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Biomedical subjects

J G Tew

Publications and source records attributed to J G Tew.

At least 73 records · Page 4Linked to original sources
PubMed1993

Follicular dendritic cells and B cell costimulation.

Ag-bearing follicular dendritic cells (FDC) are found throughout secondary lymphoid tissues in close association with rapidly proliferating germinal center B lymphocytes. We reasoned that FDC might provide costimulatory signals that would enhance the ability of Ag to stimulate B cell proliferation in the germinal centers. To test this, FDC were cultured with B cells activated by a slg-dependent (goat anti-mouse mu conjugated to dextran (anti-mu-dex)) or -independent (LPS) pathway and their proliferation was measured by using [3H]thymidine incorporation. The addition of FDC markedly augmented B cell proliferation in a dose-dependent fashion. Depletion of FDC from cultures abrogated the increased proliferation. Addition of highly purified FDC obtained from cell sorting resulted in B cell costimulation, whereas addition of other sorted cells was without effect. The FDC accessory activity was apparent over the entire culture period and over a wide range of either polyclonal B cell activator. When B cells and activators were cultured in the absence of FDC, only about one fourth of the cells remained viable after 3 days. In contrast, virtually all cells in cultures containing FDC, B cells, and activator were viable. Cultures containing FDC and B cells from nude mice proliferated normally in the presence of anti-mu-dex plus rIL-4, implying that IL-4 provides adequate T cell help in this system. The costimulatory activity of the FDC could not replace either the anti-mu-dex or IL-4 in this system and was not MHC restricted. These data support the concept that FDC not only provide Ag but also facilitate B cell proliferation by means of other costimulatory interactions that contribute to make the microenvironment in the germinal center favorable for B cells to proliferate.

Animals↗
PubMed1993

Immunoglobulin class and subclass distribution of antibodies reactive with the immunodominant antigen of Actinobacillus actinomycetemcomitans serotype b.

The aims of this study were to determine the immunodominant antigens of Actinobacillus actinomycetemcomitans serotype b (Aab) for the different immunoglobulin (Ig) classes and subclasses and to determine the relative levels of these different Igs in serum. Seropositive early-onset periodontitis patients were sampled, and the Ig classes IgG, IgA, and IgM and subclasses IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2 were studied. Reactivity with Aab antigens was assessed by using the Western blot (immunoblot) in limiting dilution analysis and radioimmunoassay with sera from 13 early-onset periodontitis subjects. A smeared antigen in the upper portion of the immunoblots, typical of high-molecular-weight LPS, was immunodominant for IgG, IgA, IgM, IgG1, IgG2, IgG3, IgA1, and IgA2. This smeared antigen was present in every patient for all of these Igs at the endpoint. A few additional antigens were also present at the endpoint in some patients, but none were present in more than half of the subjects. The distribution of antibody titers by Ig classes reactive with the Aab immunodominant antigen was IgG > IgA > IgM. The distribution of antibody titers by IgG subclass was IgG2 > IgG1 approximately IgG3. Further quantitation by radioimmunoassay revealed that the mean concentration of IgG2 (65.7 micrograms/ml) was significantly greater than that of IgG1 (8.8 micrograms/ml). The IgA subclass distribution was IgA1 >> IgA2, with IgA1 apparently being second only to IgG2. Therefore, the Aab antigen eliciting the highest antibody level in virtually all Ig classes and subclasses appeared to be lipopolysaccharide, and IgG2 was markedly elevated over all other serum Ig classes or subclasses reactive with Aab.

Adult↗
PubMed1992

Follicular dendritic cells: B-cell proliferation and maturation.

Follicular dendritic cells (FDC) play a pivotal role in the initiation and maintenance of the secondary humoral immune response. FDC located in the follicles of secondary lymphoid tissues are part of a special mechanism that handles antigen in a specific antibody-rich environment and are integral members of the antigen transport cell-FDC-iccosome-B-cell axis that leads to the formation of germinal centers, antibody-forming cells, and memory B-cells. This review briefly outlines the basic biology of FDC function and provides a source of pertinent references.

Animals↗
PubMed1992

Murine follicular dendritic cells and low affinity Fc receptors for IgE (Fc epsilon RII).

