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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 91 records · Page 5Linked to original sources
PubMed1988

Analysis of two distinct B cell activation pathways mediated by a monoclonal T helper cell. II. T helper cell secretion of interleukin 4 selectively inhibits antigen-specific B cell activation by cognate, but not noncognate, interactions with T cells.

A single monoclonal T helper (Th) clone can activate B cells in two distinct pathways; a cognate pathway requiring a major histocompatibility complex (MHC)-restricted T-B cell interaction, and a noncognate pathway not requiring an MHC-restricted T-B cell interaction. The present study was undertaken to investigate whether Th cells mediating a given immune response provide further regulatory function to B cells other than helper function. It was demonstrated that conditions of high antigen concentration which activate a noncognate B cell activation pathway simultaneously inhibit IgG responses. The inhibition is shown to be mediated by the T cell factor interleukin 4, produced by activated cloned Th cells. The inhibitory effect of this factor is directed to B cells and is MHC-unrestricted, antigen-nonspecific, and IgG class-specific. In addition to being susceptible to the effects of augmenting cells and suppressor cells, cloned Th cell populations can therefore themselves function as regulatory cells to inhibit IgG responses when stimulated with high dose of specific antigen. These results indicate that Th cells function to regulate B cells both positively and negatively, depending upon the activation conditions.

Animals↗
PubMed1988

Evidence that the effector mechanism of skin allograft rejection is antigen-specific.

In vivo rejection responses are initiated by specific T-cell recognition of foreign histocompatibility antigens expressed by tissue allografts, but it is not certain if the effector mechanism mediating the actual tissue injury is also antigen-specific. To directly assess the specificity of the effector phase of in vivo rejection responses, we constructed B6 in equilibrium with A/J allophenic mice that are genetic mosaics whose individual cells express either H-2b or H-2a histocompatibility antigens but not both. Trunk skin from B6 in equilibrium with A/J allophenic mice was grafted onto immunoincompetent H-2b nude mice and allowed to heal and regrow hair that was both black and white, reflecting the genetic mosaicism of the allophenic grafts. One month after engraftment, the H-2b nude animals were reconstituted with syngeneic H-2b T cells reactive against H-2a allodeterminants. An obvious rejection response ensued involving antigen-nonspecific inflammatory destruction of the epidermis and complete hair loss. Despite the intensity of the nonspecific inflammatory response, the allophenic skin grafts survived. Importantly, the allophenic grafts regrew hair and the predominant color of that hair was black, providing visual proof that syngeneic B6 melanocytes and hair follicle cells had not been destroyed. Thus, these results demonstrate that although the intense inflammatory component of skin graft rejection responses is capable of damaging superficial epidermal cells nonspecifically, it does not cause rejection of skin allografts. Rather, rejection of skin allografts is mediated by antigen-specific effector T cells that assess individual cells within the dermis of the graft for expression of foreign histocompatibility antigens.

Animals↗
PubMed1988

Nonequivalent effects of PKC activation by PMA on murine CD4 and CD8 cell-surface expression.

The membrane glycoproteins CD4 (L3T4) and CD8 (Lyt2) are expressed on distinct populations of mature murine T lymphocytes, and are thought to be receptors for monomorphic determinants expressed on MHC class II and class I molecules, respectively. Although they differ in their ligand specificity, it has been presumed that CD4 and CD8 perform equivalent functions in the T cells that bear them. Since activation of protein kinase C (PKC) is known to cause rapid down-regulation of various receptors, including the T cell receptor complex (TcR complex), we treated cells with phorbol 12-myristate 13-acetate (PMA), a PKC activator, to determine whether cell-surface expression of CD4 and CD8 would be similarly affected by this intracellular mediator. Brief or relatively prolonged treatment with PMA induced mature murine T cells to reduce their surface expression of the TcR complex and of CD4, but not of CD8. Similarly, PMA rapidly induced transfected L cells to down-regulate surface CD4 expression, but had no effect on surface CD8 expression. Most significantly, PMA treatment induced CD4+CD8+ immature thymocytes to rapidly reduce their surface CD4 expression, but, again, it had no immediate effect on the surface expression of CD8. These results indicate that CD4 and TcR complex cell-surface expression are both sensitive to PKC activation by brief treatment with PMA, whereas CD8 expression is not, and suggest that CD4 and CD8 surface expression levels are regulated by distinct intracellular mechanisms.

