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Biomedical subjects

A Singer

Publications and source records attributed to A Singer.

At least 271 records · Page 15Linked to original sources
PubMed1985

Specificity, phenotype, and precursor frequency of primary cytolytic T lymphocytes specific for class II major histocompatibility antigens.

Most cytolytic T lymphocytes (CTL) recognize class I rather than class II MHC determinants, and relatively little is known about those CTL that do recognize class II MHC determinants. The present study was undertaken to document the specificity, phenotype, and precursor frequency of primary class II allospecific CTL. It was found that class II-allospecific CTL could be consistently generated in vitro from unprimed spleen or thymus populations in the presence of exogenously added helper factors. The class II MHC specificity of both the precursor and CTL effectors activated in primary cultures by Ia-disparate stimulator cells was documented both by blocking experiments with anti-Ia mAb and by the use of L cell transfectants. The mechanism by which primary allospecific CTL effectors lysed their targets appeared to involve direct cell-cell contact, because they failed to lyse bystander target cells. The frequency in unprimed spleen populations of precursor CTL specific for class II alloantigens was examined by limiting dilution analysis and was found to be as high as 1/15,000 splenocytes and approximately 10% of the frequency reported for primary class I allospecific CTL. Finally, the Lyt phenotype of primary class II allospecific CTL precursors and effectors was determined. It was found that anti-class II CTL derive from at least two distinct precursor subpopulations that are either L3T4+Lyt-2- or L3T4-Lyt-2+, and that the Lyt phenotype expressed by the CTL effectors are concordant with that of their precursors. No correlation was found between the I subregion gene products recognized by CTL effectors and the Lyt phenotype they expressed in that both I-A- and I-E-specific CTL were both L3T4+Lyt-2- and L3T4-Lyt-2+.

Animals↗
PubMed1984

Impact of introduction of colposcopy to a district general hospital.

During the first 18 months of operation of a new colposcopy clinic, established in a district general hospital, 608 women were seen. Most (568 (93.0%] were referred from within the local district, on the whole by their general practitioner. In 466 cases a repeat cervical smear was taken, and all women underwent colposcopic examination together with directed punch biopsy of any abnormal area. Positive cytology was seen in 356 women, but 85 (23.9%) of these were found to have no histological evidence of malignancy or premalignancy and were consequently discharged from the clinic. Cervical intraepithelial neoplasia was confirmed histologically in 379 women, of whom 259 were under 35 and 175 nulliparous. As a result of the use of colposcopy and local destructive methods of treatment only 42 patients (11.1%) were required to undergo cone biopsy. The initial overall incidence of success in the treatment of cervical intraepithelial neoplasia was 86.2% for cone biopsy, 88.5% for diathermy, and 81.1% for laser ablative treatment. Colposcopy has an important role in the management of cervical neoplasia in the district general hospital.

Adolescent↗
PubMed1984

Dichotomy in the tissue origin of schistosome acquired class I and class II major histocompatibility complex antigens.

Schistosoma mansoni schistosomula recovered from the lungs of mice have previously been shown to express host-derived class I and class II major histocompatibility complex (MHC) antigens. To investigate the tissue origin of parasite-acquired MHC products, lung-stage schistosomula were obtained from a series of parent leads to F1 and F1 leads to parent bone marrow chimeras and the parasites typed by immunofluorescence for the presence of haplotype-specific K region and I region MHC determinants. The results of these experiments indicated that, despite their intravascular residence in the host, schistosomula derive all of their class I antigen from a nonhemapoietic tissue source. In contrast, the class II antigens expressed on the surface of schistosomula were found to originate from bone marrow-derived donor cells. These results support the hypothesis that MHC product acquisition by schistosomes involves selective and specific interactions with host tissue and, in the case of class I antigens, suggest that the endothelium may be a major site of host molecule uptake for the parasite.

Animals↗
PubMed1984

Human papillomavirus infection of the uterine cervix: histological appearances in 28 cases identified by immunohistochemical techniques.

Twenty eight biopsy specimens of the cervix showed positive immunohistochemical staining when treated with an antiserum raised against an internal capsid antigen of human papillomavirus (HPV). Histological examination of adjoining sections from the same blocks showed a much wider range of abnormalities than those already described in association with HPV infection. The picture was usually diagnostic. It rested chiefly on identifying the koilocyte--the cell with the perinuclear halo that carries the viral antigen in its nucleus--but abnormal keratinisation was also a feature. The accompanying epithelial findings ranged from normal to CIN III (cervical intraepithelial neoplasia). The latter was of an unusual but distinct appearance, in which cytoplasmic maturation was preserved to some degree but in which gross nuclear atypia was seen in all layers of the epithelium.

