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Biomedical subjects

F D Finkelman

Publications and source records attributed to F D Finkelman.

At least 217 records · Page 12Linked to original sources
PubMed1984

Role of surface immunoglobulin in B lymphocyte activation.

Studies of polyclonal and antigen-specific activation of B lymphocytes were compared to generate a model that addresses the roles of ligand-surface (s) IgD and ligand-sIgM interactions as well as the roles of antigen-specific, T cell-mediated help and nonspecific helper lymphokines in the activation of mature, resting B lymphocytes. The major features of the model are 1) cross-linking of sIg renders B cells more receptive to T cell help; 2) DNA synthesis in activated B cells can be induced by weak sIg cross-linking signals in the presence of antigen-specific T cell help or by stronger sIg cross-linking signals in the absence of help; 3) sIgD has a more dominant role than sIgM in direct, sIg-mediated B cell activation whereas sIgM has a more dominant role than sIgD in focusing antigen-specific T cell help onto activated B cells; 4) the loss of sIgD from activated B cells limits the transmission of sIg-mediated signals that can inhibit the differentiation of B cells into antibody-secreting cells; and 5) the cross-linking of sIg, the focusing of antigen-specific T cells, and nonspecific helper lymphokines are all required for induction of rapid, effective antibody responses against bacterial pathogens.

Animals↗
PubMed1983

Establishment of an inbred line of mice that express a synergistic immune defect precluding in vitro responses to type 1 and type 2 antigens, B cell mitogens, and a number of T cell-derived helper factors.

Introduction of the CBA/N X-linked gene into C3H mice has resulted in the establishment of a new strain of mice that has profound immunologic defects. B cells from these mice show significantly impaired in vitro immune responses to the T cell-independent type 1 antigen trinitrophenyl-Brucella abortus (TNP-BA) as well as markedly reduced proliferative responses to a number of B cell mitogens when compared with the responses of the parental control mice. The in vivo response of such mice to TNP-BA is, however, comparable to that of CBA/N mice. Furthermore, B cells from C3.CBA/N mice are unresponsive to the plaque-forming cell enhancing effects induced by EL4-derived supernatant in the presence of TNP-BA, unlike B cells obtained from CBA/N or C3H/Hen mice whose responsiveness to TNP-BA can be significantly enhanced in the presence of EL4-derived supernatant. The model we have presented to best explain these results suggests that B cells from C3.CBA/N mice can be stimulated only under conditions in which they can interact with carrier-specific T cell help and not under conditions where factor-dependent responses are dominant.

Animals↗
PubMed1983

A method for size separation of murine spleen cells using counterflow centrifugation.

A method for the rapid separation of murine spleen cells into subpopulations on the basis of their size has been developed using counterflow centrifugation. Upon separation of normal spleen cells with a mean cell volume of 125.5 +/- 6.0, 5 fractions of cells were obtained with mean cell volumes which ranged from 107.8 +/- 3.2 microns3 in fraction 1 to 152.7 +/- 4.9 microns3 in fraction 5. The cells in these 5 fractions were characterized by analysis on a fluorescence activated cell sorter (FACS) after staining with fluorescein conjugated anti-mu, delta, Ia, or Thy 1.2 antibodies, and by assaying for the presence of non-specific esterase activity. Surface Ig+, Ia+ B lymphocytes and Thy 1.2 T lymphocytes were present in all 5 fractions. However, while these T and B lymphocytes accounted for virtually all of the cells in the first 3 fractions, non-T, non-B cells were found in fractions 4 and 5, and represented 30% of the total population in the 5th fraction. Comparison of the intensity of anti-mu, delta or Ia staining of the B cells in fractions 1-5 revealed differences which suggested that B cell size correlated with different activation states of these cells. Increases in the intensity of the staining of T lymphocytes by anti-theta antibodies were also noted in the various fractions. The capacity of the B and T cells in each fraction to proliferate to B or T cell mitogens, respectively, was proportional to their frequency within the fractions. By contrast, the fractions containing larger cells were enriched in cells which proliferated in vitro in the absence of added mitogen. Furthermore, only fractions containing larger cells had the capacity to stimulate allogeneic T cell proliferation in a mixed lymphocyte reaction. Our data suggest that this technique provides a useful method for separating splenocytes on the basis of cell size. Use of this methodology provides a way to correlate cell size with phenotypic surface markers and functional abilities.

Animals↗
PubMed1983

Polyclonal activation of the murine immune system by an antibody to IgD. III. Ontogeny.

