Search PubMed⌕ Search

Biomedical subjects

C J Elson

Publications and source records attributed to C J Elson.

At least 37 records · Page 2Linked to original sources
PubMed1999

Splenic but not thymic autoreactive T cells from New Zealand Black mice respond to a dominant erythrocyte Band 3 peptide.

Previous work from our laboratory suggested that erythrocyte Band 3 peptide 861-874 is the dominant epitope recognized by splenic T cells from adult New Zealand Black (NZB) mice that are developing autoimmune haemolytic anaemia (AIHA). Here, it is shown that splenic T cells from 6-week-old NZB mice mount a vigorous in vitro proliferative response to peptide 861-874 and some other selected Band 3 peptides. As the donors grow older, splenic T cells respond to an increasing number of Band 3 peptides and the magnitude of their response also becomes greater. Splenic T cells from 3-week-old NZB mice still responded vigorously to peptide 861-874 and Band 3. By contrast, neither thymocytes nor single-positive CD4-enriched thymus cells from NZB mice responded to peptide 861-874 or Band 3, although they responded to concanavalin A (Con A). However, thymocytes from mice expressing a transgenic T-cell receptor (TCR)-specific for myelin basic protein (MBP) peptide Ac 1-9 responded vigorously to Ac 1-9. It is considered that the T-cell response of NZB mice to Band 3 is initially focused on peptide 861-874 and later spreads to other Band 3 peptides as the disease progresses and that peptide 861-874-reactive T cells are primed in the periphery rather than the thymus.

Aging↗
PubMed1999

Ability of T cells from patients with rheumatoid arthritis to respond to immunoglobulin G.

The ability of T cells from rheumatoid factor (RF)-positive patients with rheumatoid arthritis (RA) to respond to immunoglobulin G (IgG) was assessed. Peripheral blood mononuclear cells (PBMC) from RA patients and normal individuals were cultured with and without human IgG or Mycobacterium tuberculosis-purified protein derivative (PPD) for 7 days and their proliferative response measured at intervals by their ability to take up tritiated thymidine. PBMC from 14/26 RA patients proliferated in response to IgG (taking a stimulation index of 3 or above as positive). The peak response varied between individuals but usually occurred on day 5, the same day, or 1 day later than the peak response to PPD. By contrast, PBMC from a significantly lower proportion (1/9) of normal individuals and patients with other arthritides (0/6) responded to IgG, although all responded to PPD. PBMC from 9/14 RA patients responded to Fab fragments of IgG but only 3/9 to the Fc fragment. Higher proliferative responses from RA PBMC were elicited by IgG aggregates than the original IgG preparation, but PMBC from 5/5 normal individuals and 5/6 patients with other arthritides failed to respond to the aggregates. The response to IgG was human leucocyte antigen (HLA)-DR restricted and mediated by CD4+ T cells. It is considered that these results advance the hypothesis that IgG-reactive T cells contribute to the initiation or perpetuation of RA.

Adult↗
PubMed1999

Serial changes in the galactosylation of autoantibodies and serum IgG in autoimmune haemolytic anaemia.

A number of systemic autoimmune diseases are associated with increased levels of the agalactosyl (G0) IgG isoforms that lack a terminal galactose from the C(H)2 domain oligosaccharide. The aims were to determine whether there are also persistently high levels of G0 autoantibodies or serum IgG in autoimmune haemolytic anaemia (AIHA), and whether any changes in galactosylation over time are related to the course of disease. Autoantibodies eluted from red blood cells, and serum IgG, were obtained from a patient with chronic AIHA over a 21 month period, and the degree of galactosylation measured using a lectin-binding assay. There were wide fluctuations in the galactosylation of autoantibody and serum IgG, but these changes were unrelated to the severity of the anaemia. The galactosylation of autoantibody and serum IgG varied independently, and the autoantibodies were preferentially G0 in comparison with serum IgG in only half of the serial samples. We conclude that AIHA differs from other, systemic autoimmune conditions in that high levels of G0 autoantibodies or serum IgG are not persistent, and that changes in galactosylation do not parallel the course of disease.

Anemia, Hemolytic, Autoimmune↗
PubMed1998

An immunodominant epitope from mycobacterial 65-kDa heat shock protein protects against pristane-induced arthritis.

