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Biomedical subjects

B Heyman

Publications and source records attributed to B Heyman.

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

Importance of CD23 for collagen-induced arthritis: delayed onset and reduced severity in CD23-deficient mice.

Increased expression of the low affinity receptor for IgE, FcepsilonRII/CD23 has been observed in rheumatoid arthritis. In view of this, we have investigated the expression and influence of CD23 in collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. CD23+ cells were analyzed in lymph nodes of DBA/1 mice immunized with bovine collagen type II (BCII) in CFA or with CFA only. The percentage of CD23+ lymph node cells was increased in both BCII/CFA- and CFA-immunized mice at 1, 3, and 7 wk after immunization compared with unimmunized mice, indicating a role for the adjuvant to trigger general inflammation and CD23 expression. To investigate the functional role of CD23 in CIA, CD23-deficient mice on the DBA/1 genetic background were studied. After immunization with BCII/CFA, these mice developed CIA with delayed onset and reduced severity compared with wild-type mice. These findings suggest that an increased number of CD23+ cells is part of an inflammatory response and that CD23 expression is of pathogenic importance in the arthritic process.

Animals↗
PubMed1999

Efficient IgG-mediated suppression of primary antibody responses in Fcgamma receptor-deficient mice.

IgG antibodies can suppress more than 99% of the antibody response against the antigen to which they bind. This is used clinically to prevent rhesus-negative (Rh-) women from becoming immunized against Rh+ erythrocytes from their fetuses. The suppressive mechanism is poorly understood, but it has been proposed that IgG/erythrocyte complexes bind to the inhibitory Fc receptor for IgG (FcgammaRIIB) on the B cell surface, thereby triggering negative signals that turn off the B cell. We show that IgG induces the same degree of suppression of the response to sheep erythrocytes in animals lacking the known IgG-binding receptors FcgammaRIIB, FcgammaRI + III, FcgammaRI + IIB + III, and FcRn (the neonatal Fc receptor) as in wild-type animals. Reinvestigation of the ability of F(ab')2 fragments to suppress antibody responses demonstrated that they were nearly as efficient as intact IgG. In addition, monoclonal IgE also was shown to be suppressive. These findings suggest that IgG inhibits antibody responses through Fc-independent mechanisms, most likely by masking of antigenic epitopes, thereby preventing B cells from binding and responding to antigen. In agreement with this, we show that T cell priming is not abolished by passively administered IgG. The results have implications for the understanding of in vivo regulation of antibody responses and Rh prophylaxis.

Adoptive Transfer↗
PubMed1999

Low responsiveness to immunization with immunoglobulin E/antigen and immunoglobulin G/antigen complexes in H-2Ab mice.

Immunoglobulin (Ig)E and IgG antibodies specific for 2,4, 6-trinitrophenyl (TNP) are able to enhance the carrier-specific antibody response to TNP-conjugated soluble proteins such as bovine serum albumin (BSA). We have recently reported that mice carrying the MHC class II Ab molecule are low responders to immunization with IgE/antigen complexes and now show that H-2Ab mice are also low responders to IgG/antigen complexes. In addition, we found that spleen cells from naive low- and high-responder mice captured IgE/antigen complexes exclusively on B cells, and that the binding was completely inhibited by monoclonal antibodies (MoAbs) against the low-affinity receptor for IgE (FcepsilonRII or CD23). The IgG/antigen complexes were targeted both to B cells and macrophages. The binding of IgG/antigen to B cells primarily seemed to be dependent on the low-affinity receptor for IgG (FcgammaRII or CD32), although some influence of complement receptor 2 (CR2 or CD21) was seen. Capture of IgG/antigen complexes on macrophages was partially blocked by MoAbs against FcgammaRII/III. There was no difference in expression of FcepsilonRII, FcgammaRII/III, CR1, CR2, and CR3 between low- and high-responder strains, thus excluding low levels of these FcRs and CRs as a reason for low responsiveness in H-2Ab mice.