It has recently been demonstrated that the injection of adult mice with an affinity-purified goat antibody to mouse IgD (GaM delta) stimulates activation of the humoral immune system that resembles, on a polyclonal level, specific B cell activation by a T cell-dependent antigen. One to 2 days after adult BALB/c mice are injected with 200 micrograms of GaM delta, their splenic B lymphocytes undergo a series of T-independent activation steps that include increases in surface (s) Ia expression, cell size and DNA synthesis. Seven days after GaM delta injection, these cells undergo T-dependent activation steps, that include further proliferation as well as differentiation into IgG1-secreting cells. We have now studied the ontogeny of the T-independent (day 2) and T-dependent (day 7) activation steps by injecting 100-200 micrograms of GaM delta into 3-day- to 10-week-old BALB/c mice. GaM delta failed to induce increases in B cell sIa expression or size 2 days after injection of mice 2 weeks old or younger and failed to stimulate increased DNA synthesis 2 days after injection of 4-week-old mice. In contrast, increases in spleen cell sIa expression, size and DNA synthesis were seen 7 days after injection of 6- to 8-day-old mice. Furthermore, increases in the numbers of spleen cells with large amounts of intracytoplasmic IgG1 were seen at the same time, although these increases were much less than were seen in GaM delta-treated adult mice. Thus, the ability of GaM delta to induce T help and to act in concert with such help to stimulate B cell proliferation and differentiation precedes in ontogeny the ability of GaM delta to directly induce B cell proliferation and early differentiative events. In addition, the early activating events that we have studied are not required for T-dependent B cell proliferation and antibody production to occur, although they appear to contribute to the magnitude of clonal expansion and antibody production.

Aging↗
PubMed1983

Induction of a B-lymphocyte receptor for a T cell-replacing factor by the crosslinking of surface IgD.

The observation that anti-immunoglobulin antibodies and T cell-replacing factor (TRF) have a synergistic effect on the stimulation of B lymphocytes to differentiate into antibody-secreting cells suggested to us the possibility that the crosslinking of B-cell surface immunoglobulin by antigen or anti-immunoglobulin antibody might induce the expression of a B-cell receptor for TRF. In order to test this possibility we studied whether spleen cells from mice injected with 400-800 micrograms of anti-IgD antibody 1-3 days before sacrifice had an enhanced capacity to adsorb TRF activity from a partially purified culture supernatant of concanavalin A-stimulated mouse spleen cells. We found that spleen cells from euthymic or congenitally athymic mice injected 24-30 hr prior to sacrifice with either affinity-purified goat anti-mouse IgD antibody or a monoclonal allospecific anti-IgD antibody had greater than 100 times the TRF adsorptive capacity of spleen cells from control mice. In contrast, spleen cells from anti-IgD treated DBA/2Ha mice, which have been shown to have an immune defect associated with the lack of a TRF receptor, were unable to adsorb TRF activity from concanavalin A-stimulated helper supernatants. This suggests that the crosslinking of B-cell surface immunoglobulin may induce B lymphocytes to express a receptor or receptors for TRF and thus enhance B-cell responsiveness to this helper factor.

Animals↗
PubMed1983

Lyb-5- B cells of CBA/N mice can be induced to synthesize DNA by culture with insolubilized but not soluble anti-Ig.

The use of anti-immunoglobulin (anti-Ig) antibodies to stimulate B cell proliferation (1-4), and to stimulate B cell differentiation in the presence of T cell derived-lymphokines (5-8), has simplified investigations into the mechanisms of B cell growth and maturation that are dependent on the cross-linking of surface Ig (sIg). It is only the ontogenetically late appearing Lyb-5+ murine splenic B cells, however, that proliferate in response to anti-Ig antibodies, whereas B cells of the Lyb-5- phenotype obtained from neonatal mice or from mice with the xid immune defect cannot be induced to proliferate in response to this stimulus (1, 9, 10). Thus, the analysis of B lymphocyte physiology of the Lyb-5- B cell population has been hampered by the unavailability of B cell stimulants that mimic an antigen-induced sIg cross-linking event that leads to B cell activation. The inability of soluble anti-Ig antibodies to induce the proliferation of Lyb-5- cells has been particularly difficult to explain because these cells can be induced to increase in size (11) and to show an increase in their expression of surface Ia (sIa) after exposure to anti-Ig (12). Apparently, therefore, these cells are not entirely refractory to this stimulus but are simply unable to progress to the latter stages of cell activation. In view of our observations that the cells of CBA/N mice cannot respond to soluble trinitrophenyl-(TNP) dextran or TNP-polyacrylamide (13) but can respond to insolubilized forms of these antigens, we evaluated their ability to respond to insolubilized anti-Ig. In this paper we report that B cells from CBA/N mice can be stimulated to proliferate in response to anti-Ig conjugated to Sepharose beads, but in contrast to normal B cells they need to be stimulated with beads expressing a high-epitope density of anti-Ig antibodies.

