John G. Tew

Follicular Dendritic Cells as Accessory Cells

Follicular dendritic cells (FDC) represent a novel cell type found in the B-cell regions of all secondary lymphoid tissues. The name follicular dendritic cell and the abbreviation FDC have been recommended by a committee on nomenclature (Tew et al. 1982) but a number of names have been used in the literature including: dendritic reticulum cells (DRC), antigen retaining reticular cells, follicular ii6mune complex retaining cells, follicular antigen-binding dendritic cells, follicular reticular cells, follicular dendritic reticulum cells, Nossals follicular dendritic reticulum cells and dendritic macrophages (Tew et al. 1982). However, in recent years the name follicular dendritic cell has been generally adopted. Two features differentiate FDC from other accessory cells and are considered diagnostic or cardinal: 1) these dendritic cells are restricted to lymphoid follicles and 2) they trap and retain immune complexes on their surfaces for long periods of time (Tew et al. 1982). It was these two features that caught the attention of Szakal & Hanna as well as Nossal et al. in 1968, when both groups identified FDC as the cells responsible for retaining antigen. Important features which help to further characterize FDC are listed in Table I. This is a selected series of markers chosen to emphasize relationships between FDC and other leukocytes as well as discrepancies in the literature. References at the bottom of Table I contain some further phenotypic information. In addition to the cardinal features relating to anatomical location and retention of surface immune complexes, a number of other features appear to be highly consistent among FDC in different species. These include: lack of phagocytie activity, highly convoluted dendritic processes, an irregularly shaped euchromatic nucleus, presence of receptors for complement fragments, and the expression of the adhesion molecule ICAM-1. As indicated in Table I, there are features where the

The Follicular Dendritic Cell: Long Term Antigen Retention During Immunity

The obligatory need for antigen in the induction of a specific immune response has long been recognized. However, much less in known about the possible continuing requirement for antigen for the maintenance of adequate levels of immunity. If immunity is to be protective, the maintenance of an adequate level of immunity, cellular and/or humoral, is as important as is its induction. There is a vast body of evidence demonstrating that once a satisfactory degree of immunity has been produced, it tends to be maintained by the continued production of antibody as well as by a well developed capacity to respond rapidly and accurately to a fresh antigenic challenge. In humoral immunity it has long been known that antibody levels can be maintained for very long periods even in the absence of fresh exogenous immunogenic stimulation. The possible role of retained antigen in regular restimulation of specific memory cells has been postulated and it has been suggested that small quantities of antigen are retained as antigen-antibody complexes at certain strategic sites such as lymphoid organs (Graf & Uhr 1969, Bystryn et al. 1970, 1971, Kitces et al.

Follicular dendritic cells and presentation of antigen and costimulatory signals to B cells

Summary: This review focuses on how immunogens trapped by FDC In the form of Ag‐Ab complexes productively signal B cells. In vitro, Ag‐Ab complexes are poorly immunogenic but m vivo immune complexes elk ii potent recall responses. FDC trap Ag‐Ab complexes and make immune complex mated bodies or “iccosomes”. B cells endocytose iccosomes, the Ag is processed, and T‐cell help is elicited. In vitro, addition of FDC bearing appropriate Ag‐Ab complex to memory T and B cells provoke potent recall responses (IgG and IgE). FDC also provide nonspecific costimulatory signals which augment B‐cell proliferation and Ab production. B cell‐FDC contact is important and interference with ICAM‐1‐LFA‐1 interactions reduces FDC‐mediated costimulation. Preliminary data suggest that a costimulatory signal may be delivered via CRZL on FDC binding CR2 on B cells. FDC can also stimulate B cells to become chemotactically active and can protect lymphocytes from apoptosis. FDC also appear to be rich in that groups and may replace reducing compounds such as 2 mercaptoethanol in cultures. In short, FDC‐Ag specifically signals B cells through BCR, and FDC provide B cells with iccosomal‐Ag necessary for processing to elicit T i ell help. In addition, FDC provide nonspecific signals that are important to promote B‐cell proliferation, maintain viability, and induce chemotactic responsiveness.

