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PubMed2006

A soluble BAFF antagonist, BR3-Fc, decreases peripheral blood B cells and lymphoid tissue marginal zone and follicular B cells in cynomolgus monkeys.

BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21(high) B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21(med) B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21(high) B-cell subset to a greater extent than it reduced CD21(med) B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.

Animals↗

PubMed1988

Gut-associated lymphoid tissue in the large intestine of calves. I. Distribution and histology.

Gut-associated lymphoid tissue (GALT) in the large intestine was characterized in 12 calves (10 to 84 days old) obtained at necropsy (7, group A) or healthy animals (5, group B). Patches of mucosal lymphoid follicles were in all calves at ileocecal entrances (ICE), 23-42 cm distal to the ICE in the proximal loop of the ascending colon (proximal colon [PC] patch), and in the terminal rectum. PC patches varied from 8 to 30 cm in length. Solitary lymphoid follicles were found in the cecum of three calves, between the ileocecal entrances and the PC patch in four calves, adjacent to the PC patch in all calves, and in the ampulla recti. GALT occupied 7.8% of the large intestinal wall in animals of group A: 0.6% at the ileocecal entrance, 4.8% in the proximal colon, and 2.4% in the rectum. There were two different types of mucosal lymphoid follicles in group B: propria nodules with lymphoid follicles predominantly in the lamina propria, and lymphoglandular complexes with lymphoid follicles in the submucosa. In three 3-, 6-, and 7-day-old, germfree calves, distinct follicle-associated epithelium covered propria nodules and covering folds in depths of the lymphoglandular complexes; it was characterized by numerous intraepithelial cells and lack of goblet cells.

Animals↗

PubMed2004

Impact of tobacco smoke on interleukin-16 protein in human airways, lymphoid tissue and T lymphocytes.

CD4(+) and CD8(+) lymphocytes are mobilized in severe chronic obstructive pulmonary disease (COPD) and the CD8(+) cytokine interleukin (IL)-16 is believed to be important in regulating the recruitment and activity of CD4(+) lymphocytes. In the current study, we examined whether tobacco smoke exerts an impact not only on IL-16 in the lower airways but also in CD4(+) or CD8(+) lymphocytes or in lymphoid tissue. The concentration of IL-16 protein was measured by enzyme-linked immunosorbent assay (ELISA) in concentrated bronchoalveolar lavage fluid (BALF) collected from 33 smokers with chronic bronchitis (CB), eight asymptomatic smokers (AS) and seven healthy never-smokers (NS). The concentrations of IL-16 and soluble IL-2 receptor alpha (sIL-2Ralpha) protein were also measured in conditioned medium from human blood CD4(+) and CD8(+) lymphocytes stimulated with tobacco smoke extract (TSE) in vitro. IL-16 mRNA was assessed in vitro as well, using reverse transcription-polymerase chain reaction (RT-PCR). Finally, the intracellular immunoreactivity for IL-16 protein (IL-16IR) was assessed in six matched pairs of palatine tonsils from smokers and non-smokers. BALF IL-16 was higher in CB and AS than in NS. TSE substantially increased the concentration of IL-16 but not sIL-2Ralpha in conditioned medium from CD4(+) and CD8(+) lymphocytes. There was no corresponding effect on IL-16 mRNA. IL-16IR in tonsils was lower in smokers than in non-smokers. The current findings demonstrate that tobacco smoke exerts a wide impact on the CD8(+) cytokine IL-16, in the airway lumen, in blood CD4(+) and CD8(+) lymphocytes and in lymphoid tissue. The effect on IL-16 release may be selective for preformed IL-16 in CD4(+) lymphocytes. New clinical studies are required to evaluate whether tobacco smoke mobilizes T lymphocytes via IL-16 in the lower airways and whether this mechanism can be targeted in COPD.

Adult↗

PubMed1997

Oral immunization with the saliva-binding region of Streptococcus mutans AgI/II genetically coupled to the cholera toxin B subunit elicits T-helper-cell responses in gut-associated lymphoid tissues.

