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The dendritic cell-T cell milieu of the lymphoid tissue of the tonsil provides a locale in which SIV can reside and propagate at chronic stages of infection.

Previous studies described the presence of numerous human immunodeficiency virus (HIV)-positive cells within and just beneath the mucosal surfaces of the tonsillar tissue of HIV-1-infected individuals. The virus-positive cells were most abundant in the dendritic cell (DC)-T cell rich areas of the lymphoepithelia lining the crypts, and consisted of multinucleated syncytia that contained DCs. This suggested that such cells within the tonsillar tissue might represent a site for chronic virus replication in infected individuals. Using the simian immunodeficiency virus (SIV)-macaque system, we chose to study further the viral distribution within the tonsillar tissue of animals infected via the vaginal route 8-10 months earlier. Our initial studies demonstrated that in situ hybridization (ISH)-positive DCs and T cells could be identified within the genital mucosa and draining lymph nodes of these infected animals even at this chronic stage of infection. Here we specifically examined the distal mucosa-associated lymphoid tissues of the tonsil. ISH-positive cells were mostly restricted to the DC-rich T cell areas of the underlying lymphoid tissue. However, T cells were the most commonly infected cell type and virus-positive cells were rarely found within the epithelia. In isolated cell suspensions, ISH-positive lymphocytes were often tightly associated with ISH-negative DCs, although few ISH-positive lymphocytes were often tightly associated with ISH-negative DCs, although few ISH-positive DCs could be identified within these clusters. Therefore, the naturally occurring DC-T cell milieu of the lymphoid tissue of the tonsil provides a locale in which SIV can reside and propagate on a chronic basis, even many months after the animals were infected by virus crossing the genital mucosa.

Animals↗

Long-term antibody production after lung immunization and challenge: role of lung and lymphoid tissues.

After localized lung immunization and challenge, antigen-specific antibody continues to be produced in the immunized lung lobes of dogs for years after the last antigen exposure. Lavage fluid from immunized lung lobes contains significantly more antigen-specific antibody than lavage fluid from control lung lobes, and only cells from lung lobes exposed to antigen produce antibody. Although cells lavaged from the lung produce antibody, it is possible that cells in the lung interstitium or lymphoid tissues may be more important in long-term antibody production after lung immunization and challenge. The goal of this study was to compare the levels of antibody production by cells from dogs 2 yr after pulmonary immunization and challenge. Cells were evaluated from lung lavage, lung tissue, tracheobronchial lymph nodes, and distant lymphoid tissues. The results showed that cells lavaged from lung lobes immunized and challenged with sheep red blood cells (SRBC) were producing anti-SRBC IgG antibody 2 yr after the last antigen challenge. However, cells obtained by mincing tissues from immunized lung lobes were producing significantly higher levels of antibody than lavage cells. In contrast, lavage or tissue cells obtained from the control lobes did not produce detectable antibody. Only a low level of anti-SRBC IgG was produced by cells from the tracheobronchial lymph nodes, and minimal antibody was produced by cells from blood, spleen, or mesenteric and popliteal lymph nodes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Distribution and quantitation of plasma cells, T lymphocyte subsets, and B lymphocytes in bronchus-associated lymphoid tissue of chickens: age-related differences.

Development of the lymphoid cell compartment in bronchus-associated lymphoid tissue (BALT) of specific pathogen free chickens was examined. Specifically, B lymphocytes, T cell subsets (CD4 and CD8), and IgA-, IgG-, and IgM-producing plasma cells were labeled using immunocytochemical methods. Immunoglobulin-producing cells (IgPC) were quantitated, and comparisons of IgPC numbers were made among chickens of different ages, among immunoglobulin isotypes, and between lymphoid (BALT) and nonlymphoid (non-BALT) areas in the primary bronchus. At hatching, BALT was devoid of IgPC, but by 2 weeks of age cells producing IgA, IgG, and IgM were present. Initially, there were approximately equal numbers of IgA-, IgG-, and IgM-PC; after 2 weeks of age, however, IgG- and IgM-PC outnumbered IgA-PC. At all ages, IgPC were more numerous in non-BALT regions of the primary bronchus than in BALT regions. Small numbers of T and B lymphocytes were present in BALT from 1-day old chickens, but substantial populations of these cells were not seen until 1-2 weeks of age. T helper (CD4+) cells were found near B cell regions in BALT lymphoid nodules, while T cytotoxic/suppressor (CD8+) cells were more evenly distributed throughout the nodules and in the epithelium. B lymphocytes predominated in germinal centers and also overlapped CD4+ populations adjacent to germinal centers. Lymphocyte cell types needed to initiate and regulate immune responses are present in chicken BALT and may be involved in protecting poultry from respiratory pathogens.