Animals↗
PubMed1984

T cell-accessory cell interactions that initiate allospecific cytotoxic T lymphocyte responses: existence of both Ia-restricted and Ia-unrestricted cellular interaction pathways.

The specificity of the T-accessory cell interactions that initiate primary allospecific cytotoxic T lymphocyte (CTL) responses were found to be surprisingly diverse and of three distinct major histocompatibility complex (MHC) specificities, involving responder T cell recognition of: a) self-Ia accessory cell determinants, b) allo-Ia accessory cell determinants, or c) allo-K/D accessory cell determinants. Any one of these T-accessory cell interactions was sufficient to initiate allospecific CTL responses. It was observed that when accessory cells did not express foreign class I MHC determinants, primary allospecific CTL responses were invariably initiated by Ia-restricted T-accessory cell interactions. In contrast, it was observed that when accessory cells did express foreign class I MHC determinants, primary allospecific CTL responses could be initiated by Ia-independent T-accessory cell interactions that were specific for allogeneic, but not self, K/D determinants and that did not involve recognition of polymorphic Ia determinants. The MHC specificities of the T-accessory cell interactions that initiate primary allospecific and primary trinitrophenyl (TNP)-self CTL responses were also compared. It was observed that primary allospecific and primary TNP-self CTL responses could be initiated by self-Ia-restricted T-accessory cell interactions, and that in both responses the Ia determinants that the responding T cells recognized as self-specificities on the accessory cell surface were those that their precursors had encountered on radiation-resistant thymic elements in their differentiation environment. In contrast to the initiation of primary TNP-self CTL responses that required the activation by accessory cells of Ia-restricted T helper (TH) cells, allospecific CTL responses could also be initiated by class I-restricted T cells specific for accessory cell K/D determinants. Interestingly, such class I-restricted T cells present in primary responder cell populations were triggered only by recognition of allogeneic, but not self, K/D accessory cell determinants, even when the accessory cells were modified with TNP. Thus, the present study demonstrates that primary allospecific CTL responses, but not TNP-self CTL responses, are initiated by Ia-restricted or Ia-independent cellular interaction pathways. These results raise the possibility that unprimed class I-restricted TH cells that mediate the Ia-independent cellular interaction pathway may predominantly express an allospecific, but not a self + X-specific, receptor repertoire. Possible mechanisms by which these distinct T-accessory cell interactions initiate primary allospecific CTL responses are discuss

Animals↗
PubMed1984

Role of accessory cell processing and presentation of shed H-2 alloantigens in allospecific cytotoxic T lymphocyte responses.

The present study was undertaken to evaluate the role of accessory cell processing of MHC alloantigens in the initiation of primary allospecific CTL responses. To first determine whether antigen processing by accessory cells is involved in the initiation of allospecific CTL responses, accessory cells were retreated with the lysosomotropic drug chloroquine before their addition to culture. It was found that chloroquine pretreatment abrogated their ability to function as accessory cells only when they were of responder haplotype and had no effect when the accessory cells were of stimulator haplotype. Although accessory cells of either responder or stimulator haplotype can initiate allospecific CTL responses, we have previously demonstrated that they do so by activating distinct classes of T helper TH) cells. Indeed, the differential effects of chloroquine on accessory cells of responder or stimulator haplotypes were shown to reflect the fact that chloroquine pretreatment markedly impaired the ability of accessory cells to activate self-Ia-restricted TH cells, but had little effect on the ability of the same accessory cells to activate either allo-class I- or allo-class II-specific TH cells. We next examined the possibility that accessory cells of responder haplotype mediate alloresponses by acquiring and processing shed MHC alloantigens derived from the stimulator cell population. In these experiments, accessory cell-depleted stimulator cells were fixed with paraformaldehyde to inhibit shedding of their surface MHC alloantigens. It was observed that even though mixed stimulator cells were recognized normally by allospecific CTL precursors, they completely failed to stimulate CTL responses mediated by responder haplotype accessory cells, indicating that the function of such accessory cells is dependent upon their acquisition of shed MHC alloantigens. Taken together, the data presented in this report demonstrate that accessory cells of responder haplotype function in allospecific CTL responses by acquiring and processing shed class I MHC alloantigens, and by then presenting the processed alloantigens in association with self-Ia determinants to self-Ia-restricted TH cells. Thus, these data indicate that the self-Ia-restricted TH cells that are involved in allospecific CTL responses recognize processed class I alloantigens in association with self-Ia determinants.

Animals↗
PubMed1983

Role of the H-2 complex in the induction of T cell tolerance to self minor histocompatibility antigens.