Animals↗
PubMed1983

Enhancement of the mixed lymphocyte reaction by in vivo treatment of stimulator spleen cells with anti-IgD antibody.

The injection of anti-IgD antibody into mice has been shown to increase the expression of Ia antigens on splenic B cells. These antigens are the most potent lymphocyte-activating determinants (LAD) that trigger proliferation in an H-2-defined mixed lymphocyte reaction (MLR) and may play a role in the recognition of minor lymphocyte-stimulating (MIs) determinants. Therefore, we wished to investigate a possible correlation between apparent quantitative alterations in B cell Ia expression after anti-IgD activation with changes in the functional capacity to present allogeneic major histocompatibility complex (MHC) and MIs antigens to responsive T cells. We observed that the capacity of splenocytes removed 24 hr after the in vivo injection of anti-IgD to stimulate T cell proliferation across an H-2 barrier was most frequently enhanced two- to fourfold when a suboptimal concentration of stimulator cells was used or an early time point in the MLR was examined. In contrast, the capacity of splenocytes to stimulate across an MIsa, d difference after exposure to heterologous or hybridoma anti-IgD antibody often was increased 10-fold or more. Optimal MLR stimulatory capacity was induced by injection of 100 to 200 micrograms of heterologous anti-IgD. Augmented MIs stimulatory capacity of spleen cells peaked 24 hr after such treatment and continued to decline from this value at day 3 and at day 7 after injection. In contrast, the H-2 stimulatory capacity increased 1 day after injection of anti-IgD and remained at that elevated level 3 and 7 days after injection. The spleen cells from B cell-defective (CBA/N x DBA/2)F1 male mice were unaffected in their capacity to stimulate across an MIsa barrier after in vivo anti-IgD treatment; however, spleen cells from phenotypically normal (DBA/2 x CBA/N)F1 male mice after exposure to anti-IgD did evidence a considerably enhanced ability to stimulate in an MIsa-defined MLR. Because anti-IgD antibodies presumably have their major initial effect on surface IgD-bearing B cells, these studies suggest that anti-immunoglobulin-activated B cells may have a role (direct or indirect via interaction with accessory cells) in the presentation of allogeneic MHC and MIs antigens to responsive T cells.

Animals↗
PubMed1983

The ontogeny and distribution of B cells in normal and mutant immune-defective CBA/N mice: two-parameter analysis of surface IgM and IgD.

A dual-laser fluorescence-activated cell sorter was utilized to study the distribution of the surface IgM and IgD on individual B cells of normal and immune-defective CBA/N mice. Cells from different lymphoid organs and from developing mice were studied. Two major populations of cells were seen. Those with low densities of surface IgM and intermediate-high densities of surface IgD were relatively or totally absent from the bone marrow, spleens, and lymph nodes of adult, immune-defective (CBA/N x DBA/2)F1 male mice, and developed late in ontogeny in the lymphoid organs of normal F1 female mice. By contrast, the second major population, with intermediate-high surface IgM and low surface IgD, was found in highest frequency in the lymphoid organs of immature mice, the bone marrow of adult mice, and the lymphoid organs of F1 male mice compared to F1 female mice at any age. These two major populations of B cells were further subdivided into five groups of cells to better define the surface IgM and IgD characteristics of developing B cells of immune-defective and normal mice. The relationship of these groups of cells to populations defined by other criteria are discussed.

Animals↗
PubMed1983

Effects of neonatal anti-delta antibody treatment on the murine immune system. I. Suppression of development of surface IgD+ B cells and expansion of a surface IgM+ IgD- B lymphocyte population.

Lymphocytes that bear surface (s) IgD make up the majority of B cells in mature mice and are the precursors of most antibody secreting cells in primary immune responses made by these mice. In order to study the functional capabilities of the minority sIgD- B lymphocyte population and to gain insight into the possible roles of sIgD, we attempted to abort the development of sigD+ B cells and to expand the sigM+IgD- B cell population by treating mice from birth with affinity-purified rabbit antibodies specific for mouse IgD (RaM delta). RaM delta-suppressed mice had no detectable sIgD+ spleen, lymph node, or bone marrow cells and, on average, only 20% as many sIgM+Ia+ splenic B cells as control mice but had normal numbers of splenic T cells. Lymph nodes from anti-delta suppressed mice were even more depleted of B cells than were spleens from these mice, whereas the percentage of bone marrow B cells in these mice was relatively normal. Germinal centers of anti-delta suppressed mice were fairly normal in appearance, whereas follicular mantle layers, the locus of most sIgD+ B cells in normal mice, were greatly depleted. In addition to their lack of sIgD, splenic B cells of anti-delta suppressed mice differed from those found in control mice in that they bore, on average, twice as much sIgM as control cells, and in that they included an increased percentage of large, DNA synthesizing cells as compared with spleen cells from control mice. However, most sIgM+IgD- splenic B cells from anti-delta suppressed mice were small, nonproliferating cells. B cells from anti-delta suppressed mice insert little or no sIgD into their cell membranes since they continued to bear no detectable sIgD 2 days after in vivo neutralization of RaM delta and since, unlike B cells from control mice, they failed to be activated by a single in vitro injection of a goat anti-mouse delta antibody. Despite their lack of sIgD+ B cells, anti-delta suppressed mice had relatively normal levels of serum IgG as well as normal to increased levels of serum IgM. Thus, sIgM+IgD- B cells appear to have the potential of differentiating into Ig secreting cells in vivo without acquiring sIgD.

