Expression of lymphocyte homing receptors and vascular addressins in low-grade gastric B-cell lymphomas of mucosa-associated lymphoid tissue.

In this study, we examined lymphocyte homing receptor and vascular addressin expression in a case of primary gastric B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) with a secondary intestinal spread. We compared the findings with that observed in B cells of normal MALT and MALT acquired as a consequence of Helicobacter pylori-associated gastritis and other low-grade gastric B-cell MALT lymphomas. The neoplastic B cells in the gastric tumor were alpha 4 beta 7-, CD62L+, whereas the intestinal secondary was alpha 4 beta 7+, CD62L-. Incubation of isolated tumor cells from the stomach by H. pylori generated T-cell-dependent proliferation of neoplastic B cells and induced expression of alpha 4 beta 7 integrin similar to the intestinal tumor. These observations indicate that reversal of homing receptor profile in the gastric tumor by antigen specific stimulation may be responsible for secondary intestinal dissemination. In normal stomach and normal MALT, alpha 4 beta 7 and CD62L expression reflected the differentiation of the B cell. Plasma cells were alpha 4 beta 7+, CD62L-, whereas a subset of memory B cells were alpha 4 beta 7-, CD62L+. Homing receptor expression in MALT lymphoma B cells was heterogeneous, however, in line with their memory B-cell phenotype in the majority of cases, the neoplastic B cells were alpha 4 beta 7-, CD62L+. Neoplastic plasma cells were always alpha 4 beta 7+, CD62L-. The venules in normal gastric mucosa expressed mucosal addressin cell adhesion molecule-1 but not peripheral lymph node addressin. In normal MALT, H. pylori-associated follicular gastritis and MALT lymphomas high endothelial venules coexpressed mucosal addressin cell adhesion molecule-1 and peripheral lymph node addressin. These findings suggest expression of lymphocyte homing receptors by B cells and vascular addressins by mucosal venules are similar in normal MALT and MALT lymphomas, and factors controlling normal mucosal B-cell traffic are also operational in MALT lymphomas.     

Preferential expression of the mucosal homing receptor integrin alpha 4 beta 7 in gastrointestinal non-Hodgkin's lymphomas.

Recent studies have identified the integrin alpha 4 beta 7 as a mucosal homing receptor that mediates lymphocyte migration to the intestinal mucosa by binding to MAdCAM-1, a vascular recognition molecule (addressin) selectively expressed on mucosal endothelium. In the present study, we have assessed the expression of alpha 4 beta 7 on B- and T-cell non-Hodgkin's lymphomas of different primary localization and on related normal lymphocytes. Among B-lineage lymphomas, expression of alpha 4 beta 7 was present in the majority of cases of malignant lymphomatous polyposis of the intestine and low-grade lymphoma of the mucosa-associated lymphoid tissue/monocytoid B-cell lymphoma and in some cases of precursor B-cell lymphoma. CLL/small lymphocytic lymphoma, (nodal) mantle cell lymphoma, follicular center cell lymphoma, Burkitt's lymphoma, and diffuse large B-cell lymphoma were virtually always alpha 4 beta 7 negative, as was the case when localized in the mucosa-associated lymphoid tissue. The normal B cells of the follicle mantles and part of the B cells of the extrafollicular B-cell compartment of lymphoid tissues expressed moderate levels of alpha 4 beta 7. By contrast, follicular center cells were alpha 4 beta 7 negative. Among T-lineage lymphomas, expression of alpha 4 beta 7 was also strongly related to the primary localization; in mucosal, nodal, and cutaneous T cell lymphomas the percentage of positive cases was 56%, 17%, and 0%, respectively. All cases of precursor T-cell lymphoma were alpha 4 beta 7 negative. High expression of alpha 4 beta 7 was found on a subset of peripheral blood memory T cells as well as on lymphocytes in the intestinal mucosa. We conclude that non-Hodgkin's lymphomas that are related to mucosa-associated B- and T-lymphocyte populations selectively express the mucosal homing receptor alpha 4 beta 7. The presence of this receptor underscores their distinctive character and may play an important role in determining their characteristic mucosal dissemination pattern.     

Gastrointestinal lymphomas of T- and B-cell types.

