Biomedical subjects

A Basten

Publications and source records attributed to A Basten.

At least 37 records · Page 2Linked to original sources

PubMed1997

Lymphomas in E mu-Pim1 transgenic mice exposed to pulsed 900 MHZ electromagnetic fields.

Whether radiofrequency (RF) fields are carcinogenic is controversial; epidemiological data have been inconclusive and animal tests limited. The aim of the present study was to determine whether long-term exposure to pulse-modulated RF fields similar to those used in digital mobile telecommunications would increase the incidence of lymphoma in E mu-Pim1 transgenic mice, which are moderately predisposed to develop lymphoma spontaneously. One hundred female E mu-Pim1 mice were sham-exposed and 101 were exposed for two 30-min periods per day for up to 18 months to plane-wave fields of 900 MHz with a pulse repetition frequency of 217 Hz and a pulse width of 0.6 ms. Incident power densities were 2.6-13 W/m2 and specific absorption rates were 0.008-4.2 W/kg, averaging 0.13-1.4 W/kg. Lymphoma risk was found to be significantly higher in the exposed mice than in the controls (OR = 2.4. P = 0.006, 95% CI = 1.3-4.5). Follicular lymphomas were the major contributor to the increased tumor incidence. Thus long-term intermittent exposure to RF fields can enhance the probability that mice carrying a lymphomagenic oncogene will develop lymphomas. We suggest that such genetically cancer-prone mice provide an experimental system for more detailed assessment of dose-response relationships for risk of cancer after RF-field exposure.

Animals↗

PubMed1996

The fate of self-reactive B cells depends primarily on the degree of antigen receptor engagement and availability of T cell help.

Self-reactive B cells from tolerant double-transgenic (Dbl-Tg) mice coexpressing hen egg lysozyme (HEL) and rearranged anti-HEL immunoglobulin genes have a relatively short life span when compared to normal B cells, irrespective of whether they are exposed to antigen in multivalent membrane-bound form (mHEL-Dbl-Tg mice) or soluble form (sHEL-Dbl-Tg mice). The factors responsible for determining the fate of these B cells after encounter with self-antigen were investigated using a cell-tracking technique in which anti-HEL Ig-Tg spleen cells were labeled with the intracellular dye 5-carboxyfluorescein diacetate-succinimidyl ester (CFSE) and injected either into non-Tg recipients or a variety of HEL-Tg hosts. In non-Tg recipients, HEL-binding B cells persisted in the circulation and could be detected in the follicles of the spleen for at least 5 d. On transfer into either mHEL-Tg or sHEL-Tg hosts, they underwent activation and then rapidly disappeared from the blood and spleen over the next 3 d, consistent with the short life span reported previously. Immunohistology of spleens from sHEL-Tg recipients indicated that the transferred B cells had migrated to the outer margins of the periarteriolar lymphoid sheath (PALS), where they were detectable for 24 h before being lost. The positioning of B cells in the outer PALS depended on a critical threshold of Ig receptor binding corresponding to a serum HEL concentration between 0.5 and 15 ng/ml, but was not restricted to endogenously expressed HEL in that the same migratory pattern was observed after transfer into non-Tg recipients given exogenous (foreign) HEL. Moreover, bone marrow-derived immature Ig-Tg B cells homed to the outer PALS of sHEL-Tg mice and then disappeared at the same rate as mature B cells, indicating that the stage of maturation did not influence the fate of self-reactive B cells in a tolerant environment. On the other hand, HEL-binding B cells transferred into sHEL-Dbl-Tg recipients persisted over the 3-d period of study, apparently due to insufficient availability of antigen, as indicated by the fact that the degree of Ig receptor downregulation on the transferred B cells was much less than in sHEL-Tg recipients. If T cell help was provided to Ig-Tg B cells at the time of transfer into sHEL-Tg recipients in the form of preactivated CD4+ T cells specific for major histocompatibility complex-peptide complexes on the B cell surface, HEL-binding B cells migrated through the outer PALS of the spleen to the follicle, where they formed germinal centers, or to adjacent red pulp, where they formed proliferative foci and secreted significant amounts of anti-HEL antibody. Taken together, these results indicated that the outcome of the interaction between self-antigen and B cells is largely determined by a combination of the degree of receptor engagement and availability of T cell help.