Mice immunized intragastrically (i.g.) with a genetically constructed chimeric protein consisting of the saliva-binding region (SBR) of Streptococcus mutans AgI/II coupled to cholera toxin (CT) A2 and B subunits (CTA2/B) develop serum immunoglobulin G (IgG) and mucosal IgA antibody responses against AgI/II that are enhanced by the coadministration of CT as an adjuvant. To investigate the development of antigen-specific T cells in the gut-associated lymphoid tissues, mice were immunized i.g. with SBR, SBR-CTA2/B, or SBR-CTA2/B plus CT. AgI/II-specific T cells in Peyer's patches (PP), mesenteric lymph nodes (MLN), and spleen were assayed by lymphoproliferation and flow cytometry for the expression of T-cell surface markers, and cytokine mRNA expression was evaluated by reverse transcription-PCR. T-cell responses were consistent with antibody responses but were detectable after the first immunization. Proliferative responses of PP and MLN cells upon stimulation with AgI/II in vitro were low and delayed in mice given SBR alone, and these cells displayed a mixed type 1 and 2 (or Th0) pattern of cytokine expression. Immunization with SBR-CTA2/B resulted in greater AgI/II-specific proliferative responses in PP cells and an increase in the proportion of CD4+ T cells. Coadministration of CT with SBR-CTA2/B led to greater proliferative responses especially in the MLN cells, which then showed an increase in CD4+ cells. Immunization with SBR-CTA2/B (with or without CT) skewed the cytokine expression pattern in PP and MLN cells toward Th2. The results indicate that T helper cells were induced in gut-associated lymphoid tissues by i.g. immunization with SBR-CTA2/B, concomitantly with and prior to the appearance of circulating and mucosal antibodies.

Administration, Oral↗

PubMed1975

Prolonged effects of nitrogen mustard on mouse haematopoietic and lymphoid tissues.

Groups of mice have been autopsied at regular intervals during the period of lymphomyeloid tissue regeneration which follows the phase of hypocellularity induced by the i.v. injection of 100 mug (4 mg/kg bodyweight) nitrogen mustard. The marrow cellularity recovered to levels in the normal range by the 8th day and remained in this range up to the 40th day. Subsequently, the marrow showed a slight degree of hypocellularity up to day 120. Granulocytes were predominant during the initial phase of marrow regeneration during the second week post-injection. The thymus exhibited periodic size variations such that it was substantially larger than the thymus of age-matched controls from 20-30 d, 46-73 d, and 75-100 d after injection. The lymph nodes and lymphoid tissue of the spleen regenerated only slowly to reach control values by 40-50 d. Superimposed on the recovering lymphoid tissue of the spleen was a phase of erythroid hyperplasia lasting from 10-18 d post-injection. This coincided with a shift from granulocytosis to erythroid hyperplasia in the marrow. This erythroid hyperplasia lasted until day 30 when the cellular composition of the marrow and spleen returned to normal. A possible explanation of these results is that nitrogen mustard introduces a degree of synchrony into stem cell proliferation and differentiation. Additionally, these results emphasize the role of the haematopoietic microenvironment in the control of stem cell differentiation.

Animals↗

PubMed2000

Treatment-induced decline of human immunodeficiency virus-1 p24 and HIV-1 RNA in lymphoid tissue of patients with early human immunodeficiency virus-1 infection.

We report detailed quantitative analysis of human immunodeficiency virus-1 (HIV-1) p24 and HIV-1 RNA in tonsil biopsies from 13 patients with early, asymptomatic HIV infection before and during combination antiretroviral therapy. Using fluorescent microscopy in conjunction with reverse transcriptase-polymerase chain reaction of frozen tissue sections, we show that plasma and tissue viral loads decreased by approximately 3 logs during the 1-year treatment period, with good correlation between the HIV-1 p24 and HIV-1 RNA response in tissue. The decrease of tissue viral load was delayed compared to plasma viral load, possibly explained by the observation that the amount of follicular dendritic cell-associated virus correlated best with the area under the curve of plasma HIV-1 RNA throughout the last 12 weeks. Before and during treatment, the relative proportions of HIV-1 on follicular dendritic cells and within mononuclear cells remained constant, suggesting similar decay characteristics in these two lymphoid tissue compartments. However, viral p24 or RNA remained almost always detectable in tissue despite full suppression of HIV-1 RNA in plasma, and increased even after short-term rebounds in plasma viral load. Thus, full and sustained suppression of viral replication was required to efficiently decrease viral load in lymphoid tissue, but complete abolition of residual viral replication was not achieved.