Gastrointestinal lymphomas comprise a group of distinctive clinicopathological entities of B- or T-cell type, with primary gastrointestinal Hodgkin's disease being extremely uncommon. Most low-grade B-cell gastrointestinal lymphomas are of mucosa-associated lymphoid tissue (MALT) type, so called because they recapitulate the features of MALT rather than those of lymph nodes. Paradoxically, however, most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. Gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacter pylori and their growth can be inhibited by eradication of this organism from the stomach. Low-grade MALT lymphomas, which usually have a very favorable clinical course, may undergo high-grade transformation but high-grade diffuse large B-cell lymphomas may also arise de novo. Immunoproliferative small intestinal disease (IPSID) is a special form of MALT lymphoma characterized by synthesis of alpha heavy-chain immunoglobulin and a restricted geographic distribution. Other B-cell lymphomas that tend to arise in the gastrointestinal tract include mantle cell lymphoma, which presents as lymphomatous polyposis, Burkitt's lymphoma, and B-cell lymphomas associated with immunodeficiency states. Enteropathy (celiac disease)-associated T-cell lymphoma (EATL) is the most common primary gastrointestinal T-cell lymphoma This is a clinically aggressive tumor that arises from the intraepithelial T-cell population.     

Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.

Lymphocyte homing to normal tissues and recruitment to inflammatory tissue sites are controlled, in part, by the selective expression of chemokines, pro-inflammatory cytokines and mediators, and various adhesion proteins and molecules. In the mouse, mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed on endothelium of high endothelial venules in gut and gut-associated lymphoid tissue. By interaction with its integrin ligand, alpha 4 beta 7, lymphocytes presumed to be involved in mucosal immunity are selectively recruited to these intestinal sites. After generating monoclonal antibodies against a murine cell line expressing recombinant human MAdCAM-1, we qualitatively and semiquantitatively assessed MAdCAM-1 expression in human tissue sections from various normal and inflammatory disorders. We found that human MAdCAM-1, as in the mouse, is expressed in a tissue-selective manner. In normal tissues, MAdCAM-1 is constitutively expressed to endothelium of venules of intestinal lamina propria. Interestingly, using computer-assisted morphometric analysis, the proportion of venular endothelium within lamina propria that expresses MAdCAM-1 is increased, compared with normal tissues, at inflammatory foci associated with ulcerative colitis and Crohn's disease. Moreover, for the most part, MAdCAM-1 is not detected in the majority of normal or inflamed extra-intestinal tissues, including those with mucosal surfaces. These results are consistent with a role, as originally defined in the mouse, for human MAdCAM-1 in the localization of alpha 4 beta 7+ lymphocytes in the gastrointestinal tract and associated lymphoid tissue. As such, the pathway defined by MAdCAM-1/alpha 4 beta 7 may be a relevant tissue-specific therapeutic target for the modulation of inflammatory bowel disease activity.     

Characterization of tumor-infiltrating T lymphocytes in B-cell lymphomas of mucosa-associated lymphoid tissue.

B-cell lymphomas of mucosa-associated lymphoid tissue invariably contain large numbers of reactive tumor-infiltrating T cells. In the stomach, these lymphomas develop secondary to Helicobacter pylori infection, and clinical and in vitro studies have shown that their growth depends on help provided by H. pylori-specific T cells. In this study we characterized tumor-infiltrating T cells in low- and high-grade B-cell lymphomas of mucosa-associated lymphoid tissue using immunohistochemistry. In most cases, CD4+ T cells dominated and almost all T cells were CD45RO+ memory cells. In 11 of 13 cases studied, the proliferating T cells were CD4+ and no proliferation was observed in the CD8+ subset. In low-grade lymphomas, between 7 and 24% of T cells expressed CD40L whereas no CD40L expression was observed in the majority of high-grade tumors. Examination of homing receptor profile showed that both alpha 4 beta 7 integrin+ and L-selectin+ T cells were present. Examination of T cell diversity by a panel of antibodies against different T-cell receptor V beta regions and by analysis of T-cell receptor genes using polymerase chain reaction suggested that the T cells in these tumors were polyclonal. These results show that low-grade B-cell lymphomas of mucosa-associated lymphoid tissue contain a significant population of activated helper T cells that may be important in supporting tumor growth.     