Amino Acid Sequence↗

PubMed1996

Mechanisms of tolerance to self.

Several mechanisms exist to prevent lymphocytes from reacting against self-antigens. As T cells develop in the thymus and express antigen-specific receptors, those with high-affinity to self-antigens existing within the thymus are deleted. Low-affinity self-reactive T cells and T cells with receptors against antigens not represented intrathymically will mature and join the peripheral T cell pool. They may either ignore self-antigens expressed by tissues unable to activate T cells through a lack of the appropriate costimulator signals, or they may, under certain conditions, be deleted or rendered anergic and unable to respond. Likewise, B cells that express surface Ig receptors with high binding affinity to membrane-bound self-antigens present in the bone marrow will be rescued by receptor editing or will be deleted, whereas those of lower affinity will migrate to the periphery in either an anergic or indifferent state depending on the degree of receptor engagement by antigen. Once there, their ultimate fate is determined by the availability of T cell help.

Animals↗

PubMed1996

Detection of malignant tumors using Tc-99m labeled Fab' fragments from a monoclonal antibody with specificity for D-dimer of cross-linked fibrin.

The authors present the case studies of two patients whose malignant tumors were detected with a Tc-99m labeled antifibrin monoclonal antibody (DD-3B6/22), which is specific for cross-linked fibrin. The first case was a malignant fibrous histiocytoma involving the proximal aspect of the left thigh, whereas in the second case, the patient was receiving treatment for a squamous cell carcinoma of the right mainstem bronchus. The results highlight the potential of this anti-D-dimer radiopharmaceutical for noninvasive detection of malignant tumors.

Aged↗

PubMed1995

DH element reading frame selection is influenced by an Ig heavy chain transgene, but not by bcl-2.

Mouse B cell precursors containing Ig DHJH junctions in one particular reading frame are selectively lost during B cell development. In this register, arbitrarily referred to as reading frame 2, DHJH junctions give rise to an open reading frame starting upstream of the DH element and including the DHJH-peptide fused to the constant region of IgM. Expression of this protein, called D mu, has been strongly implicated in the loss of B cell precursors containing reading frame 2 DHJH junctions. In an attempt to elucidate the means of D mu counterselection, we have examined the reading frame distribution of DHJH junctions in peripheral B cells from mice transgenic for either the human bcl-2 oncogene or for a functionally rearranged Ig mu heavy chain. In bcl-2 transgenic mice, reading frame 2 accounted for < 5% of the DHJH junctions in peripheral B cells, a value not significantly different from controls. Reading frames 1 and 3 were equally represented among the remaining junctions. By contrast, the reading frame distribution of endogenous DHJH junctions in splenic B cells from Ig mu heavy chain transgenic mice showed no evidence of bias against D mu encoding DHJH junctions. Reading frames 2 and 3 accounted for 27% and 30% of the sequenced DHJH junctions, respectively, and the remaining 43% were reading frame 1. Thus although the presence of BCL-2 cannot prevent the selective loss of reading frame 2 DHJH B cells, a functional mu heavy chain can. These results suggest that D mu-expressing B cell precursors may be selectively lost because of the premature and inappropriate cessation of heavy chain gene rearrangement rather than because of the induction of an apoptotic process which can be blocked by BCL-2.

Animals↗

PubMed1995

IgD expression on B cells is more efficient than IgM but both receptors are functionally equivalent in up-regulation CD80/CD86 co-stimulatory molecules.