Anti-HIV Agents↗

PubMed1984

Endogenous avidin-binding activity in human lymphoid tissue.

Biotin-avidin systems can be used as an alternative to indirect antibody sandwich methods in the detection of T lymphocyte subsets in cryostat sections of human lymphoid tissue. Appreciable endogenous avidin binding activity (EABA) has been found, however, in human lymph nodes and tonsils. Such EABA can be a source of false positive staining when biotin-avidin detection systems are used to identify cells in cryostat sections. The finding that avidin binding cells may also contain endogenous peroxidase activity and are morphologically similar to histiocytes suggests that such cells may be of histiocytic lineage. EABA is not seen in intrafollicular "tingible body" macrophages, however, and only rarely in medullary sinus histiocytes. Thus further studies are necessary to identify the lineage of avidin binding cells in lymphoid tissues. EABA can be effectively blocked by treatment of cryostat sections with 1% avidin followed by 0.01% biotin before specific staining with biotinylated antibodies and avidin-peroxidase or avidin-fluorochrome conjugates.

Avidin↗

PubMed1996

BCL-6 expression in reactive lymphoid tissue and in B-cell non-Hodgkin's lymphomas.

Chromosomal abnormalities involving 3q27 have recently been associated with diffuse large B-cell lymphomas and, less frequently, with follicular lymphomas. Molecular studies have led to the identification of the BCL-6/LAZ-3 gene, located at 3q27 and coding for a putative zinc-finger protein that might act as a transcriptional regulator during cell differentiation and development. Rearrangement of BCL-6 results in truncation of the gene in its 5' portion, leaving the protein intact; a resultant deregulation of its expression has been hypothesized. In order to test this hypothesis, the expression of BCL-6 protein was investigated in human reactive lymphoid tissue and compared with a group of non-Hodgkin's lymphomas (NHLs) with or without 3q27 anomalies and/or BCL-6 gene rearrangement. BCL-6 protein is consistently expressed in reactive lymphoid tissues, where it is restricted to the follicle centre. The protein is also widely expressed in NHL: all follicular lymphomas tested showed a pattern of expression similar to the reactive B follicle, independently of the presence of BCL-6 gene rearrangement and/or 3q27 anomalies. In the diffuse large B-cell lymphomas, there was more variation in BCL-6 expression, but a correlation with 3q27 anomalies and/or BCL-6 rearrangement was not found. Deregulation of the BCL-6 gene did not result in an aberrant tissue expression as detected by immunohistochemistry.

Antibody Specificity↗

PubMed1991

Expression of a dietary protein in E. coli renders it strongly antigenic to gut lymphoid tissue.

Bacteria that colonize the intestinal mucosa elicit a strong mucosal immune response, whereas food antigens such as ovalbumin are very weakly immunogenic to the gut-associated lymphoid tissue. This may either be due to special physico-chemical properties of bacterial substances versus proteins from animals and plants, or to stimulating properties of the bacteria on, e.g., antigen presentation, rendering all substances contained within bacteria antigenic. To test these hypotheses, ovalbumin was expressed in wild-type Escherichia coli and germ-free female rats were colonized with this strain. The systemic and mucosal antibody response of these rats was compared with that of rats given large amounts of dietary ovalbumin. Biliary IgA antibodies, which reflect the local IgA antibody production in the intestine, were only found in the rats colonized with ovalbumin-synthesizing E. coli. IgG antibodies in the bile were also only seen in these rats. We conclude that mucosal immunogenicity depends on the context in which a protein is presented to the gut-associated lymphoid tissue, rather than to special antigenic characteristics of the protein in itself.