Animals↗
PubMed1988

Psychosexual trauma of an abnormal cervical smear.

The psychosexual sequelae of diagnosis and treatment of pre-invasive cervical atypia were assessed in three groups of women. The first group included 30 women referred to a colposcopy clinic with an abnormal cervical smear indicating cervical intraepithelial neoplasia (CIN), the second comprised 50 women who were traced as sexual partners of men with penile human papillomavirus (HPV) infection; 26 of them had histologically proven cervical atypia and 24 had no such evidence. The third group included 25 women traced as partners of men with non-specific urethritis and who did not have cervical disease. Before and after questionnaires assessed six aspects of sexual behaviour and responses before diagnosis and 6 months after treatment in women with cervical atypia. These were compared with answers given by women investigated and treated, if necessary, as partners of men with sexually transmitted disease (control group). There were statistically significant adverse psychosexual sequelae associated with diagnosis and treatment of pre-invasive cervical epithelial disease.

Adult↗
PubMed1988

Subclinical penile human papillomavirus infection and dysplasia in consorts of women with cervical neoplasia.

Fifty men whose sexual partners were 50 women with histologically proved cervical intraepithelial neoplasia (CIN) grade III (severe dysplasia or carcinoma in situ) were studied. A further 25 men whose current regular sexual partners were 25 women with chlamydial cervicitis were recruited as controls. If either of the partners in either group had genital condylomata acuminata or a known history of similar lesions, the couple was excluded from the study. Abnormal penile epithelium, which was detected by colposcopy after application of 5% acetic acid to the penile skin, was reported in 25 men in the study group compared with three in the control group. Histologically proved subclinical penile infection with human papillomavirus (HPV) was present in 23 men in the study group compared with three in the control group (p less than 0.01). Of the 50 men in the study group, four had histologically proved severe penile dysplasia or carcinoma in situ with evidence of HPV infection, the disease being subclinical in each case and diagnosed on histology of a specimen obtained by colposcopically directed biopsy. HPV DNA was detected on filter hybridisation of penile scrapes from 15 of the 23 men in the study group with histologically proved penile HPV infection, HPV16 DNA being detected in 10 of them. HPV DNA was detected on DNA-DNA hybridisation of biopsy material in seven of 18 men with histologically proved penile HPV infection. Five of these biopsy specimens were positive for HPV16 DNA. Only one man in the control group had HPV DNA detected in a penile scrape. This patient had histologically proved subclinical penile HPV infection. Such lesions may represent an important male reservoir of HPV types implicated in genital squamous carcinogenesis in both sexes.

Adult↗
PubMed1988

Immune mechanisms of tissue destruction in vivo.

In vivo rejection responses are initiated by specific T cell recognition of foreign histocompatibility antigens expressed by tissue allografts, but it is not certain if the effector mechanism mediating the actual tissue injury is also antigen specific. To directly assess the specificity of the effector phase of in vivo rejection responses, we constructed B6 less than----greater than A/J allophenic mice which are genetic mosaics whose individual cells express either H-2b or H-2a histocompatibility antigens, but not both. Trunk skin from B6 less than----greater than A/J allophenic mice was grafted onto immunoincompetent H-2b nude mice and allowed to heal and regrow hair that was both black and white, reflecting the genetic mosaicism of the allophenic grafts. One month after engraftment, the H-2b nude animals were reconstituted with syngeneic H-2b T cells reactive against H-2a allodeterminants. An obvious rejection response ensued involving antigen-nonspecific inflammatory destruction of the epidermis and complete hair loss. Despite the intensity of the nonspecific inflammatory response, the allophenic skin grafts survived Importantly, the allophenic grafts regrew hair and the predominant color of that hair was black, providing visual proof that syngeneic B6 melanocytes and hair follicle cells had not been destroyed. Thus, destruction of skin allografts is mediated by antigen specific effector T cells that assess individual cells within the dermis of the graft for expression of foreign histocompatibility antigens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Quantitative DNA analysis of low grade cervical intraepithelial neoplasia and human papillomavirus infection by static and flow cytometry.