The present study was undertaken to determine whether mouse follicular dendritic cells (FDC) bear Fc epsilon RII (CD23) and whether IgE-immune complexes are retained by FDC. Mouse Fc epsilon RII was localized by both L and electron microscopy using the mAb B3B4. In lymph nodes of normal mice, Fc epsilon RII was low but detectable on FDC. By 14 days after Nippostrongylus brasiliensis infection, the level of Fc epsilon RII increased on B lymphocytes located in the cortex of draining mesenteric lymph nodes. However, the Fc epsilon RII level on FDC remained low. Although numerous IgE-producing plasma cells were seen at day 14, very little IgE was associated with FDC. By 26 days after infection, Fc epsilon RII was observed on FDC in increased levels and IgE binding was clearly associated with FDC. Unexpectedly, FDC of control mice immunized with albumin in CFA to elicit an IgG response showed intense labeling for Fc epsilon RII. In contrast, the B cells exhibited very little Fc epsilon RII. IgE immune complexes were observed in association with FDC in the CFA-immunized mice. When mice were given a hapten-specific monoclonal of the IgE isotype, hapten carrier complexes were trapped and retained on Fc epsilon RII-bearing FDC. In conclusion, FDC were clearly one of the major murine cell types bearing Fc epsilon RII. IgE immune complexes were found in association with FDC and Fc epsilon RII appeared to play a major role in trapping and retaining IgE immune complexes. FDC Fc epsilon RII was subject to regulatory control, but the Fc epsilon RII level on FDC was regulated very differently from the Fc epsilon RII level on B cells.

Animals↗
PubMed1992

Immunodominant antigens of Actinobacillus actinomycetemcomitans serotype b in early-onset periodontitis patients.

Previous work with Actinobacillus actinomycetemcomitans strain Y4 (serotype b) indicates that the immunodominant antigen in high-responding patients (top 10%, 80% of which were black) is the serotype-specific antigen. In this study we examined the immunodominant antigens of A. actinomycetemcomitans strain Y4 in both black and white patients having a range of antibody titers. We sought to test the hypothesis that the immunodominant antigen in these subjects was the same antigen found in high responders. Seropositive white early-onset periodontitis (EOP) patients were selected from 99 EOP patients. Black subjects were then selected with comparable antibody titers. Double immunodiffusion and competition assays were used to determine whether reactive antibodies were A. actinomycetemcomitans serotype b-specific or whether the response was to serotype a or c. The immunodominant antigens were then determined for the patients reacting specifically to A. actinomycetemcomitans Y4 using limiting dilution analysis on Western blots. The immunodominant antigen for the A. actinomycetemcomitans Y4-specific patients appeared to be the serotype-specific carbohydrate for most subjects (19/20 or 95%, including: 13/14 black and 6/6 white patients). In conclusion, the immunodominant antigen for A. actinomycetemcomitans Y4 was the serotype-specific carbohydrate regardless of antibody titer for both black and white specifically reactive patients.

Adolescent↗
PubMed1992

Follicular dendritic cells in the alternative antigen transport pathway: microenvironment, cellular events, age and retrovirus related alterations.

Follicular dendritic cells (FDC) are located in lymphoid follicles of secondary lymphoid tissues and play a pivotal role in the initiation and maintenance of the secondary antibody response. FDC are an integral part of the microenvironment of the follicle and function as members of the 'alternative antigen transport pathway.' This pathway consisting of the antigen transport cell-FDC-ICCOSOME-B cell axis, leads to the formation of germinal centers where antibody-forming cell and memory B cell development are initiated through interaction of FDC-retained antigen, B cells and T helper cells. Evidence suggests that these interactions are down-regulated through antibody feedback, or as needed, reactivated with the utilization of FDC-retained antigen for the maintenance of antibody levels. Age- and retrovirus-related FDC defects seriously compromise the capacity of this pathway to maintain immunity.

Aging↗
PubMed1991

Germinal center B cells and antibody production in the bone marrow.

