomic location in the proximal aspect of the nasal cavity between the SE and RE, (2) the presence of numerous nonciliated cuboidal or columnar surface cells and basal cells, (3) few ciliated cells and a scarcity of goblet cells, and (4) an abrupt morphologic border with SE, but a less abrupt border with RE. In T1 of rodents, TE lines the luminal surfaces of the lateral wall, maxilloturbinate, and medial aspect of the nasoturbinate. These epithelial surfaces border the lateral meatus in the proximal nasal airways. Rodent TE is thin (one or two cells thick), pseudostratified, and composed of three nonciliated cell types (basal, columnar, and cuboidal) and scattered ciliated cells. In contrast, TE of primates is thick (four or five cells), stratified, and composed of at least five different epithelial cell types including goblet cells (Fig. 6.4).

Luminal, nonciliated TE cells in rodents rarely contain secretory granules, but do have abundant smooth endoplasmic reticulum (SER) in their apices. SER is an important intracellular site for xenobiotic-metabolizing enzymes, including cytochrome P450. The prominence of SER in these cells, as well as in the sustentacular cells of OE, suggests metabolizing capability for certain inhaled and noninhaled xenobiotics.

In both rodents and humans, the lamina propria beneath the TE and RE is a highly vascularized and innervated, loose fibroelastic connective tissue containing serous and seromucous secretory glands. Cavernous venous plexuses, sometimes referred to as "swell bodies," are also present in the lamina propria of the nasal mucosa and located in distinct regions along the nasal airway. Dilation of these vessels is thought to alter nasal airflow by thickening the mucosa, narrowing air passages, and diverting inhaled air. Prominent swell bodies in rodents are found in the maxilloturbinates and lateral wall in the proximal nasal passage.

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Nose, Larynx, and Trachea

Ronald A. Herbert , ... Rodney A. Miller , in Boorman's Pathology of the Rat (Second Edition), 2018

6.1.1.1 Squamous Cell Hyperplasia

Hyperplasia of the stratified squamous epithelium in the anterior portion of the nasal passages is rare as a spontaneous lesion. Even in inhalation studies of irritant or reactive chemicals, proliferative lesions are less common in the squamous than in the respiratory or olfactory epithelia. Hyperplasia of the stratified squamous epithelium occurs in the nasal vestibule, ventral meatus, and the nasolacrimal and incisive ducts and is characterized by focal to diffuse increase in the number of cell layers. Because the thickness of the epithelium varies slightly, depending on location in the vestibule of the nose, it may be difficult to identify subtle lesions or lesions of minimal to mild severity. The hyperplastic epithelium is usually well differentiated; however, the cells in the affected area may have larger nuclei with more prominent nucleoli and more abundant cytoplasm. Minimal to mild hyperkeratosis may present with prolonged exposure. Focal cellular atypia may occur in areas of squamous hyperplasia; it is characterized by cellular and nuclear pleomorphism and increased nucleolar size. These changes may occur with exposure to carcinogens, and may precede the development of squamous cell carcinoma.

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Sexually transmitted diseases

Sheena Kakar , Adrian Mindel , in Antibiotic and Chemotherapy (Ninth Edition), 2010

Pathogenesis

HPV infects the stratified squamous epithelium of the genital tract. The infection does not result in cell lysis; rather, infected cells are shed from the surface of the skin or mucous membranes. This means that no viral proteins are released, and consequently immune response is limited. It takes approximately 6 months after infection for natural immunity to develop. 155 T-cell function appears to be critical in modifying the effects of HPV and allows for persistence or spontaneous regression. Individuals with depressed cellular immunity often have persistent and proliferative lesions. 156

In benign lesions, HPV remains extrachromosomal. However, in cervical and other genital tract tumors, viral DNA is incorporated into the host chromosome. 155

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