Previous studies showed that mice with pristane-induced arthritis (PIA) and those protected from the disease by preimmunization with mycobacterial 65-kDa heat shock protein (hsp65) possess raised immune responses to hsp65. Additionally, T cells from hsp65-protected mice, but not from pristane-injected or normal mice, produced the Th2-associated cytokines IL-4, IL-5, and IL-10 in response to stimulation with hsp65. Here we demonstrate that the specificity of the immune response to hsp65 and related heat shock protein (hsps) differs between protected and PIA mice. T cells from hsp65-protected mice respond to the bacterial hsps tested but not to the mammalian homologue, hsp58. Similarly, they exhibit high serum titers of anti-hsp65 Abs, yet they have virtually undetectable levels of anti-hsp58 IgG. By contrast, both cellular and humoral immune responses are detectable to bacterial and mammalian hsps in mice with PIA. An immunodominant T cell epitope has been identified in hsp65-protected mice corresponding to amino acids 261-271 from hsp65. Immunization of mice, either before or after the induction of arthritis, with this bacterial peptide, but not its mammalian homologue, protects mice from the development of PIA, and protection is associated with the production of Th2-type cytokines. Other experiments revealed that T cells primed with bacterial 261-271 or the mammalian homologue do not cross-react at the proliferative or cytokine level. These results demonstrate that an hsp65 peptide-specific Th2 response confers protection from PIA but do not support the idea that protection is mediated by a cross-reaction with self hsp58 in the joints.

Animals↗
PubMed1998

Effect of T-helper cytokine environment on specificity of T-cell responses to mycobacterial 65,000 MW heat-shock protein.

The purpose of this work was to determine if the fine specificity of T cells differed between mice immunized with an antigen in a T helper 1 (Th1) cytokine-dominated environment as compared with a T helper 2 (Th2) cytokine-dominated environment. It was found that splenic T cells from mice immunized with mycobacterial heat-shock protein (hsp 65) and interleukin-12 (IL-12) produced less interleukin-4 (IL-4) and more interferon-gamma (IFN-gamma) in response to stimulation with hsp 65 in vitro than did T cells from mice immunized with hsp 65 alone. The T-cell proliferative response to hsp 65 did not differ between the two groups of mice, although the responses were higher than those of T cells from non-immunized mice. Strikingly, T cells from mice given hsp 65 and IL-12 gave significantly higher responses to six peptides (corresponding to the sequence of hsp 65) to which T cells from mice immunized with hsp 65 alone did not respond. It is considered that different epitopes are presented to T cells (possibly owing to changes in antigen processing) if the environment is shifted, by IL-12, from Th2 towards Th1 cytokines.

Animals↗
PubMed1998

Osteoarthritic synovial fluid and synovium supernatants up-regulate tumor necrosis factor receptors on human articular chondrocytes.

OBJECTIVE: To determine whether the up-regulation of chondrocyte tumor necrosis factor receptor (TNF-R) expression in osteoarthritis (OA) is due to molecules released within the OA knee joint. DESIGN: Non-arthritic (NA) human articular chondrocytes were incubated with normal serum, OA synovial fluid, or supernatants from either cultured NA or OA synovium, and TNF-R expression measured by flow cytometry. RESULTS: OA synovial fluid, but not normal serum, significantly up-regulated the proportion of chondrocytes expressing p55 TNF-R as well as the number of p55 TNF-R/chondrocyte. Similarly, supernatants from OA, but not NA, synovia significantly up-regulated chondrocyte p55 TNF-R expression. Chondrocyte p75 TNF-R expression was also significantly increased by some of the OA supernatants but not others, and overall no significant increase was seen. OA synovium supernatants contained higher concentrations of interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) than NA synovium supernatants and neutralizing antibodies to these cytokines either partially or totally abrogated the ability of the OA supernatants to increase chondrocyte p55 TNF-R expression. Finally, various concentrations of recombinant human (rh)IL-1 beta and rhIL-6 up-regulated chondrocyte p55 TNF-R expression. CONCLUSION: These results suggest that IL-1 and IL-6 produced by OA synovium contribute to the progression of the disease by rendering chondrocytes more susceptible to stimulation by catabolic cytokines.

Aged↗
PubMed1998

Changes in the galactose content of IgG during humoral immune responses.

