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Biomedical subjects

B Heyman

Publications and source records attributed to B Heyman.

At least 19 recordsLinked to original sources
PubMed2006

Antibody-mediated regulation of the immune response.

Antibodies administered in vivo together with the antigen they are specific for can regulate the immune response to that antigen. This phenomenon is called antibody-mediated feedback regulation and has been known for over 100 years. Both passively administered and actively produced antibodies exert immunoregulatory functions. Feedback regulation can be either positive or negative, resulting in >1000-fold enhancement or >99% suppression of the specific antibody response. Usually, the response to the entire antigen is up- or downregulated, regardless of which epitope the regulating antibody recognizes. IgG of all isotypes can suppress responses to large particulate antigens like erythrocytes, a phenomenon used clinically in Rhesus prophylaxis. IgG suppression works in mice lacking the known Fc-gamma receptors (FcgammaR) and a likely mechanism of action is epitope masking. IgG1, IgG2a and IgG2b administered together with soluble protein antigens will enhance antibody and CD4+ T-cell responses via activating FcgammaR, probably via increased antigen presentation by dendritic cells. IgG3 as well as IgM also enhance antibody responses but their effects are dependent on their ability to activate complement. A possible mechanism is increased B-cell activation caused by immune complexes co-crosslinking the B-cell receptor with the complement-receptor 2/CD19 receptor complex, known to lower the threshold for B-cell activation. IgE-antibodies enhance antibody and CD4+ T-cell responses to small soluble proteins. This effect is entirely dependent on the low-affinity receptor for IgE, CD23, the mechanism probably being increased antigen presentation by CD23+ B cells.

Animals↗
PubMed2005

IgG3-mediated enhancement of the antibody response is normal in Fc gammaRI-deficient mice.

Antibodies, administered together with their specific antigen, can feedback-regulate antibody responses to this antigen. IgG1, IgG2a and IgG2b enhance antibody responses to soluble protein antigens. This effect is primarily mediated by FcRs as enhancement is impaired in FcR gamma-/- mice, reported to lack Fc gammaRI and Fc gammaRIII because of deletion of the common FcR gamma chain. Also IgG3 can enhance antibody responses. However, this effect is unperturbed in FcR gamma-/- mice but severely impaired in complement-depleted animals and in animals lacking complement receptor 1 and 2. Although this argues against involvement of Fc gammaRs, FcR gamma-/- mice may express one-fifth of the normal levels of Fc gammaRI and, in addition, Fc gammaRI has been suggested to bind IgG3. We re-investigated the dependence of IgG3-mediated enhancement on Fc gammaRs using a mouse strain selectively lacking Fc gammaRI and found that IgG3-mediated enhancement is completely normal. Unlike IgE and IgG2a, which are both thought to enhance T-cell proliferation via FcR-mediated antigen presentation, IgG3 was a poor enhancer of T-cell proliferation both in vivo and in vitro. These findings argue against a significant involvement of Fc gammaRs in IgG3-mediated enhancement of antibody responses and support our previous conclusion that complement plays a major role.

Adoptive Transfer↗
PubMed2003

Patients' views on follow up of colorectal cancer: implications for risk communication and decision making.

BACKGROUND: Medical views about the clinical value and potential detrimental effect on quality of life of postoperative follow up are divided. There is no literature on the views of British patients with colorectal cancer towards the follow up process. AIM: To investigate patients' views and experiences of follow up of colorectal cancer, and to assess their attitudes towards suggested changes to follow up policy. PATIENTS AND METHODS: A total of 156 asymptomatic and disease-free patients with colorectal cancer were identified from the follow up clinic. Recurrence-free status was confirmed through retrieval of computerised clinic letters. A postal survey using a 39 item piloted questionnaire was undertaken. Data analysis generated descriptive statistics and logistic regression models. RESULTS: A response rate of 61% (95) was obtained. Among these respondents, 63% (60) had undergone initial surgery within three years of the time of the survey, and 86% (82) patients expected a further follow up appointment. Majorities of the sample, ranging from 71% (67) to 96% (91), expressed satisfaction with respect to clinic delays, staff conduct and knowledge about their case, consultation time, and being able to discuss personal problems freely. However some patients reported difficulty in discussing sexual problems at the clinic. Appointment imminence caused anxiety, sleep problems, and decreased appetite in 35% (35), 27% (26), and 8 % (8) of patients respectively. However, 78% (74) patients felt reassured and optimistic for the future after receiving results. Such optimism is not necessarily justified in terms of estimated mortality risks. A majority (78%, 66) stated that they would value finding out about the presence of recurrence even if there would be no survival benefit. Nearly half of the sample (48%, 43) felt that they would disagree with the cessation of follow up in any circumstances. Only 47% (42) and 27% (24) indicated that they would accept follow up by a specialist nurse or their general practitioner, respectively. Attitude to follow up was unrelated to reported anxiety before appointments. Only 22% (19) of the sample could identify risk indicators for recurrence, but 64% (61) agreed that they would like to be told what to look for. DISCUSSION: A sample of patients with colorectal cancer expressed a high degree of satisfaction with hospital follow up. Although a substantial minority reported suffering from pre-visit anxiety, most felt that this disadvantage was compensated for by reassuring results, and believed that investigations did not have a significant negative impact on their quality of life. Respondents valued hospital follow up, and half would reject complete discharge or alternative forms of follow up. These findings demonstrate that patients have a different perception of the risk of recurrence than clinicians who would consider the survival prospects for most patients to be more or less unaffected by follow up interventions. Attempted modifications to follow up policies should be introduced with caution, and should take account of patient understanding of medical reasoning. The findings also raise questions about risk communication with patients.

