bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pagetoid variant of actinic keratosis with or without squamous cell carcinoma of sun‐exposed skin: a lesion simulating extramammary Paget's disease
Authors: Mai K T , Alhalouly T , Landry D , Stinson W A , Perkins D G , Yazdi H M 
Published: March 2003

Background: Extramammary Paget's disease usually occurs in anogenital skin. We present five cases of squamous cell carcinoma in situ of sun‐exposed skin and non‐squamous cell carcinoma in situ actinic keratosis that displayed atypical keratinocytes disposed in intraepithelial cell nests and immunohistochemical staining simulating extramammary Paget's disease.Methods and results: Two pilot cases—one squamous cell carcinoma in situ and one non‐squamous cell carcinoma in situ actinic keratosis with formation of intra‐epidermal nests of atypical keratinocytes with a pagetoid spread pattern—were encountered at our institution. Fifty‐four consecutive cases of squamous cell carcinoma in situ including bowenoid actinic keratosis and 34 cases of non‐squamous cell carcinoma in situ actinic keratosis were reviewed to identify pagetoid spread of atypical cells. Representative sections of all cases with pagetoid spread of atypical keratinocytes were submitted for special stains for mucin, and immunostaining for cytokeratin 7 (CK7), cytokeratin 20 (CK20), cytokeratin CAM 5.2 (CAM 5.2), carcinoembryonic antigen (CEA), vimentin and S100 protein. In the group of squamous cell carcinoma in situ, 10 cases displayed pagetoid spread of atypical keratinocytes with cytoplasm ranging from clear to pale and atypical hyperchromatic nuclei. One review squamous cell carcinoma in situ was multicentric with three separate lesions. The atypical keratinocytes tended to form well to poorly defined cell groups extending from the basal cell layer to the corneal layer. No similar cases were identified in the group of non‐squamous cell carcinoma in situ actinic keratosis. Two pilot cases and three of 10 review cases with a total of seven separate lesions displayed a moderate to marked immunohistochemical reactivity for CK7 similar to extramammary Paget's disease. CEA immunoreactivity was also detected in two of these cases. In addition, two of 44 squamous cell carcinomas in situ without pagetoid spread of atypical keratinocytes showed a moderate reactivity for CK7 in very occasional atypical keratinocytes. The remaining seven squamous cell carcinomas in situ with pagetoid spread of atypical keratinocytes were not immunoreactive for CEA and CK7. Immunostaining for CK20, vimentin, S100 protein was negative in all atypical cells in all study cases.Conclusions: Actinic keratosis, particularly squamous cell carcinoma in situ of sun‐exposed skin, may have histopathological and immunohistochemical features similar to extramammary Paget's disease and probably represents a variant of actinic keratosis. Awareness of the pagetoid variant of actinic keratosis arising in sun‐exposed skin is helpful to avoid the over‐diagnosis of extramammary Paget's disease.
Immune responses and protection against vaginal infection after nasal or vaginal immunization with attenuated herpes simplex virus type‐2
Authors: Parr E. L. , Parr M. B. 
Published: March 2003

SummaryWe compared nasal and vaginal immunizations using attenuated herpes simplex virus type‐2 (HSV‐2) for protection against vaginal infection with wild‐type HSV‐2. Mice were immunized once intranasally, intravaginally after progestin (DP) treatment, or intravaginally with scarification after oestradiol treatment. Compared with vaginal immunizations, nasal immunization did not increase immunoglobulin A (IgA) plasma cell numbers in the vagina or elicit a higher antiviral IgA titre in vaginal secretions. Both types of vaginal immunizations increased the number of immunoglobulin G (IgG) plasma cells in the vagina and the secretion/serum titre ratio of IgG antiviral antibody, indicating local production of virus‐specific IgG in these groups. Cell‐mediated immunity in the vagina, as indicated by memory T‐cell secretion of interferon‐γ (IFN‐γ) in situ 20 hr after HSV‐2 challenge, was essentially equivalent in the vaginally immunized groups but significantly lower in the nasal group, while lymphocyte recruitment to the vagina was similar in all three groups. All three immunizations protected all mice from neurological disease after challenge, but vaginal DP immunization induced the greatest immunity against reinfection of the vaginal epithelium.
Effects of α‐galactosylceramide (KRN7000), interleukin‐12 and interleukin‐7 on phenotype and cytokine profile of human Vα24+ Vβ11+ T cells
Authors: Van Der Vliet H. J. J. , Nishi N. , Koezuka Y. , Peyrat M. A. , Von Blomberg B. M. E. , Van Den Eertwegh A. J. M. , Pinedo H. M. , Giaccone G. , Scheper R. J. 
Published: March 2003

