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Biomedical subjects

S Lederman

Publications and source records attributed to S Lederman.

14 recordsLinked to original sources
PubMed1992

Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help.

In lymphoid follicles, CD4+ T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed Th function. The CD4+ T cell-restricted surface activation protein, 5c8 Ag (T-BAM), has recently been shown to be a component of the contact-dependent helper signal to B cells. To further dissect this process, we utilized a Jurkat T cell lymphoma clone, termed D1.1, that constitutively expresses T-BAM and activates peripheral B cells to express surface CD23 in a contact-dependent mechanism that is inhibited by mAb anti-T-BAM (5c8). Similar to its effect on peripheral B cells, Jurkat D1.1 activates B cells from lymphoid organs, as well as a B cell lymphoma clone, RAMOS 266,4CN 3F10 (RAMOS 266), to up-regulate surface CD23. Interestingly, mAb to the B cell surface molecule, CD40 (mAb G28-5 and B-B20), inhibit D1.1 induced activation of RAMOS 266 and peripheral and lymphoid B cells. In contrast, mAb to CR2 or the adhesion molecules, LFA1, LFA3, or ICAM-1, have little effect. The inhibitory effect of anti-CD40 mAb on B cell activation induced by D1.1 is specific because anti-CD40 potentiates, rather than inhibits, the up-regulation of CD23 on B cells induced by rIL-4. Moreover, cross-linking CD40 molecules by anti-CD40 mAb bound to Fc gamma RII+ (CD32) L cells induces B cell CD23 expression. In vivo, T-BAM-expressing cells are CD4+ T cells that are restricted to lymphoid organs and are localized in the mantle and centrocytic zones of lymphoid follicles and the spleen periarteriolar lymphoid sheath in association with CD40+ B cells. Taken together, these data demonstrate that T-BAM on T cells and CD40 on B cells are involved in contact-dependent T-B help interactions that occur in lymphoid follicles.

Antigens, CD↗
PubMed1992

Identification of a novel surface protein on activated CD4+ T cells that induces contact-dependent B cell differentiation (help).

CD4+ T lymphocytes provide contact-dependent stimuli to B cells that are critical for the generation of specific antibody responses in a process termed T helper function. The surface structures on activated CD4+ T cells that mediate this function are not fully known. We previously reported the isolation of a functionally unique subclone of the Jurkat leukemic T cell line (D1.1) that constitutively expressed contact-dependent helper effector function. To identify T cell surface molecules that mediate contact-dependent T helper function, a monoclonal antibody (mAb), designated 5c8, was generated that inhibits D1.1-mediated B cell activation and immunoprecipitates a novel 30-kD protein structure from surface-iodinated D1.1 cells. Normal CD4+ T cells express 5c8 antigen (Ag) transiently 5-6 h after activation by phorbol myristate acetate and phytohemagglutinin with maximal expression 5-6 h after activation and absence of expression by 24 h. In contrast, neither resting nor activated CD8+ T cells express 5c8 Ag. In functional studies, mAb 5c8 inhibits the ability of fixed, activated CD4+ T cells to induce B cell surface CD23 expression. In addition, mAb 5c8 inhibits the ability of CD4+ T cells to direct terminal B cell differentiation driven by pokeweed mitogen. Taken together, these data suggest that 5c8 Ag is a novel, activation-induced surface T cell protein that is involved in mediating a contact-dependent element of the helper effector function of CD4+ T lymphocytes.

Antibodies, Monoclonal↗
PubMed1992

The gp120 glycoprotein of HIV-1 binds to sulfatide and to the myelin associated glycoprotein.

We investigated the binding of the gp120 glycoprotein of the human immunodeficiency virus (HIV-1) to neural glycolipids and glycoproteins by ELISA. The gp120 protein bound to sulfatide (GalS), a sulfated glycolipid autoantigen implicated in sensory neuritis, and to the myelin associated glycoprotein (MAG), an autoantigen in demyelinating neuropathy. Binding of gp120 to MAG was inhibited by the HNK-1 antibody, which recognizes a sulfated glucuronic acid epitope, suggesting that the interaction involves carbohydrate determinants. Sulfatide and MAG are potential receptors for gp120 in peripheral nerve and may have a role in the neuropathy associated with HIV-1 infection.

Animals↗
PubMed1992

Sulfated polyester interactions with the CD4 molecule and with the third variable loop domain (v3) of gp120 are chemically distinct.