The expression and function of IgM and IgD antigen receptors were studied in a series of anti-hen egg lysozymes (HEL) immunoglobulin (Ig)-transgenic mice expressing either IgM alone, IgD alone, or both IgM and IgD. B cell surface expression of IgD was found to be more efficient than that of IgM. Thus antigen receptor density on IgD+, IgM- B cells was twofold higher than on IgM+, IgD- B cells despite the presence of sevenfold lower levels of membrane heavy chain mRNA, and coexpression of IgD with IgM led to almost complete inhibition of surface IgM. In addition, less extensive down-regulation of IgD occurred following exposure to antigen in vitro. When regulation of CD80/CD86 co-stimulatory molecules by surface Ig was examined, up-regulation of the former was initiated at lower antigen concentrations on IgM-, IgD+ compared to IgM+, IgD- B cells. On correcting for antigen receptor density, however, induction of CD80/CD86 by IgM and IgD was comparable. Taken together, these results reinforced the functional similarity of IgM and IgD antigen receptors while at the same time revealing differences in expression which may explain their simultaneous presence on mature B cells.

Animals↗

PubMed1995

B cell activation, tolerance and antigen-presenting function.

Recent advances in the understanding of the collaboration between T cells and B cells have provided a novel framework within which to analyse the mechanisms of B-cell tolerance and its breakdown. Of particular interest has been the finding that B cell anergy is due to defective antigen receptor mediated functions, while the antigen-processing machinery and CD40-dependent activation pathways are unaffected. Thus, the anergic B cell, which otherwise has a short lifespan, can be rescued by a number of regimes to participate in autoimmune responses.

Animals↗

PubMed1995

T cell clones from a non-leprosy exposed subject recognize the Mycobacterium leprae 18-kD protein.

Although Mycobacterium leprae shares many protein antigens with other mycobacterial species, there is a degree of specificity in the T cell response to the organism. This is evident in the failure of cross-protection between mycobacterial species and the specific unresponsiveness to M. leprae in lepromatous leprosy patients. The antigenic basis of this specificity is unresolved, but the M. leprae 18-kD protein is one candidate because of its restricted distribution and the isolation of M. leprae-specific T cell clones reactive with the protein from M. leprae-vaccinated subjects. In the course of analysing the human T cell repertoire to mycobacteria we have isolated further CD4+ T cell clones reactive with this protein from a subject who had never been exposed to M. leprae. These clones did not respond to other mycobacteria, including M. tuberculosis and M. bovis (BCG). In addition, they were unreactive with the M. tuberculosis 16-kD protein which has recently been shown to have limited amino acid identity with the M. leprae 18-kD protein. Both clones reacted with peptide 38-50 from the M. leprae 18-kD protein, the T cell response to which is restricted by HLA-DR4. Although homologues for the gene encoding the M. leprae 18-kD antigen have been identified in M. avium and M. intracellulare, the clones failed to respond to preparations of M. avium. Both clones secreted interferon-gamma (IFN-gamma) and tumour necrosis factor-beta (TNF-beta) and were cytolytic against autologous targets pulsed with peptide 38-50 or the 18-kD protein. The nature of the antigen which stimulates this apparently 'M. leprae-specific' response is unknown. Nevertheless the recognition of the 18-kD protein by individuals not exposed to leprosy indicates that this protein may not be suitable as a reagent to distinguish between infection with M. leprae and other pathogenic mycobacteria.

Adult↗

PubMed1994

Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions.

