Showing papers in "Current Topics in Microbiology and Immunology in 1999"

Vascular permeability factor/vascular endothelial growth factor and the significance of microvascular hyperpermeability in angiogenesis.

Abstract: Vascular permeability factor/vascular endothelial growth factor (VPF/VEGF) was originally discovered in the late 1970s because of its capacity to increase the permeability of microvessels to plasma and plasma proteins (Dvorak et al 1979a,b) Using plastic-embedded, light microscopic section and, subsequent, immunohistochemistry, we noted that transplantable tumors growing in guinea pigs and rodents exhibit substantial deposits of fibrin in their stroma Fibrin results from the clotting of fibrinogen, a 340kDa plasma protein which, under normal circumstances, is retained almost quantitatively within the blood vasculature For fibrin to be deposited outside of blood vessels in tumor stroma, it was necessary that two requirements be met; namely, (1) that microvessels be abnormally hyperpermeable to permit the escape of fibrinogen and other plasma proteins necessary for blood clotting and (2) that there be a mechanism in place for activating the clotting system In fact, both requirements were found to be met in tumors The microvessels supplying tumors were hyperpermeable to fibrinogen and other plasma proteins, and both tumor cells and host stromal cells were capable of initiating extravascular coagulation via the tissue-factor pathway Encouraged by these findings, we initiated a search for a tumor product that could account for tumor-vessels hyperpermeability A potent vascular permeabilizing protein was soon found in serum-free tumor culture supernatants (Dvorak et al 1979a,b) and was subsequently purified to homogeneity and given the name vascular permeability factor (VPF) (Senger et al 1983, 1986, 1987, 1990)

Vascular endothelial growth factor: molecular and biological aspects.

Abstract: The development of a vascular supply is a fundamental requirement for organ development and differentiation during embryogenesis as well as for wound healing and reproductive functions in the adult (Folkman 1995) Angiogenesis is also implicated in the pathogenesis of a variety of disorders: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis and psoriasis (Folkman 1995; Garner 1994)

The Angiopoietins: Yin and Yang in Angiogenesis

Abstract: Embryonic vascular development involves a complex series of events during which endothelial cells differentiate, proliferate, migrate, and undergo morphological organization in the context of their surrounding tissues (Risau 1991, 1995). Vascular development is generally classified into two successive phases. The first, known as vasculogenesis, refers to the process whereby newly differentiated endothelial cells spontaneously coassemble into tubules that fuse to form a rather homogeneous primary vasculature in the embryo. Subsequent remodeling of this primary vascular network into large and small vessels brings into play a different process, termed angiogenesis. Angiogenesis in the embryo also leads to the sprouting of vessels into certain initially avascular organs, such as the brain. In the adult, angiogenesis accounts for neovascularization that accompanies the normal remodeling of the female reproductive organs during the menstrual cycle and pregnancy, in wound healing, and in various clinically significant pathological processes, such as tumor growth and diabetic retinopathy (Folkman 1995; Ferrara 1995; Hanahan and Folkman 1996).

Structure, Expression and Receptor-Binding Properties of Placenta Growth Factor (PlGF)

Abstract: Placenta growth factor (PlGF) (Maglione et al 1991, 1992), vascular endothelial growth factor (VEGF) (Ferrara and Henzel 1989; Gospodarowicz et al 1989; Keck et al 1989; Levy et al 1989; Conn et al 1990), VEGF-B (Olofsson et al 1996), VEGF-C (Joukov et al 1996) and Fos-induced growth factor (FIGF) (Orlandini et al 1996) are members of a family of structurally related growth factors These factors are all dimeric glycoproteins and share a number of biochemical and functional features (for review, see Bussolino et al 1997) Intra- and interchain disulphide bonds among eight characteristically spaced cysteine residues are involved in the formation of the dimeric active proteins PIGF and VEGF can form heterodimeric molecules in cells where both genes are expressed (DiSalvo et al 1995; Cao et al 1996a) VEGF, the first member of this family to be isolated, was identified for its ability to stimulate the proliferation of endothelial cells (ECs) VEGF exerts its action through the binding to the two receptors, VEGF receptor-1 (VEGFR-1; also denoted Flt-1) and VEGFR-2 (also denoted Flk-l/KDR), abundantly expressed on the ECs

Role of Vascular Endothelial Growth Factor and Vascular Endothelial Growth Factor Receptors in Vascular Development

Abstract: Distinct cellular processes mediate blood-vessel formation during embryogenesis (Beck and D’Amore 1997; Carmeliet and Collen 1998a; Folkman and D’Amore 1996; Noden 1989; Risau 1997; Wilting and Christ 1996) (Fig. 1). Initially, mesodermal cells differentiate in situ into early haemangioblasts and form cellular aggregates (blood islands), in which the inner-cell population develops into haematopoietic precursors and the outer-cell population gives rise to the primitive endothelial cells. In vitro findings suggest that basic fibroblast growth factor (bFGF or FGF2) may participate in angioblast differentiation via induction of a cellular receptor for vascular endothelial growth factor (VEGF-A) (Flamme and Risau 1992).