Aging↗

Immune cell distribution in gut-associated lymphoid tissue and synthesis of IL-6 in experimental porcine peritonitis.

This study aimed to evaluate the possibility to detect early changes in gut-associated lymphoid tissue related to an inflammatory response. Anaesthetised pigs were subjected to faecal peritonitis (n = 9) or to a sham procedure (n = 8). Blood from the vena cava and the superior mesenteric vein was repeatedly sampled, and the levels of interleukin-6 (IL-6) were analysed. Biopsies of the small intestine and mesenteric lymph nodes (MLNs), harvested at 300 min, were incubated with monoclonal antibodies specific for CD2 (T lymphocytes), IgM (B lymphocytes) and CD11a/CD18 (leucocyte adhesion molecule). The number of positive (+) cells was scored. During peritonitis, IL-6 increased significantly. Compared to controls, the number of CD2+ cells decreased, IgM+ cells tended to increase and CD11a/CD18+ cells increased in the mucosa during peritonitis. In MLNs, the number of cells positive for all studied markers increased during peritonitis. We conclude that peritonitis causes an inflammatory response in the gut reflected by changes in the distribution of immune cells in gut-associated lymphoid tissue and release of IL-6 to venous blood.

Animals↗

[Oropharyngeal lymphoid tissue as a bursa-equivalent structure: embryological and clinical considerations].

If we examine with an ontogenetic viewpoint the tissues giving origin to both thymus and avian bursa of Fabricius, we can't ignore that they are primary lymphoid organs connected to areas of ecto-entodermic junctions. They have a strong development in the embryonic life while tending to regress in the adult. The analysis of the organogenesis clarifies this affirmation. In the human cephalic district we know of various ectoentodermic stratification areas: the branchial pockets and the Remake pharyngeal membrane. The oral-pharyngeal lymphoid tissue is histogenetically linked to the stem-cells of the marrow which migrate to occupy an initially ecto-entodermic milieu. Structural and ontogenetic analogies of embryological nature lead to an identification of the oral-pharyngeal lymphoid tissue in man with the avian bursa of Fabricius. Therefore we deem it very indicative that a humoral immunological deficiency syndrome appears in subjects with the atrophy of the Waldeyer ring; above all considering that an experimental model of the humoral immunological deficit has been reproduced in chicken surgically or hormonally bursectomized.

Animals↗

Productive HIV infection of resting CD4+ T cells: role of lymphoid tissue microenvironment and effect of immunomodulating agents.

The ability of resting CD4+ T cells to support HIV replication is relevant to understanding how the reservoir of HIV-1-infected resting CD4+ T cells is generated, maintained and, hopefully, how it might be reduced or eliminated. We have utilized a tonsillar histoculture system to demonstrate that HIV, particularly X4 strains, can productively infect phenotypically resting CD4+ T cells in vitro and that this event is largely dependent on the lymphoid tissue microenvironment. Highly purified CD4+ tonsillar T cells that lack expression of both cell surface and nuclear antigens characteristic of classic T cell activation produce X4 HIV-1 mRNA, p24, and infectious virus while maintaining a resting phenotype when cultured in a tonsillar tissue microenvironment; in contrast, comparable purified resting CD4+ tonsillar T cells that have been exposed to X4 HIV do not support HIV replication when cultured in the absence of a lymphoid tissue microenvironment. HIV production from phenotypically resting CD4+ T cells is dramatically inhibited by anti-proinflammatory cytokine agents or immunosuppressive cytokines, but is only modestly suppressed by an inhibitor of the cell cycle. The ability of resting CD4+ T cells to support HIV replication in the microenvironment of the lymphoid tissue has implications in the pathogenesis of HIV disease and may provide an additional avenue for therapeutic intervention.

