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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 289 records · Page 16Linked to original sources
PubMed1983

Homologies between cell interaction molecules controlled by major histocompatibility complex- and Igh-V-linked genes that T cells use for communication; both molecules undergo "adaptive" differentiation in the thymus.

We have previously described two types of immunoregulatory interactions between T cell subsets; in one an Ly-1; I-J+ inducer cell makes a soluble product (Ly-1 T suppressor inducer factor, TsiF) that is also I-J+ and which activates the effector cells of a suppressor circuit. Under normal circumstances the Ly-1 TsiF activity is restricted by Igh-V-linked genetic polymorphisms. However, we now find the genotype of the inducer cell does not control this restriction. The inducer cell acquires a new Igh-V-linked self repertoire if it ("adaptively") differentiates in an appropriate F1 radiation chimera or in an F1 thymus graft in a homozygous nude mouse. Conversely, cells from F1 mice cannot acquire this "dual" self repertoire if the host in which they differentiate does not express the relevant selecting structure(s). A previously demonstrated H-2-restricted suppressor factor (Ly-2 T suppressor factor) has also been examined and it is shown that this molecule is subject to the same differentiation constraints as is the Igh-V-linked restricted factor except, or course, in this case H-2-linked genes are the "restricting" elements. Thus, Igh-V restrictions are related to major histocompatibility complex (MHC) restrictions in the parameter that has been termed "adaptive" differentiation. The results also imply that the I-J-marked Igh-V-linked self recognition molecule(s) has a variable and constant region, since the adaptively differentiated molecules that show a new self recognition specificity retain the genetic I-J polymorphism of the mice that supplied the bone marrow precursor cells and not the one of the thymus in which they differentiated. It may be considered surprising to find a structure in the thymus that acts to select MHC-positive molecules that see Igh-V-linked structures as self. The F1 into parent experiments make it unlikely that the thymus is passively armed by circulating molecules that might act as the selecting elements. Since there is such a striking parallelism in the "adaptive" differentiation of cells that recognize Igh-V and MHC as self, one must consider the possibility that Igh-linked gene products are expressed by cells in the thymus and function there to select for those Ly-1 TsiF producer cells that can recognize these Igh-V-linked cell interaction structures as self.

Animals↗
PubMed1983

Phenotypic characterization of early events of thymus repopulation in radiation bone marrow chimeras.

The phenotype of murine thymocytes repopulating the thymus of radiation bone marrow chimeras shortly after irradiation and bone marrow reconstitution was analyzed by immunofluorescence and flow microfluorometry. Thymuses in these chimeras, while essentially devoid of lymphoid cells at day 7, were repopulated by days 10 to 12 after irradiation. It was found that this initial repopulation arose from a radioresistant intrathymic precursor that expanded to an almost complete complement of host-type thymocytes. However, these host-derived thymocytes were unusual in that they were relatively deficient in Lyt 1+2- and peanut agglutinin "dull" cells as compared with normal thymocytes. Donor bone-marrow-derived cells first appeared in the irradiated chimeric thymuses between days 12 and 15 after irradiation and bone marrow transfer. By day 19, chimeric thymuses contained more than 98% donor cells. This course was identical for three chimeric combinations, each made across different genetic barriers. In contrast to the cells that populate the fetal thymus during normal ontogeny, the first donor bone-marrow-derived cells that can be detected within the irradiated chimeric thymuses already expressed phenotypically normal adult T cell subpopulations in that they contained significant numbers both of Lyt 1+2- and of Lyt 1+2+ thymocytes. Thus, the Lyt phenotype of donor cells that initially repopulate an adult thymus after irradiation is markedly different from the Lyt phenotype of cells that initially populate the fetal thymus. The differences between adult and fetal thymic development that are observed in radiation bone marrow chimeras may be important in our understanding of T cell differentiation in these animals.

Animals↗
PubMed1983

Colposcopy in the diagnosis of papillomavirus infection of the uterine cervix.