Structure, Expression and Receptor-Binding Properties of Novel Vascular Endothelial Growth Factors

Abstract: Vascular endothelial growth factor (VEGF), an important regulator of endothelial cell physiology, was identified some 10 years ago and has, since then, been recognised as the major growth factor relatively specific for endothelial cells (reviewed in Ferrara and Davis-Smyth 1997). VEGF is a dimeric glycoprotein, closely related to placenta growth factor (PIGF). Both VEGF and PIGF are distantly related in structure to the platelet-derived growth factors A and B (PDGF A and PDGF B) (Heldin et al. 1993). Three novel growth factors belonging to the family of VEGF, PIGF and the two PDGFs were recently discovered. These growth factors, termed vascular endothelial growth factor B/VEGF-related factor (VEGF-B/VRF) (Grimmond et al. 1996; Olofsson et al. 1996a), vascular endothelial growth factor C/VEGF-related protein (VEGF-C/VRP) (Joukov et al. 1996; Lee et al. 1996)] and c-fos-induced growth factor (F1GF) (Orlandini et al. 1996) share structural features typical of the VEGF/PDGF growth factor family. The prominent structural similarities between VEGF-related growth factors, several of which target endothelial cells, and FIGF suggest the possibility that F1GF also targets endothelial cells, despite its identification as a fibroblast growth factor. Based on these criteria, we propose that the name FIGF should be changed to VEGF-D to indicate its structural and functional relatedness to other VEGFs.

Structure and Function of Vascular Endothelial Growth Factor Receptor-1 and -2

Abstract: Receptor-type tyrosine kinases are known to be involved in a wide variety of biological processes, such as cell growth, differentiation, morphogenesis and malignant transformation. The endothelial cell-specific growth factors, denoted vascular endothelial growth factors/vascular permeability factors (VEGF/VPF), constitute a growing family of factors that bind to at least three different receptor-type tyrosine kinases (Fig. 1). A wealth of data indicates the important functions of these receptors in the normal development and for physiological and pathological angiogenesis. This review will focus on the structure and function of two of these receptors which, in many respects, are similar to other receptor-type tyrosine kinases. Thus, the VEGF receptors appear to dimerize in response to growth factor binding, become activated, tyrosine phosphorylated and couple to downstream signal transduction chains, much like other growth factor receptors. We aim to outline these similarities, but also to highlight the unique characteristics of the VEGF receptors, which are the key to our understanding of the critical roles of these receptors in fundamental biological processes.

Aptamers as tools in molecular biology and immunology.

Abstract: In 1990 Tuerk and Gold introduced the first RNA aptamer for bacteriophage T4 DNA polymerase, obtained by a new combinatorial technique which they designated as SELEX (systematic evolution of ligands by exponential enrichment). In parallel, ELLINGTON and Szostak (1990) showed that it is also possible to select RNA aptamers which are able to specifically complex organic molecules of low molecular weight, thus serving as receptor molecules based on nucleic acids rather than proteins. Since then, considerable progress has been achieved in the field of in vitro selection of combinatorial nucleic acid libraries, which demonstrates its impressive potential as a tool in molecular biology, diagnostics, molecular medicine, drug discovery, and bio-organic chemistry. Today, the SELEX process has been applied to more than a hundred different target molecules, and aptamers are known for almost every kind of targets such as organic dyes, amino acids, biological cofactors, antibiotics, peptides and proteins or even whole viruses (Bell et al. 1998; Gal et al. 1998; Ellington and Osborne 1997; Kraus et al. 1998; Yang et al. 1998; Eaton 1997; Pan et al. 1995), showing that aptamers can be obtained for almost any desired target whether complex or small.