Adult↗

Upper respiratory tract resistance to influenza infection is not prevented by the absence of either nasal-associated lymphoid tissue or cervical lymph nodes.

The murine nasal-associated lymphoid tissue (NALT) and cervical lymph nodes (CLN) are involved in the generation of local immune responses within the upper respiratory tract (URT). However, their involvement in these responses does not imply the necessity for resistance to URT infections. We surgically removed NALT or CLN to address the necessity of these lymphatic tissues for the development of a local protective immune response after a URT influenza infection. No histological evidence of the re-establishment of either tissue was detected after surgery and the subsequent infection. Removal of NALT did not elicit changes in serum or nasal mucosa-associated influenza-specific Ig levels. However, increases in PR8-specific serum IgG and nasal mucosa-associated IgA were detected after removal of CLN. Recruitment of influenza-specific CD4 T cells into the nasal mucosa was not altered by removal of NALT. The removal of NALT or CLN did not alter the recruitment of influenza-specific CD8 T cells into the URT. However, increased levels of influenza-specific CD8 T cells were observed in the tracheal-bronchial lymph nodes after CLN surgery. The rate of viral clearance from nasal mucosa and lungs was not altered by removal of NALT or CLN. These studies demonstrate that despite the participation of NALT and CLN in the generation of local immunity to influenza infections, neither tissue is essential for the development of protective immunity and viral clearance in URT.

Animals↗

A novel gene, MALT1 at 18q21, is involved in t(11;18) (q21;q21) found in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue.

The t(11;18) (q21;q21) translocation is a characteristic chromosomal aberration in low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type. We previously identified a YAC clone y789F3, which includes the breakpoint at 18q21 in a MALT lymphoma patient. BAC and PAC contigs were constructed on the YAC, and BAC 193f9 was found to encompass the breakpoint region. In the present study, we further narrowed down the breakpoint region at 18q21 in five MALT lymphoma patients by means of FISH and Southern blot analyses using the plasmid contig constructed from BAC 193f9. The breakpoints at 18q21 in three of the five MALT lymphoma patients were found to be clustered approximately within the 20 kb region. By using exon amplification and cDNA library screening, we identified a novel cDNA spanning the breakpoint region that exhibited aberrant mRNA signals in four of the five MALT lymphoma patients. The nucleotide sequence predicted an 813 amino acid protein that shows significant sequence similarity to the CD22beta and laminin 5 alpha3b subunit. We refer to the gene encoding this transcript as MALT1 (Mucosa-Associated Lymphoid Tissue lymphoma translocation gene 1). The alteration of MALT1 by translocation strongly suggests that this gene plays an important role in the pathogenesis of MALT lymphoma.

Amino Acid Sequence↗

Immunohistochemical studies of lymphoid tissues of rabbits infected with rinderpest virus.

The pathogenesis of infection with the L-strain of rinderpest virus (RPV) in rabbits was investigated. Of several lymphoid tissues examined, those associated with the gut showed the most marked virus growth. The virus titres were maximal 4 days after inoculation but had declined at day 6. The distribution of viral antigen was examined immunohistochemically with the recently established anti-rabbit CD5 monoclonal antibody (MoAb), which is a pan-T-cell marker, and the anti-RPV-nucleoprotein MoAb. The virus antigen was localized in the CD5+ area at the initial stage of infection but spread to all areas of the lymphoid tissues at the later stages. By flow cytometric analysis with both rabbit CD5 and CD4 MoAbs, a decrease of the CD4+ and CD5+ subpopulations was observed in the spleen and mesenteric lymph nodes.

Animals↗

Uptake of concentrated perfluorocarbon emulsions into rat lymphoid tissues.