Attitude to Health↗
PubMed2001

FcgammaRIIB in IgG-mediated suppression of antibody responses: different impact in vivo and in vitro.

The suppressive effect of IgG on Ab responses to particulate Ags such as erythrocytes is well documented. IgG-mediated suppression is used clinically in rhesus prophylaxis to prevent RhD-negative mothers from becoming immunized against their Rh D-positive fetuses. We have recently shown that IgG anti-SRBC, passively administered together with SRBC, can induce efficient suppression of primary Ab responses to SRBC in mice lacking the known FcRs for IgG (FcgammaRI, FcgammaIII, and FcgammaRIIB or the neonatal FcR). The lack of a demonstrable effect of the inhibitory FcgammaRIIB was particularly surprising, and, in this study, the involvement of this receptor is further investigated during broader experimental conditions. The data show that SRBC-specific IgG administered up to 5 days after SRBC can induce suppression both in wild-type and FcgammaRIIB-deficient mice. Suppression of secondary Ab responses to SRBC in vivo was similar in the two strains. In contrast, IgG-mediated suppression of Ab responses in vitro was impaired in cultures with primed FcgammaRIIB-deficient spleen cells. In conclusion, inhibition of in vivo Ab responses to SRBC by passively administered IgG can take place via an FcgammaRIIB-independent pathway. This pathway causes >99% suppression and operates during all experimental conditions studied so far. The nature of the mechanism can at present only be hypothesized. Masking of epitopes and/or rapid elimination of IgG-Ag complexes would both be compatible with the observations.

Adoptive Transfer↗
PubMed2001

IgE-mediated suppression of primary antibody responses in vivo.

The ability of immunoglobulin (Ig)G to feedback suppress antibody (Ab) responses is a well known property clinically used to prevent haemolytic disease of newborns. We recently found that IgG was able to suppress the primary Ab response to sheep red blood cells (SRBC) in mice lacking the known Fc-receptors for IgG. In addition, IgE and F(ab')2 fragments of IgG were able to suppress the response to SRBC in wild-type mice. These results suggested that the IgG-mediated suppression can take place independently of the IgG (Fc) portion and that masking of the epitopes is an important mechanism. In the present report we investigated whether the suppression caused by IgE is Fc-dependent. Monoclonal IgE anti-2,4,6-trinitrophenyl (TNP), administered with TNP-coupled SRBC (SRBC-TNP), can induce an efficient suppression in mice lacking FcgammaRI + RIII + FcepsilonRI (owing to the lack of the common gamma chain, FcRgamma), FcgammaRIIB or FcepsilonRII (CD23). Because the known IgE-binding receptors are FcepsilonRI, CD23, FcgammaRIIB and FcgammaRIII, the results suggest that also the IgE-mediated suppression can take place independently of the Fc-receptors. A slightly less efficient suppression in CD23-deficient animals, suggests a minor involvement of this receptor.

Animals↗
PubMed2001

IgG2a-mediated enhancement of antibody responses is dependent on FcRgamma+ bone marrow-derived cells.