Animals↗

PubMedDate not supplied

[Nuclease activity in leukemia altered lymphoid tissue].

Activities of DNAase I, DNAase II, RNAase I and RNAase II were altered in lymphoid tissue during development of lymphoid leukosis in mice of AKR strain, during survival of the leukemic cells as well as in leukemic spleen tissue of mice C57BI with transplantable leukosis La. The enzymatic activity correlated with the step of the process, the rate of leukemic cells proliferation, with dimensions of organs. Variations in the enzymatic activity, as compared with normal state were dissimilar in development of leukosis; activity of the enzymes was either increased or decreased apparently due to their multiple functions in metabolism of nucleic acids.

Animals↗

PubMed1999

Migration of antigen-presenting B cells from peripheral to mucosal lymphoid tissues may induce intestinal antigen-specific IgA following parenteral immunization.

Parenterally administered immunizations have long been used to induce protection from mucosal pathogens such as Bordetella pertussis and influenza virus. We previously found that i.m. inoculation of mice with the intestinal pathogen, rotavirus, induced virus-specific Ab production by intestinal lymphocytes. We have now used adoptive transfer studies to identify the cell types responsible for the generation of virus-specific Ab production by gut-associated lymphoid tissue (GALT) after i.m. immunization. Three days after i.m. immunization with rotavirus, cells obtained from the draining peripheral lymph nodes of donor mice were transferred into naive recipient mice. We found that intestinal lymphocytes produced rotavirus-specific Igs (IgM, IgA, and IgG) 2 wk after transfer of either unfractionated cells, or unfractionated cells rendered incapable of cellular division by mitomycin C treatment. Additional studies demonstrated that rotavirus-specific IgA, but not IgG, was produced by intestinal lymphocytes after transfer of purified B cells. Ig allotype analysis revealed that rotavirus-specific IgA was produced by intestinal B cells of recipient origin, suggesting that migration of Ag-presenting B cells from peripheral lymphoid tissues to GALT may contribute to the generation of mucosal IgA responses after parenteral immunization. Strategies that promote Ag uptake and presentation by B cells may enhance mucosal IgA production following parenteral immunization.

Adoptive Transfer↗

PubMed1993

The immunohistochemical heterogeneity of atheroma macrophages: comparison with lymphoid tissues suggests that recently blood-derived macrophages can be distinguished from longer-resident cells.

We studied the antigenic markers of macrophages (Mphs) in atherosclerotic human arteries by immunohistochemistry and compared them with the patterns in Mph subpopulations of tonsil and lymph node, which are also described. The staining of atheroma intimal Mphs was assessed semiquantitatively in the subendothelial, mid, and outer intima. Three patterns of reactivity with Mph antibodies were recognized. (a) Pan-Mph (antibodies HAM56, EBM11, and CD14 group). Staining was maximal in the mid-intimal zone. (b) Subendothelial Mphs (anti-muramidase, anti-alpha-1-antitrypsin and MAC387). In lymphoid tissue, sinusoidal Mphs and a few inflammatory Mphs were stained, as well as blood monocytes. This group of antibodies recognizes Mphs that are likely to be recently blood-derived (RBD-Mphs). (c) Antibodies reactive with various histiocyte populations in lymphoid tissues (anti-Factor XIII; anti-HLA Class II and LN2) also gave maximal staining in the mid-intimal zone, but differences between lesion types suggest that they are recognizing heterogeneous subpopulations of Mphs. These observations demonstrate the heterogeneity of tissue Mphs and suggest that an insight into the dynamics of tissue Mphs can be obtained from the cell phenotype. They indicate that all stages of atherosclerosis can have an outward traffic of Mphs from the blood through the arterial intima.

Antibodies, Monoclonal↗

PubMed1992

Ultrastructural and immunohistochemical studies on the ontogenic development of bronchus-associated lymphoid tissue (BALT) in the rat: special reference to follicular dendritic cells.