The effects of injecting (10-30 mL kg-1) either perfluorodecalin (FDC) emulsions of increasing phase fraction (20-60% w/v) or the commercial formulation, Fluosol, on lymphoid tissues have been studied for up to 7 days in male rats. Tissue weights increased by up to 123% (P < 0.05) in proportion with quantity of perfluorochemical (PFC) injected, with spleen responses consistently greater than those of the liver. PFC droplets recovered from these tissues at 72 h after injection of 30% (w/v) FDC emulsion (10 mL kg-1) had mean diameters in the 1-10 microns range, with those from the spleen being larger than those from the liver. Recovered droplet diameters were considerably greater than freshly-prepared emulsion mean particle sizes (0.21-0.25 microns). These results suggest that coalescence of emulsion droplets following accumulation in lymphoid tissue is a pre-requisite for the eventual excretion of PFC vapour through the lungs.

Animals↗

Adhesion of B cell lines to endothelial cells from human lymphoid tissue modulates tyrosine phosphorylation and endothelial cell activation.

Through the production of cytokines and growth factors the endothelium of secondary lymphoid organs plays a crucial role in controlling lymphocyte migration to the lymphoid microenvironment, an essential step in the initiation of the immune response. Here we demonstrate that direct contact of B cell lines with tonsil-derived human endothelial cells resulted in changes in the phosphorylation state of endothelial cells, causing their functional activation. We found a rapid (<15-s) and transient dephosphorylation, followed by a rapid rephosphorylation of tyrosine residues of the focal adhesion kinase, paxillin, and ERK2. Maximal rephosphorylation occurred after 15-30 min of B cell contact. Preincubation of lymphoid B cells with an adhesion-blocking Ab directed against alpha(4)beta(1) integrin abrogated adhesion-mediated changes of endothelial cell tyrosine phosphorylation, suggesting that cell contact was essential. Similar patterns of tyrosine phosphorylation, but with slightly different kinetics were induced after cross-linking of beta(1) integrin or CD40 on endothelial cells. Functional activation of endothelial cells by B cell adhesion was confirmed by the production of IL-6, IL-8, monocyte chemoattractant protein-1, M-CSF, and macrophage inflammatory protein-1beta mRNA. However, direct cross-linking of beta(1) integrin and CD40 failed to accomplish the same functional activation. These data indicate that direct contact of lymphoid B cells with the endothelium from lymphoid tissue induce endothelial cell signaling, resulting in chemokine and cytokine production. This phenomenon may provide a mechanism for the remodeling of the endothelium from lymphoid tissues, thus contributing to the free migration of lymphocytes and other cells into the lymphoid organs.

Animals↗

Biochemical and biophysical characterization of glucocorticoid receptors in normal lymphoid tissue.

3H-triamcinolone acetonide labeled glucocorticoid receptors in normal lymphoid tissues can be resolved into two component by DEAE chromatography: peak I elutes at 0.04 M salt and peak II is 0.22 M salt. By glycerol gradient centrifugation, peak I is 3.5S and peak II 8.5S. Peak I binds to DNA and chromatin, while peak II binds to neither. After heat activation, peak II alters its coefficient of sedimentation to 3.5S and on DEAE rechromatography changes its elution position to 0.04 M salt (peak I area) and acquires affinity for DNA. Glucocorticoid receptors in lymphoblastic leukemia cells can now be characterized using these techniques and compared to receptors in normal lymphoid cells.

Animals↗

Follicular dendritic cell (FDC) precursors in primary lymphoid tissues.

