bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of Age and Breeding Conditions on the Number and Proliferation of Intraepithelial Lymphocytes in Pigs
Authors: Rothkötter  , Möllhoff  , Pabst
Published: March 2003

The number and subset composition of intraepithelial lymphocytes (IEL) were studied in pigs in different age groups ranging from 1 day to 4.5 years. There were no major differences between the numbers of IEL in the jejunum and ileum. The postnatal increase of IEL largely depended on the breeding conditions: in germ‐free animals there was a constant level, while in conventionally bred pigs the numbers increased more obviously than in specified pathogen‐free (SPF) pigs. As the numbers of IEL can rise due to increased influx from other organs, decreased emigration, decreased apoptosis or local proliferation, the incorporation of the DNA precursor bromodeoxyuridine (BrdU) by IEL was studied after different labelling protocols. There were low but definite numbers of BrdU+ IEL 1 h after BrdU, indicating in‐situ proliferation in conventional animals with a tendency to a higher index in the jejunum than the ileum. Repetitive labelling protocols for 14 days resulted in 12–20% BrdU+ IEL, which may be caused by local proliferation and immigration of lymphocytes produced in other lymphoid organs as documented for the pig. Future studies need to focus on the factors regulating local proliferation and the migration of IEL in different species.
Salivary Antigliadin and Antiendomysium Antibodies in Coeliac Disease
Authors: Lähteenoja  , Toivanen  , Räihä  , Syrjänen  , Viander
Published: March 2003

The definitive diagnosis of coeliac disease is based on typical changes in the small intestine biopsy specimens. To screen individuals for coeliac disease serum IgA and IgG antigliadin (AGA), IgA antireticulin (ARA) and IgA antiendomysium (EmA) antibodies are used. The aim of this study was to investigate whether these antibodies can also be detected in saliva as diagnostic markers of coeliac disease. The study population comprised 30 patients with coeliac disease treated with a gluten‐free diet, 14 patients with untreated coeliac disease and 13 healthy control subjects. Sera and saliva were tested simultaneously for the presence of IgA and IgG AGA and IgA EmA. None of patients studied had a selective IgA deficiency. There was no significant difference in salivary IgA AGA levels between the three groups tested and there was no correlation between the individual serum and salivary values of IgA AGA. Salivary IgG AGA levels were very low or undetectable. Serum IgA AGA showed a low sensitivity (36.4%) to detect an untreated patient with coeliac disease. All salivary samples, regardless of the study group were negative for IgA EmA. Serum IgA EmAs were universally detected in the sera of patients with newly diagnosed coeliac disease and also in the sera of five of 30 patients with treated coeliac disease. No IgA EmA was detected in the sera of controls. None of the patients studied had a selective IgA deficiency either. Serum IgA EmA is the most sensitive, and IgA and IgG AGA are good indicators for coeliac disease, but salivary IgA or IgG AGA and salivary IgA EmA are not helpful for the diagnosis or follow‐up of coeliac disease patients.
Regulation of Effector Cell Functions Through the Ligation of Lymphocyte Function‐Associated Antigen‐1 and Intracellular Adhesion Molecule‐1 Leads to Spontaneous Regression of a Rat Histiocytoma
Authors: Divya Jyothi  , Varalakshmi  , Khar
Published: March 2003

Cell adhesion molecules mediate cell‐to‐cell interactions, thereby regulating effective immune response against target cells. We have investigated the intercellular cross‐talk between lymphocyte function‐associated antigen‐1 (LFA‐1) and its counter‐receptor, intercellular adhesion molecule‐1 (ICAM‐1). This interaction regulates the postadhesion events leading to the regression of a rat histiocytoma, AK‐5, which is mediated by natural killer (NK) cells through antibody‐dependent cell cytotoxicity (ADCC). Repeated systemic administration of anti‐cell adhesion molecule (anti‐CAM) monoclonal antibodies (MoAbs), i.e. anti‐LFA‐1 and anti‐intracellular adhesion molecule‐1 (anti‐ICAM‐1), in AK‐5 tumour‐bearing animals enhanced tumour growth and caused delayed regression. The immune suppression achieved after the administration of these antibodies could be attributed to the diminished cytotoxic, as well as apoptotic, activity of NK cells. The MoAbs selectively reduced the adhesion of NK cells to the tumour cells in vitro. Flow cytometric analysis showed down‐regulation of Fas‐ligand expression on NK and T cells following MoAb administration in vivo. Marked reduction in the lymphokine‐activated killer (LAK) activity of NK cells was also observed after in vitro blocking of LFA‐1 and ICAM‐1 molecules. In addition, continuous MoAb administration induced suppression of the cytokine response. These results underline the importance of ligand binding between LFA‐1 and ICAM‐1, which could provide co‐stimulation for the effector‐cell functions via signalling events to induce cytotoxicity, apoptosis and cytokine production, resulting in the efficient regression of AK‐5 tumour in syngeneic hosts.
Cloning, Expression and Immunological Reactivity of Two Mammalian Cell Entry Proteins Encoded by the mce1 Operon of Mycobacterium tuberculosis
Authors: Ahmad  , Akbar  , Wiker  , Harboe  , Mustafa
Published: March 2003

