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Biomedical subjects

M Salmon

Publications and source records attributed to M Salmon.

At least 127 records · Page 7Linked to original sources
PubMed1992

The immunogenetic component of susceptibility to rheumatoid arthritis.

The precise nature of the HLA element associated with rheumatoid arthritis has been identified as a short sequence of amino acids on the alpha helix of a range of DR beta alleles. Recently the range of alleles known to bear this sequence and to be associated with rheumatoid arthritis has increased considerably. Although these findings lend further weight to the validity of the original hypothesis, they have also made it very difficult to propose a mechanism for the association. It has also become clear that the simple model of dominant susceptibility is unsatisfactory. Patients with early disease show little or no association with any HLA alleles, whereas patients with severe forms of rheumatoid arthritis are frequently homozygous for DR4, showing a disproportionate tendency toward compound heterozygocity--expressing two different molecules sharing the conserved sequence.

Arthritis, Rheumatoid↗
PubMed1991

Human CD4+CD45R0+ and CD4+CD45RA+ T cells synergize in response to alloantigens.

Alloantigens, unlike recall antigens, activate both CD45RA+ (naive) and CD45R0+ (memory) CD4+ cells to the same extent. These T cell subsets may therefore interact with each other in response to alloantigens on transplanted grafts. We have investigated if the ability of activated CD4+CD45RA+ and CD4+CD45R0+ T cells to produce and respond to interleukin 2 (IL2) and IL4 may be involved in this interaction. After activation, both subsets up-regulate their IL2 receptor (IL2R) and IL4R expression, yet IL4 substantially enhanced the proliferation of the CD4+CD45RA+ but not of the CD4+CD45R0+ T cell subset, while IL2 increased the proliferation of CD4+CD45R0+ but not of the CD4+CD45RA+ T cells. Significantly, the CD4+CD45RA+ T cells synthesized two- to threefold more mRNA for IL2 than the CD4+CD45R0+ subset, while the CD4+CD45R0+ T cells synthesized mRNA for IL4 and interferon-gamma exclusively. The addition of IL2 to alloactivated CD4+CD45R0+ T cells further up-regulated their production of all three lymphokine mRNA; in contrast, IL4 induced an increase in mRNA for IL2 in only the alloactivated CD4+CD45RA+ subset. The reciprocity in the ability of both these CD4+ T cells to synthesize and respond to IL2 and IL4 may provide a rationale for the regulation of lymphokine interactions in vivo. Furthermore, the synergy between these subsets in response to alloantigens, which was directly quantitated by co-culturing CD4+CD45RA+ and CD4+CD45R0+ cells together prior to activation, may potentiate the alloreactivity against transplanted grafts in vivo.

Antigens, CD↗
PubMed1991

Primed and naive helper T cells in labial glands from patients with Sjogren's syndrome.

This study has investigated the presence and distribution of B cells, T cells and T-cell subsets within labial glands of patients with primary Sjogren's syndrome (n = 9) and secondary Sjogren's syndrome associated with rheumatoid arthritis (n = 8) using a sequential double immunoperoxidase technique and true colour image analysis. The composition of the inflammatory infiltrates was similar in glands from both patient groups. B cells were normally present within large foci with few detected in diffuse infiltrates such that the ratio of T:B cells in foci (2.4:1) was significantly lower than in diffuse infiltrates (7.3:1; P less than 0.001). In all infiltrates helper T cells (CD8-, CD3+) predominated over suppressor/cytotoxic cells (CD8+, CD3+; 2.7:1). Analysis of primed (CD45RA-, CD45RO+) and naive (CD45RA+, CD45RO-) CD8- T cells showed that the ratio of the primed to naive subset was significantly higher in focal (4.2:1) compared to diffuse (1.5:1; P less than 0.001) areas of lymphoid infiltration. These results indicate that the focal lymphocytic infiltrates characteristic of Sjogren's syndrome contain B cells associated with a T-cell population consisting predominantly of primed CD8- helper T cells. This latter population may be responsible for upregulating glandular B-cell activity in Sjogren's syndrome.

Antigens, CD↗
PubMed1991

The synergy between naive and memory T cells during activation.