In secondary antibody (Ab) responses, Ag processing and presentation occur in secondary lymphoid organs but most serum Ab is produced by cells in the bone marrow. Plasma cells in the bone marrow are derived from B cells activated by Ag in secondary lymphoid organs. We hypothesized that germinal center (GC) B cells, which acquire Ag from follicular dendritic cells in draining lymph nodes during the first few days of the secondary response, migrate to the bone marrow to terminally differentiate and produce specific Ab. To test this we looked for GC B cells in the thoracic duct lymph and in peripheral blood after secondary challenge using the peanut agglutininhi phenotype and blast cell morphology as markers for GC B cells. In addition, GC B cells were injected i.v. into naive recipients to determine if they would home to the bone marrow. Finally, to determine if the bone marrow environment supports maturation and Ab production by GC B cells, we cocultured GC B cells with bone marrow cells or bone marrow supernatants. The results indicate that blast cells bearing the GC B cell phenotype were present in both the thoracic duct and the peripheral blood 3 days after antigenic challenge. Day 3 peripheral blood cells secreted specific Ab, whereas cells isolated on day 0, 8, or 11 did not. Furthermore, in adoptive transfer experiments, only the day 3 GC B cells produced specific Ab and migrated to the bone marrow of naive mice. Finally, either bone marrow cells or factor(s) produced by bone marrow cells markedly enhanced Ab production by day 3 GC B cells. These data support the hypothesis that during the first few days after secondary challenge GC B cells seed the bone marrow and differentiate into plasma cells which produce the large quantities of Ab typical of secondary responses.

Animals↗
PubMed1991

Kinetics of the tingible body macrophage response in mouse germinal center development and its depression with age.

Although tingible body macrophages (TBM) have been recognized in germinal centers for over 100 years, their role in the germinal center response is not clear. In this study, the kinetics of the TBM response was quantitatively assessed and correlated with the kinetics of germinal center development in young mice. The TBM response in old mice (which have an age-related depression of germinal center development; Szakal et al., 1990) was analyzed for comparison. Young and old immune mice were challenged with human serum albumin and 0, 1, 3, 5, 7, 10, and 14 days later the popliteal and axillary lymph nodes were evaluated. Germinal centers were localized histochemically in alternate serial sections using horseradish peroxidase conjugated peanut agglutinin. TBM numbers were determined per germinal center on adjacent sections by the presence of tingible bodies or histochemically by using the monoclonal antibody Mac-2. Analysis of lymph nodes from young mice showed that TBM numbers decreased with the dissociation of preexisting germinal centers. TBM reappeared 5 days after challenge and the TBM kinetics paralleled the increase in size of de novo germinal centers. In fact, a constant ratio of one TBM to every 350-450 B cells was maintained from day 5 to day 10. In old lymph nodes, TBM were generally absent throughout germinal center development. The lack of TBM prior to germinal center development and their absence in aged mice are inconsistent with the concept that TBM are required for the induction of the germinal center reaction. However, the data are consistent with a role for TBM in regulating the magnitude of the germinal center reaction.

Aging↗
PubMed1991

Chemotaxis of germinal center B cells in response to C5a.

An infiltrate of B cells and plasma cells is characteristic of certain chronic inflammatory lesions. However, mechanisms involved in the local accumulation of these cells have not been established. Efforts to demonstrate that B cells from normal animals can migrate in response to inflammation-induced chemoattractants have been inconclusive. The objective of this study was to determine if murine germinal center (GC) B cells could respond chemotactically to a C5a gradient. On successive days after secondary immunization, draining lymph nodes were harvested and the activated GC B cells isolated. These GC B cells were placed in modified Boyden chambers, incubated for 3 h and the distance the leading front of cells migrated through the filters was determined. The results show that GC B cells migrated to factors in zymosan- and lipopolysaccharide-activated serum. The migratory response demonstrated distinct kinetics. Cells isolated between 2 to 4 days after secondary immunization migrated, whereas cells isolated at day 0 and beyond day 6 did not. Checkerboard analysis revealed that the migratory response was attributable to both chemokinesis and chemotaxis. Anti-C5 inhibited the migration of day-3 GC B cells implicating C5 in the migration mechanism. Studies using recombinant C5a established that this C5 fragment was chemotactically active. In conclusion, GC B cells generally were not chemotactically active. However, at a particular stage of maturation B cells in the GC become responsive to C5a as a chemotactic agent. Thus, B cells from normal animals may respond chemotactically, and C5a may play a role in recruitment of recently activated B cells into inflammatory sites.

Animals↗
PubMed1991

Immunodominant antigens of Actinobacillus actinomycetemcomitans serotypes a and c in high-responder patients.