Animals↗
PubMed1999

Interaction with complement receptor 1 (CD35) leads to amelioration of sepsis-triggered mortality but aggravation of arthritis during Staphylococcus aureus infection.

The aim of this study was to assess the importance of complement receptor 1 (CR1, CD35) in Staphylococcus aureus arthritis and sepsis. The murine model of haematogenously acquired septic arthritis was used, injecting toxic shock syndrome toxin 1 (TSST-1)-producing S. aureus LS-1 intravenously. CR1 was blocked using immunoglobulin G (IgG) rat antimouse CR1 monoclonal antibody (MoAb) (8C12). Evaluation of arthritis was performed clinically and histopathologically. In addition, the effect of blocking CR1 was assessed on the phagocytic activity of leucocytes and on T-cell dependent and independent inflammation. Seven days after inoculation with bacteria, 96% of CR1 MoAb-treated mice had clinical symptoms of arthritis compared with 58% of the control animals (P < 0.01). The severity of arthritis, expressed as mean arthritic index, was 2.9 +/- 0.5 and 1.4 +/- 0.5, respectively (P = 0.004). Fifteen days after bacterial inoculation, all CR1 MoAb-treated mice had severe arthritis (mean arthritic index 6.3 +/- 0.6), while only 77% of controls were affected (mean arthritic index 2.9 +/- 0.6; P = 0.002). The potential explanation of these findings is that treatment with CR1 MoAb significantly increases the polymorphonuclear cell-dependent inflammatory response as a result of enhanced vasodilatation in treated animals. We conclude that treatment with CR1 MoAb leads to amelioration of sepsis-induced mortality during S. aureus infection, possibly as a result of the increased phagocytic activity of peripheral phagocytes.

Animals↗
PubMed1998

Impaired antibody responses in H-2Ab mice.

In murine in vivo systems, Ags administered in physiologic solutions together with specific IgE induce a significantly higher Ab response than Ags administered alone. In vitro, IgE in complex with Ag enhances B cell-mediated presentation of the Ag to T cells. Both phenomena require an intact low affinity receptor for IgE (Fc epsilon RII/CD23), suggesting that the effect on in vivo Ab responses is caused by increased Ag presentation. We here show that mice carrying the MHC class II Ab molecule (e.g., C57BL/6 and 129/Sv) do not produce Abs to BSA when immunized with BSA-2,4,6-trinitrophenyl (TNP) in complex with monoclonal IgE anti-TNP. In contrast, strains of all other MHC haplotypes tested (H-2d, H-2k, H-2p, H-2q, and H-2s) respond vigorously to IgE/BSA-TNP complexes, with Ab responses several hundred-fold higher than the responses in H-2b mice. C57BL/6 mice were unable to produce a carrier-specific response also after immunization with IgE/OVA-TNP, IgE/diphtheria toxoid-TNP, or IgE/tetanus toxoid-TNP. Although the low responsiveness mapped to the Ab region, responsiveness was not restored in C57BL/6 mice carrying transgenic Ak, suggesting that a nonclassical A-region-encoded gene product is involved. Most importantly, our data call attention to the fact that the C57BL/6 and 129 mouse strains, which are widely used for producing transgenic animals, have defective immune responses.

Animals↗
PubMed1998

Probabilities and health risks: a qualitative approach.

Health risks, defined in terms of the probability that an individual will suffer a particular type of adverse health event within a given time period, can be understood as referencing either natural entities or complex patterns of belief which incorporate the observer's values and knowledge, the position adopted in the present paper. The subjectivity inherent in judgements about adversity and time frames can be easily recognised, but social scientists have tended to accept uncritically the objectivity of probability. Most commonly in health risk analysis, the term probability refers to rates established by induction, and so requires the definition of a numerator and denominator. Depending upon their specification, many probabilities may be reasonably postulated for the same event, and individuals may change their risks by deciding to seek or avoid information. These apparent absurdities can be understood if probability is conceptualised as the projection of expectation onto the external world. Probabilities based on induction from observed frequencies provide glimpses of the future at the price of acceptance of the simplifying heuristic that statistics derived from aggregate groups can be validly attributed to individuals within them. The paper illustrates four implications of this conceptualisation of probability with qualitative data from a variety of sources, particularly a study of genetic counselling for pregnant women in a U.K. hospital. Firstly, the official selection of a specific probability heuristic reflects organisational constraints and values as well as predictive optimisation. Secondly, professionals and service users must work to maintain the facticity of an established heuristic in the face of alternatives. Thirdly, individuals, both lay and professional, manage probabilistic information in ways which support their strategic objectives. Fourthly, predictively sub-optimum schema, for example the idea of AIDS as a gay plague, may be selected because they match prevailing social value systems.