Two distinct lymphocyte homing systems involved in the pathogenesis of chronic inflammatory gastrointestinal diseases

Under normal and pathological conditions, lymphocyte migration into the gastrointestinal mucosa to form gut-associated lymphoid tissue is mediated by the L-selectin ligand peripheral lymph node addressin and the integrin α4β7 ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) expressed on high endothelial venules (HEVs) and HEV-like vessels. In this review, we discuss these two distinct lymphocyte homing systems involved in the pathogenesis of chronic inflammatory gastrointestinal diseases with reference to our and others’ previously published works. We also describe a recently developed recombinant integrin α4β7 heterodimeric IgG chimera that can be used as an immunohistochemical reagent to stain functional MAdCAM-1.     

The small GTP-binding proteins Rho and Rac induce T cell adhesion to the mucosal addressin MAdCAM-1 in a hierarchical fashion.

Here we report that an activator (AIF4-) of heterotrimeric GTP-binding proteins (G-proteins) and inhibitors (lovastatin and C3 exoenzyme) of small GTP-binding proteins regulate the induction of alpha4beta7-mediated adhesion of TK-1 T lymphoma cells (alpha4+beta7+beta1-) to the mucosal addressin cell adhesion molecule MAdCAM-1. Activation of cell adhesion by AIF4- was abrogated by lovastatin, thereby establishing a link between heterotrimeric G-proteins and small GTP-binding proteins in the regulation of alpha4beta7-mediated cell adhesion. Increased numbers of cells bound MAdCAM-1-coated microspheres following activation with AIF4-, discounting an obligatory role for cell spreading in alpha4beta7-mediated cell adhesion. MAdCAM-1-Fc dimers triggered ligand-induced clustering of alpha4beta7 in response to AIF4- and Mn2+-induced activation of integrins. Hence alpha4beta7 cluster formation may be responsible, at least in part, for inducing cell adhesion in response to both extracellular and intracellular signals that impact on integrin function. Electroporation of constitutively active V14RhoA and V12Rac1 recombinant proteins into TK-1 cells revealed that both RhoA and Rac1 induce alpha4beta7 adhesion to MAdCAM-1. Activation is hierarchical since Rac1 is unable to directly activate alpha4beta7, but induces cell adhesion via RhoA, whereas the transient induction of cell adhesion mediated by RhoA is dependent on the activities of protein tyrosine kinases and protein kinase(s) C.     

Epitheliotropism in high-grade lymphomas of mucosa-associated lymphoid tissue

Low-grade lymphomas of mucosa-associated lymphoid tissue (MALT) characteristically show centrocyte-like cells, plasmacytic differentiation, follicular colonization and lymphoepithelial lesions (epitheliotropism). High-grade lymphomas of MALT are thought to lack these features and can only be identified as MALT lymphomas with confidence if they are admixed with residual low-grade tumours. We studied 23 cases of MALT lymphoma of the thyroid. Six were predominantly low-grade, 12 were predominantly high-grade, and five contained both low- and high-grade areas. All cases were stained for cytokeratin, epithelial membrane antigen and laminin using an immunoperoxidase technique. The low-grade lymphomas all contained lymphoepithelial lesions, generally in the form of clusters of intra-acinar centrocyte-like cells. Eleven of the 12 high-grade MALT lymphomas of the thyroid also showed lymphoepithelial lesions. These appeared in three forms: follicles or clusters of epithelial cells infiltrated by groups of centrocyte-like cells, intra-acinar clusters of blast cells, or irregular invasion of islands of epithelial cells by blast cells. The first pattern presumably represented residual low-grade tumour over-run by high-grade lymphoma. The second two patterns indicated that the factors that result in epitheliotropism in low-grade MALT lymphomas are also prsent in high-grade tumours. Following this study we identified epitheliotropism in single examples of high-grade MALT lymphomas of the bronchus and small intestine. Previous failure to recognize epitheliotropism in high-grade MALT lymphomas of the gastrointestinal tract may be due to loss of the affected epithelium. The localization and relatively good prognosis of high-grade MALT lymphomas may be related to retention of MALT characteristics including epitheliotropism.     