The present study has utilized cytotoxic T lymphocyte (CTL) responses specific for minor histocompatibility (minor H) antigens as an experimental approach to determining whether recognition of self MHC determinants is involved in the induction of T cell tolerance to self antigens. It was observed that C3H.SW splenic T cells from C3H.SW leads to B10 X B10.BR radiation bone marrow chimeras contained CTL precursors (pCTL) reactive against self C3H minor H antigens + H-2k but were tolerant to self C3H minor H antigens + H-2b. Precursor CTL with the reciprocal reactivity pattern were observed for C3H leads to B10 X B10.BR chimeras. In addition, it was observed that C3H.SW thymocytes from C3H.SW leads to B10 X B10.BR chimeras could generate minor H-specific CTL responses and were reactive against self C3H minor H antigens + H-2k, but were tolerant to self C3H minor H antigens + H-2b. Thus, the present study demonstrates that for peripheral and intrathymic T cell populations at least a component of T cell tolerance to self antigens is restricted by products of the MHC.

Animals↗
PubMed1983

Presence of human papillomavirus DNA sequences in cervical intraepithelial neoplasia.

Twenty two patients referred to a district colposcopy clinic because of an abnormal cervical cytology report or a suspicious cervix and found to have a cervical epithelial abnormality were studied. The techniques of cytology, histology, immunohistochemistry, and DNA-DNA hybridisation were used to detect infection by human papillomavirus. Using an indirect immunoalkaline phosphatase technique human papillomavirus antigen was found in biopsy specimens from six of the 22 patients and DNA of papillomavirus type 6 in biopsy specimens from 13 of these women, including four out of six whose histological diagnosis was cervical intraepithelial neoplasia grade 3. In eight cases where cytological, colposcopical, and histological investigations all indicated the presence of wart virus infection, papillomavirus type 6 DNA was found in seven. Papillomavirus type 6 DNA was found in more than half of the proved cases of cervical intraepithelial neoplasia. The presence of this viral DNA in women with no cervical abnormality is to be studied.

Adolescent↗
PubMed1983

T cell tolerance to non-H-2-encoded stimulatory alloantigens is induced intrathymically but not prethymically.

The present report has evaluated the differentiation compartment in which T cells are tolerized to non-major histocompatibility complex (MHC)-encoded minor lymphocyte-stimulating locus (MLS) alloantigens. It was observed that T cell precursors are not tolerized prethymically to MLS alloantigens but are tolerized intrathymically and postthymically to MLS alloantigens. The failure of prethymic T cells to be tolerized indicates either that T cell precursors are unable to be tolerized to MLS alloantigens or that cells in the prethymic compartment are unable to induce MLS-specific tolerance. In either case, these results demonstrate that the thymus is the initial site in which T cell tolerance to MLS alloantigen is induced. The present results also demonstrate a striking disparity in the reactivity of thymocytes to MHC and MLS alloantigens expressed in the extrathymic host through which their precursors had migrated. In the experimental mice constructed for these studies, intrathymic T cells were tolerant to the MHC alloantigens but were reactive to the MLS alloantigens expressed by the extrathymic host. This observation is consistent with the concept that T cell precursors may be tolerized to MHC alloantigens at an earlier point in their differentiation than they are tolerized to non-MHC-encoded MLS alloantigens.

Alleles↗
PubMed1983

Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells.

Monoclonal antibodies to I-Ak were injected into neonatal H-2k mice for a period of 3 wk. The spleens of such mice are devoid of Ia-positive cells. Allo- and trinitrophenyl (TNP)-self-specific cytotoxic T lymphocyte (CTL) responses in such anti-I-A-treated mice were almost completely abrogated at the end of the 2-3 wk in vivo treatment period. Development of suppressor cells, carry-over of blocking antibodies, lack of responder accessory cells, or defective CTL function were not responsible for the observed defect. As concanavalin A supernatant could restore the defect, it is more likely that the defect is due to the absence of competent Ia-specific T helper cells. In addition, anti-I-A-treated mice exhibit reduced I-A antigen expression in the thymus and defective Ia-bearing accessory cell function in the spleen. It is postulated that, for development of Ia-specific T cells to occur, precursor T cells need to interact with Ia-encoded products in the thymus, and anti-Ia treatment interferes with this process. Finally, the mechanism of this interference was shown to be due to actual removal or functional inactivation of those I-A-positive elements responsible for the education of I-A-recognizing T cells, since in (H-2b X H-2k)F1 mice, treatment with anti-I-Ak antibodies results in abrogation of CTL responses to TNP in association with both parental haplotypes, while in the thymus of these mice expression of both I-Ak and I-Ab was reduced.

Animals↗
PubMed1983

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-Ficoll. A novel cell interaction pathway requiring self-recognition of accessory cell H-2 determinants by both T cells and B cells.

In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways.

Animals↗
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↗