SummaryThe α‐galactosylceramide KRN7000 was reported to be presented by CD1d to natural killer (NK) T cells, cells that are thought to play an important role in the rejection of malignant tumours and in the regulation of several autoimmune diseases. Here we analysed human peripheral blood (PB) NK T cells (Vα24+ Vβ11+ T cells) before and after a short‐term culture in the presence of KRN7000. KRN7000 strongly activated PB Vα24+ Vβ11+ T cells and, when stimulated, the vast majority of these cells expressed interferon‐γ (IFN‐γ). Exposure of these KRN7000‐cultured Vα24+ Vβ11+ T cells to interleukin‐12 (IL‐12), but not to IL‐7, resulted in a relative increase in IFN‐γ‐expressing Vα24+ Vβ11+ T cells, compared with IL‐4‐expressing Vα24+ Vβ11+ T cells, indicating a shift towards a T‐helper type 1 (Th1) phenotype. KRN7000 strongly up‐regulated the expression of the cytotoxic molecule granzyme B (GrB) in Vα24+ Vβ11+ T cells. Although IL‐7 resulted in a decrease in GrB levels in KRN7000‐cultured Vα24+ Vβ11+ T cells, IL‐12 increased GrB levels in both Vα24+ Vβ11+ T cells and in Vα24+ Vβ11+ T‐cell clones and increased cytotoxicity against hCD1d‐transfected HeLa cells. Our data provide further insight into the characteristics of human Vα24+ Vβ11+ T cells and indicate that KRN7000 is a potent activator of Vα24+ Vβ11+ T cells. Combined with the established anti‐tumour effects of KRN7000 in mouse models, these results may support the use of KRN7000 as an anti‐tumour agent in man.
The intercellular adhesion molecule type‐1 is required for rapid activation of T helper type 1 lymphocytes that control early acute phase of genital chlamydial infection in mice
Authors: Igietseme J. U. , Ananaba G. A. , Bolier J. , Bowers S. , Moore T. , Belay T. , Lyn D. , Black C. M. 
Published: March 2003

SummaryRecent studies in animal models of genital chlamydial disease revealed that early recruitment of dendritic cells and specific T helper type‐1 (Th1) cells into the genital mucosae is crucial for reducing the severity of the acute phase of a cervico‐vaginal infection and arresting ascending disease. These immune effectors are therefore important for preventing major complications of genital chlamydial infection. Other in vitro studies showed that intercellular adhesion molecule‐1 (ICAM‐1) plays a role in the antichlamydial action of specific CD4+ and CD8+ T cells. In the present study, we investigated the clinicopathological consequences of ICAM‐1 deficiency during chlamydial genital infection in ICAM‐1 knockout (ICAM‐1KO) mice, and analysed the cellular and molecular immunological bases for any observed pathology or complication. Following a primary genital infection of female ICAM‐l–/– and ICAM‐1+/+ mice, the intensity of the disease during the first 3 weeks (as assessed by shedding of chlamydiae in the genital tract) was significantly greater in ICAM‐1KO mice than in ICAM‐1+/+ mice (P < 0·0001), although both ICAM‐l–/– and ICAM‐1+/+ mice subsequently cleared the primary infection. There was greater ascending disease during the initial stage of the infection, and a higher incidence of tubal disease (hydrosalpinx formation) after multiple infections in ICAM‐l–/– mice. Analysis of the cellular and molecular bases for the increased acute and ascending disease in ICAM‐l–/– mice revealed that the high affinity of ICAM‐1 for leucocyte function antigen type‐1 is a property that promotes rapid activation of specific Th1 cells, as well as their early recruitment into the genital mucosa. Moreover, ICAM‐1 was more important for naive T‐cell activation than primed Th1 cells, although its absence delayed or suppressed immune T‐cell activation by at least 50%. Taken together, these results indicated that ICAM‐1 is crucial for rapid T‐cell activation, early recruitment and control of genitally acquired Chlamydia trachomatis.
Inflammatory cytokine production by immunological and foreign body multinucleated giant cells
Authors: Hernandez‐Pando R. , Bornstein Q. L. , Aguilar Leon D. , Orozco E. H. , Madrigal V. K. , Martinez Cordero E. 
Published: March 2003

