bluuebunny/crossref_metadata_2025 huggingface dataset:
Intravenous Granulocyte Colony‐Stimulating Factor Increases the Release of Tumour Necrosis Factor and Interleukin‐1β into the Cerebrospinal Fluid, But Does Not Inhibit the Growth of Streptococcus pneumoniae in Experimental Meningitis
Authors: Schmidt  , Stuertz  , Brück  , Chen  , Stringaris  , Fischer  , Nau
Published: March 2003

Granulocyte colony‐stimulating factor (G‐CSF) possesses an antimicrobial effect in several animal models of infection. To evaluate a possible effect of G‐CSF on the course of pneumococcal meningitis, rabbits infected intracisternally (i.c.) with Streptococcus pneumoniae type 3 (n = 7) received 50 μg/kg of rhG‐CSF intravenously (i.v.) 1 h prior to infection. Seven infected animals served as controls. Uninfected rabbits received 10 μg of G‐CSF (n = 3), 2 μg G‐CSF (n = 3) or saline (n = 3) i.c. G‐CSF injected i.c. did not produce cerebrospinal fluid (CSF) leucocytosis. Compared with the control group, i.v. G‐CSF given prior to i.c. infection increased the percentage of granulocytes in blood 6 h and 12 h after infection. Twelve hours after infection, CSF tumour necrosis factor (TNF) activity and CSF interleukin (IL)‐1β concentrations were significantly higher in G‐CSF‐treated animals. G‐CSF did not decrease bacterial growth in the subarachnoid space and the CSF leucocyte densities were not influenced. At 24 h after infection, G‐CSF did not reduce the CSF concentrations of neurone‐specific enolase and the density of apoptotic neurones in the dentate gyrus of the hippocampus. In conclusion, i.v. G‐CSF increased the concentration of pro‐inflammatory cytokines in the CSF but did not decrease the growth of Streptococcus pneumoniae in the subarachnoid space.
Interleukin‐8, Interleukin‐10, Intercellular Adhesion Molecule‐1 and Vascular Cell Adhesion Molecule‐1 Expression Levels are Higher in Synovial Tissue from Patients with Rheumatoid Arthritis than in Osteoarthritis
Authors: Furuzawa‐Carballeda  , Alcocer‐Varela
Published: March 2003

The aim of this work was to determine differences in pro‐ and anti‐inflammatory cytokine and adhesion molecule expression in synovial tissue from patients with rheumatoid arthritis (RA) or osteoarthritis (OA). Synovial tissue samples were obtained from patients with RA and OA, and from healthy individuals. The expression of mRNA of interleukin (IL)‐1β, IL‐4, IL‐6, IL‐8, IL‐10, IL‐13, tumour necrosis factor‐α (TNF‐α) and transforming growth‐factor‐β1 (TGF‐β1) was evaluated by the polymerase chain reaction (PCR). In addition, IL‐8 and IL‐10 transcripts were measured by quantitative PCR. The expression of IL‐8 and IL‐10 proteins was determined by immunoperoxidase staining. To evaluate the inflammatory stage of synovial tissue, vascular cell adhesion molecule‐1 (VCAM‐1) and intercellular adhesion molecule‐1 (ICAM‐1) protein expression was also determined. RA patients were found to display higher levels of adhesion molecules than patients with OA. PCR analysis showed a similar profile of cytokine transcripts between the OA and RA groups. Gene expression of IL‐4 and IL‐13 in synovium was undetectable. In contrast, IL‐1β, IL‐6, IL‐8, IL‐10, TNF‐α and TGF‐β1 transcripts were expressed by both groups. Increased levels of IL‐8 and IL‐10 transcripts and their proteins were observed in synovium from RA patients when compared to patients with OA and healthy controls. Thus, our data show that IL‐8, IL‐10, ICAM‐1 and VCAM‐1 expression levels are higher in synovial tissue from patients with RA than in similar tissue from patients with OA.
Low and Nontoxic Levels of Ionic Mercury Interfere With the Regulation of Cell Growth in the WEHI‐231 B‐Cell Lymphoma
Authors: Mccabe Jr  , Santini  , Rosenspire
Published: March 2003