Vascular Endothelial Growth Factor Receptor-3

Abstract: Cell-cell communication during vascular development and tumour angiogenesis seems to involve at least five endothelial cell-specific tyrosine kinase receptors belonging to two distinct subclasses: two receptors of the Tie family, and three vascular endothelial cell growth factor receptors, VEGFR-1, -2 and -3, originally named Fltl (Fms-like tyrosine kinase), KDR/Flk-1 (Kinase insert-domain containing receptor or fetal-liver kinase-1) and Flt4, respectively. VEGFRs are subclass-III receptor tyrosine kinases, homologous to the platelet-derived growth factor (PDGF)-receptor family, having seven immunoglobulin homology domains in the extracellular domain, and a tyrosine kinase intracellular domain split by a kinase insert sequence (for recent reviews, see Klagsbrun and D’Amore 1996; Folkman and D’Amore 1996; Mustonen and Alitalo 1995; Korpelainen and Alitalo, 1998, Claesson-WELSH, this book).

Mechanisms of Helicobacter pylori infection: bacterial factors.

Abstract: The pathogenesis of Helicobacter pylori can be described in three steps: (a) gain of entry and colonization of the unique niche of the human gastric mucosa; (b) avoidance, subversion, or exploitation of the nonspecific and specific human immune system; and (c) multiplication, tissue damage, and transmission to a new susceptible host or spread to adjacent tissue (Falkow 1991, 1997) (Fig. 1). A virulence factor is a gene product involved in one or more of these steps. To properly assess whether a particular gene is involved in virulence, the candidate gene must be cloned, disrupted in H. pylori and be shown to have reduced virulence in an appropriate animal model. This is best determined by testing the interaction of H. pylori with human gastric epithelial cells or phagocytic cells or by assessment of infection in H. pylori animal models. Finally, “molecular Koch’s postulates” (Falkow 1988) can be completed by cloning the wild-type gene into a shuttle plasmid, which should then complement the H. pylori chromosomal defect, resulting in recovery of virulence.

Bacterial Toxins as Mucosal Adjuvants

Abstract: The 1995 World Health Organization report of infectious-disease deaths indicated there had been more than 13 million deaths world-wide during that year. The majority of those deaths were caused by organisms that first make contact with and then either colonize or cross mucosal surfaces to infect the host. The overall morbidity caused by these organisms and other pathogens that interact with mucosal surfaces is impossible to calculate.

Interleukin-12: basic principles and clinical applications.

Abstract: The most important advance in the last 10 years in our understanding of how to direct the immune response by vaccination or immunotherapy has been the description and subsequent refinement of the T helper type 1/2 (Th 1/2) paradigm. (Mosmann and Coffman 1989). This paradigm has provided the framework necessary to formulate basic questions related to defining the cues pathogens provide that shape the immune response. A major advance in this area came with the discovery of interleukin-12 (IL-12) (Kobayashi et al. 1989; Stern et al. 1990) and the subsequent demonstration that IL-12 promotes the development of Th 1 cells in vitro (Hsieh et al. 1993; Manetti et al. 1993). Thus, in naive T cell populations exposure to antigen in the presence of IL-12 for several days, followed by restimulation with antigen alone, led to the development of interferon (IFN)-γ producing T cells. Moreover, it was found that one could link together IL-12, the innate immune response, pathogens, and Th 1 cell development. This was done by showing that bacteria, such as Listeria monocytogenes, induced Th l cell development and that this occurred by stimulation of macrophages to produce IL-12 (D’Andrea et al. 1992; Hsieh et al. 1993). This observation has led to the description of a common pathway leading from the innate immune response to adaptive immunity, in which intracellular pathogens stimulate macrophages to produce IL-12, which promotes the development of Th 1 cells from a naive cell population. This pathway can now be exploited to develop approaches for the design of new immunotherapies and vaccines.

The Epidemiology of Helicobacter pylori

Abstract: In the world of modern medicine it is rare that the understanding of a previously described clinical disease is so completely revolutionized that clinical textbooks must be rewritten This, however, has been the outcome of the isolation ofHelicobacter pylori from the human stomach Only 15 years after its initial isolation, this bacterium has been proven to be the etiological agent of acute on chronic gastritis, and a predisposing factor in peptic ulcer disease, gastric carcinoma and B cell mucosa-associated lymphoid tissue (MALT) lymphoma (Graham et al 1992; IARC 1994; Marshall et al 1985; Parsonnet et al 1994)

M Cells in Antigen Sampling in Mucosal Tissues

Abstract: The mucosal surfaces of the gastrointestinal and respiratory tracts are lined by epithelial barriers composed of cells joined by tight junctions. These gasket-like junctional structures are generally effective in excluding peptides and macromolecules with antigenic potential (Madara et al. 1990). Mucosal surfaces are also provided with other defenses such as local secretions containing mucins and secretory immunoglobulin A (IgA) antibodies that tend to prevent antigens and pathogens from contacting the epithelium (Neutra et al. 1994). Nevertheless, to obtain samples from the external environment across this barrier, the mucosal immune system depends on a close collaboration between epithelial cells and antigen-presenting and lymphoid cells. These “lympho-epithelial complexes” allow transport of antigen samples across the mucosal barrier without compromising the integrity and protective functions of the epithelium.