SummaryMultinucleated giant cells (MGC) are a common feature of granulomas. The mechanism of their formation has been studied extensively, but their function has not been completely characterized. A new method for the in vivo production of MGC was developed involving subcutaneous injection of microscopic nitrocellulose particles with adsorbed mycobacterial antigens into the footpads of sensitized BALB/c mice (immune [I]‐MGC), or by nitrocellulose administration to non‐sensitized mice (foreign body [FB]‐MGC). The development of granulomas with a highly enriched MGC population was observed 2 weeks after the nitrocellulose injection. MGC were larger with a greater number of nuclei in I‐MGC than in FB‐MGC. From days 7–28 after nitrocellulose administration, the production of interleukin‐1α (IL‐1α) and tumour necrosis factor‐α (TNF‐α) was demonstrated in both MGC types by in situ reverse transcription–polymerase chain reaction (RT–PCR) and immunohistochemistry. After 2 months, the MGC had ceased production of IL‐1α and TNF‐α, but the expression of transforming growth factor‐β (TGF‐β) was very high, occurring together with extensive fibrosis. These results suggest that MGC are an active source of inflammatory cytokines, which can contribute to the initiation, maintenance and down‐regulation of granulomatous inflammation induced by immunological and inert substances.
Comparative analysis of integrin expression on monocyte‐derived macrophages and monocyte‐derived dendritic cells
Authors: Ammon C. , Meyer S. P. , Schwarzfischer L. , Krause S. W. , Andreesen R. , Kreutz M. 
Published: March 2003

SummaryBoth macrophages (MAC) and dendritic cells (DC) are members of the mononuclear phagocyte system (MPS) with monocytes (MO) as common precursor cells. Cells of the MPS are able to take up, process and present antigens to T lymphocytes, thereby inducing a primary or secondary immune response. Adhesion molecules are of crucial importance for the interaction of antigen‐presenting cells with immune cells, especially T lymphocytes. By representational difference analysis, we identified CD49c (VLA‐3), a member of the β1‐integrin family of adhesion receptors, as differentiation‐associated antigen in MO‐derived MAC. In contrast, MO‐derived DC did not express CD49c mRNA. These data prompted us to compare the integrin expression pattern of MAC and DC. Both cell types showed a low expression of the α‐chains of the β1‐integrins CD49a, CD49b, CD49d and CD49e, whereas a marked difference was observed for CD49c and CD49f. Expression of both integrins increased during MO to MAC differentiation, but was not detectable on DC. In parallel the β1‐chain (CD29) was clearly up‐regulated during MO to MAC differentiation but was only weakly expressed on DC. On the other hand, the β2‐integrins CD11a, CD11b, CD11c and CD18 were all expressed on MAC and DC. Beside their role in cell–cell interaction and adhesion, β2‐integrins are also known as possible binding molecules for bacteria and lipopolysaccharide (LPS), especially for high LPS concentrations. Therefore we investigated the LPS response of MAC versus DC in terms of tumour necrosis factor‐α (TNF‐α) release. DC were less responsive to low doses of LPS, which can easily be explained by the very low CD14 expression on DC compared for MAC. In contrast, the TNF‐α response was comparable to MAC when DC were stimulated with high LPS concentrations. Our results show a specific, differentiation‐dependent pattern of β1‐ and β2‐integrin expression on in vitro‐generated MAC and DC. We suggest that the high expression of CD11/CD18 on DC could be involved in the LPS binding of DC. As LPS is not only an activation but also a differentiation stimulus for DC, the expression of CD11/CD18 on DC may be important for the successful maturation of DC and thereby the initiation of a primary immune response.
Engineering the microflora to vaccinate the mucosa: serum immunoglobulin G responses and activated draining cervical lymph nodes following mucosal application of tetanus toxin fragment C‐expressing lactobacilli
Authors: Shaw D. M. , GaerthÉ B. , Leer R. J. , Van Der Stap J. G. M. M. , Smittenaar C. , Heijne Den Bak‐Glashouwer M.‐J. , Thole J. E. R. , Tielen F. J. , Pouwels P. H. , Havenith C. E. G. 
Published: March 2003