The DNA segments corresponding to two members of the mammalian cell entry operon 1 (mce1) encoding Mce1A and Mce1E proteins were amplified from Mycobacterium tuberculosis genomic DNA by polymerase chain reaction, cloned and subcloned into pGEM‐T and pGEX‐4T‐3 vectors, respectively, and expressed in Escherichia coli as fusion proteins with glutathione‐S‐transferase (GST) of Schistosoma japonicum as the fusion partner. The recombinant proteins appeared as major cellular proteins in SDS–PAGE gels at the expected molecular mass of 68 kDa and 64 kDa for GST–Mce1A and GST–Mce1E, respectively. The identity of each fusion protein was confirmed by reactivity with anti‐GST antibodies in Western immunoblots. The fusion proteins were purified to near homogeneity by affinity chromatography, and purified Mce1A and Mce1E, free of the fusion partner, were recovered following specific proteolytic cleavage of the GST portion by thrombin protease. Purified Mce1E appeared as a single band of 38 kDa, whereas purified Mce1A tended to exist in degraded as well as aggregated forms of different sizes. The fusion proteins, free GST and monomeric Mce1A and Mce1E reacted in Western immunoblots with antibodies in pools of human sera from six to 11 tuberculosis patients. Similar analysis showed the presence of antibodies to GST and Mce1A, in pools of human sera from M. bovis BCG‐vaccinated healthy subjects. When pure Mce1E was blotted against individual sera, antibodies in 4/10 sera from tuberculosis patients reacted, whereas no reaction was seen with 10 individual sera from M. bovis BCG‐vaccinated healthy subjects. However, when the same sera were tested for reactivity to the purified preparation of Mce1A, 8/10 sera from both tuberculosis patients and M. bovis BCG‐vaccinated healthy subjects showed positive reactivity. These findings demonstrate that both Mce1A and Mce1E are expressed and immunogenic during natural infection with M. tuberculosis.
Elevated CD40 Ligand Expressing Blood T‐Cell Levels in Multiple Sclerosis Are Reversed by Interferon‐Beta Treatment
Authors: Teleshova  , Bao  , Kivisäkk  , Özenci  , Mustafa  , Link
Published: March 2003

Myelin protein reactive CD4+ T cells are considered to be involved in the proposed immunopathogenesis of multiple sclerosis (MS). One particularly important molecule for T‐cell activation is the CD40L (gp39) that is expressed on the surface of T cells. This study focuses on the CD40 and the CD40L expression on mononuclear cells prepared from blood from patients with MS, other neurological diseases (OND) and healthy subjects. Immunostaining followed by a three channel flow cytometry was adopted. Patients with MS had higher levels of CD3+CD40L+, CD4+CD40L+ and CD8+CD40L+ T cells compared to patients with OND and healthy subjects. Cross‐sectional comparisons revealed that the elevation of CD40L+ T cell subtypes was confined to the patients with untreated MS and not observed in the patients with MS treated with interferon‐β (IFN‐β). Follow up studies showed that levels of CD3+CD40L+ and CD4+CD40L+ T cells decreased in individual patients after the initiation of the IFN‐β treatment. The enhanced expression of CD40L on CD3+, CD4+ and CD8+ T cells in patients with MS may implicate a role for this molecule in disease immunopathogenesis.
Interleukin‐12 in Human Boutonneuse Fever Caused by Rickettsia conorii
Authors: Milano  , D'agostino  , Di Bella  , La Rosa  , Barbera  , Ferlazzo  , Mansueto  , Rini  , Barera  , Vitale  , Mansueto  , Cillari
Published: March 2003

Interleukin (IL)‐12 contributes to the resistance against a number of intracellular pathogens. We examined the potential biological role of IL‐12 by studying peripheral blood mononuclear cells (PBMC), its production and its effect on cytokine synthesis in 20 Sicilian patients with boutonneuse fever (BF) caused by Rickettsia conorii. Data indicate that PBMC from acute BF patients were able to produce IL‐12 in response to in vitro stimulation with rickettsial antigen (Ag): this production was higher than that detected in healed patients. Monocytes were the main source of IL‐12 by PBMC from BF patients. IL‐12 secretion by in vitro Ag‐stimulated PBMC from BF patients was potentiated by recombinant interferon gamma (IFN‐γ) or anti‐IL‐10 monoclonal antibodies (MoAbs). Furthermore, the treatment with anti‐IL‐12 MoAbs reduced the IFN‐γ synthesis. These results indicate that treatment of PBMC from acute BF patients with IL‐12 shifted the response toward a Th1‐type cytokine response. Furthermore, IL‐12 and IFN‐γ are interdependent and they may be associated with the immunity against rickettsias.
Culture Filtrate of Cryptococcus neoformans var. gattii (CneF) as a Novel Anti‐Inflammatory Compound in the Treatment of Experimental Septic Arthritis
Authors: Mirshafiey  , Chitsaz  , Attar  , Mehrabian  , Razavi
Published: March 2003

We examined the efficacy of the culture filtrate of Cryptococcus neoformansvar. gattii (CneF) as a novel anti‐inflammatory compound in experimental septic arthritis. Haematogenously infectious arthritis was induced in rats by a single intravenous injection of 109 CFU Staphylococcus aureus producing toxic shock syndrome toxin‐1. CneF solution at two different doses (36 and 72 mg/kg, based on carbohydrate concentration) was administered intraperitoneally 2 h before bacterial inoculation in the prevention groups and simultaneously with the appearance of clinical signs in the therapeutic groups. CneF administration was continued at regular 48‐h intervals for 10 injections. The results of clinical evaluation showed that CneF‐treated rats were significantly protected from disease development compared with nontreated controls. This finding correlated with the results of histological and radiological assessments of the involved joints. Synovial hypertrophy, inflammatory cell infiltration, pannus formation and cartilage/bone destruction were found to be significantly decreased in the prevention and therapeutic groups compared with arthritic controls. The data suggest that CneF may have therapeutic potential in the treatment of septic arthritis.
Neurological Disease‐Associated Autoantibodies against an Unknown Protein Encoded by a RES4‐22 Homologous Gene
Authors: Amin M. , Uhlig H. H. , Kamprad M. , Karbe J. , Osman A. A. , Grahmann F. , Hummelsheim H. , Mothes T.
Published: March 2003