The origin of follicular dendritic cells (FDC) is unresolved, and as such, remains controversial. Based on the migration of Ag-transporting cells (ATC) into lymphoid follicles and the phenotypic similarity between FDC and ATC, one hypothesis is that ATC may represent emigrating FDC precursors. This contrasts with the view that FDC originate from local stromal cells in the secondary lymphoid tissues. Mice homozygous for the severe combined immunodeficiency (prkdc(scid)) mutation (scid) lack FDC. Thus, they provide a powerful tool for assessing de novo generation of FDC. To test whether FDC precursors could be found in bone marrow or fetal liver, scid/scid mice were reconstituted with either: 1) bone marrow cells from (BALB/c x C57BL/6)F1 donors, 2) bone marrow cells from ROSA BL/6 F1 (lacZ-transfected) mice, 3) rat bone marrow cells, or 4) rat fetal liver cells. Six to eight weeks after reconstitution with F1 bone marrow, cells reactive with the FDC-labeling mAb, FDC-M1, also expressed donor class I molecules on their surfaces. Similarly in mice reconstituted with lacZ-transfected bone marrow cells, these cells were also positive for the lacZ gene product. Furthermore, in spleens of animals reconstituted with either rat bone marrow or rat fetal liver, rat FDC were identified using the specifically labeling mAb, ED5. In all cases, host FDC were also present, indicating that scid/scid mice have FDC precursors that will mature in the presence of allogeneic or xenogeneic lymphoid cells. In summary, FDC can be derived from progenitor cells present in primary lymphoid tissues.

Animals↗

The role of the gut lymphoid tissue in induction of oral tolerance.

The gut-associated lymphoid tissue (GALT) maintains a balance between immunological tolerance to dietary proteins and induction of active immune responses to pathogenic microorganisms. The oral administration of soluble protein antigens induces a state of systemic immunological unresponsiveness specific to the fed protein, termed oral tolerance. The two major mechanisms to explain oral tolerance are anergy/deletion of autoreactive lymphocytes and active suppression. This review will discuss the mechanisms of therapeutic oral tolerance in relation to events occurring at the site of antigen entry.

Animals↗

High prevalence of a 30-base pair deletion in the Epstein-Barr virus (EBV) latent membrane protein 1 gene and of strain type B EBV in Mexican classical Hodgkin's disease and reactive lymphoid tissue.

Depending on geographic location and patient age Hodgkin's disease (HD) is associated with Epstein-Barr virus (EBV), mostly type A EBV, in 20% to 100%. The highest prevalence occurs in children of developing countries. Molecular analysis of the oncogene coding for the latent membrane protein 1 (LMP-1) revealed a 30-base pair (bp) deletion in up to 46% of EBV-positive HD. We investigated the presence of EBV in a series of Mexican classical HD (n = 57) and reactive lymphoid tissues (n = 20) from a private and a public hospital with special emphasis on the prevalence of the 30-bp deletion and the type of EBV. EBV infection was analyzed at the cellular level by Epstein-Barr encoded early RNA transcripts (EBER) in situ hybridization (ISH) and by LMP-1 protein immunohistochemistry (IHC). Molecular analysis of the LMP-1 gene configuration was performed by polymerase chain reaction (PCR) with primers spanning the site of the deletion and subsequent Southern and/or dot blot hybridization using wild-type and deletion-specific probes. The prevalence of type A and type B EBV was investigated by PCR-analysis for divergence in the coding region of Epstein-Barr nuclear antigen (EBNA)-2. EBV was detected in Hodgkin- and Reed-Sternberg cells (H-RS) by LMP-1 IHC and/or EBER ISH in 35/57 (61%) Mexican HD including 18/32 (56%) with nodular sclerosis, 15/20 (75%) with mixed cellularity and 2/4 (50%) with lymphocyte depletion. In addition, LMP-1 gene sequences were detected by PCR in 9 cases of HD without LMP/EBER expression by H-RS cells and in 17/20 (85%) reactive lymph nodes, supposedly originating from rare latently infected B cells. Surprisingly, the 30-bp LMP-1 deletion was found in 28/35 (80%) EBV-positive HD. This deletion, however, was also found in all 9 (100%) HD with H-RS cells negative for EBV and in 10/17 (59%) reactive lymph nodes. Thus, the overall LMP-1 del prevalence in reactive tissue is 73% (19/26). Typing of EBV was successful in 26 cases of EBV-positive HD, 10 of these were infected by type B EBV (38%). Of the reactive lymphoid tissue, 9 (47%) were infected by type A, and 10 (53%) by type B; All 20 cases (100%) associated with type B, whether neoplastic or reactive, displayed the LMP-1 del variant compared with 18/25 (72%) infected by type A EBV. To our knowledge, this is the highest incidence for both the LMP-1 deletion variant and the infection by type B EBV in HD reported so far worldwide. Our data suggest that EBV infection contributes to the pathogenesis of the majority of Hodgkin's disease cases in Mexico. The specific tumorigenic role of the LMP-1 deletion variant, however, is doubtful with regard to its high frequency in nonneoplastic lesions. Moreover, type B infection frequently occurs in Mexican HD and reactive lymphoid tissue and is consistently associated with the deletion variant pointing to a pathogenetic role of this combined genotype.