WEHI‐231 is a mouse B‐cell line, which is a well‐established model for studying signal transduction in B lymphocytes, normally responding to cross‐linking of the B‐cell receptor (BCR) complex by the rapid upregulation of protein tyrosine kinase activity, followed by increased intracellular calcium and activation of protein kinase C. In WEHI‐231, activation of protein kinase C is functionally associated with downregulation of DNA synthesis, followed by the induction of apoptosis. We have found in WEHI‐231, that at low and environmentally relevant exposure levels (0.1 μm) mercury is not toxic, but still interferes with signal transduction in that it attenuates the growth inhibitory effects of BCR cross‐linking. The molecular target for mercury resulting in attenuation of the BCR‐mediated growth inhibitory signal is likely proximal to activation of the BCR complex, as HgCl2 had no effect on the negative growth signal generated downstream by direct activation of protein kinase C with phorbol 12‐myristate 13‐acetate. Treatment of WEHI‐231 cells with high and toxic concentrations of Hg results in a marked increase in protein tyrosine phosphorylation in a great many proteins; whereas treatment of WEHI‐231 cells with 0.1 μm mercury is not toxic. Under these conditions mercury selectively perturbed BCR‐mediated protein tyrosine phosphorylation of a 75 kDa protein, without grossly affecting tyrosine phosphorylation levels of most other proteins. These data suggest that low levels of mercury, which are not toxic, may still contribute to immune dysfunction by interfering with antigen‐receptor‐mediated and protein‐kinase‐dependent signal transduction in lymphocytes.
Different Properties of T‐Cell Epitopes Within Complementarity‐Determining Regions 1 and 2 of Idiotypic VH in B‐Lymphoma
Authors: Wen  , Lim
Published: March 2003

The idiotypic protein expressed by B‐lymphoma cells can evoke an autologous idiotype‐specific T‐cell response in both animal studies and lymphoma patients. However, the locations within the idiotypic protein of the immune epitopes remains unclear. In this study, we determined the nature of any immune responses generated by peptides corresponding to the complementarity‐determining region 1 (CDR1) and complementarity‐determining region 2 (CDR2) sequences of idiotypic heavy chain variable region (VH) to identify the clinical potential of the peptides for immunotherapy of lymphoma. We found that a synthetic peptide corresponding to CDR1 sequence contains a functional T‐cell epitope able to evoke a major histocompatibility complex (MHC) class II‐dependent T‐cell proliferative response and cytokine release without direct cytotoxicity for peptide‐pulsed target or fresh autologous lymphoma cells. Although a peptide corresponding to CDR2 was able to generate MHC class I and class II dependent T‐cell proliferative responses and cytokine release, T‐cell epitopes within the peptide were cryptic in the context of intact idiotypic protein. Our results therefore suggest that the CDR1 sequence could be used for the immune targeting of B‐lymphoma.
Changes in Plasma Apolipoprotein AI and AII Concentrations in Murine Reactive Amyloidosis
Authors: Yamada  , Wada  , Fukuda  , Itoh  , Itoh
Published: March 2003

Based on the recent findings that patients with systemic amyloidosis have reduced plasma apolipoprotein AII (apoAII) concentrations, this study assessed the behaviour of apolipoprotein AI (apoAI) and apoAII in a murine model of reactive amyloidosis. ICR mice were subjected to a single inflammatory stimulus and then sacrificed at the end of week 1 (group I), week 2 (group II) or week 8 (group III). Amyloid deposits were found in approximately one‐half of the animals. Plasma apoAI and apoAII concentrations were reduced in all stimulated animals compared with control animals. In groups II and III, apoAII and apoAII/apoAI ratios were lower in the amyloidotic animals than in nonamyloidotic animals, similar to findings in the human amyloidosis patients. Both apoAI and apoAII mRNA in the liver were reduced in group I, but not in group II or III. Both apoAI and apoAII were detected immunohistochemically in the amyloid deposits in groups I and II, but not in group III. Thus, the reduction of plasma apoAs in the amyloid‐forming phase may be due, in part, to the involvement of high‐density lipoproteins in the deposits. However, that in the chronic phase may be affected by other mechanisms.
Functional Definition of a B Cell Epitope, KGEQGEPGA, on C1q the Fc‐Binding Subunit of the First Component of Complement
Authors: Trinder  , Märker‐Hermann  , Loos  , Maeurer
Published: March 2003