SummaryThe delivery of antigens to mucosal‐associated lymphoid tissues in paediatric and immunocompromised populations by safe, non‐invasive vectors, such as commensal lactobacilli, represents a crucial improvement to prevailing vaccination options. In this report, we describe the oral and nasal immunization of mice with vaccines constructed through an original system for heterologous gene expression in Lactobacillus in which the 50 000‐molecular weight (MW) fragment C of tetanus toxin (TTFC) is expressed either as an intracellular or a surface‐exposed protein. Our data indicate that L. plantarum is more effective in this respect than L. casei and that, under the experimental conditions investigated, delivery of TTFC expressed as an intracellular antigen is more effective than cell‐surface expression. Immunization of mice with live recombinant lactobacilli induced significant levels of circulating TTFC‐specific immunoglobulin G (IgG) following nasal or oral delivery of vaccine strains. In addition, following nasal delivery, secretory immunoglobulin A (sIgA) was induced in bronchoalveolar lavage fluids, as were antigen‐specific antibody‐secreting cells and antigen‐specific T‐cell activation in draining lymph nodes, substantiating their potential for safe mucosal delivery of paediatric vaccines.
Staphylococcal enterotoxin B induces potent cytotoxic activity by intraepithelial lymphocytes
Authors: Roberts A. I. , Blumberg R. S. , Christ A. D. , Brolin R. E. , Ebert E. C. 
Published: March 2003

SummaryIn food poisoning, Staphylococcus aureus secretes staphylococcal enterotoxin B (SEB), a superantigen that causes intense T‐cell proliferation and cytotoxicity. The effects of SEB on lytic activity by human intestinal intraepithelial lymphocytes (IEL) were investigated. Jejunal IEL, from morbidly obese individuals undergoing gastric bypass operations, were tested for SEB‐induced cytotoxicity against C1R B‐lymphoblastoid cells, HT‐29 adenocarcinoma cells, or CD1d‐transfected cells using the 51Cr‐release assay. Fas and Fas ligand expression were detected by immunofluorescence and flow cytometry and soluble ligand by enzyme‐linked immunosorbent assay (ELISA). In the presence of SEB, IEL became potently cytotoxic against C1R cells and interferon‐γ (IFN‐γ)‐precultured HT‐29 cells, causing 55 ± 10% and 31 ± 6% lysis, respectively, greater than that by phytohaemagglutinin (PHA)‐, interleukin‐2 (IL‐2)‐, or anti‐T‐cell receptor (TCR)‐activated IEL. SEB‐stimulated peripheral blood (PB) CD8+ T cells lysed similar numbers of C1R cells but fewer HT‐29 cells (53 ± 13% and 8 ± 5%, respectively). IEL killing of C1R cells involved interaction of major histocompatibility complex (MHC) class II with TCR, CD2 with CD58, and CD11a with CD54, and was perforin mediated. SEB‐induced IEL lysis of HT‐29 cells, in contrast, was caused by an unknown target cell structure, not MHC class II or CD1d, and resulted from a combination of perforin and Fas‐mediated events. The potent cytotoxic activities of IEL promoted by SEB utilize two different mechanisms, depending on the surface receptors expressed by the target cells.
Professional and non‐professional antigen‐presenting cells in the porcine small intestine
Authors: Haverson K. , Singha S. , Stokes C. R. , Bailey M. 
Published: March 2003

SummaryWe have previously presented evidence of a highly organized and compartmentalized structure of the small intestinal lamina propria of the pig. In this work, we have identified at least two major populations of cells in this site expressing high levels of major histocompatibility complex (MHC) class II antigens. One is CD45 positive and is a potent initiator of a primary immune response, this is a function usually associated with dendritic cells. These cells have characteristic dendritic morphology, but show evidence of phagocytosis as well as other phenotypic markers of immature dendritic cells. Some cells show evidence of ongoing immune maturation. We have also isolated CD45 negative endothelial cells bearing significant amounts of MHC class II, which do not trigger a mixed lymphocyte reaction. These findings have implications for the functional role of healthy gut lamina propria and clearly implicate this site as capable of differential antigen presentation by a heterogeneous population of antigen‐presenting cells.
Cellular but not humoral immune responses generated by vaccination with dendritic cells protect mice against leukaemia
Authors: Colombo B. M. , Lacave R. , Pioche‐durieu C. , Masurier C. , Lemoine F. M. , Guigon M. , Klatzmann D. 
Published: March 2003