Screening a human small intestinal library with human serum yielded a clone which encoded a protein res4‐22 the gene of which was highly homologous to a recently described gene located in the Huntington's disease locus. Autoantibodies against res4‐22 (anti‐res4‐22), mainly of the immunoglobulin (Ig)A type, were detected in patients with neurological disorders at a higher frequency (18.4%) than in healthy blood donors (8.0%). In neurological patients with cerebral ischaemia anti‐res4‐22 was found significantly more often (47.4%) than in the total group of neurological patients. Anti‐res4‐22 positive sera showed significantly more frequently myelin staining in cerebellum and nerve sections than anti‐res4‐22 negative sera. Our findings demonstrate a new species of human autoantibodies against a newly described protein the function of which is still unknown.
In vitro Evaluation of an Enhanced Human Serum Amyloid A (SAA2) Promoter‐Regulated Soluble TNF Receptor Fusion Protein for Anti‐Inflammatory Gene Therapy
Authors: Rygg M. , Uhlar C. M. , Thorn C. , Jensen L. E. , Gaughan D. J. , Varley A. W. , Munford R. S. , Göke R. , Chen Y. , Whitehead A. S.
Published: March 2003

Tumour necrosis factor (TNF)‐α contributes to the pathogenesis of many inflammatory diseases. Recombinant soluble TNF receptor fusion proteins (sTNFR:Ig) are potent TNF antagonists, both in vitro and in vivo. The concentration of serum amyloid A (SAA) increases by up to 1000‐fold during inflammation, largely owing to cytokine‐driven transcriptional upregulation. A reporter plasmid, comprising the proximal 0.7 kb of the human SAA2 promoter fused to a luciferase gene, was used in transient transfection experiments in human HepG2 hepatoma cells to assess the quantitative and qualitative TNF antagonist properties of a construct in which sTNFR:Ig synthesis is under the control of a chimera of the SAA2 promoter and a tat/HIV element. The SAA2‐tat/HIV‐sTNFR:Ig construct retained the fine‐tuned cytokine responsiveness of the SAA2 promoter, while exhibiting the quantitatively enhanced level of protein expression conferred by the tat/HIV element. It produced a biologically significant TNF inhibition that was at least as strong as that achieved using a CMV promoter‐driven sTNFR:Ig construct. There was a dose‐ and time‐dependent relationship between the pro‐inflammatory cytokine used, and the generation of TNF antagonist activity by SAA2‐tat/HIV‐sTNFR:Ig. Although sTNFR:Ig protein can be induced by either TNF‐α or interleukin (IL)‐1β, its antagonist activity is limited to the former cytokine. The SAA2‐tat/HIV‐sTNFR:Ig construct, and derivatives thereof, may therefore be ideally suited to gene therapy applications that require the local production of potent and specific immune modifiers only when there is active pathology. It may consequently be of particular use in the future treatment of diseases such as rheumatoid arthritis.
Genetic Control of Resistance to Mercury‐Induced Immune/Autoimmune Activation
Authors: Abedi‐Valugerdi M. , Hansson M. , Möller G.
Published: March 2003

Previous studies have shown that genetic factors control the susceptibility to mercury‐induced immunoglobulin (Ig)G1 antibody formation, IgE synthesis, renal IgG deposits and antinucleolar autoantibodies (ANolA) production in the susceptible mice. In this study, we examined the genetic control of resistance to these characteristics after HgCl2 injection in F1 hybrid crosses between the highly mercury resistant DBA/2 and mercury susceptible NZB (H‐2d), SJL (H‐2 s), A.CA (H‐2f) and DBA/1 (H‐2q) mice and also in backcross hybrids between (DBA/2 × SJL)F1 and SJL mice. We observed that mercury‐induced immune/autoimmune manifestations were profoundly downregulated in most (if not all) of the F1 hybrids, indicating that the resistance to mercury was a dominant trait. Analysis of mercury‐induced immune/autoimmune responses in the (DBA/2 × SJL) × SJL backcross hybrids suggested that only one gene or a cluster of genes determined the resistance to the ANolA production, whereas the resistance to other characteristics was controlled by two and/or three gene loci. By H‐2 genotyping the backcross mice, it was found that H‐2d haplotype per se could confer resistance to ANolA production. However, we did not find any significant association between the H‐2d haplotype and the resistance to increase of IgG1 and IgE synthesis and the development of renal IgG1 deposits. Thus, while in DBA/2 mice, gene(s) in the H‐2 loci strictly contribute to the inheritance of resistance to ANolA production; non‐H‐2 genes mainly govern the inheritance of unresponsiveness regarding other characteristics.
Lymphocyte Homing and Ig Secretion in the Murine Mammary Gland
Authors: Van Der Feltz M. J. M. , De Groot N. , Bayley J.‐P. , Lee S. H. , Verbeet M. PH. , De Boer H. A.
Published: March 2003