Indium-labelled human gut-derived T cells from healthy subjects with strong in vitro adhesion to MAdCAM-1 show no detectable homing to the gut in vivo

Integrin alpha4beta 7 is the principal gut-homing receptor, and it is assumed that expression of this specific integrin directs lymphocytes to the gut in vivo. Adoptive cellular immunotherapy against inflammatory bowel disease (IBD) may depend on the expression of integrin alpha4beta 7 to accomplish local delivery of intravenously injected regulatory T cells in inflamed gut mucosa. The present study aimed to investigate whether in vitro expanded human T cells from the colonic mucosa maintain integrin expression, show in vitro adhesion and retain in vivo gut-homing properties during cultivation. Whole colonic biopsies from healthy subjects were cultured in the presence of interleukin-2 (IL-2) and IL-4. The integrin expression of the cultured T cells was determined by flow cytometry and in vitro adhesion was assessed in a mucosal addressin cell adhesion molecule 1 (MAdCAM-1) adhesion assay. We studied the homing pattern after autologous infusion of 3 x 10(8 111)Indium ((111)In)-labelled T cells in five healthy subjects using scintigraphic imaging. The cultured CD4(+)CD45RO(+) gut-derived T cells express higher levels of integrin alpha4beta 7 than peripheral blood lymphocytes (PBLs) and show strong adhesion to MAdCAM-1 in vitro, even after (111)In-labelling. Scintigraphic imaging, however, showed no gut-homing in vivo. After prolonged transit through the lungs, the T cells migrated preferentially to the spleen, liver and bone marrow. In conclusion, it is feasible to infuse autologous T cells cultured from the gut mucosa, which may be of interest in adoptive immunotherapy. Despite high expression of the gut-homing integrin alpha4beta 7 and adhesion to MAdCAM-1 in vitro, evaluation by (111)In-scintigraphy demonstrated no gut-homing in healthy individuals.     

Epstein-Barr virus-associated high-grade B-cell lymphoma of mucosal-associated lymphoid tissue in a 9-year-old Boy

We report an unusual case of Epstein-Barr virus (EBV)-associated mucosal-associated lymphoid tissue (MALT) lymphoma involving the lungs, kidneys, and axillary lymph nodes in a child with congenital hypoadrenalism and panhypopituitarism. The patient presented with an aggressive clinical course and histologic evolution. Initial biopsies (1994) of the lung and kidney revealed histologic features of low-grade B-cell MALT lymphoma with lymphoepithelial lesions within the renal tubules and bronchial epithelium. Subsequent biopsies (1996, 1997, and 1999) revealed progressively greater cytologic atypia, polymorphism, and necrosis; an increased mitotic rate; and a preponderance of large cells, indicative of progression from a low-grade to a high-grade MALT lymphoma. Immunophenotyping of the lung and lymph node lesions revealed identical surface marker profiles: cells were CD19(+), CD20(+), immunoglobulin (Ig) G(+), kappa(+), lambda(-), CD5(-), CD10(-), CD23(-), and IgM(-), and also negative for T-cell markers. Genotypic analysis demonstrated the presence of immunoglobulin heavy chain rearrangement and monoclonality of EBV in the lung lesion by Southern blot hybridization and polymerase chain re()action (PCR). The clinicopathologic features suggest that these lesions might represent an immunosupression-related continuum of low-grade to high-grade MALT lymphomas. Infection with EBV may have contributed to this tumor's aggressive clinical and histologic evolution.     

Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease

Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is selectively expressed in the endothelial cells of intestinal mucosa and gut-associated lymphoid tissue (GALT). Engagement of MAdCAM-1 to its ligand, integrin alpha4beta7, on lymphocytes is associated with the homing of gut-associated lymphocytes to normal gastrointestinal tract and inflammation sites. The present study was designed to elucidate differences between Crohn's disease (CrD) and ulcerative colitis (UC) from the expression patterns of MAdCAM-1. Samples were taken from 40 patients with CrD and 24 patients with UC at surgical resection. Using frozen sections, immunohistochemistry was performed for MAdCAM-1, E-selectin and CD34. MAdCAM-1+ venules were abundant in inflamed mucosa in both UC and CrD. In contrast, clear differences were noted between UC and CrD in the inflammatory area in the ulcer base, that is, MAdCAM-1+ venules were more abundant in CrD than in UC (P < 0.001), while E-selectin was expressed equally in these venules in both diseases. Furthermore, CrD was characterized by the occurrence of MAdCAM-1+ venules in deeper layers of the intestinal tissue, mainly in lymphoid aggregates. Our data indicated more extensive expression of MAdCAM-1 in CrD, which could contribute not only to mucosal inflammation, but also to transmural inflammation in CrD.     

Expression of the mucosal vascular addressin, MAdCAM-1, on sinus-lining cells in the spleen.