B-cell tolerance to soluble protein self antigens such as hen egg lysozyme (HEL) is mediated by clonal anergy. Anergic B cells fail to mount antibody responses even in the presence of carrier-primed T cells, suggesting an inability to activate or respond to T helper cells. To investigate the nature of this defect, B cells from tolerant HEL/anti-HEL double-transgenic mice were incubated with a membrane preparation from activated T-cell clones expressing the CD40 ligand. These membranes, together with interleukin 4 and 5 deliver the downstream antigen-independent CD40-dependent B-cell-activating signals required for productive T-B collaboration. Anergic B cells responded to this stimulus by proliferating and secreting antibody at levels comparable to or better than control B cells. Furthermore, anergic B cells presented HEL acquired in vivo and could present the unrelated antigen, conalbumin, targeted for processing via surface IgD. In contrast, the low immunoglobulin receptor levels on anergic B cells were associated with reduced de novo presentation of HEL and a failure to upregulate costimulatory ligands for CD28. These defects in immunoglobulin-receptor-mediated functions could be overcome in vivo, suggesting a number of mechanisms for induction of autoantibody responses.

Animals↗

PubMed1994

Reduced life span of anergic self-reactive B cells in a double-transgenic model.

The life span of anergic self-reactive B cells was determined by 5-bromo-2'-deoxyuridine (BrdU) loading of tolerant double-transgenic (Dbl-Tg) mice produced by mating hen egg lysozyme (HEL)-transgenic mice with the corresponding immunoglobulin-transgenic (Ig-Tg) mice, the B cells of which express anti-HEL IgM and IgD. B cells from Dbl-Tg mice, despite being exposed to soluble antigen throughout their development, are not deleted, but persist in an anergic state. As a prelude to studying the life span of these anergic B cells, BrdU was administered to nontransgenic mice; B cells from the bone marrow, spleen, and lymph nodes displayed distinct kinetic profiles based on reciprocal expression of the B220 isoform of CD45 and heat-stable antigen (HSA). Thus, immature B220lo/HSAhi B cells incorporated BrdU rapidly suggesting recent generation from dividing precursors, whereas uptake by B cells expressing the mature B220hi/HSAlo phenotype was significantly slower, consistent with a longer life span. Such gating allowed analysis to be directed at the stable mature B cell population in transgenic mice. Comparison of BrdU uptake in Ig- and Dbl-Tg mice indicated that B cells from Dbl-Tg mice were renewed at a much higher rate (50% renewal times of 0.64 vs. 3.4 wk for total B cells, and 1.2 vs. 5.0 wk for mature B200hi/HSAlo cells from Dbl- and Ig-transgenic mice, respectively). This difference was even more marked when analysis in Dbl-Tg mice was restricted to HEL-binding cells, which had a 50% renewal time of 3-4 d compared with 4-5 wk for non-HEL-binding B cells. While the proportion of B cells in cell cycle, and the rate of entry of newly generated B cells into the spleen of Ig- and Dbl-Tg mice, were similar, B cell numbers were reduced in Dbl-Tg mice. It was therefore concluded that anergic B cells have a markedly decreased life span in the periphery. According to studies in radiation chimeras produced by reconstituting HEL-transgenic recipients expressing different serum levels of antigen with Ig-Tg bone marrow, the reduced life span of anergic B cells was associated with the anergic state per se, the serum concentration of HEL being important only in attaining the critical threshold necessary for tolerance induction. B cells rendered tolerant by exposure to soluble self-antigen therefore survive for a relatively short period in an anergic state once they have reached peripheral lymphoid tissue and fail to enter the long-lived compartment.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1994

Differential regulation of early and late stages of B lymphocyte development by the mu and delta membrane heavy chains of Ig.