Naive and memory T-cell subsets differ in their ability to synthesize and respond to a variety of cytokines in vitro and each subset can produce cytokines that amplify the response of the other subset. The significance of these interactions to antigen responsiveness has, until now, been unclear. In this article Arne Akbar and colleagues point out that both subsets are activated to the same extent by alloantigen and suggest that synergy may be an important event in initiating potent responses against transplanted allografts.

Animals↗
PubMed1991

The immune response. 2. Systemic mediators of inflammation.

This article deals with the mechanisms by which local immune stimulation is transmitted to the periphery, leading to systemic inflammation. We concentrate on the role of three signalling molecules: interleukin-1, interleukin-6, and tumour necrosis factor alpha. These cytokines provide a direct link between local and systemic inflammation.

Acute-Phase Reaction↗
PubMed1991

The immune response 1. The local response and understanding T cell specificity.

In recent years there have been major advances in our knowledge of the mechanisms that determine the specificity of the interaction between T cells and antigen. This specificity determines self-recognition, controls responses to foreign proteins and when disordered leads to autoimmunity. In this article we describe some of these advances and discuss the implications for our understanding of the inflammatory process and disease.

Antigen-Presenting Cells↗
PubMed1990

Clinical trial of calcium alginate haemostatic swabs.

The influence of a new haemostatic material on surgical bleeding was evaluated in 100 patients who were prospectively randomized to either normal surgical gauze or calcium alginate swabs used throughout cholecystectomy (n = 40), simple mastectomy (n = 18) or inguinal hernia repair (n = 42). Overall, median (range) blood loss was 91 (3-329) ml for gauze and was significantly reduced by calcium alginate swabs to 72 (2-181) ml (P less than 0.05). Unexpectedly, operation times were also shortened from 45 (17-95) min for gauze to 35 (13-70) min with calcium alginate swabs (P less than 0.02). This reduction in blood loss and operating time was greatest for mastectomy, was still statistically significant for cholecystectomy, but was unimportant in inguinal hernia repair. Calcium alginate haemostatic swabs may become routine in major surgery, particularly where blood loss leads to the need for transfusion.

Alginates↗
PubMed1990

Comparison of anti-fetal colonic microvillus and anti-CEA antibodies in peroperative radioimmunolocalisation of colorectal cancer.

Local recurrence of colorectal cancer may result from failure to assess accurately the extent of tumour at operation. It has been suggested that peroperative radioimmunolocalisation may improve this assessment. The degree to which this is possible has been studied using a hand-held gamma detecting probe and comparing two 125I-labelled monoclonal antibodies to colorectal tumours. The antibodies were to fetal colonic microvillus membrane (FM1D10) and to carcinoembryonic antigen (A5B7). Sixty-nine per cent (9/13) of the FM1D10 and 98% (43/44) of A5B7 labelled tumours took up significant amounts of antibody with a tumour to normal colon ratio of more than 1.5:1. The uptake was significantly better for A5B7 with a median tumour to normal colon ratio of 3.3 (1.1-13.8) compared to 1.85 (0.75-7.7) for FM1D10 (P less than 0.001). The tumour: colon ratio of both antibodies was independent of the serum CEA, Dukes' stage or the degree of histological differentiation. There was a linear correlation for tumour to normal colon ratios between the gamma detecting probe and the same tissue examined in a conventional well counter (correlation coefficient r = 0.78, P less than 0.001). Colorectal tumours demonstrate a rapid and reliable uptake of anti-CEA monoclonal antibody A5B7. This antibody can be detected with a peroperative gamma detecting probe and has the potential to improve the surgeon's appreciation of the extent of tumour and therefore may influence the surgery performed. Detailed clinical studies are now being carried out.

Adult↗
PubMed1989

Phosphoinositide hydrolysis in mitogen-stimulated human peripheral-blood T lymphocytes.

Both phytohaemagglutinin and antibodies to the CD3 molecule induced proliferation and phosphoinositide hydrolysis in human peripheral-blood T lymphocytes, but the magnitude of the inositol phosphate response was small and the rate of accumulation slow [significant increases in Ins(1,4,5)P3 were observed only after 10 min]. Hence this response differs from the well-characterized Ins(1,4,5)P3 responses of many other systems. This slow response, its abrogation in Ca2+-depleted medium, the slow and maintained increase in Ca2+ as measured by Quin-2, and the ability of the Ca2+ ionophore A23187 to stimulate Ins(1,4,5)P3 accumulation all suggest that the increase in Ins(1,4,5)P3 occurs, at least in part, as a result of receptor-mediated Ca2+ influx in mitogen-stimulated T lymphocytes.