Morphological criteria are described for the diagnosis of papillomavirus lesions at colposcopy. Using these criteria, evidence of cervical papillomavirus infection was found in 58 (29.0%) of 200 women referred for colposcopy because of an abnormal cytology report. Directed biopsies were obtained from 152 of these patients and histological changes suggestive of papillomavirus infection were found in 47 (30.9%); additional biopsy material from 139 was studied using an immunohistochemical technique and human papillomavirus antigen was demonstrated in 28 (20.1%). Comparison between the colposcopic results and those obtained by histology suggests that whereas it is not possible to make a distinction at colposcopy between lesions due to papillomavirus and those of cervical intraepithelial neoplasia, it is possible to identify those epithelial abnormalities that are most likely to be associated with a papillomavirus infection.

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PubMed1983

Natural history of cervical epithelial abnormalities in patients with vulval warts. A colposcopic study.

The natural history of intraepithelial abnormalities of the cervix associated with human papillomavirus infection was investigated in a prospective study of 50 women with vulval warts, of whom 28 had colposcopic evidence of a cervical epithelial abnormality and 22 a normal cervix. Of the 28 with a cervical abnormality, 26 were re-examined by colposcopy after three months; the epithelial abnormality had persisted in 23 women. Nineteen women who had initially shown abnormality by colposcopy were re-examined six months after their first attendance; the epithelial abnormality had persisted in 14 women. Of the 22 women who initially had a normal cervix, 19 were re-examined after three months; the cervix remained normal in 18, but an epithelial abnormality had developed in one. Fourteen women who initially had a normal cervix were re-examined six months after their first attendance; the cervix was still normal in 11, but an epithelial abnormality had developed in three. Colposcopically directed biopsy specimens were obtained from 21 women who showed an epithelial abnormality; of these, evidence of wart virus infection was present in four, cervical intraepithelial neoplasia in two, both conditions in 13, and no abnormality in two. It is concluded that lesions of the cervix associated with wart virus infection show little evidence of short term regression.

Adult↗
PubMed1983

Functional heterogeneity of the Lyb-5- B cell subpopulation: mutant xid B cells and normal Lyb-5- B cells differ in their responsiveness to phenol-extracted lipopolysaccharide.

In the present study, responses stimulated by phenol-extracted lipopolysaccharide (LPS(phenol)) and butanol-extracted LPS (LPS(butanol)) were used to assess the possibility that xid B cells might not be identical to the Lyb-5- B cells present in normal mice. It was found that xid B cells responded well only to LPS(butanol) whereas normal B cells responded well to both LPS(butanol) and LPS(phenol). Thus, LPS(butanol) appeared to be a TI-1 antigen and LPS(phenol) appeared to be a TI-2 antigen. In contrast to classical TI-2 responses, however, responses stimulated by LPS(phenol) did not exhibit a stringent requirement for accessory cells. Furthermore, if LPS(phenol) were a classical TI-2 antigen, it should only activate Lyb-5+ B cells. To determine if the responsiveness of normal B cells to LPS(phenol) were due, at least in part, to the stimulation of normal Lyb-5- B cells, the responsiveness of normal neonatal B cells and normal adult B cells that had been pretreated with anti-Lyb-5.1 + C was assessed. It was found that both normal neonatal B cells and normal adult Lyb-5- B cells did respond well to LPS(phenol). Thus, even though LPS(phenol) does not stimulate xid B cells, these data demonstrate that LPS(phenol) is different from other TI-2 antigens. More importantly, these data also demonstrate that xid B cells and normal Lyb-5- B cells are not identical. It is hypothesized that the normal Lyb-5- B cell subpopulation is heterogeneous, consisting of an Lyb-5(1)- and an Lyb-5(2)-B cell subset with the xid mutation blocking the differentiation of Lyb-5(1)-B cells into Lyb-5(2)-B cells.