Regulation of B lymphocyte development by the mu-membrane (mu m) and delta-membrane (delta m) heavy chains of Ig was examined in an Ig transgenic mouse model. Mice were bred on a common C57BL/6 (B6) background, and expressed rearranged and hypermutated heavy and light chain transgenes encoding high-affinity receptors for the foreign antigen hen egg lysozyme (HEL). At no stage were they exposed to HEL. Variation of the Ig heavy chain construct yielded four different types of Ig transgenic mice in which developing B lineage cells either expressed mu m and delta m in the normal physiological sequence (mu m then mu m + delta m), or produced mu m alone, delta m alone or mu m + delta m from the onset of heavy chain expression in the bone marrow. Immature B220low, HSAhigh and mature B220high, HSAlow B cells were produced in all mice regardless of their developmental pattern of mu m and delta m expression. However, production of immature B cells was most efficient when mu m heavy chain was expressed alone during early B cell development. Thus expression of delta m during this period either in the presence or absence of mu m resulted in a 2- to 3-fold reduction in the numbers of immature B cells in the spleen as well as altered levels of surface B220 and HSA on these cells in spleen and bone marrow respectively. By contrast, normal maturationally regulated expression of delta m led to the presence of increased numbers of mature B cells in the spleen and lengthened the average lifespan of these cells as determined by in vivo incorporation of 5-bromo-2'-deoxyuridine. These results pointed to selective effects of mu m and delta m heavy chains on regulation of the early and late stages of B cell development respectively, and provided a rational basis for co-expression of mu m and delta m as well as the delayed expression of delta m during normal B cell development.

Animals↗

PubMed1994

Individuals from different populations identify multiple and diverse T-cell determinants on mycobacterial HSP70.

The 70 kDa heat-shock protein (HSP) of Mycobacterium leprae stimulates both cellular and antibody responses in leprosy patients and subclinically infected individuals despite partial homology with host HSP70. Furthermore, mycobacterial HSP70 can act as a carrier protein in unprimed mice, suggesting the presence of widely shared T-cell determinants on this protein. In order to elucidate the frequency and genetic restriction of these T-cell epitopes, we have undertaken a systematic analysis of the proliferative responses to 20mer peptides encompassing the whole protein in different populations. Caucasian BCG vaccinees who responded to recombinant M. leprae HSP70 identified multiple scattered T-cell determinants, four of which were recognized by 60% of subjects in association with a variety of HLA-DR haplotypes. When a group of Nepali leprosy and tuberculosis patients were tested, significant differences in the pattern of peptide recognition were observed. The dominant peptides recognized by Caucasian subjects were infrequently reactive and other peptides were stimulatory, again in association with a variety of HLA-DR phenotypes. The C-terminal 70 residues of the M. leprae HSP70 are specific to M. leprae and sera from lepromatous leprosy patients bind to this region. However, few T-cell determinants were identified in these residues, indicating that this region is unhelpful as a diagnostic tool for detecting M. leprae-specific T-cell responses. When compared with the equivalent regions of the human HSP70, the commonly recognized peptides showed significant differences in amino-acid sequence. When taken in conjunction with the failure of human HSP70 to stimulate M. leprae HSP70-reactive T-cell clones (E. Adams et al., unpublished observations), this finding indicates that the human T-cell response to this protein is largely directed at mycobacterial-specific determinants. The presence of multiple T-cell epitopes on M. leprae HSP70 with varied patterns of HLA-DR association suggests that the whole protein is required for stimulating effective T-cell responses in genetically diverse populations.

Amino Acid Sequence↗

PubMed1994

Whither the anergic B-cell?

The kinetics of potentially autoreactive B-cells were investigated in a double-transgenic model of self-tolerance. Two types of transgenic mice were created for this purpose. In the first the great majority of B-cells expressed the rearranged heavy and light chain genes encoding a high affinity receptor for hen egg lysozyme (HEL), while the second type expressed HEL in either soluble (sHEL) or membrane-bound (mHEL) form. Double-transgenic (Dbl-Tg) mice were produced either by mating the two types of founders or by transferring bone marrow cells from Ig-transgenic (Ig-Tg) donors into irradiated HEL-Tg recipients. The lifespan of B-cells from the Dbl-Tg mice was measured by oral loading with the thymidine analogue, 5-bromo-2'-deoxyuridine (BrdU) for periods varying from three days to six weeks. Experiments in various combinations of Dbl-Tg mice revealed a three-tiered hierarchy of B-cell unresponsiveness, each level of which was characterised by a different B-cell lifespan. Exposure to mHEL led to rapid deletion of B-cells at an immature stage in their development with a median lifespan of approximately 15 hours. B-cells exposed to sHEL above a critical tolerogenic threshold were not deleted in the bone marrow but migrated to the spleen in an anergic state where they died within three days. If the receptor occupancy of sHEL was below the tolerogenic threshold, B-cells were neither deleted nor rendered anergic (ie were "indifferent") and had a normal median lifespan of four to five weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Hen egg-white lysozyme-specific T cells elicited in hen egg-white lysozyme-transgenic mice retain an imprint of self-tolerance.