In mice the majority of the immunoglobulins (Ig) in milk belongs to the IgA class. Prior to its transepithelial transportation into the milk, dimeric IgA (dIgA) is bound to the transmembrane form of the secretory component or polymeric Ig receptor (SC/pIgR). The latter is synthesized in the epithelial cells lining the ducts and alveoli of the mammary gland. A candidate for playing the role of adhesion molecule to primed lymphocytes present in the murine mammary gland might be the mucosal addressin cell adhesion molecule‐1 (MAdCAM‐1). We studied the correlation between the levels of IgA in colostrum and milk, the number of IgA producing plasma cells in the mammary gland and the expression of MAdCAM‐1 in mammary gland endothelial cells during pregnancy and lactation. The relation between the IgA levels in the milk and the expression levels of pIgR in mammary gland epithelial cells was also investigated. We found that the expression of MAdCAM‐1 and pIgR starts in early–mid pregnancy; the number of IgA‐producing plasma cells and the IgA concentration in milk increase from early lactation onwards. The MAdCAM‐1 expression declines during lactation whereas the pIgR levels and IgA‐producing plasma cell numbers rise until the end of lactation. Because the MAdCAM‐1 level starts to rise several days before the rise of the IgA‐producing plasma cell level, MAdCAM‐1 cannot be the rate determining factor governing extravasation of primed B cells to the mammary gland. We also conclude that the pIgR is present in sufficient amounts to enable increasing S‐IgA secretion into the milk during lactation.
Switch in Chemokine Receptor Phenotype on Memory T Cells without a Change in the Cytokine Phenotype
Authors: Aarvak T. , Strand E. , Teigland J. , Miossec P. , Natvig J. B.
Published: March 2003

Th1 and Th2 cells as defined by their cytokine profile are associated with the expression of the chemokine receptors CCR5 and CCR3, respectively. In committed human memory Th1 cells the cytokine profile is irreversibly expressed. However, it is not known if the chemokine receptor phenotypes of Th1 and Th2 cells are permanently associated to the cytokine profile or if it can be changed. To analyze the possibility of inducing a switch in chemokine receptor phenotype on memory Th cells we used differentiated memory Th cells isolated from synovial tissue (ST) samples of patients with rheumatoid arthritis (RA). Freshly isolated T cells, T‐cell lines and T‐cell clones from these tissues were manipulated with Th1 (interleukin (IL)‐12 + anti IL‐4) or Th2 (IL‐4 + anti IL‐12) inducing conditions. The surface expression of CCR5 and CCR3 was analyzed by flowcytometry and interferon (IFN)‐γ and IL‐4 production by ELISA. A Th1‐inducing cytokine environment increased the expression of CCR5 in Th1 cells and induced the expression of CCR5 in Th2 cells as compared to culture condition with only IL‐2. Induction of CCR5 expression on Th2 clones was associated with secretion of some IFN‐γ. Moreover, the Th2‐associated chemokine receptor CCR3 could be expressed on both Th1‐dominant cell lines, and clones of Th1 and Th0 type after culture conditions with IL‐4. This expression of CCR3 was associated with a reduced IFN‐γ production, but no IL‐4 production could be induced. The IL‐4‐treated Th1 clones had a reduced migratory capacity against chemokines produced by ST cells compared to nonmanipulated T‐cell clones. In contrast, the same IL‐12‐treated Th1 clones showed an increased migratory potential. Induction of the Th2‐associated marker CCR3 on memory Th1 cells demonstrates that a change in chemokine receptor phenotype related to the Th2 type can be induced on terminally differentiated Th1 cells, without a change in the cytokine profile.
A Transgenic Marker Expressed on Discrete Populations during B‐Cell Development
Authors: Wrammert J. , Vingsbo Lundberg C. , Leanderson T.
Published: March 2003

We describe a transgenic mouse strain that selectively express a surface marker (huCD25) on transitional B cells, pre‐B cells and a lineage unidentified bone marrow (BM) population. We show that a subpopulation of B cells in Peyer's patches, spleen, blood and BM expressed the transgenic huCD25 marker on the cell surface. In the spleen, the huCD25 expression was found on transitional B cells, that had not yet been recruited into the recirculating pool. In the BM a fraction of the B220low surface immunoglobulin (Ig) negative PB493+ pre‐B cells were huCD25+. HuCD25 expression was also seen on practically all immature B cells while the mature recirculating B cells did not express huCD25. A huCD25+B220− cell population was also found in the BM that had not rearranged the Ig heavy chain locus and did not express the lineage markers CD3, T‐cell receptor (TCR), CD19 and Mac‐1. A low expression of CD4 on these cells may indicate that they represent a noncommitted, hematopoetic progenitor cell population.
Immunological Characterization of Antigens Encoded by the RD1 Region of the Mycobacterium tuberculosis Genome
Authors: Brusasca P. N. , Colangeli R. , Lyashchenko K. P. , Zhao X. , Vogelstein M. , Spencer J. S. , Mcmurray D. N. , Gennaro M. L.
Published: March 2003

Development of immunoassays specific for the diagnosis of tuberculosis requires antigens unique to Mycobacterium tuberculosis. In a search for such antigens we tested six proteins encoded by RD1, a region present in M. tuberculosis and virulent M. bovis genomes but missing from the DNA of all substrains of M. bovis Bacillus Calmette‐Guerin (BCG). The six proteins (Rv3871, Rv3872, Rv3873, MTSA‐10, ESAT‐6 and Rv3878) were purified to near‐homogeneity from recombinant Escherichia coli. When tested for the ability to elicit antibody responses and delayed type hypersensitivity in tuberculous guinea pigs, only two of six antigens, ESAT‐6 and MTSA‐10, elicited strong skin reactions, while vigorous antibody responses were observed to all six proteins. When antibody responses to RD1 antigens were evaluated in sera from patients having pulmonary tuberculosis and from control subjects (patients having mycobacterioses other than tuberculosis, and healthy persons), a sizeable proportion (25%) of tuberculosis patients but none of the control subjects, had antibodies against MTSA‐10 and/or ESAT‐6. We conclude that MTSA‐10 and ESAT‐6 are promising candidates for immunodiagnostic assays specific for tuberculosis.
Shoulder‐Pad Sign of Amyloidosis: Structure of an Ig Kappa III Protein
Authors: Liepnieks J. J. , Burt C. , Benson M. D.
Published: March 2003