The Fc region of IgG bears two oligosaccharides of variable composition. The serum level of one variant which lacks terminal galactose and sialic acid (agalactosyl IgG) is raised in a number of autoimmune diseases and animal models thereof. Here it is shown that such changes in IgG glycosylation occur during non-pathological humoral immune responses. It was found that if specific pathogen free (SPF) CBA/Ca mice are transferred from a sterile to a conventional environment, their levels of total serum IgG rise whereas the degree of IgG galactosylation falls. Next, mice were immunised with bovine serum albumin (BSA) in incomplete Freund's adjuvant. As anti-BSA titres rose the antibodies became less galactosylated and later, as the titres fell, the antibodies became more galactosylated. By contrast, there was little or no variation in the relative galactosylation of total IgG. It is considered that the galactosylation of IgG antibodies varies during an immune response.

Animals↗
PubMed1998

Lymphocytic choriomeningitis virus-induced alterations of T helper-mediated responses in mice developing autoimmune hemolytic anemia during the course of infection.

The effect of LCMV on CD4+ T lymphocytes was analyzed in C3HeB/FeJ mice after infection with the Docile strain of this virus. Our results indicated that LCMV triggers: i) an inhibition of Th2 lymphocyte differentiation induced by concomitant immunization with a nonviral protein antigen; ii) a depression of T helper-dependent antibody responses elicited by such an immunization; and iii) a CD4+ cell-mediated proliferation of spleen cells leading to increased interleukin-4 and interferon-gamma message expression and IgG2a-restricted total immunoglobulin secretion. Taken together, these results indicate that LCMV profoundly affects CD4+ cell-mediated immune responses in infected animals. Such modulations of T-helper functions may explain the preponderance of IgG2a in the antierythrocyte autoimmune response induced by the virus in C3HeB/FeJ mice.

Anemia, Hemolytic↗
PubMed1997

CD4+ Th2 cells specific for mycobacterial 65-kilodalton heat shock protein protect against pristane-induced arthritis.

Previous studies showed that mice with pristane-induced arthritis (PIA) and those protected from the disease by preimmunization with mycobacterial 65-kDa heat shock protein (hsp65), possess raised immune responses to hsp65. Thus, a paradox exists whereby T cells from both arthritic and hsp65-protected animals proliferate vigorously in response to the same Ag. Here we demonstrate that T cells from mice with PIA and hsp65-protected mice produce different cytokines in vitro in response to hsp65. The use of a sensitive CelELISA to measure Ag-driven lymphokine production revealed that spleen cells from hsp65-protected mice, but not those from pristane-injected or normal mice, produced the Th2-associated cytokines IL-4, IL-5, and IL-10 in response to stimulation with hsp65. By contrast, the Th1-associated cytokines IL-2 and IFN-gamma were produced by spleen cells from mice of all groups in response to hsp65. Furthermore, there was a dramatic increase in the IgG1 to IgG2a ratio of anti-hsp65 Abs from arthritic to protected mice. Thus, it appears that a Th2 response is protective against PIA. To examine this theory, a regimen of IL-12 administration which polarizes the hsp65-specific (Th2) immune response toward Th1 was identified. This regime abolished hsp65-mediated protection against PIA. Other experiments revealed that the specificity of the response to hsp65 was important, as other bacterial proteins known not to protect against PIA induced similar Th2-associated cytokines in vitro. It is considered that the protection afforded by hsp65 preimmunization is mediated by Th2-associated cytokines produced by hsp65-specific CD4+ T cells.

Animals↗
PubMed1997

Identification of T-cell epitopes on the Rhesus polypeptides in autoimmune hemolytic anemia.