Tobacco and Smoking: Environmental Factors That Modify the Host Response (Immune System) and Have an Impact On Periodontal Health

This review summarizes the current data on the effects of smoking and tobacco on the immune system and its potential impact on periodontal health. Smokers are 2.5-6 times more likely to develop periodontal disease than non-smokers, and there is evidence for a direct correlation between the number of cigarettes smoked and the risk of developing disease. Tobacco users also tend to exhibit increased severity of periodontal disease. Direct correlations between tobacco use and increased attachment loss and pocket depth and reduced bone crest height have been reported. Although the correlation between tobacco use and periodontal disease is quite strong, the role of tobacco in the pathogenesis of periodontal disease is uncertain. Recent studies indicate that one potential mechanism is that tobacco use exacerbates periodontal disease because it alters the immune response to periodontal pathogens. Indeed, smokers exhibit increased numbers of peripheral blood mononuclear phagocytes which appear to be functionally compromised. Inadequate phagocyte activity could reduce the clearance of pathogens from the oral cavity and thereby facilitate the development of periodontal disease. Tobacco-exposed B- and T-lymphocytes exhibit reduced proliferative capacities which could limit the production of protective immunoglobulins against oral pathogens. The risk factors for periodontal disease can be broadly classified as genetic, environmental, host-response factors, and host-related factors such as age. Tobacco, an environmental factor, undermines the host response and may facilitate the development and progression of periodontal disease. This review highlights the inter-relatedness of two of the risk factors associated with periodontal disease.

Fcγ Receptor IIB on Follicular Dendritic Cells Regulates the B Cell Recall Response

Generation of the B cell recall response appears to involve interaction of Ag, in the form of an immune complex (IC) trapped on follicular dendritic cells (FDCs), with germinal center (GC) B cells. Thus, the expression of receptors on FDC and B cells that interact with ICs could be critical to the induction of an optimal recall response. FDCs in GCs, but not in primary follicles, express high levels of the IgG Fc receptor FcγRIIB. This regulated expression of FcγRIIB on FDC and its relation to recall Ab responses were examined both in vitro and in vivo. Trapping of IC in spleen and lymph nodes of FcγRII−/− mice was significantly reduced compared with that in wild-type controls. Addition of ICs to cultures of Ag-specific T and B cells elicited pronounced Ab responses only in the presence of FDCs. However, FDCs derived from FcγRIIB−/− mice supported only low level Ab production in this situation. Similarly, when FcγRIIB−/− mice were transplanted with wild-type Ag-specific T and B cells and challenged with specific Ag, the recall responses were significantly depressed compared with those of controls with wild-type FDC. These results substantiate the hypothesis that FcγRIIB expression on FDCs in GCs is important for FDCs to retain ICs and to mediate the conversion of ICs to a highly immunogenic form and for the generation of strong recall responses.

Persistence of Infectious HIV on Follicular Dendritic Cells

Follicular dendritic cells (FDCs) trap Ags and retain them in their native state for many months. Shortly after infection, HIV particles are trapped on FDCs and can be observed until the follicular network is destroyed. We sought to determine whether FDCs could maintain trapped virus in an infectious state for long periods of time. Because virus replication would replenish the HIV reservoir and thus falsely prolong recovery of infectious virus, we used a nonpermissive murine model to examine maintenance of HIV infectivity in vivo. We also examined human FDCs in vitro to determine whether they could maintain HIV infectivity. FDC-trapped virus remained infectious in vivo at all time points examined over a 9-mo period. Remarkably, as few as 100 FDCs were sufficient to transmit infection throughout the 9-mo period. Human FDCs maintained HIV infectivity for at least 25 days in vitro, whereas virus without FDCs lost infectivity after only a few days. These data indicate that HIV retained on FDCs can be long lived even in the absence of viral replication and suggest that FDCs stabilize and protect HIV, thus providing a long-term reservoir of infectious virus. These trapped stores of HIV may be replenished with replicating virus that persists even under highly active antiretroviral therapy and would likely be capable of causing infection on cessation of drug therapy.

Follicular dendritic cells: beyond the necessity of T-cell help

Follicular dendritic cells (FDCs) are potent accessory cells for B cells, but the molecular basis of their activity is not understood. Several important molecules involved in FDC-B-cell interactions are indicated by blocking the ligands and receptors on FDCs and/or B cells. The engagement of CD21 in the B-cell coreceptor complex by complement-derived CD21 ligand on FDCs delivers a crucial signal that dramatically augments the stimulation delivered by the binding of antigen to the B-cell receptor (BCR). The engagement of Fc gamma receptor IIB (FcgammaRIIB) by the Ig crystallizable fragment (Fc) in antigen-antibody complexes held on FDCs decreases the activation of immunoreceptor tyrosine-based inhibition motifs (ITIMs), mediated by the crosslinking of BCR and FcgammaRIIB. Thus, FDCs minimize a negative B-cell signal. In short, these ligand-receptor interactions help to signal to B cells and meet a requirement for B-cell stimulation that goes beyond the necessity of T-cell help.