While amyloid infiltration of articular structures is rare, the ‘shoulder‐pad’ sign resulting from periarticular soft tissue amyloid deposition is essentially pathognomonic for immunogloblin (Ig) (AL) amyloidosis. We report the characterization of an amyloid protein (GRA) which produced articular amyloid deposits and the shoulder‐pad sign. Amyloid fibrils were isolated from soft tissue shoulder mass of a patient with systemic AL amyloidosis. The fibrils were solubilized in guanidine HCl and proteins separated by Sepharose chromatography. Amino acid sequence of fractionated protein was determined after tryptic digestion. Sequence analysis of the major amyloid protein yielded a kappa III Ig light chain structure. The entire variable region (VL) plus the constant region (CL) to residue 207 was identified; but lesser amounts of CL than VL were present. A number of amino acid residues previously not observed in kappa III VL proteins, plus a two amino acid insert (95A, 95B), were identified. Kappa III VL amyloid proteins are rare and may show an increased predilection for soft tissue deposition. While several unique amino acid residues that were identified in protein GRA may contribute to soft tissue amyloid deposition, no definite pattern is obvious from comparison with other reported kappa III amyloid proteins.
Stimulation of Antiviral Antibody Response in SHIV‐IIIB‐Infected Macaques
Authors: Muller S. , Margolin D. H. , Min G. , Lou D. , Nara P. , Axthelm M. K. , Kohler H.
Published: March 2003

Three macaques infected with SHIV‐IIIB and expressing the shared 1F7‐idiotypic marker on antibodies against HIV‐1 gp120, were injected intravenously with 1F7 monoclonal antibodies (MoAb). As controls, a SHIV‐IIIB‐infected macaque was injected with a HIV‐unrelated mouse monoclonal isotype antibody (TEPC‐183) and two healthy, noninfected macaques were injected with MoAb 1F7. 1F7‐id‐expressing antibodies against gp120‐IIIB decreased in two of the three MoAb 1F7‐treated macaques and then rebounded. Importantly, antibodies binding to envelope proteins of heterologous HIV‐1 strains MN, CM, and SF2, which were low or not detectable before the MoAb 1F7 treatment, increased rapidly following MoAb inoculations in all three 1F7 MoAb treated macaques, but not in the macaque injected with control MoAb TEPC‐183. Newly arising antibodies reacting with heterologous virus, i.e. HIV‐1 gp120‐MN, SF2, and CM did not express 1F7‐id. Surprisingly, significant increases of antibodies were also observed in the 1F7‐inoculated macaques' antibodies directed to non‐HIV antigens (DNP, peptides and BSA). The noninfected control animals did not produce antibodies to these antigens despite MoAb 1F7 treatment. These data show that the MoAb 1F7 injections of chronically SHIV‐IIIB‐infected macaques resulted in idiotype‐specific clonal suppression with broadening the antibody response to HIV envelope proteins.
Human Cytomegalovirus (HCMV)‐Infected Endothelial Cells and Macrophages are Less Susceptible to Natural Killer Lysis Independent of the Downregulation of Classical HLA Class I Molecules or Expression of the HCMV Class I Homologue, UL18
Authors: Odeberg J. , Cerboni C. , Browne H. , Kärre K. , Möller E. , Carbone E. , Söderberg‐Nauclér C.
Published: March 2003

A number of reports have suggested that human cytomegalovirus (HCMV)‐infected fibroblasts are resistant to natural killer (NK) lysis, and that the HCMV‐encoded human leucocyte antigen (HLA) class I homologue UL18 may be responsible for this effect. While fibroblasts are easy to infect in vitro, their role in HCMV pathogenesis in vivo is unclear. Here, we have established systems to address NK recognition of infected endothelial cells and macrophages, two important HCMV cellular reservoirs in vivo. The HCMV‐infected endothelial cells exhibited increased resistance to NK killing, and, in most experiments, infected macrophages demonstrated a decreased susceptibility to NK lysis. Infection with the mutant HCMV strain RV670, lacking the genes US1‐9 and US11 that are responsible for downregulation of HLA class I molecules, also led to decreased NK susceptibility. Furthermore, reduced NK susceptibility was independent of the expression of the HLA class I homologue UL18, since cells infected with the UL18Δ HCMV strain were also less susceptible to NK killing. These results suggest that HCMV‐induced resistance to NK cytotoxicity in endothelial cells and macrophages is independent of known pathways that interfere with the expression of cellular HLA class I A, B and C surface antigens and the HCMV encoded class I homologue UL18.
The Life and Work of Niels Kaj Jerne as a Source of Ethical Reflection*
Authors: Söderqvist T.
Published: March 2003

Niels Kaj Jerne, one of the leading theoreticians in 20th century immunology, was awarded the 1984 medical Nobel Prize for the natural selection theory of antibody formation, the haemolytic plaque technique, and the idiotypic network theory. A number of reasons for remembering Jerne are discussed, and three aspects of his life and work from three different life‐phases are analysed. Drawing upon the classical tradition for writing biographies as ‘ethical exemplars’, the paper concludes that a major reason for remembering Jerne is that his life story addresses fundamental questions about how to live as a scientist in contemporary culture.
Apoptosis of the Teratocarcinoma Cell Line Tera‐1 Leads to the Cleavage of HERV‐K10gag Proteins by Caspases and/or Granzyme B
Authors: BEYER T. D. , KOLOWOS W. , DUMITRIU I. E. , VOLL R. E. , HEYDER P. , GAIPL U. S. , KALDEN J. R. , HERRMANN M.
Published: March 2003

Redistribution, post‐translational modifications and coclustering with viral antigens contribute to the immunogenicity of apoptotic cell‐derived autoantigens. Almost all known targets of the humoral autoimmune response in systemic lupus erythematosus (SLE) are cleaved by caspases or granzyme B during apoptosis. Antibodies against retroviral proteins can frequently be detected in the sera of SLE patients without overt retroviral infections. These antibodies may represent cross‐reactive antibodies or may have been induced by proteins encoded by endogenous retroviral sequences. We used Tera‐1 cells that abundantly express a group‐specific antigen of human endogenous retroviruses, HERV‐K10gag polyprotein, to investigate its processing during apoptosis. Tera‐1 cells induced to undergo apoptosis showed an altered HERV‐K10gag processing compared with viable cells. In addition, granzyme B was able to cleave HERV‐K10gag isolated from viable Tera‐1 cells.