Adolescent↗

Reconstitution of lymphoid tissues under the influence of a subclinical level of graft versus host reaction induced by bone marrow T cells or splenic T cell subsets.

Reconstitution of lymphoid tissues under the influence of subclinical graft versus host reaction (GVHR) has been investigated. Lethally irradiated AKR mice were reconstituted with B10 bone marrow (BM) cells which had been treated with anti-Thy-1 antibody alone without complement (GVHR chimera). Their immunological reconstitution was analyzed and compared with that of AKR recipients which had been reconstituted with B10 BM cells treated with anti-Thy-1 antibody plus complement (control chimera). One hundred percent of both chimeras survived more than 100 days without showing clinical signs of GVHR. However, full donor chimerism was accomplished at an early stage after reconstitution in the former GVHR chimeras, whereas a substantial number of recipient T cells persisted in control chimeras for the entire observation period. When reconstitution of various lymphoid tissues was compared between control and GVHR chimeras, no difference in the reconstitution of the thymus and spleen was noted. By contrast, the cellularity of peripheral lymph nodes in GVHR chimeras was regularly considerably lower than that of the control chimeras. The apparent insufficiency of lymph node reconstitution appeared to be attributable to the impairment of lymph node structure itself which may be involved in lymphocyte homing. Furthermore, clonal deletion of V beta 6+ T cells which are reactive to recipient (Mls-1a) antigens was abrogated in the GVHR chimeras but was normally induced in the more completely T cell-depleted control chimeras. This abrogation of clonal deletion of V beta 6+ T cells appeared to result from the early disappearance of recipient T cells in these chimeras. Thus, it appeared that donor T cells in the BM that survive anti-Thy-1 treatment in vitro plus subsequent BM transplantation induced a subclinical level GVHR which contributed to the full donor chimerism as well as abrogation of clonal elimination of V beta 6+ donor T cells. Indeed, inoculation of CD8+ T cells along with the transplantation of the T cell-depleted BM cells (anti-Thy-1 plus C-treated cells) from donor mice into the AKR recipients was also shown to induce a similar state in the recipients.

Animals↗

Tumor necrosis factor receptors in lymphoid tissues and lymphomas. Source and site of action of tumor necrosis factor alpha.

Tumor necrosis factor alpha (TNF alpha), which is produced by germinal center dendritic reticulum cells (DRC) in lymphoid tissue, plays a regulatory role in a local immune response. However no information is available on the nature and location of cells responding to this cytokine. Thus TNF receptor distribution was investigated in situ by immunohistochemistry using monoclonal antibodies directed against the p75 and p55 receptor proteins. Receptor expression was unique and restricted to the lymphoreticular tissue. The p75 receptor was found on activated lymphocytes and interdigitating reticulum cells of the T-cell area, whereas the p55 receptor was confined to the germinal center DRCs, which are the main site of TNF alpha production. The two receptor proteins were expressed on distinct cell populations of the lymphoid system and no coexpression was observed. Preliminary results indicate that TNF receptor (TNFR) expression is regulated; Upregulation of TNFR proteins was found in reactive hyperplasia together with increased TNF alpha expression. In lymphoproliferative disorders, expression of the p75 receptor and TNF alpha was found mainly in high-grade malignant non-Hodgkin lymphomas. In summary, TNF alpha produced by germinal center DRCs might regulate an in vivo immune response through autocrine and paracrine pathways. Thus TNF alpha might signal, through the distinct TNFR proteins, the p55 and p75 receptor, which are expressed on different cell types in lymphoid tissue.

Humans↗