Germinal Centers and Antibody Production in Bone Marrow

The bone marrow is the major site of immunoglobulin production during anamnestic antibody respotises (Benner et al. 1974, I98Ib, 1981a. Haaijman et al. 1979). However, antigen trapping, processing and presentation occur in secondary lymphoid tissues tiear the site of immunological challenge (Mandel et ah 1980, Szakal et al. 1989). It appears that B cells stimulated by antigen in the secondary lymphoid tissues migrate from these tissues to the bone marrow where they produce the large amounts of antibody associated with secondary immune responses (Koch et al. 1981, Betiner et al. 1977). Thus the site where antigen presentation takes place may be separated by a considerable distance from the site where most immunogiobuiin production occurs. The emigration of these stimulated B cells appears to occur within a few days after secotidary challenge (Koch et al. 1981, Benner et al. 1977). For example, splenectomy of mice 4 or more days after a booster immunization does not influence the bone marrow plaque-forming cell response, whereas splenectomy on the 2nd d prevents antibody formation in bone marrow (Benner et al. 1977). Furthermore, it is known that large numbers of antigen-specific B-cell blasts are present in the efferent lymph of the draining lymph nodes of sheep by 60 hours following secondary immunization (Hay et al. 1972). About 40% of these cells in the efferent lymph of sheep are classified as blast cells and 50-66% of these blast cells were specific immature antibody-forming cells (AFC) (Hay et al. 1972). In other studies, an intlux of blast cells in the bone marrow was detected usitig autoradiography and this inllux also occurred a few days after antigen challenge (Koch et al. 1981), Germinal centers are characterized as loci of rapidly proliferating B cells

Cytokine Induction by Streptococcus mutans and Pulpal Pathogenesis

ABSTRACT Chronic pulpal inflammation under caries appears to be elicited by bacterial antigens that diffuse into the pulp through dentinal tubules. This prompted the hypothesis that cytokines elicited by antigens fromStreptococcus mutans, which frequently dominates shallow lesions, could play a major role in eliciting the initial T-cell response in the pulp. To test this, we examined the ability of S. mutans to stimulate T cells and elicit cytokines and usedLactobacillus casei, which often predominates in deep carious lesions where B cells and plasma cells predominate, as a control. In addition, the presence of cytokines in the pulp was analyzed at the mRNA level. S. mutans elicited potent gamma interferon (IFN-γ) responses in peripheral blood mononuclear cell cultures and reduced the CD4/CD8 ratio by promoting CD8+ T cells. Multiple inflammatory cytokine mRNAs (IFN-γ, interleukin 4 [IL-4], and IL-10) were detected in human dental pulp. A higher prevalence of IFN-γ (67%) than IL-4 (19%) or IL-10 (29%) was obtained in shallow caries, suggesting a type 1 cytokine mechanism in early pulpitis where S. mutanspredominates. In contrast, in deep caries no differences in cytokine frequency were observed. Furthermore, the presence of IFN-γ in the pulp correlated with the presence of S. mutans. The extraordinary induction of type 1 cytokines and the preferential activation of CD8+ T cells by S. mutans offers an explanation for the etiology of the CD8+ T-cell-dominant lesion in early pulpitis and suggests that S. mutans may have a major impact on the initial lesion and pulpal pathology.

Invasion of human vascular endothelial cells by Actinobacillus actinomycetemcomitans via the receptor for platelet-activating factor

ABSTRACT Strains of the periodontal pathogen Actinobacillus actinomycetemcomitans are variable with respect to display of phosphorylcholine (PC)-bearing antigens. We have examined strains ofA. actinomycetemcomitans with and without PC to assess their ability to invade endothelial cells via the receptor for platelet-activating factor (PAF). Results of antibiotic protection assays indicate that PC-bearing A. actinomycetemcomitansinvade human vascular endothelial cells by a mechanism inhibitable by CV3988, a PAF receptor antagonist, and by PAF itself. The invasive phenotype was verified by transmission electron microscopy. A PC-deficient strain of this organism was not invasive. This property, in addition to the established ability of A. actinomycetemcomitans to invade epithelial cells, may provide this organism with access to the systemic circulation. The ability of PC-bearing oral bacteria to access the circulation may also explain the elevated levels of anti-PC antibody in serum found in patients with periodontitis.