Similar to nuclear autoantigens, endogenous retroviral proteins are cleaved during the execution phase of apoptosis. These post‐translational modifications may result in the generation of T‐cell neoepitopes or a changed epitope hierarchy of retroviral proteins. Therefore, immunogenicity of retroviral antigens in SLE patients may result from a similar mechanism as described for nuclear autoantigens.
Macrophages from High‐Risk HLA‐DQB1*0201/*0302 Type 1 Diabetes Mellitus Patients are Hypersensitive to Lipopolysaccharide Stimulation
Authors: Plesner A. , Greenbaum C. J. , Gaur L. K. , Ernst R. K. , Lernmark Å.
Published: March 2003

Levels of nonantigen‐induced pro‐inflammatory cytokines and prostaglandin in macrophages isolated from human leucocyte antigen (HLA)‐matched type 1 diabetes mellitus patients, first‐degree relatives and healthy controls were determined. We hypothesize that monocytes isolated from patients are sensitized or preactivated and therefore, have an altered response to in vitro stimulus compared with control groups as measured by levels of pro‐ and anti‐inflammatory mediators. In this study, peripheral blood monocytes were differentiated to macrophages with macrophage‐colony stimulating factor (M‐CSF) to determine lipopolysaccharide (LPS)‐stimulated tumour necrosis factor (TNF)‐α, interleukin (IL)‐1β, IL‐6, IL‐12 and prostaglandin E‐2 (PGE‐2) secretion from hetero‐ or homozygous HLA DQB1*0201 and *0302 type 1 diabetes mellitus patients, first‐degree relatives and homozygous HLA DQB1*0602 healthy controls. LPS‐stimulated secretion of TNF‐α, IL‐1β and IL‐6 was immediate and markedly higher in the HLA‐DQB1*0201/*0302 type 1 diabetes patients compared with all other groups including HLA‐matched healthy first‐degree relatives. In DQB1*0201/*0302 diabetes patients PGE‐2 secretion was delayed but increased by LPS stimulation compared with HLA‐matched healthy relatives. IL‐12 was not detected at any condition. These data suggest that macrophages from DQB1*0201/*0302 type 1 diabetes patients are sensitized to secrete both cytokines and PGE‐2 following nonantigenic stimulation. Sensitized macrophages may be important to high‐risk DQB1*0201/*0302‐associated type 1 diabetes.
CD14‐Mediated Induction of Interleukin‐8 and Monocyte Chemoattractant Protein‐1 by a Heat‐Resistant Constituent of Porphyromonas gingivalis in Endothelial Cells
Authors: Mao S. , Maeno N. , Yoshiie K. , Matayoshi S. , Fujimura T. , Oda H.
Published: March 2003

Viable and inactivated Porphyromonas gingivalis dose‐dependently induced interleukin‐8 (IL‐8) and monocyte chemoattractant protein‐1 (MCP‐1) secretion in human umbilical vein endothelial cells (HUVECs). The inactivated P. gingivalis, in comparison with viable bacteria, tended to enhance the production of both chemokines more strongly. The production of MCP‐1 protein began increasing immediately after stimulation by P. gingivalis, and there was a nearly linear increase from 0 to 8 h of incubation, whereas IL‐8 production showed a linear increase between 4 and 12 h of incubation. The IL‐8 and MCP‐1 mRNA expressions in HUVECs as determined by reverse transcriptase‐polymerase chain reaction (RT‐PCR) or Quantikine mRNA colorimetric quantification kits were found to be enhanced by P. gingivalis. Furthermore, the time courses of IL‐8 and MCP‐1 mRNA expressions were in accordance with those of protein production. Addition of polymyxin B or boiling did not weaken the stimulatory effect of P. gingivalis, which inhibited the effect of Escherichia coli lipopolysaccharide (E. coli LPS) and tumour necrosis factor‐α (TNF‐α), respectively. In contrast, the induction of IL‐8 and MCP‐1 by P. gingivalis was significantly reduced by anti‐CD14 antibody. Our results suggest that some heat‐stable component of P. gingivalis, including LPS, may be responsible for the induction of IL‐8 and MCP‐1 in HUVECs by a CD14‐dependent mechanism. These effects might be involved in the accumulation and activation of neutrophils and monocytes at an early stage of the periodontal pathogenesis.
Staphylococcal Enterotoxin B Upregulates Fas‐Mediated Apoptosis of Peripheral Blood Mononuclear Cells in Childhood Atopic Dermatitis
Authors: Sohn M. H. , Kim J.‐W. , Kim W. K. , Jang G. C. , Kim K.‐E.
Published: March 2003

