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Histopathology of Mucosa-Associated Lymphoid Tissue
C. Frieke Kuper
TNO Nutrition and Food Research, 3704 HE Zeist, The Netherlands
Correspondence: Address correspondence to: C. Frieke Kuper, TNO Nutrition and Food Research, P.O. Box 360, 3704 HE Zeist, The Netherlands; e-mail:frieke.kuper{at}tno.nl
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Abstract
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Mucosa-associated lymphoid tissue (MALT) is a generalized term incorporating a disseminated collection of lymphoid tissues in multiple sites throughout the body. MALT sites that have been/are primarily studied include bronchus-associated lymphoid tissue (BALT), gut-associated lymphoid tissue (GALT), and nasopharynx-associated lymphoid tissue (NALT). Since MALT sites are often under-sampled in conventional toxicity studies, MALT lesions have not been extensively documented in these lymphoid effector sites. Lesions of the nasopharyngeal lymphoid tissue and Peyer’s patches include degeneration, inflammation, and both primary and metastatic neoplasia.
Key Words: Lymphatic ectasia • macrophage aggregates • granulomas • MALT lymphoma
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Introduction
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The organized mucosa-associated lymphoid tissues, collectively denoted MALT, and the mucosa-draining lymph nodes are considered to be the inductive sites for mucosal immunity, i.e., trigger the näive immune cells and generate the memory-effector cells (Brandtzaeg and Pabst, 2004; Cesta, 2006). The effector sites are the sites where secretory immunoglobulins are generated and where e.g., allergic inflammation is effectuated. The effector sites consist of histological compartments, which are distinctly different from the inductive sites, including the lamina propria, the stroma of exocrine glands and surface epithelia. It should be acknowledged that the distinction between immune response-induction and effector sites is not strict, for example the lamina propria is also involved in the differentiation of lymphocytes.
The focus of the paper is on the histopathology of part of MALT, namely the Peyer’s patches (PP) and nasopharynx-associated lymphoid tissues (NALT), whereas the mucosa-draining lymph nodes are described elsewhere (Willard-Mack, 2006; Elmore, 2006a).
Semi-Quantitative Changes in Cellularity, Compartment Size, and Germinal Center Development
Induced decreases or increases in cell density (cellularity) and MALT compartment sizes as well as alterations in germinal centre development are described under ‘Enhanced Histopathology of MALT’ by Elmore (2006b). Changes that accompany increased cellularity, enlarged compartments and germinal centre development (‘activation’ of MALT) are dilatation of lymph vessels (Figure 1), increased prominence of high endothelial venules or HEV (Figure 2) and lymphocyte-rich lymph vessels in or closely associated with MALT (Figure 3).
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Figure 1 Lacrimal duct-associated lymphoid tissue (LDALT) from a rat. (A). Dilatation of the lymph vessels in activated LDALT. (B). Higher magnification of LDALT with dilatation of lymph vessels.
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Figure 2 Gut-associated lymphoid tissue (MALT) from a rat. (A) Normal interfollicular area of Peyer’s patch in small intestine. Normal high endothelial venules (HEVs) (arrows). (B) Prominent high endothelial venules (HEVs) (arrows) in the interfollicular compartment of an activated Peyer’s patch. The MALT activation is associated with enlargement of the interfollicular compartment secondary to treatment with hexochlorobenzene. Photomicrograph courtesy of Dr. Hans Harleman.
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Figure 3 Gut-associated lymphoid tissue (MALT) from a rat. Lymphocyte rich lymph (chyle) vessels (arrows) in the small intestinal villi overlying activated Peyer’s patches. 4.—Gut-associated lymphoid tissue (MALT) from a Wistar rat. (A) Lipid vacuoles (arrows) in Peyer’s patch from jejunum, following ingestion of a high fatty acid diet. (B) Aggregates of multinucleated Langhans’ type giant cells macrophages (synonyms: macrophage aggregates, focal histiocytosis, histiocyte infiltration) in Peyer’s patches (arrows) following exposure to a high fatty acid diet.
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Inflammation, Macrophage Aggregates and Granulomata
Macrophage aggregates and granulomatous inflammation (Figures 4 and 5) may be formed in MALT upon uptake of macromolecules and microorganisms by the specialized lymphoepithelium of MALT. Macrophage aggregates and granuloma formation in MALT is reported occasionally. It has been reported for example in PP by intramural injection with bacterial peptidoglucan-polysaccharide complex (Tanaka et al., 1995) and in paratuberculosis infection in goats (Corpa et al., 2000). Macrophage aggregates have been observed in PP and BALT of rats, but not in NALT of Wistar rats (Kuper, unpublished observations).