Animals↗
PubMed1983

Effects of neonatal anti-delta antibody treatment on the murine immune system. II. Functional capacity of a stable sIgM+sIa+sIgD- B cell population.

Mice were injected from birth with rabbit anti-mouse IgD (RaM delta). Studies in the accompanying paper indicated that the B cells from these mice have a stable sIgM+sIa+sIgD- B cell population. In the studies presented herein the in vivo and in vitro antibody responses of these mice were examined as well as their responsiveness to various B cell mitogens. The results indicate that splenic B cells from RaM delta-suppressed mice differ from normal adult murine splenic B cells by failure to express increased sIa antigen after in vitro stimulation with soluble anti-mu antibodies and failure to proliferate in response to in vitro stimulation with either soluble or Sepharose-bound anti-mu antibody. Nevertheless, these mice generate relatively normal in vivo IgM and IgG antibody responses to TI-2 and to both high and low epitope density forms of TD antigens as well as secondary IgG antibody responses to a TD antigen. In addition, B cells from RaM delta-treated mice generate relatively normal primary in vitro IgM antibody responses to TI-1, TI-2, and TD antigens. These data suggest that sIgD- B cells can produce antibody responses to the majority of antigenic signals even though they appear to lack one or more differentiative pathways.

Animals↗
PubMed1983

Polyclonal activation of the murine immune system by an antibody to IgD. IV. In vivo activation of B lymphocytes from immune defective CBA/N mice.

Previous studies with BALB/c mice have established that the injection of a goat antibody to IgD (GaM delta) induces splenic B lymphocytes to undergo T-independent, polyclonal increases in cell surface (s) Ia expression, size, and DNA synthesis 1 day after injection, as well as T-dependent maintenance of this activation and differentiation into sIgG1+ cells and IgG1-secreting cells 6 to 7 days after injection. Because B lymphocytes from mice homozygous or hemizygous for the CBA/N X-linked immune defect fail to proliferate in vitro when cultured with soluble anti-Ig antibodies, yet can make in vivo primary antibody responses to T-dependent antigens, we studied the effects of injecting (CBA/N X DBA/2)F1 male mice (immune defective) and (CBA/N X DBA/2)F1 female mice (phenotypically normal) with 800 to 1600 micrograms of GaM delta. B cells from immune defective mice demonstrated definite but distinctly subnormal increases in B cell size, DNA synthesis, and sIa expression 1 to 5 days after GaM delta injection, but by day 7 showed increases in these parameters as well as in the percentages of splenic sIgG1+ cells and IgM-secreting cells that were similar to those exhibited by the immunologically normal mice. However, IgG1 secretion by the immune defective mice was at this time only one-fourth to one-half as great as that observed with normal mice. Our data raises the possibility that the differentiation of B cells into IgG1-secreting cells may be more dependent upon the GaM delta-induced activation steps that are defective in CBA/N mice than is the differentiation of B cells into IgM-secreting cells or into sIgG1 cells.

Animals↗
PubMed1982

Role of the thymus in directing the development of a subset of B lymphocytes.

In an effort to evaluate the role of the thymus in influencing the development of Lyb-5- B lymphocytes, mice expressing both the xid and nu gene defects were studied. Mice expressing either of these defects respond to both trinitrophenylated Brucellus abortus and lipopolysaccharide; whereas mice with the combined defect show markedly suppressed responses. The other abnormalities included: (a) greater than 80 percent diminution of serum Ig levels; (b) significant increase in the number of sIgM+ sIgD- B lymphocytes; (c) reduced expression of IgD on sIgD+ cells; and (d) a strikingly abnormal histology of their lymphoid tissue. Because nu/nu mice that do not express the xid defect appear relatively normal, it would suggest that the development of Lyb-5- B lymphocytes require a thymic influence for normal maturation, whereas, Lyb-5+ B lymphocytes are relatively independent of such influences.

Animals↗