Staphylococcal infection‐producing superantigens, such as staphylococcal enterotoxin B (SEB), are presumed to play an important role of inflammatory processes in atopic dermatitis (AD). The aim of this study was to elucidate the apoptotic response of peripheral blood mononuclear cells (PBMCs) from children with AD. PBMCs from AD children were sampled and cultured with SEB stimulation. Levels of apoptosis and Fas expression were measured using flow cytometry; the soluble Fas ligand (sFasL) was also measured using the enzyme‐linked immunosorbent assay method, and the expression of FasL in PBMCs was observed using reverse transcriptase‐polymerase chain reaction. There was no difference in the initial levels of apoptosis and Fas expression in precultured PBMCs of AD patients and healthy donors. After culturing for 48 h under SEB stimulation, the apoptosis level and Fas expression were significantly upregulated in the PBMCs from AD children compared with that from the normal controls. In patients, the sFasL was significantly increased, and the expression of FasL was observed in messenger RNA of peripheral monocytes. These results suggest that the Fas/FasL system is involved in the apoptosis induced by SEB in AD, with simultaneous increases in sFasL and expression of FasL.
Carbonate platform‐to‐basin correlation by means of grain‐composition logs: an example from the Vercors (Cretaceous, SE France)
Authors: EVERTS ARNOUT J. W. , SCHLAGER WOLFGANG , REIJMER JOHN J. G.
Published: March 2003

Quantitative logs of grain composition for several sections of platform top and flank of the Vercors carbonate platform (Early Cretaceous, SE France) provide platform‐to‐basin correlation with a resolution of a few metres over an area of 70 km2. Grain composition was determined by point‐counting thin sections. Point‐count groups that characterize palaeoenvironmental realms (i.e. open sea, platform margin) were defined for the platform–basin trajectory. Grain‐composition logs revealed marked peaks in the number of open‐sea biota and peaks in ooid abundance. The peaks in open‐sea biota correspond to back‐stepping intervals and deepening upward facies successions at the platform margin. These peaks probably relate to incipient drowning of the platform and may be used to delineate marine‐flooding surface‐bounded sequences. Peaks in ooid occurrence show no relationship with the progradation, aggradation or retreat of the platform. Apparently, the oolitic sands were not part of a facies tract that shifted up and down the platform. Instead, they represent a depositional mode that was either on or off. Times of prolific ooid production and shedding probably occurred during wide but shallow submergence of the platform, accompanied by suitable water chemistry. Peaks in both ooids and open‐sea biota are excellent markers for platform‐to‐basin correlation, as they are recorded in successions on the platform top as well as on the flank. Altogether, the grain‐composition logs show that each of the lithologically rather similar platform tongues of the Vercors has a unique signature or compositional fingerprint. These compositional fingerprints are most helpful in evaluating the lateral extent of different stratigraphic units. In outcrops of the Vercors platform, the physical tracing of bedding surfaces delineate wedges of toe‐of‐slope sediments that show a conspicuous thinning towards the platform. However, our correlation shows that these sediment bodies are not truly basin‐restricted wedges but have a platform top equivalent. This implies that these units were, at least partly, deposited during high stands of sea level that flooded the platform.
Tectonic and eustatic control on deposition and preservation of Upper Cretaceous ooidal ironstone and associated facies: Peace River Arch area, NW Alberta, Canada
Authors: Donaldson W. Steven , Plint A. Guy , Longstaffe Fred J.
Published: March 2003

The Late Coniacian, shallow‐marine Bad Heart Formation of the Western Canada foreland basin is very unusual in that it contains economically significant ooidal ironstone. Deposition of shallow‐water and iron‐rich facies appears to have been localized over the crest and flanks of a subtle intrabasinal arch, in part interpreted as a forebulge and partly attributed to reactivation of the long‐lived Peace River Arch. The formation comprises two upward‐shoaling allomembers, typically 5–10 m thick, that are bounded by regionally mappable ravinement surfaces. The lower unit, allomember 1, grades up from laminated mudstone to bioturbated silty sandstone, which is abruptly overlain by bioturbated ooidal silty sandstone grading into an almost clastic‐free ooidal ironstone up to 7 m thick. Ooidal ironstone was concentrated into NW‐ to SE‐trending ridges, kilometres wide and tens of kilometres long. Ironstone formation appears to have been promoted by: (a) drowning of the arch, which progressively curtailed sediment supply; and (b) enhanced reworking over the shallowly submerged arch and over a fault‐bounded block that underwent episodic vertical movement of 10–20 m during Bad Heart deposition. Allomember 2 also shoals upwards from mudstone to bioturbated and laminated silty sandstone but lacks ooids, apparently reflecting a rejuvenated supply of detrital sediment from the arch. The marine ravinement surface above allomember 2 is a Skolithos firmground, above which is developed a regional blanket of ooidal sediment. In the east, ooids are dispersed in a bioturbated silty sandstone with abundant evidence of repeated reworking and early siderite and phosphate cements. Westwards, this facies grades, over about 40 km, into almost clastic‐free ooidal ironstone about 5 m thick; the lateral facies change may reflect progressive clastic starvation distal to a low‐relief source area. The two allomembers are interpreted to reflect eustatic oscillations of about 10 m, superimposed on episodic tectonic warping and block‐faulting events. The development of ooidal ironstone immediately above initial marine flooding surfaces indicates a close relationship to marine transgression, reflecting sediment‐starved conditions. Ironstone does not appear to be related to either sequence boundaries or maximum flooding surfaces. The Bad Heart Formation is blanketed by marine mudstone deposited in response to major flexural subsidence and rejuvenation of clastic sources in the Cordillera to the SW.
Nanotopography of synthetic and natural dolomite crystals
Authors: Kessels Lisa A. , Sibley Duncan F. , Nordeng Stephan H.
Published: March 2003