Animals↗
PubMed1983

Role of the major histocompatibility complex in T cell activation of B cell subpopulations. Ir gene regulation of the T cell-dependent activation of distinct B cell subpopulations.

Antibody responses to (T,G)-A--L and (H,G)-A--L or to the TNP conjugates of these polypeptides, are regulated in the mouse by Ir genes encoded in the I-A subregion of the mouse MHC. To study the mechanism by which Ir genes function, it is essential to identify the cell interactions that are regulated by these genes. In the present report, it was specifically determined whether Ir gene function is expressed differently in the activation of B cell subpopulations that participate in two different pathways of B cell activation for in vitro antibody responses to TNP-(T,G)-A--L and TNP- (H,G)-A--L. The results of these studies demonstrate that under conditions that activate the Lyb-5- b cell subpopulation via MHC-restricted TH cell-B cell and TH cell-APC interactions, Ir gene function regulates TH cell interactions with these B cells as well as with APC. In addition, under conditions that activate the Lyb-5+ B cell subpopulation via MHC-restricted TH cell-APC but not TH cell-B cell interaction, Ir gene function regulates only TH cell interactions with APC but not with B cells.

Animals↗
PubMed1983

Differences in the MHC-restricted self-recognition repertoire of intra-thymic and extra-thymic cytotoxic T lymphocyte precursors.

The MHC specificity of TNP-specific pCTL from the thymus and spleen of F1 leads to parent chimeras was evaluated. It was found that in the presence of exogenously added helper factor IL 2, thymic pCTL were restricted to recognizing TNP only in association with host MHC determinants, whereas splenic pCTL recognized TNP in association with either host or donor MHC determinants. Thus, the spleens of F1 leads to parent chimeras contain a pCTL repertoire that is not present intrathymically. Data are presented which suggest that such pCTL did nevertheless differentiate into functional competence in the chimeric host. These results are consistent with extra-thymic differentiation as the mechanism by which such nonthymically restricted pCTL may have developed.

Animals↗
PubMed1983

Self recognition of accessory cell Ia determinants is required for the in vitro generation of hapten-specific cytotoxic T lymphocyte responses.

The present study has addressed the involvement of Ia determinants in the in vitro generation of antigen-specific cytotoxic T lymphocyte (CTL) responses. It demonstrated that the in vitro generation of TNP-specific CTL responses strictly requires responder T cell recognition of self-Ia determinants expressed by accessory cells, and that this recognition could be specifically inhibited by monoclonal anti-Ia-antibodies. The generation of TNP-specific CTL responses was unaffected by the presence of anti-I-A antibodies or the absence of accessory cells when cultures were performed in the presence of an exogenous source of T helper cell factors, Con A SN. Thus, these results indicate that T helper cell recognition of self-Ia determinants expressed by accessory cells is required for the generation of TNP-specific CTL responses. These results preclude the possibility that accessory cells perform only immunologically nonspecific roles in the generation of hapten-specific CTL, but instead demonstrate that accessory cells function in such responses as Ia-bearing antigen-presenting cells for the activation of self-Ia-specific T cells.

Animals↗
PubMed1983

Congenital measles--1982.

Measles acquired in utero has a broad spectrum of illness, ranging from mild to rapidly fatal disease. We encountered two case of perinatal measles during the 1982 epidemic. In both cases the mother became febrile 4 to 5 days before admission, and a typical morbilliform rash appeared a few hours prior to delivery. Physical examination of both infants was within normal limits. They were each treated with human serum globulin (0.25 ml/kg body weight). In one of them, a maculopapular rash appeared on the neck after 5 days, which rapidly spread to all the body. No catarrhal or constitutional signs were noted. Hyperbilirubinemia occurred in both infants, requiring an exchange transfusion in one. Both were discharged in excellent condition. Viral cultures were negative in both infants, while serological studies revealed hemagglutination inhibition antibodies in rising titers.

