Biomedical subjects

S Redpath

Publications and source records attributed to S Redpath.

9 recordsLinked to original sources

PubMed2001

Hijacking and exploitation of IL-10 by intracellular pathogens.

Macrophages play a central role in infections, as a target for pathogens and in activation of the immune system. Interleukin-10 (IL-10), a cytokine produced by macrophages, is a potent immunosuppressive factor. Some intracellular pathogens specifically target macrophages for infection and use IL-10 to dampen the host immune response and stall their elimination from the host. Certain viruses induce production of cellular IL-10 by macrophages, whereas other viruses encode their own viral IL-10 homologs. Additionally, specific bacteria, including several Mycobacteria spp. and Listeria monocytogenes, can survive and replicate in macrophages while inducing cellular IL-10, highlighting a potential role for IL-10 of macrophage origin in the immunosuppressive etiology of these pathogens. Thus, the exploitation of IL-10 appears to be a common mechanism of immunosuppression by a diverse group of intracellular pathogens that can infect macrophages.

Cytomegalovirus↗

PubMed2001

Immune checkpoints in viral latency.

The dynamics of the relationship between the immune system and latent viruses are highly complex. Latent viruses not only avoid elimination by the host's primary immune response, they also remain with the host for life in the presence of strong acquired immunity, often exhibiting periodic reactivation and recurrence from the latent state. The continual battle between reemergent infectious virus and immunological memory cells provides an essential virus-host regulatory loop in latency. In this review, we speculate on the critical importance of immune interference mechanisms by viruses contributing to the regulatory loop in viral homeostasis of latency. Central to the notion of viral homeostasis, we further invoke the concept of threshold limits in naive and memory states of immunity to account for the failure of the host to completely eradicate these intracellular parasites.

HIV↗

PubMed2000

T cell receptor binding kinetics and special role of Valpha in T cell development and activation.

The kinetics of the interaction between T cell receptor (TCR) and major histocompatibility complex (MHC) has an important role in determining thymocyte-positive and -negative selection in the thymus, as well as in T cell activation. The alpha chain of the TCR is the major player in determining how the TCR fits onto the MHC ligand, and thus has a major role in determining whether a T cell develops as class I or class II restricted. In this article, we summarize recent data from our laboratory and others on the role of polymorphism in the Valpha combining site in determining MHC class restriction, and on kinetic parameters in thymocyte selection.

Animals↗

PubMed1999

Cutting edge: trimolecular interaction of TCR with MHC class II and bacterial superantigen shows a similar affinity to MHC:peptide ligands.

Bacterial superantigens such as Staphylococcus aureus enterotoxin A (SEA) are very potent stimulators of T cells. They bind to the Vbeta region of the TCR and to MHC class II, stimulating T cells at nanomolar concentrations. Using surface plasmon resonance measurements, we find that binding between the individual components of the complex (TCR-class II, TCR-SEA, SEA-class II) is very weak, but that the stability of the trimolecular complex is considerably enhanced, reaching an affinity similar to that found for TCR interactions with MHC:peptide ligand. Thus, the potency of SEA in stimulation of T cells is not due to particularly strong affinities between the proteins, but to a cooperative effect of interactions in the TCR-SEA-MHC class II trimolecular complex that brings the kinetics into a similar range to binding of conventional Ags. This range may be the optimum for T cell activation.

Animals↗

PubMed1999

Murine cytomegalovirus infection down-regulates MHC class II expression on macrophages by induction of IL-10.

Herpesviruses utilize many strategies for weakening the host immune response. For CMV, this includes avoidance of NK clearance and inhibition of MHC class I and class II presentation pathways. In this study, we report that mouse CMV (MCMV) specifically causes a premature and transient activation of host IL-10 very early in the course of infection, resulting in a dramatic and selective reduction in MHC class II surface expression. The expression of IL-10 is normally late in the immune response to a pathogen, serving to dampen the response by suppression of the production of inflammatory cytokines. In infection of macrophages, we show that MCMV induces the production of IL-10, leading to an early and selective reduction in the expression of MHC class II on the surface of the cells. Inhibition of MHC class II expression was not observed in the presence of neutralizing Abs to IL-10 or in macrophages from IL-10-deficient mice. Moreover, MCMV-infected IL-10-deficient mice developed an early and significantly more robust macrophage MHC class II induction than normal mice. Altogether, our results demonstrate that viral induction of an IL-10 autocrine pathway plays an essential early role in selectively reducing MHC class II expression on the surface of APC prior to stimulation by IFN-gamma.