Examination with scanning electron microscopy (SEM) and scanning force microscopy (SFM) revealed etch pits, layers and islands on dolomite crystal faces synthesized from calcite in Ca‐Mg‐Cl solutions at 200 °C and a wide variety of natural dolomites. Layers are broad, flat structures bounded by steps less than 100 nm high and greater than 1 μm wide. Islands are rounded topographic highs <20 nm high and <200 nm wide. The nanotopography of synthetic dolomite changed from islands throughout most of the reaction to layers at 100% dolomite. Island nanotopography formed on both Ca‐rich and near‐stoichiometric dolomite. Analyses of reaction products from dolomite synthesis indicates that there are no SFM‐detectable products formed in <10 h. SEM‐detectable products formed in 15 h. X‐ray diffraction (XRD)‐detectable products formed in ≈18 h, and the reaction went to completion in ≈40 h. Based on SFM analyses, the induction period for dolomitization in these experiments accounts for ≈20% of the total reaction time necessary to dolomitize CaCO3 completely under the experimental conditions used here. Island nano‐ topography is inferred to occur at higher degrees of supersaturation than layer nanotopography for three reasons. First, island nanotopography on synthetic calcite and gypsum forms at higher supersaturations than layer nanotopography. Secondly, island nanotopography formed in solutions with higher degrees of supersaturation with respect to dolomite. Thirdly, the greater surface roughness of a crystal face composed of islands compared with layers indicates that island surfaces have higher surface energy than layer surfaces. Therefore, the stability of island surfaces requires a higher degree of supersaturation. Because islands and layers form under a wide range of conditions, their presence provides broadly applicable criteria for evaluating relative degrees of supersaturation under which ancient dolomite formed. Comparison of synthetic dolomites with natural dolomites demonstrates (1) similar nanotopography on natural and synthetic dolomites and (2) both natural planar and non‐planar dolomite may have island nanotopography.
Latest Pleistocene and Holocene dune construction at the north‐eastern edge of the Rub Al Khali, United Arab Emirates
Authors: Goudie Andrew S. , Colls Alison , Stokes Stephen , Parker Adrian , White Kevin , Al‐Farraj Asma
Published: March 2003

Optical dating of two dune profiles developed in linear dunes in Ras Al Khaimah, United Arab Emirates, has been used to establish the timing and rate of dune accretion. One section at Awafi was over 17 m high, while that at Idhn was over 40 m high. The Awafi dune appears to have accumulated very rapidly ≈10 000 years ago, with a vertical accumulation rate of about 3·3 m ka−1. The Idhn dune appears to have accumulated over the past 1000 years, with 20 m of sediment accumulating in a time period of about 270 years. The Awafi dune may have accumulated in response to the transgression of the Persian Gulf by rising sea levels in late Pleistocene and Holocene times. The Idhn dune may have accumulated rapidly because of intensified human activity, a short‐lived climatic event, or because it may periodically be reactivated after erosion by fluvial action at its base.
Description and numerical model of Pleistocene iceberg scours and ice‐keel turbated facies at Toronto, Canada
Authors: Eden David J. , Eyles Nicholas
Published: March 2003

Near Toronto, in Southern Ontario, Canada, glaciolacustrine muds and shoreface sands of Late Pleistocene age (Early Wisconsin glaciation; ≈45 ka) were deformed by icebergs ploughing the floor of an ancestral ice‐dammed Lake Ontario. Outcrop mapping and a ground‐penetrating radar survey identify ice scour structures up to 4 m deep, up to 10 m wide and at least several hundred metres long with high‐standing lateral margins (berms). Ploughing of lake‐floor sediment is also recorded by ice‐keel turbated facies in which storm‐deposited shoreface sands have been mechanically mixed with underlying muds. Palaeoenvironmental information for one prominent scour, such as water depths, estimates of the mass and draft of the ice mass and scouring forces, can be determined using a simple finite element numerical model. A mass of 0·04 million tonnes, a keel draft of between 10 and 30 m and a scouring force of 5 × 103 kN is consistent with scouring by a small iceberg (‘bergy bit’) or pressure‐ridged lake ice; the former is preferred because of the considerable depth of the scour and the overall glacial depositional setting. Estimates of ice‐mass dimensions agree with independent reconstructions of palaeobathymetry (no greater than 20 m) derived from storm‐deposited hummocky and swaley cross‐stratified facies that fill the scour. Data presented here aid the identification of ice‐scour structures and turbated sediment in the ancient record; despite being a common process on modern high‐latitude shelves, descriptions of ancient structures and facies are few.
The Vigny limestones: a record of Palaeocene (Danian) tectonic‐sedimentary events in the Paris Basin
Authors: Montenat Christian , Barrier Pascal , D'Estevou Philippe Ott
Published: March 2003

Danian marine sedimentation in the Paris Basin occurred between two major erosional phases. The earlier was responsible for the stripping of presumably deposited Maastrichtian sediments and of a variable thickness of Campanian chalk. The later occurred during the late Palaeocene and resulted in the erosion of almost all Danian deposits, which are now limited to small and scattered outcrops. One of these outcrops corresponds to reefal and peri‐reefal limestones of middle to late Danian age, exposed in the quarries of Vigny (NW of Paris). Danian deposits here show intricate relations with the surrounding Campanian chalk. Danian sedimentation was contemporaneous with faulting, which generated signifiant sea‐floor relief and resulted in contrasting depositional areas: topographic highs with coralgal reefs, and depressions where calcirudite channel fill accumulated. Normal faulting occurred along WNW–ESE master faults. The generation of submarine fault scarps gave rise to various types of gravity‐driven phenomena, including the sliding and slumping of large blocks of reefal limestone and the deposition of carbonate debris flows. Along with the redeposition of the Danian carbonates, flows of fluidized and reworked Campanian chalk resulted from the peculiar physical properties of the undercompacted chalks. Erosion and faulting occurred predominantly during the Palaeocene and represent a major episode in the physiographic evolution of the Paris Basin.