The characteristics of T cell self-tolerance were examined in hen egg-white lysozyme (HEL)-transgenic (Tg) mice that were tolerant to a dose of HEL that was immunogenic in non-Tg littermates. HEL-specific T cells were identified in the periphery of the Tg mice after immunization with 100-times more HEL than was required to achieve a response in normal littermates. The Tg T cells were functional in vivo as they were capable of providing help to generate a HEL-specific antibody response. Selective deletion of T cells specific for the dominant T cell determinant of the native protein was not the primary mechanism of T cell tolerance in the HEL-Tg mice because, similar to non-Tg littermates, the majority of lymph node (LN) and T cell clones from HEL-Tg mice were specific for the dominant T cell determinant of HEL. Rather, our findings support the idea that the HEL-reactive T cells were anergic in vivo, but could be partially activated with a strong stimulus to the immune system (i.e., 20 nmol HEL and CFA). This conclusion is based on three observations: 1) proliferation in vitro to HEL by Tg LN T cells was subnormal (25% of control) and required 2 log more Ag to proliferate when compared with proliferation of LN from non-Tg littermates; 2) T cell clones isolated from HEL-Tg mice also proliferated poorly upon stimulation with HEL and Con A, although lymphokine production from the same stimuli was similar to that obtained from non-Tg clones; 3) invariably, upon repeated antigenic stimulation in vitro, the Tg T cell clones acquired full proliferative capacity to Ag and mitogens.

Animals↗

PubMed1993

Elimination of self-reactive B lymphocytes proceeds in two stages: arrested development and cell death.

In transgenic mice, self-reactive B lymphocytes are eliminated if they encounter membrane-bound self antigens during their development within the bone marrow. We show here that two separate and sequential events, arrested development and cell death, bring about B cell elimination. Developmental arrest is an early outcome of antigen binding in immature B cells, blocks acquisition of adhesion molecules and receptors important for B cell migration and activation, and is rapidly reversible by removal of antigen. Death of the arrested B cells occurs within 1 to 3 days and can be delayed by expression of a bcl-2 transgene, which results in escape of large numbers of self-reactive B cells from the bone marrow but fails to override the developmental arrest. These findings define a novel pathway for B cell elimination, involving an initial stage vulnerable to breakdown in autoimmune disease.

Animals↗

PubMed1993

Threshold detection of self-antigen/MHC class II complexes formed in vivo: constitutive presentation of an immunodominant epitope of hen egg lysozyme (HEL) in HEL-transgenic mice.

Hen egg lysozyme (HEL)-specific T hybridomas were used to study the presentation of HEL as a self component in tolerant, HEL-transgenic mice expressing different serum levels of HEL (AL3, 3-7 nM: ML5, 1-3 nM). Constitutive presentation of the HEL46-61 determinant was detectable in antigen presenting cell (APC)-enriched preparations of spleen, thymus, and lymph node from AL3 transgenic mice. The most likely cell responsible for constitutive presentation of HEL antigen was a non-B cell. In addition, constitutive presentation of HEL46-61 was clearly evident in thymic rosettes (complexes of macrophages or dendritic cells and lymphoid cells) derived from AL3 HEL-transgenic mice, but not from ML5 HEL-transgenic mice. In contrast to the HEL46-61 determinant, constitutive presentation of the HEL25-43 and HEL112-129 determinants was not detectable on APC-enriched preparations from either of the HEL-transgenic lines tested. Thus, although T cell tolerance was evident in transgenic mice expressing a range of serum HEL concentrations, constitutive presentation of processed HEL antigen was not detectable on APCs from mice expressing less than 3-7 nM. This threshold of detectable antigen presentation is consistent with the notion that the concentration of nominal antigen needed for tolerizing T cells is less than that required for activation of mature T cells.