Antibodies, Monoclonal↗
PubMed1989

The kinetics of interaction between lymphocytes and magnetic polymer particles.

Magnetic polymer-coated particles linked to antibodies are considered to be an efficient rosetting matrix for immunoselection. We have shown that a 20:1 bead:target cell ratio and a 90 min incubation period are the optimal conditions for specific binding of monoclonal antibody-labelled cells to goat anti-mouse IgG-coated beads. Higher ratios or longer incubation periods resulted in considerable non-specific binding. Characterisation of the optimal conditions for specific depletion of lymphocyte subpopulations showed that (a) a range of bead:target cell ratios and incubation periods can be used, with resulting high efficiency and specificity; (b) multiple monoclonal antibodies can be used simultaneously for the depletion of diverse lymphocyte subpopulations; (c) non-specific bead-to-cell binding does not affect the specificity and efficiency of magnetic depletion; (d) specific binding of one bead only was adequate for effective magnetic separation. These findings define the most economical, specific and efficient conditions of use of beads for negative immunoselection but preclude the use of beads as an analytical rosetting medium.

Antibodies, Monoclonal↗
PubMed1989

Purification of human blood eosinophils by negative selection using immunomagnetic beads.

A simple method for isolating highly purified eosinophils from human blood is described. Buffy coats from normal individuals (eosinophil counts less than 0.4 x 10(9)/litre) were centrifuged through a two layer Percoll density gradient, to produce a granulocyte fraction containing neutrophils and eosinophils. Neutrophils were extracted from this fraction using a monoclonal antibody (CLB FcR gran 1) against CD 16 (Fc gamma R III) in a direct or indirect selection procedure using immunomagnetic beads (Dynabeads). This negative immunoselection produced eosinophils of greater purity and with a superior capacity to mount a respiratory burst than eosinophils isolated by a method employing metrizamide.

Antigens, Differentiation↗
PubMed1989

Production of lymphokine mRNA by CD45R+ and CD45R- helper T cells from human peripheral blood and by human CD4+ T cell clones.

The expression of lymphokine mRNA by human CD4+CD45R+ and CD4+CD45R- Th cells was assessed after mitogen stimulation. These Ag have previously been shown to relate closely to virgin and primed T cells, respectively. CD4+CD45R+ (virgin) and CD4+CD45R- (primed) cell fractions were isolated by sorting double-labeled cells with a fluorescence-activated cell sorter. CD4+CD45R+ cells produced high levels of IL-2 mRNA when stimulated with either PMA together with calcium ionophore, or with PHA, but they expressed only trace quantities of mRNA for IL-4 or IFN-gamma. In contrast, CD4+CD45R- cells produced high levels of mRNA for IL-2, IL-4, and IFN-gamma. After 14 days of continuous culture, CD4+CD45R+ Th cells lost expression of the CD45R Ag, but gained high level expression of CDw29, such that they were indistinguishable from the cell population which originally expressed this Ag. At the same time, they acquired the ability to synthesize IL-4 mRNA. It seemed likely that the broad lymphokine profile of primed Th cells might mask clonal heterogeneity. Analysis of 122 CD4+ T cell clones showed that all of them synthesized IL-2 mRNA. One clone failed to express IL-4 mRNA, but did produce those for IL-2 and IFN-gamma. A total of 34 of the clones was investigated to determine expression of IFN-gamma mRNA; two of these clones were negative for IFN-gamma mRNA, and both expressed IL-2 and IL-4 message. These data suggest that while fresh virgin and primed peripheral blood T cells show a clear resolution of lymphokine production, a simple subdivision of human CD4+ T cell clones on the basis of their lymphokine production (such as that reported for mouse Th cell clones) is not possible.

Antigens, Differentiation↗
PubMed1989

Lymphopenia in rheumatoid arthritis.