Antibodies (Ab) administered in complex with antigens (Ag) have the capacity to regulate the out-coming specific immune response. Primary immunization with complexes of bovine serum albumin-2,4,6-trinitrophenyl (BSA-TNP) and immunoglobulin (Ig)G2a anti-TNP induced a significant enhancement of IgG1 and IgG2a BSA-specific Ab response compared to immunization with the Ag alone. Enhancement was absent in nude mice, demonstrating the requirement of T cells for this regulation. Secondary immunization with BSA alone in mice previously primed with BSA-TNP/IgG2a led to a dramatic increase of Ab production, showing that immune complexes are efficient inducers of immunological memory. IgG-mediated enhancement of Ab responses has previously been shown to be impaired in mice lacking FcgammaRI, FcgammaRIII and FcepsilonRI owing to gene targeting of the common FcRgamma subunit (FcRgamma-/-). Here we show that enhancement after immunization with BSA-TNP/IgG2a complexes is restored in irradiated FcRgamma-/- recipients transferred with wild-type (FcRgamma+/+) bone marrow (BM) cells. In contrast, no enhancement is seen in FcRgamma+/+ irradiated animals reconstituted with FcRgamma-/- BM cells. We conclude that IgG2a-mediated enhancement of Ab responses is dependent on the presence of FcgammaRI and/or FcgammaRIII on BM-derived cells and that the presence of these receptors on the radioresistant follicular dendritic cell is not essential.

Animals↗
PubMed2000

Antibody production in mice deficient for complement receptors 1 and 2 can be induced by IgG/Ag and IgE/Ag, but not IgM/Ag complexes.

Deficiencies in C factors C2, C3, or C4 as well as lack of C receptors 1 and 2 (CR1/2) lead to impaired Ab production. Classical pathway activation plays a major role, as mice deficient in factor B, a key factor in the alternative pathway, have normal Ab production. Abs in complex with their specific Ag are known to feedback regulate the Ab response, and enhanced responses are initiated by IgM, IgE, and IgG. IgM acts via the C system, whereas IgE and IgG can operate independently of C via Fc receptors. Here we have investigated whether these isotypes are able to enhance Ab responses in mice lacking CR1/2. SRBC-specific IgM, administered with SRBC, does not enhance Ab responses in these animals. In contrast, 2,4, 6-trinitrophenyl-specific IgE and IgG2a, administered with BSA-2,4, 6-trinitrophenyl, induce potent Ab responses in CR1/2-deficient mice. Additionally, BSA administered with CFA or alum induced strong Ab responses in the absence of CR1/2. These results indicate that CR1/2 is needed to promote IgM-mediated induction of primary Ab responses. The data also show that the need for CR1/2 can be circumvented by Abs typical of a secondary immune response forming complexes with Ag or by conventional adjuvants, presumably mimicking physiological inflammatory reactions.

Adjuvants, Immunologic↗
PubMed2000

Induction and suppression of collagen-induced arthritis is dependent on distinct fcgamma receptors.

Receptors for immunoglobulin (Ig)G (FcgammaRs) are important for the antibody-mediated effector functions of the immune system. FcgammaRI and FcgammaRIII trigger cell activation through a common gamma chain, whereas FcgammaRII acts as a negative regulator of antibody production and immune complex-triggered activation. Here we describe the in vivo consequences of FcgammaR deficiency in a mouse model of human rheumatoid arthritis. FcRgamma chain-deficient mice on arthritis-susceptible DBA/1 background were immunized with collagen for induction of collagen-induced arthritis. The DBA/1 mice lacking FcRgamma chain were protected from collagen-induced arthritis in contrast to wild-type mice, although both groups produced similar levels of IgG anticollagen antibodies. In comparison, DBA/1 mice lacking FcgammaRII developed an augmented IgG anticollagen response and arthritis. These observations suggest a crucial role of FcgammaRI and FcgammaRIII in triggering autoimmune arthritis.

Animals↗
PubMed2000

Restoration of the antibody response to IgE/antigen complexes in CD23-deficient mice by CD23+ spleen or bone marrow cells.

Mice immunized with IgE/Ag complexes produce significantly more Ag-specific Abs than mice immunized with Ag alone. The enhancement is mediated via the low-affinity receptor for IgE (FcepsilonRII or CD23), as shown by its complete absence in mice pretreated with mAbs specific for CD23 and in CD23-deficient mice. Because the constitutive expression of murine CD23 is limited to B cells and follicular dendritic cells (FDCs), one of these cell types is likely to be involved. One of the suggested modes of action of IgE/CD23 is to increase the ability of B cells to present Ag to T cells, as demonstrated to take place in vitro. Another possibility is that FDCs capture the IgE/Ag complexes and present these directly to B cells. The purpose of the present study was to determine whether CD23+ B cells or FDCs are responsible for the IgE/CD23-mediated enhancement of specific Ab responses in vivo. We show that the enhancement is completely restored in irradiated CD23-deficient mice reconstituted with CD23+ spleen or bone marrow cells. In these mice, the B cells are CD23+ and the FDCs are presumably CD23- because the FDCs are radiation resistant and are reported not to be replaced by donor cells after this type of cell transfer. In contrast, enhancement was not restored in irradiated wild-type mice reconstituted with CD23- cells. These results indicate that CD23+ B cells, and not FDCs, are the cells that capture IgE/Ag complexes and induce enhancement of Ab responses in vivo.