We have shown previously that the Rhesus (Rh) polypeptides are the commonest targets for pathogenic anti-red blood cell (RBC) autoantibodies in patients with autoimmune hemolytic anemia (AIHA). The aim of the current work was to determine whether activated T cells from such patients also mount recall responses to epitopes on these proteins. Two panels of overlapping 15-mer peptides, corresponding to the sequences of the 30-kD Rh proteins associated with expression of the D and Cc/Ee blood group antigens, were synthesized and screened for the ability to stimulate the in vitro proliferation of mononuclear cells from the peripheral blood or spleen of nine AIHA cases. Culture conditions were chosen that favor recall proliferation by previously activated T cells, rather than primary responses. In seven of the patients, including all four cases with autoantibody to the Rh proteins, two or more peptides elicited proliferation, but cells from eight of nine patients with other anemias and seven of nine healthy donors failed to respond to the panels. Multiple peptides were also stimulatory in two positive control donors who had been alloimmunized with Rh D-positive RBCs. Six different profiles of peptides elicited responses in the AIHA patients, and this variation may reflect the different HLA types in the group. Stimulatory peptides were identified throughout domains shared between, or specific to, each of the related 30-kD Rh proteins, but T cells that responded to nonconserved regions did not cross-react with the alternative sequences. Anti-major histocompatibility complex class II antibodies blocked the responses and depletion experiments confirmed that the proliferating mononuclear cells were T cells. Notably, splenic T cells that proliferated against multiple Rh peptides also responded to intact RBCs. We propose that pathogenic autoantibody production in many cases of AIHA is driven by the activation of T-helper cells specific for previously cryptic epitopes on the Rh proteins.

Adult↗
PubMed1997

Alteration of cartilage metabolism by cells from osteoarthritic bone.

OBJECTIVE: To determine whether bone cells alter cartilage metabolism. METHODS: Bone cell cultures were established using explants obtained from the hip and knee joints of 9 patients with osteoarthritis (OA) and 6 subjects without arthritis (nonarthritic [NA]). NA human cartilage biopsy samples were incubated in the presence or absence of bone-derived cells, and the effects on glycosaminoglycan (GAG) release from cartilage were measured. RESULTS: Bone cell cultures secreted osteocalcin (OC) and did not contain cells expressing leukocyte common antigen. None of the 8 cultures established from NA bone, compared with 17 of 32 from OA bone, significantly altered GAG release from cartilage (P = 0.006). In knees with medial joint damage, 38% of the cultures derived from the medial side of the joint increased GAG release from cartilage. In contrast, 77% of the cultures derived from the lateral side of the joint had an effect on GAG, with 38% increasing and 38% decreasing GAG release. Seven cytokines were measured in OA bone cell supernatants. No significant difference was apparent in the concentration of any one cytokine when supernatants were compared according to their effects on GAG release. CONCLUSION: Bone cells from OA patients can influence cartilage metabolism. This might explain why increased subchondral bone activity can predict cartilage loss.

Aged↗
PubMed1997

Properties of tissue from around cemented joint implants with erosive and/or linear osteolysis.

Levels of bone remodeling agents were measured in conditioned media from cultures of periprosthetic pseudosynovial membranes and related to the radiographic features of the failed joint implants. Radiographs of both cemented hip (n = 28) and cemented knee (n = 11) implants were examined and the pattern of radiolucency was classified as erosive linear, or mixed. Similar levels of interleukin-1-beta (IL-1 beta), interleukin-6, tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta-1, and prostaglandin E2 (PGE2) were found in pseudosynovial membrane conditioned media from all 3 groups of hips and the knee group (all linear). Significant correlations were evident only between PGE2 and TNF-alpha levels in the linear hip group and PGE2 and IL-1 beta levels in the knee group. A close correlation was found between IL-1 beta and TNF-alpha in both linear and erosive hips. It is suggested that coregulation of these bone remodeling agents differs with the radiographic appearance of the failed joint implants. As all the implants were cemented and the results contrast with those of others obtained with pseudosynovial membrane conditioned media from cementless implants, it is considered that cement critically influences the process of implant failure.

Adult↗
PubMed1997

Bone-membrane interface in aseptic loosening of total joint arthroplasties.

In 19 patients who underwent revision arthroplasty for aseptic loosening of total joint arthroplasty, specimens were taken at the time of operation to include the bone-membrane interface. In 16 (84%) of the specimens, sufficient visualization of the interface was possible to allow histologic interpretation. In 13 of these cases, there was prominent evidence of classic bone remodeling with osteoclast-mediated resorption and active new bone formation. These results suggest that the osteolysis in aseptic loosening is mediated through osteoclastic bone resorption and that the bone found in such areas is extremely active. The findings help to explain the efficacy of impacted morselized bone-graft in the treatment of bone lysis in aseptic loosening.

Aged↗
PubMed1997

Chondrocyte tumor necrosis factor receptors and focal loss of cartilage in osteoarthritis.