Adult↗
PubMed1982

Cytotoxic T lymphocyte responses in allogeneic radiation bone marrow chimeras. The chimeric host strictly dictates the self-repertoire of Ia-restricted T cells but not H-2K/D-restricted T cells.

The present report has used fully H-2 allogeneic radiation bone marrow chimeras to assess the role of host restriction elements in determining the self-specificity of Ia- and H-2K/D-restricted T cells that participate in the generation of trinitrophenyl (TNP)-specific cytotoxic T lymphocytes (CTL). It was demonstrated that there exists a stringent requirement for the recognition of host thymic-type Ia determinants, but there exists only a preference for host thymic-type H-2K/D determinants. Indeed, once the stringent requirement for recognition of host Ia determinants was fulfilled, anti-TNP CTL were generated in response to TNP-modified stimulators that expressed either donor-type or host-type H-2K/D determinants. The CTL that were generated in response to TNP-modified donor-type stimulators were shown to be specific for TNP and restricted to the non-thymic H-2K/D determinants of the chimeric donor. Thus, these results demonstrate in a single immune response that the thymic hypothesis accurately predicts the self-specificity expressed by Ia-restricted T cells, but does not fully account for the self-specificity expressed by H-2K/D-restricted T cells. These results are consistent with the concept that H-2K/D-restricted T cells, but not Ia-restricted T cells, can differentiate into functional competence either intrathymically or extra-thymically. The present results are also informative for understanding the cellular interactions that are required for the generation of antigen-specific CTL responses. The Ia-restricted T cells that are required for the generation of H-2K/D-restricted anti-TNP CTL were shown to be helper T (TH) cells since (a) like TH cells functioning in antibody responses, they were specific for Ia determinants expressed by accessory cells, and (b) their function could be replaced by either TNP-primed, irradiated TH cells or by nonspecific soluble helper factors. It was also shown that the T-T cell interaction between Ia-restricted TH cells and H-2K/D-restricted precursor CTL (pCTL) is not Ia restricted. Rather, the results demonstrate that the generation of anti-TNP CTL responses involve two parallel sets of major histocompatibility complex-restricted cell interactions, an Ia-restricted TH-accessory cell interaction required for TH cell activation, and an H-2K/D-restricted pCTL-stimulator cell interaction required for pCTL stimulation. The interaction between activated TH cells and stimulated pCTL is mediated, at least in part, by nonspecific soluble helper factors.

Animals↗
PubMed1982

Homologies between cell interaction molecular controlled by major histocompatibility complex- and Igh-V-linked genes that T cells use for communication. Tandem "adaptive" differentiation of producer and acceptor cells.

We have asked the question: how do partner cells in immunoregulatory interactions between T cell subsets acquire the ability to recognize and react appropriately with one another? In particular, we have asked whether these communication events are completely determined by the cell's genetic constitution, or whether the recognition events can be learned during ontogeny. We have found that the T cells of parent into F1 chimeras and homozygous nude mice with F1 thymus grafts not only learn to react with genetically disparate acceptor cells, but that the receptors on the acceptor cells themselves learn to react with genetically disparate producer cells. This learning process can overcome both major histocompatibility complex- and immunoglobulin heavy chain variable region-linked restricted communication between T cell subsets. We interpret these findings to indicate that thymic elements can start a cascade of differential events. The thymic elements, whether endogenous or passively acquired, select from a pool of producer cells those that will react appropriately with the thymic selecting cells, and these cells become expanded. Then, the private markers (idiotype) on the expanded pool of producer cells act as selecting and expanding elements that choose from a pool of acceptor cells those that recognize the producer cells idiotype as self. This second differentiational event, although apparently thymus evidence that this type of acceptor cell differentiation could also take place during the course of an immune response.

Animals↗
PubMed1982

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-ficoll. Adaptive differentiation and self-recognition by B cells.