Adjuvants, Immunologic↗
PubMed2000

How women receiving adjuvant chemotherapy for breast cancer cope with their treatment: a risk management perspective.

Retrospective interviews were undertaken with 12 women who had received an 18-week course of adjuvant chemotherapy for positive node breast cancer 1 year previously, and who had not experienced cancer recurrence. The nonstandardized interviews covered women's preconceptions about adjuvant chemotherapy, their information needs, and the impact of treatment. The qualitative data analysis drew upon the theoretical ideas of patient career, trajectory projection and qualitative risk analysis. Some women regarded adjuvant chemotherapy as no more than an 'insurance policy'. This perception may have arisen because doctors, attempting to minimize patient anxiety, did not discuss the high risk of disease recurrence which they faced. Other women equated adjuvant with curative chemotherapy, and anticipated hair loss or almost certain death. The women tried to cope with the physical and mental suffering associated with adjuvant chemotherapy through normalizing strategies, such as keeping a brave face, maintaining previous patterns of life, looking for humour and restructuring time. However, the rapid alterations in physical and mental state resulting from cycles of adjuvant chemotherapy resulted in a 'rollercoaster' experience for women which made normalization more difficult. Health professionals caring for women who must cope with uncertain future trajectories need to manage a risk communication dilemma. A strategy of fully informing women about the risks they face may cause anxiety or depression, and even impede recovery, given the evidence for psychological influences on health outcomes. But, if women do not understand the medical thinking on which their treatment is based, their misconceptions may be equally damaging.

Adaptation, Psychological↗
PubMed2000

Immune complex-mediated enhancement of antibody responses without induction of delayed-type hypersensitivity.

Immunoglobulin (Ig)G and IgE antibodies enhance the humoral response in vivo to soluble antigens with which they form complexes. In vitro, antigen is targeted to B cells by IgE antibodies and to macrophages and dendritic cells (DCs) by IgG, thus leading to increased antigen presentation to specific T cells. Possibly these mechanisms are also responsible for antibody-mediated enhancement in vivo. We now address the question of whether IgG- and/or IgE-antigen complexes can prime for delayed-type hypersensitivity (DTH), a reaction known to require primed T helper (Th)1 cells. Mice were immunized with IgG-anti-2,4,6-trinitrophenyl (TNP)/BSA-TNP or IgE-anti-TNP/BSA-TNP. Mice given BSA-TNP alone or BSA-TNP in complete Freund's adjuvans (CFA) were used as controls. DTH and IgG-anti-BSA levels were measured after subsequent challenge with BSA. A potent BSA-specific antibody response was induced by IgE- or IgG-complexed antigen as well as by CFA/antigen but DTH-reactions were only observed in mice immunized with CFA/antigen. Both IgE and IgG enhanced the production of BSA-specific IgG1, IgG2a and IgG2b, although the most pronounced enhancement was seen in the production of IgG1. These findings suggest that Th2 cells rather than Th1 cells are involved in the immune response to IgG- and IgE-immune complexes.

Adjuvants, Immunologic↗
PubMed2000

Immunoglobulin-secreting cells of maternal origin can be detected in B cell-deficient mice.

It is well known that the transfer of immunoglobulins (Igs) from mother to young via milk contributes to the offspring's immune defense. The present study suggests that not only is IgG transmitted to progeny, but that functional maternal Ig-secreting cells (or B cells) can also be transferred to the neonate. We have used B cell-deficient (micro(-/-)) mice and found that a high proportion of them obtain long-lasting, partial reconstitution of their serum Ig levels if born to micro(+/-) mothers. In some of these serum IgG-positive micro(-/-) mice, Ig-secreting cells were detected in spleen and bone marrow. To ensure that cells of maternal origin were present in the progeny, micro(-/-) offspring born to micro(+/-) dams transgenic for green fluorescent protein (GFP) were used. In spleens and bone marrow from some of these micro(-/-)GFP(-/-) offspring, GFP-positive cells were detected, which demonstrated that cells of maternal origin could infiltrate the progeny. In addition, splenic Ig-secreting cells were detected in micro(-/-) mice that were born to micro(-/-) dams and transferred to a lactating micro(+/+) foster dam at birth. This indicates that maternal Ig-secreting cells can be transferred postnatally via milk.