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Figure 5 Gut-associated lymphoid tissue (MALT) from a Wistar rat. Granulomatous inflammation and scarring (arrow) in Peyer’s patch following exposure to a high fatty acid diet. At higher magnification the lesion was comprised of fibrosis, lymphocytes, macrophages, and a few polymorphonuclear leukocytes. 6.—Gut-associated lymphoid tissue from a Wistar rat. (A) Focal mineralization in the dome of a Peyer’s patch (arrows). Such mineralization may result from prior inflammation and necrosis. (B) Focal mineralization in a Peyer’s patch in a rat fed an industrial compound (arrow). Overlying cystically dilated crypts contain cellular debris and macrophages with foamy cytoplasm.
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Degeneration, Necrosis, and Mineralization
Several compounds induce necrosis of lymphocytes in PP (the muscle toxin azaspiracid, Ito et al., 2000; Nivalenol, Poapolathep et al., 2002; DMSO, Aita et al., 2005). Degeneration and necrosis are also encountered in inflammation and may lead to mineralization, which has been observed occasionally in PP of rats (Figure 6).
Changes in Lymphoepithelium
The lymphoepithelium of MALT is occasionally affected by exposure to xenobiotics (Figures 7 and 8). As a consequence, normal functioning of MALT may be affected as well because antigen-uptake and -presentation are either impaired or facilitated.
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Figure 7 Nasopharynx-associated lymphoid tissue (NALT) from a rat. The lymphoepithelium associated with NALT may be altered following exposure to xenobiotics and irritants. In this example, there is superficial necrosis overlying non-keratinizing squamous metaplasia of the NALT lymphoepithelium following inhalation exposure to an industrial compound. There is decreased cellularity of lymphocytes in the underlying NALT compartment. 8.—Nasopharynx-associated lymphoid tissue (NALT) from a rat. There is hyperplasia and goblet cell metaplasia of the NALT lymphoepithelium in this rat with a nasal squamous cell carcinoma due to inhalation exposure to acetaldehyde. 9.—Gut-associated lymphoid tissue (MALT) from a mouse. A specific B-cell lymphoma is believed to arise from the outer mantle/marginal zone of Peyer’s patches. This is an example of a MALT lymphoma (synonyms: maltoma, marginal zone lymphoma). (Photomicrograph courtesy of Dr. Jerrold Ward). 10.—Nasopharynx-associated lymphoid tissue (NALT) from a rat. NALT is believed to be involved in draining of the nasal mucosa and the olfactory nerves. This is an example of tumor emboli (arrows) from a neoplasm (neuroepithelial carcinoma) arising in the nasal olfactory epithelium with invasion of the brain.
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MALT Tumors
MALT houses subpopulations of T and B lymphocytes and macrophages and thus, theoretically, any type of lymphoma may arise in MALT. In man, a type of lymphoma that has been linked specifically with gut mucosal lymphoid tissues is MALT lymphoma (synonym: maltoma; belonging to the extranodal marginal zone lymphomas; WHO histological classification, Jaffe et al., 2001), which originates from post-germinal center memory B-lymphocytes in the periphery of the mantle zone of germinal centers. This outer zone is sometimes called marginal zone, hence the term marginal zone lymphoma. Infiltration of neoplastic lymphocytes into epithelium and plasma cell differentiation are characteristic findings of this tumor. Chronic inflammation, e.g. due to infection with Helicobacter pylori or to autoimmune-like diseases, are considered to be causative agents. MALT lymphoma is rarely reported in most laboratory species (Figure 9). It has been induced in mice as a model for human disease (Mueller et al., 2005).
Metastasis, Tumor Emboli and Involvement of MALT in Tumorigenesis
A portion of the cerebrospinal and interstitial fluid of the brain drains via the arachnoid sheaths of the olfactory nerves, through the cribriform plate to the nasal mucosa and from there to the cervical lymph nodes and blood (Cserr and Knopf, 1992; reviewed by Feron et al. 2001). This is especially so in small and/or young animals. Most probably, NALT is involved in this route, as is illustrated by tumor emboli in NALT lymphatics from a neuroepithelial carcinoma of olfactory epithelium origin (Figure 10).
Dimethylhydrazine (DMH) induces intestinal adenocarcinoma in rats, which is associated regularly with PP. Martin et al. (1986) observed early carcinoma in the interfollicular compartment of PP and hypothesized that the atypical glandular crypts, found often in the interfollicular compartment of PP, were the origin of the PP-associated adenocarcinomas.
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Toxicologic Pathology, Vol. 34, No. 5,
609-615 (2006)
DOI: 10.1080/01926230600867735
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Abstract
Introduction