OBJECTIVE: Osteoarthritis (OA) is characterized by focal loss of cartilage. Here we show for the first time that tumor necrosis factor (TNF) alpha can act on cartilage but only at specific sites where chondrocyte TNF alpha-receptor (R) expression is high. DESIGN: Cartilage explants from specified sites in the knee joints of both OA patients and non-arthritic (NA) subjects were cultured with and without TNF alpha for 14 days and cumulative glycosaminoglycan (GAG) release into the supernatant measured. p55 and p75 TNF-R expression was measured by flow cytometry on chondrocytes isolated from the same sites. RESULTS: Cartilage explants from different sites in knee joints from both OA patients and NA subjects varied in their susceptibility to TNF alpha. Overall, the proportion of samples that responded to TNF alpha was higher in cartilage taken from OA joints than cartilage from NA subjects. Variations in p55 and p75 TNF-R expression were found between chondrocytes from different sites. p55, but not p75 TNF-R, expression on chondrocytes was closely related to the susceptibility of explants from the same site to TNF alpha-induced GAG loss. CONCLUSION: It is considered that focal loss of cartilage will occur at sites where chondrocyte p55 TNF-R expression is high, if sufficient TNF alpha is present, and that these results identify a mechanism by which cytokine-mediated focal loss of cartilage may occur.

Adult↗
PubMed1997

Pristane-induced arthritis is CD4+ T-cell dependent.

The development of arthritis induced in mice by intraperitoneal injection of the non-antigenic mineral oil pristane (2,6,10,14-tetramethylpentadecane) was shown to depend on the presence of CD4+ T cells. Initial experiments assessed the influx of lymphoid cells into the peritoneal cavity of CBA/Igb mice after pristane injection. Both CD4+ and CD8+ cell numbers were maximal around 50 days. Other experiments confirmed our original observation that irradiated pristane-treated mice failed to develop arthritis unless they were reconstituted with spleen cells from normal donors. This finding has been extended by showing that the population of transferred splenic lymphoid cells must contain CD4+ T cells, while CD8+ T cells and B cells were not required for reconstitution. Conventionally housed and hsp 65-immunized animals are known to harbour T cells reactive with hsp 65. In addition, hsp 65-immunized mice are resistant to the development of pristane-induced arthritis (PIA). Thus, additional experiments assessed the population of splenic T cells activated and proliferating against mycobacterial 65,000 MW heat shock protein (hsp 65). In cultures of purified splenic T cells derived from both conventional and hsp 65-immunized mice, removal of CD4+ T cells significantly reduced the proliferative response to hsp 65, while removal of CD8+ T cells often enhanced the response. These proliferative responses were also shown to be major histocompatibility complex (MHC) class II restricted. The present findings demonstrate that PIA is CD4+ T-cell mediated, and immunodominant environmental antigens such as hsp 65 activate this population of lymphocytes. The CD4+ hsp 65-reactive population may be pathogenic or protective in PIA, depending upon the route of sensitization.

Animals↗
PubMed1997

Infection of C3HeB/FeJ mice with the docile strain of lymphocytic choriomeningitis virus induces autoantibodies specific for erythrocyte Band 3.

C3HeB/FeJ mice infected with the docile strain of lymphocytic choriomeningitis virus (LCMV-d) develop a persistent infection with a transient haemolytic anaemia. Immunoglobulin can be eluted from the red blood cells (RBC) of these mice but it cannot be detected on the RBC by a conventional antiglobulin test. The present study demonstrates that RBC from such mice bear erythrocyte autoantibodies which are predominantly of the IgG2a subclass, with lower levels of autoantibodies of the IgG1, IgG2b and IgG3 subclasses. To identify the target antigen the autoantibodies were eluted from the RBC of LCMV-infected mice. The eluted autoantibody bound to intact normal RBC and precipitated a 105000 MW component that corresponds to murine Band 3 protein. A monoclonal antibody derived from mice infected with LCMV-d also precipitated mouse Band 3, and reacted specifically by enzyme-linked immunosorbent assay against a purified preparation of Band 3. This study has shown that in C3H mice infected with LCMV-d which develop autoimmune haemolytic anaemia, the target autoantigen is erythrocyte membrane Band 3.

Anemia, Hemolytic, Autoimmune↗