Acute Disease↗

PubMed1998

The influence of the hinge region length in binding of human IgG to human Fcgamma receptors.

Interactions between human IgG with human FcgammaRI and FcgammaRIIa (R131) were studied to investigate the role of the hinge region of IgG3 and IgG1 in the binding of the antibodies to FcgammaR. It was found that a hinge deletion mutant of IgG3 (IgG3 m15) was reduced in its ability to bind to FcgammaRI and FcgammaRIIa but was more potent at activating ADCC by activated lymphocytes (FcgammaRIIIa-mediated), compared to the wild-type version of IgG3. The human IgG1 allotype G1m(a,z) was more efficient at binding to FcgammaRI than the two IgG3 antibodies tested. The IgG1 and IgG3 wild type antibodies were better able to bind to FcgammaRII than the hinge deletion mutant version of IgG3. The data suggest a role for the hinge region in influencing FcgammaR mediated effector functions in IgG3.

Amino Acid Sequence↗

PubMed1998

Activation of complement by human IgG1 and human IgG3 antibodies against the human leucocyte antigen CD52.

Activation of the complement cascade by immunoglobulin G (IgG) plays a major role in the host defense against pathogens. Using recombinant human antibodies specific for the leucocyte antigen CD52, different allotypes of human IgG1 subclass were compared for their ability to activate human complement. In addition the roles of the different length hinge regions of IgG1 and IgG3 were investigated. It was found that the naturally occurring allotypes G1m(a,z) and G1m(f), and one artificially created isoallotype, G1m(null), did not significantly differ in their overall ability to cause cell lysis. However, some differences in binding of individual components of the classical activation pathway were detected. More of the complement component C1s seemed to be associated with the allotype G1m(f), although this did not result in an overall improvement in lytic potency. In this system the wild-type IgG3 was found to be less effective in complement lysis than IgG1. By shortening the hinge region of IgG3 to resemble that of an IgG1 antibody, increased complement binding was observed compared with that of wild-type IgG3 and the IgG1 allotypes. The overall lytic potency of the antibody was also improved compared with wild type IgG3 and it was also slightly more effective than the IgG1 allotypes.

Antigens, CD↗

PubMed1998

Age as a factor in admission to chronic pain rehabilitation.

OBJECTIVE: To examine access to multidisciplinary pain rehabilitation programs for older patients. DESIGN: Telephone and written surveys of pain programs accredited by Commission on Accreditation of Rehabilitation Facilities. Visual Analog Scale (VAS) ratings of patient vignettes in which older patients were alternatively assigned their true age or a younger age. PARTICIPANTS: Health care professionals at pain programs. MAIN OUTCOME MEASURES: Telephone survey of admission policies and treatment services. VAS ratings of patient vignettes. RESULTS: No program excludes older pain patients by age. However, 28% of programs had admitted only the youngest old (< 70 years). Age-related criteria, such as presence of concurrent medical diagnoses that are more likely to exclude older patients, are common. In addition, VAS ratings of patient vignettes indicated an age bias: the same patients were rated as 14.8% less likely to be admitted (p < .001) and 12.5% less likely to succeed if admitted (p < .001) when their true, older age was given than when a false younger age was provided. CONCLUSION: Pain program admission policies do not exclude older patients by age but frequently include age-related criteria that disproportionately exclude the elderly. There is also evidence of an age bias in which age per se reduces perceived suitability for pain program admission.

Adolescent↗

PubMed1996

T-cell-receptor affinity and thymocyte positive selection.

Development of thymocytes involves two distinct outcomes resulting from superficially similar events. Recognition by thymocytes of major histocompatibility complex (MHC) proteins plus peptides leads to their rescue from apoptosis (positive selection), and recognition of antigenic peptide induces cell death (negative selection). Antigen analogues, and sometimes low concentrations of antigenic peptide, induce positive selection; such analogues are often antagonists of mature T-cell clones. Various models seek to explain how recognition of different peptide/MHC complexes leads to such different outcomes: quantitative models relate response to the affinity, avidity or kinetics of T-cell-antigen receptor (TCR) binding, whereas qualitative models require conformational or spatial changes in the TCR or associated molecules to modulate signal transduction. We have used surface plasmon resonance to measure the kinetics of TCR interactions with positively and negatively selecting ligands to distinguish between these models, and find that affinity correlates to the outcome of selection. A 'window' of affinity resulting in positive selection extends over a 1-log range starting threefold below the affinity for negative selection.

Amino Acid Sequence↗