Attitude of Health Personnel↗
PubMed1997

Early expansion of secondary B cells after primary immunization with antigen complexed with IgE.

IgE antibodies have potent immunoregulatory effects in vivo, and mice immunized with IgE-antigen (IgE/ Ag) complexes exhibit a several hundred-fold higher humoral Ag-specific response than mice immunized with non-complexed Ag. In vitro studies indicate that this is a result of efficient endocytosis of the IgE/Ag complexes via the low-affinity receptor for IgE (CD23) on B cells, leading to efficient antigen presentation to T cells. Previous studies of IgE-induced Ab responses in vivo have only measured serum responses. The authors have now studied the up-regulated response as the number of IgG-, IgA-, IgE- and IgM-secreting single B cells in spleen, lymph nodes and bone marrow of mice immunized with IgE-anti-TNF+BSA-TNP (2,4,6-trinitrophenylated bovine serum albumin). IgE and Ag induced a greater than 500-fold increase of specific IgG-secreting spleen cells with the peak of the response 6 days after primary immunization. The response of other Ab isotypes and the response in other lymphoid organs was marginal. The rapid increase in the number of IgG-secreting cells in the spleen suggests that IgE/Ag complexes induce a secondary type of antibody response without requirement for conventional priming.

Age Factors↗
PubMed1995

Antibodies to murine complement receptor 1 and 2 can inhibit the antibody response in vivo without inhibiting T helper cell induction.

Administration to mice of mAb against CR1/CR2 inhibits the primary and secondary in vivo Ab response. We have addressed the question of whether induction of T helper cells, in addition to B cells, is inhibited by this treatment. A hapten-carrier system was used, where one group of mice was immunized with a monoclonal CR1/CR2-specific Ab and Ag (SRBC or keyhole limpet hemocyanin (KLH)), another with Ag alone, and a third group left nonimmunized. After 2 to 15 wk, spleen cells from these mice were transferred to irradiated syngeneic recipients, together with Ag coupled to the hapten 4-hydroxy-5-iodo-3-nitro-phenacetyl (NIP). The number of NIP-specific, IgG-producing B cells, which in this system is an indication of T cell priming, was determined in an ELISPOT assay. Although the primary SRBC- or KLH-specific IgG response was inhibited markedly (74-98%) by CR1/CR2-specific Ab, no decrease in the number of NIP-specific IgG-producing B cells was detected after secondary immunization. In sharp contrast, the SRBC- or KLH-specific secondary IgG responses were low or undetectable. These findings suggest that CR1/CR2-specific Ab can inhibit the primary Ab response without affecting T helper cells and that the induction of B cell memory is decreased markedly by this treatment.

Animals↗
PubMed1995

No role of interleukin-4 in CD23/IgE-mediated enhancement of the murine antibody response in vivo.

Antigen-specific IgE up-regulates the specific IgM, IgG1, IgG2a and IgE response in vivo when given to mice together with antigen. The enhancement is mediated by the low-affinity receptor for IgE, Fc epsilon RII or CD23, as demonstrated both in CD23-deficient mice and by blocking CD23 with anti-CD23 monoclonal antibodies. A possible mechanism behind the regulatory effects of CD23 is that the IgE/CD23/antigen complex is endocytosed by B cells, leading to increased antigen processing and presentation on major histocompatibility complex (MHC) class II molecules to T helper cells. In the present study we have found that the expression of CD23 is reduced fivefold on splenic B cells in mice genetically deficient for IL-4. When IL-4-deficient mice and normal littermates were immunized with 2,4,6-trinitrophenyl (TNP)-specific IgE followed by bovine serum albumin (BSA)-TNP or with BSA-TNP alone, the BSA-specific IgG1 and IgG2a responses were equally well augmented by IgE in all mice. In addition, a low but significant IgE response was seen even in the IL-4-deficient mice. Thus, enhancement of the antibody response through IgE and CD23 occur in the absence of IL-4 and is not dependent on CD23 up-regulation.