Functions of Tie1 and Tie2 Receptor Tyrosine Kinases in Vascular Development

Abstract: Vascularization of the mouse embryo is accomplished via the collaboration of two major cellular processes. Differentiation of vascular endothelial cells de novo from their precursors, called the angioblasts, has been termed vasculogenesis (Risau 1997). Somewhat confusingly, the term vasculogenesis has also been used in a broader sense, covering all aspects of vascular development (Dumont et al. 1994; Noden 1991; Sherer 1991; Wilting and Christ 1996). Subsequent expansion of the endothelium by remodelling, migration and proliferation is called angiogenesis. Vasculogenesis is known to occur intraembryonically within the splanchnopleural and paraxial mesoderm, as well as extraembryonically in the yolk sac mesoderm, and is responsible for laying down the primitive vascular network (Pardanaud et al. 1996; Wilting and Christ 1996). Vasculogenesis is characterized by angioblast differentiation and by either the immediate aggregation of angioblast cells to give rise to endothelium, or the directed migration of these cells through the embryo to segregate eventually into vascular cords. Interestingly, angioblasts appear to have different characteristics depending on their site of origin (Pardanaud et al. 1996). Vasculogenesis both in the yolk sac and in the splanchnic mesoderm appears closely linked to haemangioblast (Pardanaud et al. 1989; Shalaby et al. 1995, 1997).

Effector and Regulatory Lymphoid Cells and Cytokines in Mucosal Sites

Abstract: The key feature of the mucosal immune system is the dual ability to respond promptly and effectively to invasive and lumen-dwelling pathogens, while retaining the ability to be unresponsive to non-pathogenic agents such as the autochthonous flora and foods To specifically ignore some antigens in the gut (ie foods) and respond to others (ie cholera vibrios) is not an option, since there is no way in which the immune system can predict the nature of a pathogen The enormous diversity of potential T-cell receptors, therefore, means that all foreign peptides in the gut are likely to be recognised One of the major goals of modern immunology is to ascertain the determinants which can predict whether recognition results in active immunity or unresponsiveness, and nowhere is this more important than in the gastrointestinal tract

Antigen sequence- and library-based mapping of linear and discontinuous protein-protein-interaction sites by spot synthesis.

Abstract: Peptides synthesized on continuous cellulose membranes by the spot synthesis technique (Frank et al. 1992) have been increasingly used to study molecular recognition events. The application of these positionally addressable peptide libraries include investigating protein/protein (literature cited throughout the text), protein/DNA (Kramer et al. 1993; Reuter et al. 1998) and protein/metal interactions (Malin et al. 1995). In addition, substrate specificities of kinases (Toomik et al. 1996; Tegge et al. 1998; Mukhija et al. 1998), proteases (Duan and Laursen 1994; Kramer et al. 1998; Reineke et al. 1999) and chaperones (Rudiger et al. 1997) have been determined. In this chapter we review protein sequence- and library-based approaches to map linear and discontinuous antibody/antigen and receptor/ligand contact sites using the spot synthesis technique.

Chemokines and B-cell homing to follicles.