Animals↗

PubMed1993

Identification of human T cell epitopes in the Mycobacterium leprae heat shock protein 70-kD antigen.

In a number of pathogens, heat shock proteins (hsp) stimulate humoral and cellular immune responses despite significant sequence identity with host hsp. The 70-kD hsp of Mycobacterium leprae, which shares 47% identity with human hsp70 at the protein level, elicited a T cell response in most Myco. bovis (bacille Calmette-Guérin (BCG)) vaccinees as well as leprosy and tuberculosis patients and their contacts. In order to locate T cell epitopes, DNA fragments encoding portions of the 70-kD hsp were expressed in the vector pGEX-2T and tested for T cell reactivity in an in vitro proliferative assay. Cultures of peripheral blood mononuclear cells (PBMC) from BCG vaccinees indicated that the C-terminal half of the molecule contained multiple T cell epitopes, as the T cells from a majority of Myco. leprae hsp70-reactive individuals responded to C-344. Lower proportions of patients with paucibacillary leprosy (36%) and tuberculosis patients (16%) responded to C-344. The smaller C-142 fragment which includes the terminal 70 residues unique to Myco. leprae and is the target for the human antibody response elicited a cellular response in few patients and no vaccinees. In order to map T cell epitopes, two series of synthetic peptides encompassing the region 278-502 were prepared. Using overlapping 12mer and 20mer peptides, this region of the molecule was found to contain several potential T cell epitopes. The longer peptides gave a clearer indication of reactive sequences including regions of the molecule which were not identified with the 12mer peptides. Fine mapping of reactive peptide pools using the 12mer peptides identified two T cell epitopes. Although both were located in regions of the molecule shared with Myco. tuberculosis, one appeared to be cross-reactive with the equivalent human sequence, and thus has the potential to initiate autoimmune responses.

Amino Acid Sequence↗

PubMed1992

Immunoglobulin M and D antigen receptors are both capable of mediating B lymphocyte activation, deletion, or anergy after interaction with specific antigen.

A series of immunoglobulin (Ig)-transgenic mice were generated to study the functional capabilities of the IgM and IgD classes of B lymphocyte antigen receptor in regulating both cellular development and responses to specific antigen. B cells from Ig-transgenic mice expressing either hen-egg lysozyme (HEL)-specific IgM or IgD alone were compared with B cells from mice that coexpressed IgM and IgD of the same anti-HEL specificity. In all three types of Ig-transgenic mice, conventional B cells specific for HEL exhibited exclusion of endogenous Ig expression and matured to populate the usual microenvironments in peripheral lymphoid tissues. These peripheral B cells could be stimulated by HEL through either IgM or IgD antigen receptors to generate T cell dependent antibody production in vivo or to enhance T cell independent proliferative responses to lipopolysaccharide in vitro. Conversely, when HEL was encountered in vivo as a self-antigen, B cells expressing HEL-specific IgM or IgD alone were both rendered tolerant. In each case this occurred by clonal anergy in response to soluble autologous HEL, and clonal deletion when HEL was recognized as a membrane-bound self-antigen. Taken together, these findings indicate that IgM and IgD antigen receptors expressed alone on conventional B cells can support normal differentiation, antigen-dependent activation, and induction of self-tolerance, the only overt difference lying in a greater degree of receptor downregulation for IgM relative to IgD after induction of clonal anergy by soluble HEL.

Animals↗