Biomedical subjects
Publications and source records attributed to A Singer.
Exfoliated cells from the precancerous cervix have an increased concentration of octadeca-9,11-dienoic acid, a diene-conjugated isomer of linoleic acid. A high-performance liquid chromatographic method which measures both has been automated. It may form the basis of a sensitive diagnostic test.
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.
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.
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Multiple markers were used to count Langerhans' cells in the cervix. In the normal cervix, thymocyte antigen (T6) and adenosine triphosphatase (ATPase) demonstrated the largest population of Langerhans' cells. MHC Class II positive cells were equivalent to 60%, and S100 positive cells were equivalent to 35% of T6 or ATPase positive cells. Whereas Langerhans' cells demonstrated by T6, ATPase, and MHC Class II antigen were evenly distributed throughout the epithelium, the S100 positive cells were seen predominantly near lymphocytic aggregates and capillaries. In human papillomavirus infection and cervical intraepithelial neoplasia the numbers of T6, ATPase, or MHC Class II positive Langerhans' cells were reduced by 60% but the S100 positive cells were almost completely depleted. These findings suggested that there were different subpopulations of Langerhans' cells in the cervical epithelium. The depletion of Langerhans' cells, particularly the selective depletion of the S100 positive subpopulation, might cause a localized immunodeficiency that impairs immune surveillance and the cell-mediated immune response to human papillomavirus infection and cervical intraepithelial neoplasia.
Lymphocyte phenotypes in cervical mucosa were studied using a panel of monoclonal antibodies. T lymphocytes were predominant both within the epithelium and in the subepithelial stroma. In the normal cervix, both the T4+ (helper/inducer) and T8+ (suppressor/cytotoxic) subsets were present in a ratio similar to that in the peripheral circulation. In human papillomavirus (HPV) infection and cervical intraepithelial neoplasia (CIN) there was depletion of intraepithelial lymphocytes, especially of T4+ subset, with reversal of the ratio of T4+ to T8+ subsets to less than one. In contrast, there was no significant reduction in the number of lymphocytes in the subepithelial stroma. Tac+ (antigen primed and clonal expanding) lymphocytes were absent both within the epithelium and in the subepithelial stroma. These findings support our suggestion that there is a localized immunodeficiency in HPV infection and CIN. The aetiological and therapeutic implications are discussed.
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Tissue macrophages in the uterine cervix were studied immunocytochemically with monoclonal antibody (MoAb) 3.9 which reacts with the majority of macrophages, and E11 which is specific for the C3b receptor, CR1. Samples from five normal women, six with human papillomavirus (HPV) infection and 10 with cervical intraepithelial neoplasia (CIN) were tested. A small population of MoAb 3.9 positive and only occasional MoAb E11 positive macrophages were found in the normal cervix. In HPV infection and CIN there was a significant infiltration of MoAb 3.9 positive and MoAb E11 positive macrophages in both the epithelium and the stroma. The pattern of infiltration in these groups of women suggests that these macrophages were most likely to be functioning as the first line of defence against the spread of the virus infection, either through a direct anti-virus mechanism or non-specific phagocytosis.
Chemotherapy was given as initial therapy to 12 women with very advanced squamous cell carcinoma of the cervix and to 19 women with recurrent disease. They received a median of four courses of POMB which comprised vincristine 1.0 mg/m2 and methotrexate 300 mg/m2 followed by folinic acid rescue, bleomycin 30 mg as a 48-h infusion or intramuscular injection and cisplatin 100 mg/m2 as a 12-h infusion. Two of the 14 assessable patients with recurrent disease (14%) had a complete response with no disease found histologically in one, and seven (50%) had a partial response. Although the actuarial median survival of all 19 patients with recurrent disease was 8 months, five patients have remained free from tumour progression for a median of 17 months from start of chemotherapy. Six of the 10 assessable patients receiving initial chemotherapy (60%) had a complete response (confirmed histologically in two) and two (20%) had a partial response. Nine patients had additional treatment with radiotherapy and or surgery. Although only four of the patients remain disease-free at 61, 51, 7 and 4 months, all but two were initially FIGO stage IV. Although cisplatin-induced emesis is controllable and the side-effects of methotrexate can be avoided, the POMB regimen remains potentially toxic. The small number of patients with very advanced disease who are long-term survivors prompts us to study further the role of aggressive chemotherapy as the initial treatment of patients with visceral or nodal involvement from carcinoma of the cervix.
A semiquantitative immunocytochemical study of natural killer (NK) cells in cervical mucosa was performed by the immunoperoxidase technique using anti-Leu-7 and anti-Leu-11 monoclonal antibodies. NK cells were present in two of the five normal controls and five of six specimens showing human papillomavirus (HPV) infection. Of the 12 CIN studied, six were positive for both Leu-7 and Leu-11 staining and three were positive for Leu-11 alone. NK cells were found predominantly in the subepithelial stroma. The frequency and pattern of distribution of these cells were similar in all grades of CIN. The number of NK cells present was usually small but the degree of infiltration by Leu-11 positive cells was pronounced in two HPV infections and in one CIN 1. NK cells may have a role in surveillance against HPV infection and the development and progression of CIN.
A prospective cytological, colposcopic and histological study was conducted in 44 women with cervical cytology showing borderline nuclear abnormalities insufficient for the diagnosis of dyskaryosis. Atypical squamous epithelium was found on colposcopy in 41 patients and cervical intraepithelial neoplasia (CIN) was diagnosed on histology in 33 patients (75%) including 10 with CIN 3. Repeat cytology obtained under colposcopic vision was negative in 12 (33.4%) patients with CIN. The high prevalence of CIN in smears showing only borderline nuclear abnormalities and the high false negative rate of repeat cytology indicate that colposcopy should be the first line of management for these patients.
The present review has focused on the specificity of the T-helper cell populations initiating MHC class I alloreactions. In contrast to conventional immune responses against soluble antigens, responses against membrane-bound class I alloantigens are initiated by two distinct antigen-specific T-helper cell populations that can be distinguished by their Lyt phenotype, MHC restriction specificity, antigen specificity, and requirement for thymically determined self-recognition. Alloresponses were shown to be a composite consisting of two distinct components: one mediated by L3T4+ Th cells and very similar to conventional self + X responses; and one mediated by Lyt2+ Th cells and unique to alloresponses against MHC class I antigens. As would befit an unusual Th cell population, the recognition/response spectrum of Lyt2+ Th cells was highly unusual and was found to be the basis for much of the uniqueness we attribute to immune alloreactions, including rapid rejection of tissue allografts in vivo.
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The Illness Behaviour Questionnaire was used to determine whether three groups of patients who had presented with multiple symptoms in different treatment settings (Briquet's syndrome, post-viral fatigue syndrome, and a heterogeneous general practice group) could be differentiated from one another and from a mixed group of psychiatric patients on the basis of their abnormal illness behaviour. All groups completed a version of the Perley and Guze diagnostic criteria for Briquet's syndrome. The three groups presenting with multiple symptoms were more similar to each other than to the psychiatric patients. The results suggest that patients presenting with multiple symptoms include similar populations of patients who are poorly distinguished using current schemes of classification.
Somatization disorder (SMD) is a chronic condition characterized by multiple complaints which are not due to any apparent organic illness but frequently involve pain. This study employs computer-aided imaging technologies to examine brain function in thousandths of a second (event-related brain potentials) and over a number of minutes (regional cerebral blood flow). Fourteen patients with SMD and 14 normal controls were investigated. Results from both studies suggest that patients with SMD have a dysfunction in the processes of attention, compared to normal controls.
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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.
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