The MAdCAM-1 adhesion molecule is involved in lymphocyte homing into mucosal sites and is expressed on high endothelial venules of Peyer's patches and mesenteric lymph nodes. In the spleen, where high endothelial venules are absent, expression can be found on cells in the marginal zone between red and white pulp. By immunohistochemistry and electron microscopy it was demonstrated that in the spleen cells expressing MAdCAM-1 belong to the population of sinus-lining cells and that the expression is restricted to the sinus-lining cells closest to the lymphoid white pulp. Lymphocytes that migrate from the blood into this white pulp area will have to pass through the rim of cells expressing MAdCAM-1. A functional role for MAdCAM-1 or its lymphocyte ligand, the alpha 4 beta 7 integrin complex, was investigated by in vivo short-term homing experiments with anti-MAdCAM-1 and anti-alpha 4 beta 7 antibodies, but no direct role for this receptor-ligand interaction could be demonstrated.     

Expression of alpha4beta7 and E-selectin ligand by circulating memory B cells: implications for targeted trafficking to mucosal and systemic sites

We have examined the expression of homing receptors on circulating memory B cells subsets. Blood IgD+ (naive) B cells homogeneously express a high level of intestinal homing receptor, alpha4beta7, but IgD- (putative memory) B cells comprise distinct alpha4beta7+ and alpha4beta7- subsets. Naive and alpha4beta7+ memory B cells but not alpha4beta7- cells bind MAdCAM-1, suggesting that alpha4beta7 expression may predict B cell intestinal homing. In contrast, alpha4beta7+ and alpha4beta7- B cells bind well to VCAM-1, possibly allowing recruitment of both subsets to extra-intestinal sites, including those tissues of the "common mucosal immune system" characterized by vascular VCAM-1 expression. sIgA+ B cells, which are associated with mucosal immunity in the gut and elsewhere, are heterogeneous in homing receptor expression--with discrete subsets expressing alpha4beta7, L-selectin, and cutaneous lymphocyte antigen (CLA). sIgA+ CLA+ B cells are enriched by binding to E-selectin, suggesting that CLA may participate in B cell homing to nonintestinal mucosal tissues characterized by vascular E-selectin expression, such as chronically inflamed bronchial or oral mucosal. We conclude that circulating human peripheral blood memory B cells, like T cells, consist of discrete homing receptor-defined subsets. This diversity in homing phenotypes is apparent even among sIgA (presumptive mucosal) memory B cells, implying heterogeneity in trafficking mechanisms to different target mucosal surfaces.     

Topographic distribution of homing receptors on B and T cells in human gut-associated lymphoid tissue: relation of L-selectin and integrin alpha 4 beta 7 to naive and memory phenotypes.

In mice, integrin alpha 4 beta 7 is the main receptor used by lymphocytes that home to the Peyer's patches, although L-selectin contributes to the initial interaction with high endothelial venules. Less is known about the expression and function of these adhesion molecules in humans. The distribution of L-selectin and alpha 4 beta 7 on various B- and T-cell subsets was examined in human Peyer's patches (n = 8) and appendix (n = 4), collectively called gut-associated lymphoid tissue. Multicolor immunophenotyping was performed on cryosections, and dispersed cells were examined by flow cytometry. In cryosections, CD45RA+ T cells around and within interfollicular high endothelial venules, as well as surface (s)IgD+ B lymphocytes in the follicle mantles, often expressed abundant L-selectin but only intermediate levels of alpha 4 beta 7. CD45RO+ T cells and sIgD- B cells expressed higher levels of alpha 4 beta 7 and were often located near putative efferent lymphatics; only a small fraction (< 20%) of such memory cells expressed L-selectin. By flow cytometry, considerably more T than B lymphocytes co-expressed L-selectin and alpha 4 beta 7 (40% versus 25% and 67% versus 39%, respectively). In samples with many L-selectin+ cells (> 30%), more of these lymphocytes co-expressed alpha 4 beta 7 than in samples with few L-selectin+ cells. Because L-selectin and alpha 4 beta 7 were co-expressed on lymphocytes located near high endothelial venules, and because such co-expression was relatively common when many L-selectin+ cells were present, both of these molecules might participate in homing to human gut-associated lymphoid tissue. Such homing is probably most pronounced for T lymphocytes that were found to express L-selectin and alpha 4 beta 7 more often than B lymphocytes. The selective and relatively high expression of alpha 4 beta 7 on memory cells located near efferent lymphatics indicated a different migratory capacity; after exit from gut-associated lymphoid tissue, such stimulated cells might home mainly to mucosal effector sites.     