SummaryDendritic cells (DC) are extremely efficient at generating both prophylactic and therapeutic anti‐tumour immunity. We aimed to analyse the respective roles of humoral and cellular immune responses generated in mice vaccinated with bone marrow (BM)‐derived DC in terms of in vivo anti‐leukaemia effect. We used the murine L1210 B lymphocytic leukaemia genetically modified to express on the cell surface of human CD4 (hCD4) (L1210/hCD4) as a model tumour‐associated antigen (TAA). DC cultures were loaded with either purified soluble hCD4 (shCD4) protein or unfractionated L1210/hCD4 extracts and injected as vaccine into mice. The efficacy of these vaccinations was compared with that of vaccination with shCD4 protein emulsified in Freund’s adjuvant (FA). We evaluated the immune responses generated after these vaccinal protocols and the survival rate of vaccinated mice subsequently challenged with a lethal injection of L1210/hCD4 cells. Our results demonstrated that vaccination with shCD4 protein or tumour extract‐loaded DC mainly generated an hCD4 antigen‐specific cell‐mediated cytotoxic immune response that was associated with a specific protection against leukaemia. In contrast, vaccination with the protein emulsified in FA only generated potent humoral immune responses that were not protective against leukaemia. Altogether, our results indicate that the unique property of loaded DC to trigger an anti‐leukaemia protective effect is mainly associated with cellular immune responses.
Interferon‐γ plays a critical role in intestinal immunity against Salmonella typhimurium infection
Authors: Bao S. , Beagley K. W. , France M. P. , Shen J. , Husband A. J. 
Published: March 2003

SummarySalmonella bacteria are a major cause of food‐borne infectious diarrhoea and there is great interest in understanding the pathogenesis of Salmonella infection and in vaccine development. Potential vaccines include the aromatic mutants of S. typhimurium. Such non‐lethal Aro mutants have also been useful for studying Salmonella infections in mouse models. Studies of systemic infection, using these Aro mutants, in both normal and cytokine gene knockout mice, indicate that interferon‐γ (IFN‐γ) plays a key role in the resolution of Salmonella infection. The present studies have investigated the outcome of oral infection in mice with attenuated Salmonella because this infection route mimics natural infection in humans. In IFN‐γ gene knockout (IFN‐γ–/–) mice, intestinal immunity was impaired and oral challenge resulted in disseminated septicaemia 2 weeks later. No dissemination of infection was seen in wild‐type mice. In wild‐type mice, both CD4 and CD8 cell numbers increased in the gut following Salmonella challenge, together with increased expression of major histocompatibility complex (MHC) II and vascular cell adhesion molecule‐1 (VCAM‐1). No such changes were seen in IFNγ–/– mice. Following oral challenge, antilipopolysaccharide (LPS) and antiphosphoryl choline antibodies increased by more than 100‐fold in both serum and faecal pellet extracts of IFNγ–/– mice compared with wild‐type mice. Our data show that IFN‐γ production is essential for resolution of enteric Salmonella infection and that antibody has little effect on this process.
Redundancy or cell‐type‐specific regulation? Tumour necrosis factor in alveolar macrophages and mast cells
Authors: Déry R. E. , Lin T.‐J. , Befus A. D. , Milne C. D. , Moqbel R. , Ménard G. , Bissonnette E. Y. 
Published: March 2003

SummaryTumour necrosis factor (TNF) is an important inflammatory cytokine produced by several cell types. To test the hypothesis that there is cell‐type‐specific regulation and not redundancy of TNF production, we investigated its production by alveolar macrophages (AM) and peritoneal mast cells (PMC). Cell lysates of freshly isolated AM and PMC contained 9 ± 3 pg and 57 ± 17 pg of TNF/106 cells, respectively. Furthermore, unstimulated PMC expressed 4 × 103‐fold more attomols of TNF mRNA/µg total RNA compared with AM. These data may explain in part the greater TNF‐dependent cytotoxicity of PMC. Furthermore, fixed PMC showed significantly higher TNF‐dependent cytotoxic activity than AM (sevenfold), suggesting that PMC express more membrane TNF than AM. Although AM and PMC contain different amounts of TNF, antigen stimulation caused a similar release of TNF from sensitized rats. Interferon (IFN)‐γ, respectively, stimulated and inhibited AM and PMC TNF‐dependent cytotoxicity whereas lipopolysaccharide (LPS) significantly stimulated TNF‐dependent cytotoxicity in both cell types. However, TNF released (AM 400‐fold and PMC threefold) and TNF mRNA expression, as measured by competitive reverse transcription–polymerase chain reaction (AM 7 × 103‐fold and PMC twofold), were considerably greater in LPS‐stimulated AM than PMC. Our data indicate that TNF is differentially expressed in these two cell types and that its production is dependent on the nature of the stimulus. These data provide vital basis in experimental approaches aimed at modulating the effect of TNF in airway disease conditions involving both AM and mast cells.