The ontogenic development of lymphoid and non-lymphoid cells in bronchus-associated lymphoid tissue (BALT) of the rat was studied ultrastructurally and immunohistochemically. In the late foetal period, only the alveolar macrophages showed a weak positivity for leucocyte common antigen, but no immune region associated (Ia) antigen was detected by monoclonal antibody, MAS 043. Mast cells were present. At 6 days of age, Ia-positive cells were observed in the alveolar wall and peribronchial interstitial tissue, and ultrastructurally there was an aggregation of the fibroblastoid mesenchymal cells. By 10 days of age, the aggregation of lymphoid cells together with S-100-positive reticulum cells had formed a BALT-like periarterial lymphoid sheath. In the adult animals, an obvious B-cell area was present in the central part and subepithelium of BALT, whilst in this area, S-100-positive, strongly Ia-positive cells with a dendritic form were observed. These dendritic cells appeared to be identical to the follicular dendritic cells (FDC) seen in the secondary follicles of lymphoid organs. Those cells may be derived from the fibroblastic reticulum cells, and may function to present antigen to lymphocytes.

Animals↗

PubMed1991

Homing receptors reexamined: mouse LECAM-1 (MEL-14 antigen) is involved in lymphocyte migration into gut-associated lymphoid tissue.

Specific recognition molecules ("homing receptors") on lymphocytes are thought to direct selective entry of cells into different organs. The lectin-related cell adhesion molecule LECAM-1 has previously been supposed to mediate lymphocyte entry into peripheral lymph nodes and, partially, mesenteric nodes but not into Peyer's patches. Here we present evidence that in vivo the molecule is also implicated in homing of mouse lymphocytes to Peyer's patches and may have a more general role as homing receptor for high endothelial venules-bearing lymphoid tissue, but not for most non-lymphoid tissue.

Animals↗

PubMed1981

Noradrenergic sympathetic innervation of lymphoid tissue in the rabbit appendix: further evidence for a link between the nervous and immune systems.

The rabbit appendix, a region of gut with well organized zones of lymphoid tissue, was examined with the glyoxylic acid histofluorescence technique for the localization of noradrenergic fibers, with high performance liquid chromatography with electrochemical detection (LCEC) for the quantitation of norepinephrine and serotonin, with Bielshowski and Giemsa stains for additional information about neural supply, and with acetylcholinesterase histochemistry for the localization of this hydrolytic enzyme. Fluorescent plexuses entered the serosal surface of the appendix associated with blood vessels, traveled longitudinally inside the muscularis interna, mainly in association with blood vessels but adjacent to enteric smooth muscle, and branched into long, linear, varicose plexuses that ran inward in a radial orientation towards the lumen in the internodular septa. As these fibers approached the interdomal regions near the epithelial surface, they passed through thymus-dependent cell zones, and arborized extensively throughout the interdomal region. A high density of varicosities was found in the subepithelial region where immunoglobulin-secreting plasma cells are found. These varicosities were sparse at 21 days of age, but were increased in number at 42 days of age. They were even further increased in number and density in adults. These fibers were further identified with a Bielshowski silver stain, and also demonstrated acetylcholinesterase activity. The noradrenergic varicosities in the interdomal regions of the adult rabbit appendix were closely associated with numerous yellow fluorescent cells of 25-40 microns diameter, which sometimes demonstrated fine varicose processes. The adult rabbit appendix contained a moderate concentration of norepinephrine (163.0 +/- 22.9 ng/g wet weight) and a very high concentration of serotonin (3981 +/- 283 ng/g wet weight). Levels in neonates were considerably lower, suggesting that the yellow fluorescent cells may contain serotonin. Acetylcholinesterase was associated with neural fibers and with non-neural regions of the lymph nodules and the domes, perhaps playing a protective role for these regions of the cellular immune system. The rabbit appendix is a well organized region of lymphoid tissue with specific zones of noradrenergic innervation and possible "paraneuronal" activity, with a readily accessible lumen for the isolation and collections of secretions. We propose this model as an excellent structure for further exploration of interactions between the nervous and immune systems.