The present study has examined the possibility of TNP-Ficoll-responsive B cells recognize the MHC determinants expressed by the accessory cells with which they interact for the generation of T cell-independent responses to "high" concentrations (10(-2) micrograms/ml) of TNP-Ficoll. In experiments with B cells from normal mice, it was found that MHC homology between the TNP-Ficoll-responsive B cells and accessory cells was not required. Nevertheless, TNP-Ficoll-responsive B cells from both fully allogeneic (A leads to B) and F1 leads to parent radiation bone marrow chimeras were triggered by accessory cells expressing host-type, but not uniquely donor-type, MHC determinants. The MHC gene products responsible for this apparent B cell-accessory restriction were encoded in the left side, i.e., the K and/or I-A region, of H-2. Such genetic restrictions were shown not to be imposed by the residual T cells contaminating the chimeric B cell populations because T cell reconstitution experiments using "unrestricted" F1 T cells from normal mice did not fully overcome the marked preference of the chimeric B cells for accessory cells expressing appropriate (host-type) MHC determinants. To directly determine whether TNP-Ficoll-responsive B cells from fully allogeneic chimeras are unable to recognize and cooperate with syngeneic strain A accessory cells, unfractionated spleen cells from A leads to B chimeras are co-cultured with unfractionated spleen cells from essentially syngeneic normal strain A mice. In such co-cultures, all the accessory cells express strain A MHC determinants, and all T cell requirements would be fulfilled by the T cells present in the normal strain A spleen cell population. After stimulation of the co-cultures with TNP-Ficoll, it was found that virtually all the PFC that had been generated in the co-cultures were derived from the normal B cell population, and essentially none were derived from the chimeric A leads to B B cell population. The failure of the chimeric B cells to be activated in such co-cultures was specifically due to their maturation in a fully allogeneic host environment because TNP-Ficoll-responsive B cells from A leads to (A X B) F1 chimeric mice were successfully triggered in co-cultures with normal spleen cells. These experiments demonstrated that the co-culture conditions did fulfill the MHC restriction requirements for activating TNP-Ficoll-responsive strain A B cells that had matured in a syngeneic or semi-syngeneic differentiation environment, but did not fulfill the MHC restriction requirements for activating TNP-Ficoll-responsive strain A B cells that had matured in a fully allogeneic differentiation environment. Taken together, these results demonstrate that (a) TNP-Ficoll-responsive B cells recognize the MHC determinants expressed by accessory cells, and (b) their MHC specificity is influenced by the MHC haplotype of the host environment in which the B cells had differentiated.

Animals↗
PubMed1982

Role of the major histocompatibility complex in T cell activation of B cell subpopulations. A single monoclonal T helper cell population activates different B cell subpopulations by distinct pathways.

It has recently been demonstrated that the Lyb-5+ and Lyb-5- B cell subpopulations differ in their requirements for major histocompatibility complex (MHC)-restricted activation by T helper (TH) cells. To determine whether these MHC-restricted and -unrestricted pathways of B cell activation result from differences in the participating TH cell populations or reflect differences exclusively in the responding B cell subpopulations, experiments were carried out using cloned TH cells for in vitro antibody responses to trinitrophenyl-keyhole limpet hemocyanin. The same cloned T helper cells were able to activate both CBA/N (Lyb-5-) B cells and CBA/CaHN (Lyb-5+ + Lyb-5-) B cells under different experimental conditions. The activation of Lyb-5-B cells by cloned T helper cells required both MHC-restricted TH cell-B cell interaction and carrier-hapten linkage. In contrast, the activation of Lyb-5+ B cells required only MHC-restricted T helper cell interaction with accessory cells, while T-B interaction was MHC unrestricted and did not require carrier-hapten linkage. Thus, the differences in activation requirements observed for the Lyb-5- and Lyb-5+ B cell subsets do not result from differences in the TH cell populations activating these B cells, but rather reflect differences in the ability of these B cells to respond to signals from the same TH cells.

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