Adoptive Transfer↗
PubMed2000

Regulation of antibody responses via antibodies, complement, and Fc receptors.

Antibodies can completely suppress or enhance the antibody response to their specific antigen by several hundredfold. Immunoglobulin M (IgM) enhances antibody responses via the complement system, and complement activation by IgM probably starts the chain of events leading to antibody responses to suboptimal antigen doses. IgG can enhance primary antibody responses in the absence of the complement system and seems to be dependent on Fc receptors for IgG (FcgammaRs). IgE enhances antibody responses via the low-affinity receptor for IgE (FcepsilonRII/CD23). The precise effector mechanisms that cause enhancement are not known, but direct B-cell signaling, antigen presentation, and increased follicular localization are all possibilities. IgG, IgE, and IgM may also suppress antibody responses when used in certain immunization regimes, and it seems reasonable that an important mechanism behind suppression is the masking of antigenic epitopes by antibodies. In addition, FcgammaRIIB, which contains a cytoplasmic inhibitory motif, acts as a negative regulator of antibody responses. This receptor, however, may prevent the antibody responses from exceeding a certain level rather than causing complete suppression.

Animals↗
PubMed1999

IgG-mediated enhancement of antibody responses is low in Fc receptor gamma chain-deficient mice and increased in Fc gamma RII-deficient mice.

Immunization with IgG/Ag or IgE/Ag complexes leads to a higher production of specific Abs than immunization with Ag alone. The enhancing effect of IgE is exclusively dependent upon the low-affinity receptor for IgE, Fc epsilon RII, whereas the mechanism behind IgG-mediated enhancement is unknown. We have investigated whether receptors for the Fc part of IgG are required for responses to IgG/Ag. Mice lacking the gamma subunit of Fc receptors (FcRs) (FcR gamma-/-), Fc gamma RII (Fc gamma RII-/-), or Fc gamma RIII (Fc gamma RIII-/-) were immunized with BSA-2,4,6-trinitrophenyl (TNP) alone or BSA-TNP complexed to monoclonal TNP-specific IgG1, IgG2a, or IgG2b. As expected, all subclasses enhanced the Ab-response to BSA in wild-type mice. Enhancement was in the same order of magnitude in Fc gamma RIII-/- mice (</=177-fold of controls administered Ag alone), whereas it was abrogated in FcR gamma-/- mice and augmented in Fc gamma RII-/- mice (</=5147-fold of controls). The response to IgE/Ag complexes in FcR gamma-/- and Fc gamma RII-/- mice was similar to that se for wild-type mice, demonstrating that non-Fc gamma R-dependent responses were normal. Our observations suggest that IgG/Ag complexes enhance Ab responses via Fc gamma Rs. Moreover, they reveal a strong negative regulation of Ab responses to IgG/Ag exerted by Fc gamma RII.

Adjuvants, Immunologic↗
PubMed1999

Antibody feedback suppression: towards a unifying concept?

IgG antibodies can negatively regulate antibody responses. When IgG anti-sheep erythrocytes (SRBC) is administered to an animal together with SRBC, the response against SRBC will frequently be less than 1% of the response in animals immunized with SRBC alone. The mechanism behind this phenomenon is not fully understood. It has been suggested that suppression is caused by masking of epitopes by IgG, thus preventing B cells from recognizing the antigen. Other possible explanations are that IgG/antigen complexes are eliminated via Fc-receptor dependent phagocytosis or that the complexes inhibit B cell activation by co-crosslinking the B cell receptor for antigen and the inhibitory Fc-receptor, FcgammaRIIB, expressed by B cells. Whereas the first mechanism would operate independently of the Fc-portion of IgG, the two latter would be Fc-dependent. In the literature data has been presented supporting both Fc-dependence and Fc-independence of suppression. It has recently been shown that IgG suppresses more than 90% of the antibody response in gene targeted mice lacking the known Fc-receptors for IgG and that F(ab')2 fragments as well as IgE are efficient suppressors. These findings strongly suggest that IgG is able to efficiently suppress antibody responses independently of the Fc-part and favor the model of epitope masking. Here, a way of interpreting available experimental data which can explain many of the discrepancies in the literature, is presented.

Animals↗