Quantitative deoxyribonucleic acid (DNA) analysis of cervical biopsy specimens from 26 women with cytological, colposcopic, and histological evidence of mild cervical atypia consistent with cervical intraepithelial neoplasia grade I, reactive atypia, or human papillomavirus infection alone or in combination was performed in a comparative evaluation of Feulgen microspectrophotometry, the fast interval processor image analysis system, and flow cytometry. The fast interval processor image analysis system showed a distinct advantage over the other methods, being faster and allowing the operator to see the cells that were selected for measurement. The three methods of measurement together showed that the DNA content of at least 2% of the cells measured exceeded 5C (C being the haploid amount of DNA in a normal cell and 2C representing the diploid complement of a normal cell) in all cases of cervical intraepithelial neoplasia grade I and reactive atypia and in 87% of those reported as showing human papillomavirus infection alone. In contrast, the DNA content of cervical biopsy specimens from the transformation zone of 11 normal controls did not exceed 4C. This study shows the value of using a DNA threshold--that is, the "5C exceeding rate"--to distinguish between normal and neoplastic appearances of the cervix. These results support the view that cervical infection by human papillomavirus is a true precursor of neoplasia.

Aneuploidy↗
PubMed1987

Phenotype, specificity, and function of T cell subsets and T cell interactions involved in skin allograft rejection.

In the present study we used an adoptive transfer model with athymic nude mice to characterize the T cells involved in initiating and mediating skin allograft rejection. It was found that skin allograft rejection in nude mice required the transfer of immunocompetent T cells and that such reconstitution did not itself stimulate the appearance of T cells derived from the nude host. Reconstitution with isolated populations of Lyt-2+/L3T4- T cells resulted in the rapid rejection of MHC class I-disparate skin allografts, whereas reconstitution with isolated populations of L3T4+/Lyt-2- T cells resulted in the rapid rejection of MHC class II-disparate and minor H-disparate skin allografts. By correlating these rejection responses with the functional capabilities of antigen-specific T cells contained within the reconstituting Lyt-2+ and L3T4+ T cell populations, it was noted that skin allografts were only rejected by mice that, as shown by in vitro assessment, contained both lymphokine-secreting Th cells and lymphokine-responsive Tk cells specific for the alloantigens of the graft. The ability of two such functionally distinct T cell subsets to interact in vivo to reject skin allografts was directly demonstrated in H-Y-specific rejection responses by taking advantage of the fact that H-Y-specific Th cells are L3T4+ while H-Y specific Tk cells are Lyt-2+. Finally, the importance of in vivo interactions between functionally distinct Th/T-inducer cells and T killer (Tk)/T-effector cells in skin allograft rejection was demonstrated by the observation that normal B6 mice retain Qala and Kbm6 skin allografts because of a selective deficiency in antigen-specific Th cells, even though they contain T-effector cells that, when activated, are able to reject such allografts. Thus, the ability to reject skin allografts is neither unique to a specialized subset of T cells with a given Lyt phenotype, nor unique to a specialized subset of helper-independent effector T cells with so-called dual function capability. Rather, skin allograft rejection can be mediated by in vivo collaborations between T-inducer cells and T-effector cells, and the two interacting T cell subsets can express different Lyt phenotypes as well as different antigen specificities.

Animals↗
PubMed1987

Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in biopsy material.

Linoleic acid (18:2(9,12)) and its diene-conjugated isomer (18:2(9,11)) were measured in 65 cervical biopsy samples. Both the 18:2(9,11) concentration and the 18:2(9,11)/18:2(9,12) molar ratio showed highly significant differences between the normal and precancerous groups. Both showed a further significant increase in 4 invasive carcinomas. The findings in histologically normal areas from organs with precancer correlated significantly with the results in the precancerous lesions.