Sulfated polyesters (SP) that inhibit HIV infection interact with both the gp120 binding region of CD4 molecules and with the v3 domain loop of gp120 molecules (gp120/v3) but the contributions of these interactions to the inhibition of HIV env-mediated fusion are presently unclear. In order to characterize the molecular mechanisms by which SP inhibit HIV env-mediated fusion, we studied the effect of SP treatment on env-mediated fusion of CD4+ cells driven by recombinant vaccinia virus (vPE-16) and on the binding of anti-HIV MAbs to cellular gp120 or purified, rgp120. SP were more effective than neutralizing anti-gp120/v3 MAbs in inhibiting env-mediated fusion. In addition, SP interacted with the v3 loop of gp120 to inhibit the binding of the neutralizing MAb 9284 but not the binding of 9305, a neutralizing anti-gp120/v3 MAb that binds to an adjacent epitope. Because SP are polyanions, we compared the chemical properties of the SP-gp120/v3 and SP-CD4 interactions. Whereas the ability of SP to inhibit the binding of MAb 9284 and rgp120 was relatively independent of NaCl concentrations, the ability of SP to interfere with rCD4-rgp120 binding depended on the NaCl concentration and was maximal at low NaCl concentrations. In addition, the SP-gp120 interaction was found to be reversible, in contrast to the SP-rCD4 interaction which was previously shown to be relatively irreversible at low salt. These data are consistent with the notions that the interaction of SP with CD4 is primarily electrostatic, but that the interaction of SP with gp120 has complex characteristics that implicate a role for protein conformation.

Animals↗
PubMed1991

A human CD4- T cell leukemia subclone with contact-dependent helper function.

Helper T lymphocytes provide a contact dependent signal to resting B cells that is required for optimal differentiation into Ig-secreting cells. The surface structure(s) on T cells that mediate helper function have not been identified but are known to be induced by T cell activation. A CD4- subclone of the Jurkat leukemic T cell line (D1.1) was isolated and found to be distinct from CD4+ Jurkat clones and a variety of other T and non-T cell leukemic lines in that coculture of D1.1 with resting B cells induced B cells to specifically express surface CD23 molecules, a marker of B cell activation. Furthermore, Jurkat D1.1 induced B cell proliferation and terminal B cell differentiation into IgG-secreting cells in the presence of T cell-dependent B cell mitogens. Similar to the helper effector function of activated T cells, the effects of Jurkat D1.1 were neither Ag nor MHC restricted. Paraformaldehyde fixed Jurkat D1.1 cells remained competent to activate B cells while D1.1 supernatants and diffusible factors were inactive. The effect of Jurkat D1.1 on B cell activation was distinct from that of rIL-4 and was not inhibited by antibodies to IL-4. Together these observations suggested that surface structures on D1.1 and not secreted factors, mediated contact-dependent helper effector function.

Antigens, CD↗
PubMed1991

A single amino acid substitution in a common African allele of the CD4 molecule ablates binding of the monoclonal antibody, OKT4.

The CD4 molecule is a relatively non-polymorphic 55 kDa glycoprotein expressed on a subset of T lymphocytes. A common African allele of CD4 has been identified by non-reactivity with the monoclonal antibody, OKT4. The genetic basis for the OKT4- polymorphism of CD4 is unknown. In the present paper, the structure of the CD4 molecule from an homozygous CD4OKT4- individual was characterized at the molecular level. The size of the CD4OKT4- protein and mRNA were indistinguishable from those of the OKT4+ allele. The polymerase chain reaction (PCR) was used to map the structure of CD4OKT4- cDNAs by amplifying overlapping DNA segments and to obtain partial nucleotide sequence after asymmetric amplification. PCR was then used to clone CD4OKT4- cDNAs spanning the coding region of the entire, mature CD4 protein by amplification of two overlapping segments followed by PCR recombination. The nucleotide sequence of CD4OKT4- cDNA clones revealed a G----A transition at bp 867 encoding an arginine----tryptophan substitution at amino acid 240 relative to CD4OKT4+. Expression of a CD4OKT4- cDNA containing only this transition, confirmed that the arginine----tryptophan substitution at amino acid 240 ablates the binding of the mAb OKT4. A positively charged amino acid residue at this position is found in chimpanzee, rhesus macaque, mouse and rat CD4 suggesting that this mutation may confer unique functional properties to the CD4OKT4- protein.

Alleles↗
PubMed1991

Human immunodeficiency virus type-1 infection of homosexual men is accompanied by a decrease in circulating B cells.

As part of the multidisciplinary effort to characterize the natural history of human immunodeficiency virus type 1 (HIV-1) infection, the cell-surface phenotypes of lymphocytes from a cohort of homosexual men were analyzed in detail and related to clinical and laboratory parameters associated with HIV-1 infection. The present study represents a cross-sectional analysis of coded specimens from 153 homosexual men, of whom 74 were seronegative and 79 seropositive for HIV-1. Fewer circulating B lymphocytes (CD19+) were found in HIV-1-seropositive subjects relative to a seronegative reference group. HIV seropositivity was not associated with decreased numbers of CD8+ T cells or activated T cells, which suggests that the number of circulating B cells specifically decreased. In addition to CD19, B cells were measured by CD20 and CD21 in a subset of subjects, and decreases in circulating CD20+ and CD21+ B cells were also apparent in HIV-1-seropositive subjects. The decrease in B-cell numbers was present at the earliest stages of HIV-1 infection (asymptomatic, clinically silent) and became more pronounced at more advanced stages of HIV-1 infection. The absolute B-cell numbers correlated with absolute CD4+ cell numbers (r = 0.59, p less than 0.001). These data suggest that HIV-1 infection is associated with progressive, selective decreases in the numbers of circulating CD4+ T cells and B cells.