L-selectin and alpha 4 beta 7 integrin homing receptor pathways mediate peripheral lymphocyte traffic to AKR mouse hyperplastic thymus.

Before the development of thymic lymphoma, AKR mice undergo a striking lymphoid hyperplasia of the thymic medulla. We have previously shown that there is a marked increase in traffic of B and T lymphocytes from the periphery into the preneoplastic, hyperplastic thymuses of these mice, in contrast to the scant traffic of such cells to normal thymuses. The traffic of lymphocytes to lymph nodes and Peyer's patches is controlled in part by the interaction of lymphocyte adhesion molecules called homing receptors with their tissue-selective endothelial ligands known as vascular addressins. We have investigated the roles of homing receptors and vascular addressins in the traffic of lymphocytes to the AKR hyperplastic thymus. We demonstrate that development of hyperplasia is accompanied by an increase in the number of thymic medullary blood vessels with high endothelial venule morphology and expression of the peripheral node addressin (PNAd) and the mucosal addressin (MAdCAM-1). In vitro and in vivo functional assays show that the addressin/homing receptor pairs PNAd/L-selectin and MAdCAM-1/alpha 4 beta 7 are involved in lymphocyte traffic to the hyperplastic thymus. These results indicate that molecular adhesion mechanisms involved in tissue-selective migration of lymphocytes to peripheral lymph node and to mucosal lymphoid tissues play a role in the recruitment of B and T lymphocytes to the AKR thymus and thus in the pathogenesis of thymic hyperplasia.     

Distinct binding specificities of integrins {alpha}4{beta}7 (LPAM-1), {alpha}4{beta}1 (VLA-4), and {alpha}IEL{beta}7

Integrin receptors are Important for regulating lymphocyte reclrculatlonand recruitment to sites of inflammation. Transfoctants of theB cell lymphoma 38C13 were generated that differ exclusivelyin the expression of integrin ß1 or ß7 subunltsallowing for a functional comparison of lymphocyte Peyer's patchHEV adhesion molecule 1 (LPAM-1) (4ß7) and very lateantigen 4 (VLA-4) (4ß1) in an Identical cellular environment.Whereas 38-ß7 transfectants bound to purified andcellular mucosal addressin cell adhesion molecule (MAdCAM-1),unstlmulated 38-ß1 cells failed to bind MAdCAM-1.Treatment of 38-ß1 cells with Mn²⁺ but not with PMAinduced low level binding to MAdCAM-1. MAdCAM-1 adhesion of38-ß7 cells was constitutive and not enhanced by Mn²⁺treatment. Similarly, MAdCAM-1-dependent adhesion to mucosalhigh endothellal venules was shown for 38-ß7 but notfor 38-ß1 cells. The results therefore establish theLPAM-1 - MAdCAM-1 Interaction as the functionally dominant adhesionpathway for regulating lymphocyte homing to mucosal sites. Nonetheless,the activated VLA-4 on some lymphocytes may be involved in MAdCAM-1recognition or promote binding to MAdCAM-1 In other tissues.By contrast, 38-ß7 and 38-ß1 transfectantsdid not differ in their binding capacity for vascular cell adhesionmolecule 1 (VCAM-1) or fibronectin and LPAM-1 did not displayany preference for interacting with either MAdCAM-1 or VCAM-1.LPAM-1 may therefore contribute significantly to cellular functionspreviously attributed to VLA-4. Interestingly, functional analysisof the intraepithellal lymphocyte integrin IELß7 whichIs structurally related to LPAM-1 did not reveal detectablebinding activity for MAdCAM-1, VCAM-1, or fibronectin.     