Biopsy↗
PubMed1987

Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells.

The molar ratio between a diene-conjugated linoleic-acid isomer (18:2(9,11)) and the parent linoleic acid (18:2(9,12)), both esterified as phospholipids, was significantly different in exfoliated cells from normal cervices and from cervices with colposcopic and cytological evidence of precancer. The measurement may provide a simple and perhaps improved alternative to cytological screening.

Adult↗
PubMed1987

Graft-vs-host reaction limited to a class II MHC difference results in a selective deficiency in L3T4+ but not in Lyt-2+ T helper cell function.

Hybrid mice of the (B6 X bm12)F1 combination were inoculated i.v. with parental B6 spleen cells to induce a class II graft-vs-host disease (GVH). Such mice failed to generate in vitro cytotoxic T lymphocyte (CTL) responses that were dependent upon L3T4+ T helper cell (Th) function (e.g., anti-B6-TNP) but were capable of generating in vitro CTL responses that could be mediated by Lyt-2+ Th cells (anti-allo class I). When Th function was assayed directly by interleukin 2 (IL 2) secretion, class II GVH animals were found to be deficient in L3T4+ but not Lyt-2+ IL 2-secreting Th cells. This selective deficiency in L3T4+ Th function correlates with a selective decrease in class II GVH mice of host-derived derived L3T4+ T cells. In addition, it was found that the spleens of class II GVH mice contained cells capable of selectively suppressing L3T4+ Th function. In contrast, mice in which a class I + II GVH occurred were depleted of both L3T4+ and Lyt-2+ Th function as assessed by IL 2 production. The findings that class II GVH selectively depletes L3T4+ T cells and T cell functions are discussed with respect to the immune function of distinct T cell subsets in normal and diseased states.

Animals↗
PubMed1987

Relationship among function, phenotype, and specificity in primary allospecific T cell populations: identification of phenotypically identical but functionally distinct primary T cell subsets that differ in their recognition of MHC class I and class II allodeterminants.

The goal of the present study was to evaluate the relationship among function, Lyt phenotype, and MHC recognition specificity in primary allospecific T cell populations. By using Lyt-2+ and L3T4+ T cells obtained from the same responder populations, we assessed the ability of T cells of each phenotype to generate cytotoxic effector cells (CTL) and IL 2-secreting helper T cells in response to either class I or class II MHC allodeterminants. It was found that a discordance between Lyt phenotype and MHC recognition specificity does exist in primary allospecific T cells, but only in one T cell subpopulation with limited functional potential: namely, Lyt-2+ T cells with cytotoxic, but not helper, function that recognize class II MHC alloantigens. Target cell lysis by these Lyt-2+ class II-allospecific CTL was inhibited by anti-Ia monoclonal antibodies (mAb), but not anti-Lyt-2 mAb, indicating that they recognized class II MHC determinants as their "restriction" specificity and not as their "nominal" specificity even though they were Lyt-2+. A second allospecific T cell subset with limited functional potential was also identified but whose Lyt phenotype and MHC restriction specificity were not discordant: namely, an L3T4+ T cell subset with helper, but not cytotoxic, function specific for class I MHC allodeterminants presented in the context of self-Ia. Thus, the present study demonstrates that primary allospecific T cell populations contain phenotypically identical subpopulations of helper and effector cells that express fundamentally different MHC recognition specificities. Because the recognition specificities expressed by mature T cells reflect the selection pressures they encountered during their differentiation into functional competence, these findings suggest that functionally distinct but phenotypically identical T cell subsets may be selected independently of one another during ontogeny. Thus, the existence of Lyt-2+ CTL specific for class II allodeterminants can be explained by the hypothesis that the association of Lyt phenotype with MHC recognition specificity results from the process of thymic selection that these Lyt-2+ effector cells avoid.

Animals↗