A synthetic peptide representing the C1q epitope KGEQGEPGA has been shown to suppress or delay the onset of CII‐induced arthritis when applied intravenously (i.v.) prior to an intradermal (i.d.) challenge, in a mouse model; the phenomenon being associated with the development of immunoglobulin (Ig)M antibodies specific for the KGEQGEPGA epitope. Here we show that this amino acid sequence provides an immunodominant B cell epitope that is recognised by autoantibodies present in the sera of patients with chronic inflammatory diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis, two diseases associated with an immune response to C1q. The peptide's ability to produce peptide specific IgM when applied i.v. in both normal and athymic mice but not in mice exhibiting the x‐linked B‐cell associated Bruton's tyrosine kinase defect permits classification of the KGEQGEPGA peptide as a T‐cell independent antigen type‐2 (TI‐2). IgM monoclonal antibodies raised against the peptide are able to functionally block activation of the complement cascade by C1q, via a mechanism that inhibits the C4 consumption. Antibodies to this immunodominant epitope may therefore modulate inflammatory processes by interfering with the activation of the classical pathway of the complement.
Regulation of Interleukin‐2 Induced Interleukin‐5 and Interleukin‐13 Production in Human Peripheral Blood Mononuclear Cells
Authors: Verheyen  , Bönig  , Kim  , Banning  , Mauz‐Körholz  , Kramm  , Körholz
Published: March 2003

Adjuvant interleukin (IL)‐2 immunotherapy has been used for many years for a variety of malignant and nonmalignant entities. In many cases, a dose escalation might have seemed desirable, but was prevented by the rather severe adverse effects of systemic IL‐2 application. Only recently has the regulation of IL‐2 induced cytotoxicity been understood better, so that now efforts can be aimed at the design of cytokine cocktails that would selectively induce cytotoxicity but result in as few adverse effects as possible. Previously, induction of IL‐5 under systemic IL‐2 therapy has been described, and a number of the side‐effects have been attributed to this event. We therefore investigated the regulation of IL‐2 induced production of IL‐5 and IL‐13 (which, similarly to IL‐5, is a mediator of allergy‐like symptoms). At the same time, the effects of regulatory cytokines, such as IL‐4, IL‐10 and IL‐12, on interferon‐γ (IFN‐γ), the major cytotoxic mediator of IL‐2 therapy, were studied. All three have been discussed as antitumour immunotherapeutics, either alone or in combination with IL‐2. In anti‐CD3‐treated peripheral blood mononuclear cells, IL‐2 induced IL‐5 and IL‐13 alongside IFN‐γ, IL‐10 and IL‐12. In the presence of IL‐2, inhibition of endogenous IL‐12 production further enhanced the IL‐5 and IL‐13 responses, while IFN‐γ and IL‐10 were markedly suppressed. Co‐incubation with IL‐2 and IL‐12 suppressed IL‐5/IL‐13 below, but enhanced IFN‐γ and IL‐10 above, levels induced by IL‐2 alone. IL‐10 was suppressive on all the investigated cytokines, while IL‐4 interfered with IL‐2 induced IFN‐γ and IL‐12 production, but was additive to IL‐2 in its effect on IL‐5 and IL‐13. These data suggest that the combination of IL‐12 with IL‐2 would enhance the cytotoxic activity of this regimen, but might reduce its adverse effects.
Effects of Interferon‐γ and Tumour Necrosis Factor‐α on CD95/Fas Ligand‐Mediated Apoptosis in Human Blood Eosinophils
Authors: Luttmann  , Dauer  , Schmidt  , Marx  , Hossfeld  , Matthys  , Virchow
Published: March 2003