Identification of an Adhesion Molecule Expressed on Adult T Cell Leukemia Cells Derived from a Patient with Gastrointestinal Involvement: Implication for a Possible Role of Integrin β7 in Leukemic Cell Infiltration into Intestinal Mucosa

Patients with adult T cell leukemia (ATL) often manifest leukemic cell infiltration into various organs such as lung, liver, skin, and gut. To analyze the mechanism of intestinal infiltration of ATL cells, we made mAbs against ATL-43T, a human T cell line derived from an ATL patient with severe intestinal mucosal infiltration. One of the mAbs, named H920, was noted for a high and relatively specific reactivity with ATL-43T. Molecular cloning was done to identify this molecule and disclosed that the Ag molecule was identical to integrin 7. Since integrin 7 and its ligand MAdCAM-1 had been reported to mediate homing of lymphocytes to endothelial cells in intestinal mucosa, we next examined whether ATL-43T cells could adhere to MAdCAM-1⁺ cells. Human MAdCAM-1 transfectants of MMCE, a mouse epithelial cell line, were made and used to evaluate cell adhesion mediated by integrin 7 and MAdCAM-1. Considerable levels of cell adhesion were observed between ATL-43T and the transfectant cells, which was inhibited by H920 mAb in a dose-dependent manner. Furthermore, peripheral blood leukemic cells or lymphoma cells from 10 ATL patients were examined for expression of integrin 7 with regard to organ involvement. Samples from three patients with gastrointestinal tract involvement showed considerably higher expression of integrin 7. These results suggest that integrin 7 may play a role in adhesion and subsequent infiltration of a certain type of ATL cells into intestinal mucosa.     

Identification of homing receptors that mediate the recruitment of CD4 T cells to the genital tract following intravaginal infection with Chlamydia trachomatis.

Murine genital infection induced with the mouse pneumonitis biovar of Chlamydia trachomatis (MoPn) elicits a short-lived protective immunity mediated primarily by Th1 CD4 cells. To understand the development of local cell-mediated immunity against C. trachomatis infection, we investigated the mechanism(s) which mediates CD4 lymphocyte migration to the genital mucosa by identifying molecules that could support this process. We found that primarily CD4 cells were recruited to the genital tract (GT) during primary and challenge MoPn infection. Peak levels were found 21 days after primary inoculation (15.4% +/- 2.7%) and 7 days (31.3% +/- 8.5%) after challenge but diminished after resolution of infection. The CD4 cells appeared to be recruited to the GT in response to infection since these cells expressed the profile of activated, or memory, cells. We also observed up-regulation of homing receptors containing LFA-1 (CD11a) and alpha4 (CD49d) on GT CD4 cells over the course of infection. Furthermore, the mucosal homing receptor chain, beta7, but not the peripheral homing receptor chain beta1 (CD29), was detected on GT CD4 cells. MoPn-infected GT tissue expressed the endothelial cell ligands vascular cell adhesion molecule 1 (VCAM-1), intracellular adhesion molecule 1 (ICAM-1), and mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1), which correspond to the homing receptors on GT CD4 cells. Interestingly, VCAM-1 and MAdCAM-1 were not expressed in the GTs of uninfected mice but were temporarily induced following infection, indicating that expression of endothelial ligands in the GT are regulated by chlamydial infection. These data suggest that recruitment of CD4 cells to the GT is mediated through LFA-1:ICAM-1 and alpha4beta7:MAdCAM-1-VCAM-1 interactions.     

Follicular colonization in thyroid lymphoma.

The presence of neoplastic (light chain restricted) B-cell follicles in low-grade B-cell gastrointestinal (GI) lymphoma of mucosa-associated lymphoid tissue (MALT) has been explained on the basis of specific colonization of reactive follicles by centrocyte-like (CCL) cells. Low-grade B-cell thyroid lymphomas have been included in the category of MALT lymphoma, but the frequent presence of a follicular pattern in these tumors has contributed to the view that they are follicle center cell (FCC) tumors. We have reviewed the histology and investigated the phenotype and genotype of nine cases of primary low-grade B-cell lymphoma of the thyroid, all of which were distinguished by a predominantly follicular pattern. All cases also demonstrated features of MALT lymphoma, including CCL cells and lymphoepithelial lesions. The appearances and immunohistology of the follicles were those of follicular colonization as described in GI MALT lymphoma rather than FCC follicular lymphoma. The predominant pattern of follicular colonization was replacement of the follicle center by slightly enlarged CCL cells that showed a strikingly high proliferation rate. No evidence of the t(14;18) translocation was found in any case, using the polymerase chain reaction (PCR) on DNA extracted from fresh (n = 1) or paraffin-embedded (n = 9) tissue. These findings argue against a FCC lineage for primary thyroid lymphomas and support their inclusion in the MALT category.