Animals↗
PubMed1994

CD23/IgE-mediated regulation of the specific antibody response in vivo.

We have recently reported that IgE Abs specific for TNP are able to enhance the specific IgG response in mice via the low affinity receptor for IgE, Fc epsilon RII, or CD23. In this study we show that IgE can up-regulate IgM, IgG1, IgG2a, and the IgE response, thereby indicating the possibility of a viscious circle in the maintenance of an allergic response. One of the suggested modes of action of IgE/CD23 is to increase the ability of B cells to present Ag to T cells. The involvement of T cells in IgE-mediated enhancement of the Ab response was studied in several ways: nude mice were resistant to the effect of IgE and a dramatic effect on the induction of immunologic memory was seen, both by in situ secondary immunizations and in adoptive transfer systems. Basic conditions for the ability of IgE to induce enhancement were established, demonstrating critical importance of factors such as type of Ag and temporal relationship between administration of IgE and Ag. Finally, no evidence for the requirement for CD23 for a normal (non-IgE induced) Ab response was found, although modulation of the receptor completely abrogated the IgE-induced Ab response.

Animals↗
PubMed1994

Local anti-type II collagen antibody production in rheumatoid arthritis synovial fluid. Evidence for an HLA-DR4-restricted IgG response.

OBJECTIVE: To investigate the production of type II collagen (CII) antibodies in the synovial fluid (SF) of rheumatoid arthritis (RA) patients, and to examine the HLA dependence of this local production. METHODS: The ELISPOT method was used for enumerating anti-CII-reactive cells. Serologic tissue typing was performed. RESULTS: Anti-CII-reactive cells were found in the SF of 16 of 31 patients, but not in any of the peripheral blood samples obtained in parallel. SF anti-CII antibody production showed no correlation with clinical parameters, but its frequency increased significantly with age. The IgG anti-CII response occurred exclusively in patients who were positive for HLA-DR4 and was significantly associated with DR4. CONCLUSION: Anti-CII production may be important in local immune complex formation. The indirect demonstration of a DR4-restricted T cell response to CII is an indication of a pathogenetic role of collagen autoimmunity in RA.

Adult↗
PubMed1993

In vivo enhancement of the specific antibody response via the low-affinity receptor for IgE.

The ability of antigen-specific IgE antibodies to modulate the in vivo antibody response was studied by comparing the antibody response in mice immunized with 2,4,6-trinitrophenyl (TNP)-specific monoclonal IgE followed by bovine serum albumin (BSA)-TNP or with BSA-TNP alone. The serum IgG antibody response against BSA, measured in enzyme-linked immunosorbent assay ELISA, was enhanced up to 100-fold in groups receiving IgE. The enhancement required specific interaction between IgE and antigen, since no effect was seen when unconjugated BSA was used as antigen. Polyclonal activation by IgE/antigen complexes did not occur. IgE given 24 h after specific antigen had no stimulatory capacity. Pretreatment of the mice with Fc epsilon receptor type II (Fc epsilon RII)-specific monoclonal antibody completely inhibited the IgE-mediated enhancement. Thus, the data demonstrate for the first time an in vivo role for Fc epsilon RII in enhancement of specific antibody production.

Animals↗
PubMed1993

Antibody feedback regulation in MRL/lpr mice.