Many cells, including eosinophils, express CD95 (Fas), a surface receptor that mediates apoptosis when ligated by specific antibodies or its natural ligand, Fas ligand (FasL). As apoptosis may play an important role in the regulation of tissue eosinophilia, factors that modulate eosinophil sensitivity to apoptosis are of great interest. It has previously been shown that interferon‐γ (IFN‐γ) and tumour necrosis factor‐α (TNF‐α) together increase CD95 surface expression on eosinophils. However, the functional consequences of this increase in CD95 expression have not been demonstrated in detail. We therefore investigated whether the increase in CD95 expression mediated by IFN‐γ/TNF‐α indeed translates into increased, FasL‐mediated apoptosis of eosinophils. For this purpose, purified eosinophils from normal donors were incubated with different concentrations of FasL and induction of apoptosis was assessed by annexin‐V/propidium iodide assay. Unlike Jurkat cells, which became apoptotic within 2 h after incubation with FasL, an increase in eosinophil apoptosis could first be dedicated after 6 h incubation with FasL. Prestimulation with IFN‐γ/TNF‐α for 24 h significantly enhanced FasL‐induced apoptosis in eosinophils. This increase in CD95/FasL‐mediated apoptosis was correlated with an IFN‐γ/TNF‐α‐mediated increase in CD95 expression. From these findings we conclude that the combination of IFN‐γ and TNF‐α enhances CD95 expression, which results in an increase in FasL‐mediated apoptosis of eosinophils in vitro.
Recent Developments in the Immunology of Inflammatory Bowel Disease
Authors: Macdonald  , Monteleone  , Pender
Published: March 2003

Crohn's disease and ulcerative colitis are caused by excessive immune reactivity in the gut wall. Analysis of the type of immune responses ongoing in diseased gut has revealed important features which suggest that these conditions are different. In Crohn's disease tissue there is considerable evidence for an ongoing T helper cell type 1 response, with excess interleukin‐12, interferon‐γ and TNF‐α. There is circumstantial evidence in patients that this response is directed against the normal bacterial flora and definitive evidence in mouse models that T cell responses to the flora cause gut disease. In ulcerative colitis, the role of tissue damaging T cell responses in the gut mucosa is much less clear and there is more evidence that the lesion is owing to antibody‐mediated hypersensitivity. Although different types of immune reactions initiate tissue injury in both Crohn's disease and ulcerative colitis, the downstream events which actually damage the tissue are the same in each condition. Elevated cytokine concentrations in the mucosa lead to the production of excess matrix degrading enzymes by gut fibroblasts, loss of mucosal integrity and ulceration. The same process also leads to an increased production of epithelial growth factors such as KGF Keratinocyte Growth Factor by gut fibroblasts and produces the crypt cell hyperplasia characteristic of all gut inflammatory conditions.
Possible Role of the Plasminogen Receptor as a Site of Interaction of the Human Immunodeficiency Virus p24 Immunosuppressive Heptapeptide Ch7 with the Host Immune System
Authors: Giacomini  , Chersi  , Giordani  , Luzzati
Published: March 2003

Previous work from our laboratory demonstrated that a synthetic heptapeptide (Ch7: RGSDIAG), corresponding to a conserved sequence of human immunodeficiency virus (HIV) core protein p24 (amino acids 232–238), was able to specifically abrogate antigen‐induced responses in cultures of normal human peripheral blood mononuclear cells (PBMC), probably acting at the level of monocytes. The Ch7 peptide displays sequence homology to human plasminogen. In the present report we show that a compound (6‐aminoexanoic acid), known to prevent plasminogen binding to monocyte‐like cells, greatly reduced the immunosuppressive capacity of Ch7. We suggest that the plasminogen receptor may represent a target structure on human monocytes for the immunosuppressive p24 sequence.
The Early Immune Response in the Liver of BALB/c Mice Infected with S. typhimurium
Authors: Barreiros  , Schirmacher  , Laufenberg‐Feldmann  , Meyer Zum Büschenfelde  , Schlaak
Published: March 2003

Gram‐negative bacteria acquired through gastrointestinal infection can be a serious cause for the development of septic shock especially in immunosuppressed patients. Thus, the aim of this study was to examine the early events of the immune reaction against S. typhimurium. Bacteria were injected into mice at different concentrations. Four animals from each group were killed at five different points of time. Liver cytokine mRNA expression was determined by semiquantitative rt‐PCR and liver histology was examined. Serum cytokine levels of interferon (IFN)‐γ, tumor necrosis factor (TNF)‐α, interleukin (IL)‐6, IL‐4 and IL‐10 were determined. intravenous (i.v.) infection with 109 bacteria led to lethal septic shock within 24 h. A delayed production of IFN‐γ, TNF‐α, IL‐18 and IL‐10 and milder histological alterations in the liver were observed in these animals. The highest expression of cytokines in the liver and the strongest histological alterations were seen after infection with 107 bacteria. Here, an increased mRNA expression of all proinflammatory cytokines began 1 h after infection. Animals infected with 1 × 102 bacteria had the highest detectable serum levels of IL‐6 and IL‐10. These data indicate that the immediate events in the immune reaction within the liver after infection with S. typhimurium are associated with the outcome of the subsequent sepsis.
Human T‐Cell Receptor BV6 Gene Polymorphism in Relation to Expression Level and CD4/CD8 Skewness
Authors: Obata  , Shiiba  , Iizuka  , Kashiwagi  , Kurosu  , Shimada  , Nishijima  , Tozawa
Published: March 2003