Acetylcholinesterase↗

PubMed2005

Active and passive intranasal immunizations with streptococcal surface protein C5a peptidase prevent infection of murine nasal mucosa-associated lymphoid tissue, a functional homologue of human tonsils.

C5a peptidase, also called SCPA (surface-bound C5a peptidase), is a surface-bound protein on group A streptococci (GAS), etiologic agents for a variety of human diseases including pharyngitis, impetigo, toxic shock, and necrotizing fasciitis, as well as the postinfection sequelae rheumatic fever and rheumatic heart disease. This protein is highly conserved among different serotypes and is also expressed in human isolates of group B, C, and G streptococci. Human tonsils are the primary reservoirs for GAS, maintaining endemic disease across the globe. We recently reported that GAS preferentially target nasal mucosa-associated lymphoid tissue (NALT) in mice, a tissue functionally analogous to human tonsils. Experiments using a C5a peptidase loss-of-function mutant and an intranasal infection model showed that this protease is required for efficient colonization of NALT. An effective vaccine should prevent infection of this secondary lymphoid tissue; therefore, the potential of anti-SCPA antibodies to protect against streptococcal infection of NALT was investigated. Experiments showed that GAS colonization of NALT was significantly reduced following intranasal immunization of mice with recombinant SCPA protein administered alone or with cholera toxin, whereas a high degree of GAS colonization of NALT was observed in control mice immunized with phosphate-buffered saline only. Moreover, administration of anti-SCPA serum by the intranasal route protected mice against streptococcal infection. These results suggest that intranasal immunization with SCPA would prevent colonization and infection of human tonsils, thereby eliminating potential reservoirs that maintain endemic disease.

Adhesins, Bacterial↗

PubMed1983

Immunomodulatory role of thyroid hormones: in vivo effect of thyroid hormones on the blastogenic response of lymphoid tissues.

In an attempt to find out the mechanism of immunomodulation by thyroid hormones (T3 and T4), their in vivo effect on the blastogenic response of lymphocytes from various lymphoid tissues of hormone-treated and thyroidectomized rats were studied. The blastogenic response of lymphocytes from thymus, peripheral blood and mesenteric lymph nodes to pokeweed mitogen (PWM) was found to be increased significantly following T3 or T4 administration for 15 days or 30 days. However, the response to phytohaemagglutinin (PHA) increased only after 1 month of T3 or T4 administration. The blastogenic response of spleen cells to both PHA and PWM was, on the other hand, found to be depressed following 15 days of hormone administration. Thyroidectomy invariably induced significant depression in the blastogenic response to both PHA and PWM in lymphocytes of all the lymphoid tissues. Thyroid hormone (T3) administration was found to restore the blastogenic response of the lymphocytes of thyroidectomized animals.

Animals↗

PubMed2005

Localized lymphoid hyperplasia of the rectum resembling polypoid mucosa-associated lymphoid tissue lymphoma: a report of three cases.

Histologically, benign lymphoid hyperplasia of the rectum is usually characterized by large lymphoid follicles with active germinal centers and by a narrow surrounding mantle zone and marginal zone (MZ). We report here three cases of benign lymphoid hyperplasia of the rectum associated with prominent marginal zone hyperplasia, which caused serious difficulty in the differential diagnosis from the polypoid type of mucosa-associated lymphoid tissue (MALT) lymphoma. Colonoscopy demonstrated small sessile polyps in all three cases. Histologically, the lesions were characterized by a hyperplastic germinal center and expanded MZs. The expanded MZs contained numerous monocytoid B-cells (MBC) and scattered large transformed B-cells. Initially, combined colonoscopic and histological findings strongly supported a diagnosis of polypoid MALT-type lymphoma of the rectum. However, there were neither colonized lymphoid follicles nor lymphoepithelial lesions in any of the three lesions. MBCs and large transformed B-lymphocytes were CD43- and bcl-2-. Moreover, immunohistochemical and genotypic studies proved the polytypic nature of the B-lymphocytes in all three lesions. The present cases indicated that benign lymphoid hyperplasia of the rectum should be included in the differential diagnosis for polypoid MALT-type lymphoma of the rectum.

Aged↗