This study was undertaken to examine the characteristics of the immunodominant antigens of Actinobacillus actinomycetemcomitans serotypes a and c. The top responders for A. actinomycetemcomitans serotypes a and c were selected (19 for serotype a and 21 for serotype c) from 150 clinically characterized patients. Competition assays revealed that 9 of 19 of these patients were reacting specifically to serotype a and 12 of 21 for serotype c. Limiting dilution analysis on Western blots revealed that most antigen bands apparent at low dilution disappeared as the patient's serum was diluted. The antigen band(s) remaining at the endpoint or the dilution corresponding to the antibody titer were defined as immunodominant. For serotype a there were several different immunodominant antigens but none was present in more than half of the subjects. For serotype c the immunodominant antigens included a number of discrete bands and a diffuse smeared polysaccharide band. Only 2 of these antigens were present in the majority of the high-responders: 92% had the smeared antigen and 67% had a 15 kDa antigen. The 15 kDa band was a protein common to all A. actinomycetemcomitans serotypes. The smeared antigen was unaffected by protease K treatment and gave a reaction of identity with the serotype c specific rabbit antiserum. This rabbit antiserum is specific for a mannan carbohydrate and does not react with LPS (23). Therefore, the smeared immunodominant antigen appears to be a polysaccharide containing mannan.

Adult↗
PubMed1991

Accumulation of plasma cells in inflamed sites: effects of antigen, nonspecific microbial activators, and chronic inflammation.

Plasma cells are common in chronically inflamed sites, including periodontal lesions. The aim of this study was to determine which factors contribute to this local accumulation of plasma cells. Specifically, we sought to evaluate the effects of specific antigen and nonspecific activators from an infectious agent associated with chronic inflammation (Fusobacterium nucleatum, an organism prominent in chronic periodontal lesions) and the effect of the chronic inflammation itself. Chronic inflammation (14 to 17 days) was induced in horseradish peroxidase (HRP)-immune rabbits by subcutaneous injection of 50 microliters of sterile alum in several sites in their backs. Controls included sites injected with saline or more acute sites examined after 3 days of alum inflammation. Sites were challenged with HRP (the antigen), sonicated F. nucleatum (the nonspecific activator), or both together to see whether F. nucleatum has an adjuvant effect. Three days after challenge, HRP-specific antibody-forming cells (AFC) were enumerated after peroxidase histochemistry. In noninflamed sites or sites with acute inflammation, virtually no HRP-specific AFC were evident. In contrast, chronic inflammation alone was sufficient to elicit a specific AFC response (congruent to 10 cells per mm2). Addition of either F. nucleatum or HRP to the chronic lesion about doubled the number of HRP-specific AFC. However, a dramatic 8- to 15-fold (80 to 150/mm2) increase was seen in chronically inflamed sites challenged with antigen and activator together. Interestingly, the activator did not have this adjuvant effect in the acute sites or in normal skin. In short, accumulation of plasma cells in inflamed sites is promoted by chronic inflammation, activators of microbial origin, and specific antigen. This milieu can be expected to develop in some periodontal lesions and could help explain why gingival crevicular fluid from some sites may contain extraordinary levels of locally produced specific antibodies for certain antigens.

Acute Disease↗
PubMed1991

Iccosomes and the secondary antibody response.

Iccosomes derived from follicular dendritic cells (FDC) are believed to play an important role in dispersion of antigen necessary for induction of anamnestic responses. Because FDC are aberrant and iccosome release has not been observed in aged mice, we hypothesized that these animals would be impaired in their ability to mount anamnestic responses. To test this, anamnestic responses were compared in aged and control mice. To ensure the presence of functional lymphocytes, some aged mice were reconstituted with T- and B-memory cells obtained from control mice. Anamnestic responses in aged mice were markedly depressed even when given functional memory cells. To more directly relate the impaired antibody response of aged mice to FDC function, antigen-bearing FDC from either aged or control mice were incubated with T- and B-memory cells from control mice to induce an anamnestic response. Antigen retained by FDC from aged mice was much less immunogenic than antigen retained by FDC from control mice. Since iccosome formation does not appear in aged mice, iccosome-like fragments were generated by sonicating FDC from aged mice and tested for their ability to induce an anamnestic response. This procedure restored the ability of antigen retained on FDC from aged mice to induce a normal anamnestic response. These data support the concept that the inability to form and disperse iccosomes contributes to the impaired ability of aged mice to mount anamnestic antibody responses and provides further support for the role of iccosomes in anamnestic responses.

Aging↗