Abstract: B cells that bind autoantigen in the periphery may be excluded from lymphoid follicles and rapidly eliminated (Cyster, 1997). To understand the basis for follicular exclusion we considered whether Gi coupled chemokine receptors might play a role by testing the effect of treatment with pertussis toxin (PTX), an inhibitor of Gi signaling, on B cell migration into splenic follicles. Strikingly, PTX treated B cells were unable to migrate into follicles or the white pulp cords of the spleen, whereas cells treated with buffer alone or with the oligomer B subunit of PTX could migrate into follicles normally (Cyster and Goodnow 1995). These observations led us to consider which chemokine receptors and chemokines might have a role in B cell positioning within lymphoid organs. We focused on two orphan receptors, BLR1 and EBI1, because these had been shown to be constitutively expressed by B cells in humans (Birkenbach et al. 1993; Dobner et al. 1992). To track expression of the mouse receptors, the amino-terminal ectodomains were expressed as GST fusion proteins and used to immunize rabbits. An antiserum against BLR1 was isolated and affinity purified using the same BLR1 fragment expressed as a fusion protein with mannose-binding protein. Flow cytometric analysis of mouse lymphoid tissues showed BLR1 expression on all mature B cells (Schmidt et al. 1998) with slightly higher surface expression on B cells with a CD21hiIgDlo marginal zone phenotype (Fig. 1). BLR1 expression was also observed on B220+CD5+ peritoneal B-l cells (Fig. 1). In B cell development, there was little or no BLR1 detectable on B220+IgM- pro/pre-B cells, whereas B220+IgM+ immature B cells showed weak expression (Fig. 1; note that as BLR1 is detected with a polyclonal antiserum it is necessary to be cautious in interpreting the significance of weak signals such as seen on many of the cells in bone marrow gate G4). BLR1 expression became strongly upregulated on immature B cells at about the same time as surface IgD and CD21 (Fig. 1). The low expression by immature B cells is consistent with findings that immature B cells are inefficient at entering follicles (Cyster 1997) and suggests that BLR1 upregulation may be an important part of the immature to mature B cell transition.

T Helper Differentiation Proceeds Through Stat1-Dependent, Stat4-Dependent and Stat4-Independent Phases

Abstract: The effort to understand Th1 and Th2 development has included defining the specific signals that determine phenotype fate upon primary T cell activation by antigen. Numerous parameters of T cell activation appear to influence the overall balance of Th1/Th2 phenotype development, including the antigen presenting cells (APCs) used for T cell priming (Chang et al. 1990), antigen dose (Parish and Liew 1972; Hosken et al. 1995; Murray et al. 1992; Constant et al. 1995), antigen structure or particularly the affinity for the major histocompatibility complex (MHC) and T cell receptor (TCR) (Murray et al. 1992; Pfeiffer et al. 1991), levels of costimulation during T cell priming (Freeman et al. 1995; Lenschow et al. 1995; Kuchroo et al. 1995), genetic background (Murphy et al. 1994; Kubin et al. 1994), pathogen-derived materials, and cytokines present in the priming milieu (Le Gros et al. 1990; Swain et al. 1990, 1991; Sadick et al. 1990; Maggi et al. 1992; Manetti et al. 1993; Seder et al. 1993; Sypek et al. 1993; Chatelain et al. 1992; Belosevic et al. 1989; Hsieh et al. 1995; Howard 1986; Heinzel et al. 1989; Scott et al. 1988; Locksley and Scott 1991). While any of these parameters can alter the overall Th1/Th2 developmental balance, some appear to act directly to deliver final Thl/Th2 inducing signals to the T cell, while others appear to act indirectly, for example through modifying APC function, other innate immune cell activity, or the levels of Thl/Th2 inducing cytokines. The cytokines interleukin (IL)-12 and IL-4 act directly on receptors expressed by activated T cells, through specific STAT factors, to deliver direct differentiation-inducing signals (Kaplan et al. 1996a,b; Thierfelder et al. 1996). IL-4 activation of Stat6 is necessary for IL-4-induced Th2 phenotype development (Le Gros et al. 1990; Swain et al. 1990; Maggi et al. 1992; Chatelain et al. 1992; Kaplan et al. 1996a; Kopf et al. 1993; Kuhn et al. 1991; Betz and Fox 1990; Hou et al. 1994; Quelle et al. 1995; Shimoda et al. 1996; Takeda et al. 1996), and IL-12 activation of Stat4 is necessary for Th1 development (Kaplan et al. 1996b; Thierfelder et al. 1996; Jacobson et al. 1995; Bacon et al. 1995; Mattner et al. 1996; Magram et al. 1996; Szabo et al. 1995). While the molecular downstream targets of Stat6 and Stat4 for Th1/Th2 development are currently unknown, at present these two factors are the most proximal known signals controlling phenotype. It is unresolved at present through what mechanisms non-cytokine parameters influence Th1/Th2 balance, although it is likely that some may act by altering the initial levels of IL-4, IL-12 or interferon (IFN)-γ available to T cells during primary activation. Whether partial signaling through the TCR acts directly to induce Thl/Th2 developmental signals is an open issue at present. Changing antigen dose can cause apparent changes in phenotype development in vitro (Hosken et al. 1995). However, this effect was lost when IL-4 was neutralized, suggesting that cytokines are dominant in the hierarchy of these parameters.