Lymphopenia is a recognized but poorly studied feature of rheumatoid arthritis (RA). We set out to establish the prevalence and significance of lymphopenia in RA. A group of 66 RA patients was studied for one year. During this time 10 (15%) had persistent lymphopenia (lymphocyte count less than 1.00 X 10(9)/l) without evidence of Felty's syndrome. A separate study of lymphocyte subsets in 13 lymphopenic RA patients showed marked reduction in T-cell numbers with normal circulating B-cell numbers. The numbers of CD4 and CD8 positive T-cells were equally depressed. Lymphopenia may indicate more severe disease. It was not influenced by changes in disease activity or therapy.

Arthritis, Rheumatoid↗
PubMed1988

T-cell functional defects in rheumatoid arthritis: intrinsic or extrinsic?

This study investigated two mechanisms which may underlie abnormal T-cell function [lymphocyte proliferation and interleukin-2 (IL-2) production] in rheumatoid arthritis (RA). These were: (a) a possible lack of the IL-2-producing CD4+2H4+ lymphocytes and (b) the possible inhibitory role of monocytes and neutrophils. Numbers of CD4+2H4+ cells did not differ between normal controls and patients with RA, although IL-2 produced by the peripheral blood mononuclear cells (PBMC) of the same individuals was markedly reduced in the patient group (P less than 0.001). Many rheumatoid peripheral blood mononuclear cell preparations, but very few control, were contaminated with neutrophils (P less than 0.001). This was more marked in patients with active RA than in those with inactive disease (P less than 0.001). Numbers of monocytes were similar in all groups. Monocyte depletion, or addition of indomethacin and/or catalase in PBMC, caused a significantly greater increase of responses in RA patients than in controls. This effect was significantly higher in patients with active disease than in the inactive group. These findings suggest that activated monocytes and neutrophils found in the rheumatoid PBMC preparations exert inhibitory effects mediated, in part, by the production of prostaglandins and reactive oxygen intermediates. Monocyte depletion and partial reconstitution resulted in significant increase of lymphocyte proliferation and IL-2 production in both controls and patients. None of the manipulations performed succeeded in normalizing the deficient rheumatoid T-cell responses. These data support the hypothesis that non-lymphoid cell populations play an important role in the T-cell dysfunction characteristic of RA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

The T cell system in rheumatoid arthritis: activated or defective?

Rheumatoid Arthritis (RA) is characterised by the presence of activated lymphocytes in the synovial compartment, which are classically considered to be of particular importance to the pathogenesis of the disease. We have shown that activated lymphocytes are also found in the rheumatoid lymph nodes and peripheral blood, and that their proportions are increased in early or active disease. Double-labelling experiments showed that T cell subsets within the activated circulating lymphocytes resemble closely those found in the synovium, and suggested an important role for circulating activated lymphoid populations in the pathogenesis of RA. In vitro studies indicate that although rheumatoid lymphocytes express activation markers, they are functionally deficient. This is well established in the case of synovial lymphocytes. We have demonstrated that functional defects are also present in circulating rheumatoid lymphocytes, which show a decreased autologous mixed leucocyte response (AMLR), corrected partially by the addition of exogenous IL-2. They also proliferate poorly in response to PHA and produce significantly less IL-2 than normal controls. This is more marked in patients with active or complicated RA. These defects cannot be explained by a lack of CD4+2H4+ cells which we have shown to be the major IL-2-producing circulating lymphocyte subpopulation. These findings suggest an intrinsic-functional rather than a numerical deficiency of the IL-2 producing T cells in RA. In recent experiments we have shown that non-lymphoid populations, such as activated phagocytic cells, are also involved in the deficient rheumatoid T cell function, partly via the production of prostaglandins and reactive oxygen intermediates. We and others have demonstrated that the latter may significantly and selectively affect lymphocyte viability and function. These findings may explain the differences in the functional capacity of lymphocytes frequently observed between cells derived from different sites or at different stages of the disease. We suggest that it is not lymphocyte activation as such, but its defective nature, that is of pathogenetical importance in RA. Furthermore, the T cell system should not be viewed and studied in isolation in this disease, but its interactions with inflammatory cells should be taken into account.

Antigens, Differentiation, T-Lymphocyte↗