Using 50 samples of umbilical cord blood lymphocytes from Japanese donors, we analysed two human T‐cell receptor beta variable (TCRBV) genes, BV6S4 and BV6S5, for their polymorphism, usage frequencies and CD4/CD8 skewness. They showed contrasting CD4/CD8 skewness, BV6S4 to CD8+ T cells and BV6S5 to CD4+ T cells. Genotyping of the BV6S4 alleles (A1, A2 and A3) revealed two of the six possible BV6S4 genotypes, A1/A2 and A2/A2. Among the two BV6S4 genotypes, no significant difference was detected in usage frequency or CD4/CD8 skewness. On the other hand, genotyping of the BV6S5 alleles (A1 and A2) revealed all three possible BV6S5 genotypes, A1/A1, A1/A2 and A2/A2, and the gene usage frequency was high, in the order A1/A1 > A1/A2 > A2/A2. These results indicate that the amino acid substitutions in BV6S5 (S36R and G70E) are in some way associated with the expression level of this gene. In the analysis of CD4/CD8 skewness, the three BV6S5 genotypes had similar skewness, indicating that A1 alleles are expressed more frequently than A2 alleles in both CD4+ and CD8+ T‐cell populations. Although BV6S5 exhibits marked skewness to CD4+ T cells, our results indicate that the higher expression of A1 alleles is not associated with the increased ratio of CD4+ T cells.
Mechanisms Involved in Protective Immune Response Generated by Secretory Proteins of Mycobacterium habana Against Experimental Tuberculosis
Authors: Divya Jyothi  , Garg  , Singh
Published: March 2003

Live mycobacteria secrete a number of unique proteins early in their multiplication which are important for both the pathogenesis and the stimulation of specific host responses. We have investigated the mechanisms by which the host mounts immune response against tuberculosis after vaccination with secretory proteins (SP) of a vaccine candidate Mycobacterium habana TMC 5135. Mice vaccinated with SP of 10th day growth of M. habana, either alone or emulsified in Freund's incomplete adjuvant (FIA) possessed antituberculous resistance and cellular immune responses against M. tuberculosis H37Rv. These proteins induced a significant cutaneous delayed type hypersensitivity response in guinea pigs vaccinated with heat killed M. tuberculosis H37Rv, which was equivalent to that observed with a standard purified protein derivative (PPD). The splenocytes of these guinea pigs have shown higher proliferative response after stimulation with SP than with PPD. The SP + FIA immunization has been found to exert maximum prophylactic effect by potentiating both the oxygen dependent arms and enzymatic activities of macrophages. Macrophages from mice vaccinated with SP of M. habana produced enhanced levels of interleukin(IL)‐2, interleukin‐12 and interferon(IFN)‐γ. The protective as well as cell mediated immune responses were upregulated in SP immunized animals when compared to whole cell (M. habana) vaccinated animals. SDS‐PAGE of SP from M. habana showed the prominent bands of 60, 32, 31 and 30 kDa. Furthermore, the western analysis of SP with pulmonary tuberculosis patient's serum has revealed the presence of immunoreactive antigens of 36, 35, 33/32 kDa. Overall study demonstrated that the secretory antigens released by actively growing M. habana bacilli could activate different arms of effective immune response.
Blockade of the B7‐CD28 Pathway by CTLA4–Ig Counteracts Rejection and Prolongs Survival in Small Bowel Transplantation
Authors: Kurlberg  , Haglind  , Schön  , Törnqvist  , Lycke
Published: March 2003