Structure and functional relationships of satellite RNAs of cucumber mosaic virus.

Abstract: The first association of a satellite RNA with cucumber mosaic virus (CMV) was established by J.M. Kaper and colleagues (1976), who also showed that CMV containing this satellite RNA induced a lethal necrosis in the tomato (Kaper and Waterworth 1977). This initial discovery followed from earlier work in France concerning the search for the etiology of a lethal tomato necrosis that had appeared in the French Alsace in 1972 (Marrou et al. 1973). By 1974, it was clear that CMV was associated with the disease (Marrou and Duteil 1974). The epidemic did not re-occur for some time, although CMV strains outside of France apparently also contained necrogenic satellite RNAs (Kaper and Tousignant 1977; Kaper and Waterworth 1977). Nonetheless, the reappearance of the tomato-necrosis epidemic in Italy (Gallitelli et al. 1988), as well as in Japan (Kosaka et al. 1989) and Spain (Jorda et al. 1992), led to the unequivocal establishment of CMV strains containing necrogenic satellite RNAs as the causal agents of tomato necrosis.

Defective and defective interfering RNAs of monopartite plus-strand RNA plant viruses

Abstract: The defective interfering (DI) RNAs represent one of several classes of symptom-modulating RNAs identified in association with RNA plant virus infections. Structurally, these molecules are derived from, and represent mutant forms of, the viral genome (Perrault 1981; Lazzarini et al. 1981). DI RNAs may contain distinct types of modifications; however, the most prevalent is the deletion of one or more large segments of sequence. Despite structural differences, the common effect of the mutation(s) is to render the DI RNAs dependent on their nondefective ‘parental’ genome for essential viral replication proteins. This, in turn, limits replication of these molecules to cells which are coinfected with the parental genome.

Molecular pathogenesis of B cell malignancy: the role of BCL-6.

Abstract: Human malignancies displaying a mature B cell phenotype include non-Hodgkin lymphoma, (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM). Analogous to most cancer types, the pathogenesis of these malignancies represents a multistep process involving the progressive and clonal accumulation of multiple genetic lesions affecting proto-oncogenes and tumor suppressor genes. However, several important features distinguish the mechanism and type of genetic alterations associated with NHL, CLL, and MM (Table 1).

Dendritic Cells and Langerhans Cells in the Uptake of Mucosal Antigens

Abstract: Dendritic cells (DC) represent heterogenous populations of bone marrow-derived cells that have central roles in the initiation and regulation of immune responses (reviewed in Steinman 1991). The cells under consideration are quite distinct from the follicular DCs found in B-cell areas of lymphoid tissues. It is, however, now clear that there is not a single DC lineage, but that cells with DC properties may arise from at least three lineages and can exist in different states of maturation and activation. The relationships between these lineages and their functional significance in immune responses are far from clear.

Antibody-mediated protection of mucosal surfaces.

Abstract: Mucosal surfaces of the oral cavity, the digestive and urogenital tracts, and the airways are protected against environmental pathogens by innate and adaptive immune defense mechanisms. Innate defense involves physical, chemical and cellular factors. Entrapment of pathogens in mucus facilitates their clearance by peristalsis in the gut and ciliary movement in the airways. The longitudinal flow of fluids across the epithelial layer mediated by chloride channels helps to flush away microorganisms and prevent their attachment to the epithelial cell surface. The apical cell surface-associated glycocalyx, which consists of a dense network of glycoproteins, also limits the access of pathogens to the epithelial surface. Chemical factors (lysozyme, lactoferrin, peroxidase and defensins) secreted by specialized epithelial cells, such as the Paneth cells in the crypts of the small intestine, gastric acid and intestinal hydrolases (proteases, lipases, nucleases) constitute an efficient defense mechanism.

The Stability and Reversibility of Th1 and Th2 Populations

Abstract: It has become widely accepted in the past decade that Th1 and Th2 cells represent alternate states of function and gene expression of CD41 T cells (Mosmann and Coffman 1989; Abbas et al. 1996). A question central to understanding the relevance of these subsets is whether they are products of an irreversible differentiation process or whether Th1 and Th2 cytokine patterns can be interchanged in an ordered or a regulated manner. Many disease states can be attributed to the activity of one specific Th subset, such as Th1-mediated autoimmune diseases or Th2-mediated allergic diseases and this implies that the ability to alter or reverse Th differentiation is a potential strategy for the treatment of such diseases.