Antigens, CD↗
PubMed1990

Recombinant, truncated CD4 molecule (rT4) binds IgG.

CD4 is a cell surface glycoprotein that identifies the subset of human T lymphocytes that induces sIg+ B lymphocytes to differentiate and secrete Ig after intimate T-B cell contact. In the course of studying a recombinant, truncated form of CD4 (rT4) we noticed that goat antibodies of apparently irrelevant specificities bound to immobilized rT4. To directly study whether rT4 interacts with Ig molecules, purified human IgG was added to rT4-coated wells and a dose-dependent interaction between IgG and rT4 was observed by ELISA. Purified myeloma IgG proteins bound to immobilized rT4 with the same avidity as polyclonal IgG that suggests that rT4-IgG binding was not due to the presence of anti-rT4 antibodies in the IgG fraction. IgG from 6 sera bound to rT4 in concentration dependent manner similar to purified IgG. Immobilized rT4 specifically bound IgG, and not IgM, IgA, IgD, or beta 2-microglobulin. The specific interaction of rT4 and IgG was also observed when IgG or IgM were immobilized, demonstrating that IgG binding was not a unique property of immobilized rT4. As with low affinity receptors for IgG, rT4 bound heat aggregated IgG with increased avidity. Neither anti-CD4 mAb nor dextran sulfate inhibited rT4-IgG binding. rT4 bound Fc but not F(ab)2 fragments. Each of the purified IgG subclasses; IgG1, 2, 3, and 4 bound to rT4 with similar avidity. Taken together, these data suggest that rT4 specifically interacts with a public structure on IgG Fc.

Antibodies, Monoclonal↗
PubMed1989

Dextran sulfate and heparin interact with CD4 molecules to inhibit the binding of coat protein (gp120) of HIV.

Dextran sulfate, heparin, and certain other sulfated polysaccharides potently inhibit the adsorption of HIV to CD4+ cells. The mechanism of this inhibition is unclear and, specifically, it is unknown if these agents act at the level of CD4-gp120 binding. For example, previous reports have demonstrated that dextran sulfate does not inhibit the cell surface binding of anti-CD4 mAb known to be directed at the gp120 binding site. In order to confirm and extend these observations, in the present study, it was shown that dextran sulfate does not inhibit the binding of OKT4A, OKT4C, Leu3a, or B66.6 to CD4+ cells as measured by cytofluorography. Next, recombinant forms of CD4 (rT4) and gp120 (rgp120) were utilized to directly study their molecular interaction in the absence of other viral or cellular structures. Reciprocal solid phase ELISA assays were developed to study directly the effects of sulfated polysaccharides on the binding of rT4 to immobilized rgp120 and vice versa. Dextran sulfate, heparin, and fucoidan, but not chondroitin sulfate, inhibited the binding of rgp120 to rT4. Importantly, dextran sulfate and heparin pre-treatment of immobilized rT4, but not immobilized rgp120, inhibited rT4-rgp120 binding. Taken together, these data suggest that while both sulfated polysaccharides and anti-CD4 mAb inhibit gp120 binding, the sulfated polysaccharides interact with sites on CD4 that are distinct from those with which the antibodies bind.

Adjuvants, Immunologic↗
PubMed1989

Haptic integration of object properties: texture, hardness, and planar contour.

Planar objects varying in shape, texture, and hardness were classified under haptic exploration. Classes were defined by values on one dimension, or redundantly, by two or three dimensions. Response times and exploratory procedures (Lederman & Klatzky, 1987) were recorded. Experiment 1 showed that a second dimension speeded responses for all combinations (redundancy gain), but a third dimension produced no further effect. In Experiments 2 and 3, classification trials began with two redundant dimensions, and subsequently one was withdrawn (held constant). When texture and hardness varied redundantly, withdrawal of either increased response time--even when subjects were initially instructed to focus on one dimension. Joint exploration for texture and hardness dominated whenever the two varied redundantly and persisted despite withdrawal. Redundancy gains (Experiment 1), but not substantial withdrawal effects (Experiments 2 and 3), were observed for combinations of texture or hardness with planar contour, indicating less integration than between substance dimensions. Compatibility of exploratory procedures appears to constrain dimensional integration.

Attention↗
PubMed1979

Myocardial infarct imaging with 99mTc-pyrophosphate and 99mTc-methylene diphosphonate: lack of correlation.

A prospective study of eight patients with recent transmural myocardial infarction was performed using 99mTc-Sn-pyrophosphate and 99mTc-Sn-methylene diphosphonate in each patient. All pyrophosphate scans were strongly positive whereas the diphosphonate scan was strongly positive in only one case. We conclude that 99mTc-Sn-pyrophosphate is preferable to 99mTc-Sn-methylene diphosphonate for myocardial imaging.

Diphosphates↗