MRL/Mp-lpr/lpr (MRL/l) mice spontaneously develop autoimmune disease, characterized by glomerulonephritis, polyarteritis and polyarthritis. The lpr mice have defects in the Fas antigen, which plays a role in apoptosis, and it has been suggested that lack of negative selection of autoreactive T cells explains the initiation of the disease. The extremely high amount of autoantibodies may reflect additional immunoregulatory abnormalities. Antibody feedback regulation is an efficient way of up- or downregulating antibody responses. We have for the first time determined whether IgG-mediated suppression as well as IgM-mediated enhancement operates normally in these mice. MRL/l and MRL/Mp(-)+/+ (MRL/n) mice of different ages were therefore immunized with sheep erythrocyte (SRBC)-specific IgG or IgM antibodies followed by SRBC. Control groups received antigen alone. Five days later, the antigen-specific plaque-forming cell response was measured. IgG induced more than 90% suppression in both MRL/l and MRL/n in mice of all ages tested. This degree of suppression is in the same range as for other, normal mouse strains. In contrast, IgM-mediated enhancement was completely absent in 12-week-old MRL/l mice but normal in 8-week-old MRL/l as well as in MRL/n mice of all ages tested. When spleens and lymph nodes were immunohistochemically studied using a mAb specific for complement receptors 1 and 2 (CR1/CR2), an abnormal follicular structure was demonstrated in 12-week-old MRL/l mice. The antibody response of both 8- and 13-week-old MRL/l mice in vivo, after downregulation of these receptors, was inhibited by 85-96%. Thus, the presented data demonstrate that MRL/l mice with overt autoimmune disease are refractory to IgM-mediated enhancement of antigen-specific antibody production. We believe that this abnormal antibody feedback regulation is due to abnormal follicular structure in lymphoid organs of old MRL/l mice, hence the inability to localize and present antigen in a normal way.

Animals↗
PubMed1993

Not worth the risk? Attitudes of adults with learning difficulties, and their informal and formal carers to the hazards of everyday life.

Twenty adults with learning difficulties (adults) living at home with informal carers, mostly parents, and attending Adult Training Centres (ATCs) were interviewed about their everyday lives and information was also obtained from informal and formal carers. The problem of dealing with the hazards of everyday life emerged as an important theme. The thinking of adults and informal carers could be understood in terms of the moral dimension of hazards, through the distinction between risks, to be calculated, and dangers, to be avoided. Adults and informal carers within families largely agreed in their categorization of hazards but differences were found. In families where the head of the household had had a professional or skilled manual occupation, adults and informal carers were most likely to agree that hazards for the adult were dangers to be avoided. In families which had a history of unemployment or unskilled occupations, adults and informal carers were most likely to treat certain hazards as risks to be taken. The latter families were also less likely to have 2 informal carers. Adults from more risk-tolerant families appeared to be achieving more of their potential in everyday living skills. Formal carers at ATCs were more accepting of risks for adults with learning difficulties than informal carers and there was misunderstanding and conflict between formal and informal carers as a result.

Activities of Daily Living↗
PubMed1992

Unexpected interaction of some anti-TNP hybridoma antibodies with Superose HPLC gel filtration resins.

Five different hybridoma antibodies (the isotypes IgG1, IgG2a and IgG2b), reactive with TNP, showed increased elution times when gel filtered on a Superose-12 HPLC column corresponding to apparent molecular weights ranging from 54 kDa to 120 kDa compared to the normal of 150 kDa. One of the antibodies (C1901-B4) was studied in detail showing that the unusual gel filtration behaviour was localized to the Fab part of the molecule. SDS-PAGE analysis showed that the intact antibodies had normal molecular weights. Gel filtration on a Toyosoda G-3000SW HPLC column and Sephadex G-150 as well as Sepharose 6B generally showed normal elution times. These results support the hypothesis that the retardation on the Superose gel is probably due to aromatic interactions between amino acid residues supposedly exposed in the hypervariable region (i.e., the antibody combining site) of the antibody, and the gel matrix which is rich in ether O-atoms created during the manufacturing process. If this hypothesis is correct one might expect such interactions between Superose resins and antibodies of many different specificities in which aromatic amino acids are exposed in the combining sites.

Chromatography, Gel↗