Allograft rejection involves T‐cell activation, requiring T‐cell receptor interactions with major histocompatibility complex (MHC) molecules and costimulatory signals delivered through the B7‐CD28 pathway. We evaluated the effect of blocking this pathway on graft rejection and survival, in a rat experimental model of small bowel transplantation. Heterotopic small bowel transplantation was performed between PVG donor rats and DA recipient rats. The recipient animals were treated with CTLA4‐Ig or irrelevant immunoglobulin (Ig)G as control and followed for 18, 30 or 90 days. The survival rate and degree of inflammation and accumulation of CD4+ T cells and macrophages were determined in the transplanted bowels. We found that administration of CTLA4–Ig significantly improved the survival rate compared to control rats: after 30 days 73% of the treated rats had survived and at 90 days 5/8 rats were still living, whereas in the control group only 2/8 rats had survived. The grafts showed preserved mucosal structure with only a mild degree of subacute inflammation and the accumulation of CD4+ T cells and macrophages was noticeably reduced in treated animals as compared to control rats. Necrosis was extensive in control rats, whereas CTLA4–Ig treated animals had grafts with at least some preserved villus morphology and no necrotic tissue. Although small bowel transplantation has proven exceptionally difficult, in this study we have shown that CTLA4–Ig treatment may provide a promising strategy to prevent rejection and induce long term tolerance and graft survival.
Expression of Fcγr1 (CD64) on Polymorphonuclear Leucocytes during Progression to Acquired Immunodeficiency Syndrome in Perinatally Human Immunodeficiency Virus‐Infected Children
Authors: Moallem  , Kalayci  , Homel  , Fikrig  , Chice  , Durkin  , Michl
Published: March 2003

CD64, the high‐affinity receptor in the family of FCγ receptors, is not expressed constitutively in polymorphonuclear leucocytes (PMN). CD64 is expressed by PMNs in the late stages of human immunodeficiency virus (HIV) infection in adults. We followed the expression of CD64 on PMNs in perinatally HIV‐infected children during disease progression. Peripheral blood leucocytes (PBL) from 45 perinatally HIV‐infected paediatric patients and 13 healthy age‐matched controls were analysed using cytofluorimetry after reaction with a fluorophore‐labelled monoclonal antibody (MoAb) to CD64. In parallel, we examined the expression of CD32, CD16, CD11b and the human neutrophil‐specific BH2‐Ag using fluorophore‐labelled MoAbs. We found that up to 79.5% of the PMNs in children in class C3 express CD64. Most importantly, we observed a continuous and significant increase in the appearance of CD64+ PMNs as a function of CDC classification (P < 0.001) but no changes in the expression of CD32, CD16, CD11b and BH2‐Ag. This suggests that following the expression of CD64 on PMNs can be useful in evaluating the progression of HIV infection in perinatally HIV‐infected children.
P64k Meningococcal Protein as Immunological Carrier for Weak Immunogens
Authors: González  , Alvarez  , Caballero  , Viña  , Guillén  , Silva
Published: March 2003

Previously, the P64k meningococcal protein, an antigen of 64 kDa expressed in Escherichia coli, has been extensively characterized. We have successfully conjugated several synthetic peptides and meningococcal group C polysaccharide to P64k. In three out of four model peptides, the murine humoral immune response against the homologous peptide, evaluated after three doses of conjugate, was higher in the animals immunized with the coupled peptide than in those that received free peptide. The fourth and largest was immunogenic by itself. Similarly, the antigroup C polysaccharide levels reached by conjugated polysaccharide were significantly higher than those produced against unconjugated polysaccharide. As a carrier for one of the peptides, P64k was compared with bovine serum albumin (BSA) and tetanus toxoid (TT), being able to induce slightly higher or similar antipeptide antibody levels than these well‐establish protein carriers. Our results suggest that recombinant P64k protein could be a readily available immunological carrier, as efficient as other commonly used large carrier molecules.
Role of Pre‐T Cells and Chemoattractants on Stress‐Associated Thymus Involution
Authors: Domínguez‐Gerpe L. , Rey‐Méndez M.
Published: March 2003

Male C57BL/6 mice were stressed by immobilization for 1, 2, 3, or 5 h per day for 14 days, with subsequent assessment of (a) thymic involution, (b) in vitro migration of stressed mice bone marrow cells toward thymocyte culture supernatants from neonates and from control or stressed mice, (c) composition of the bone marrow cell population, and (d) in vitro migration of normal bone marrow cells toward stressed mice thymocyte culture supernatants. The results obtained support the view that the reduced repopulation of thymus by precursor T cells contributes to thymus involution associated with stress. It is further shown that this effect could be owing to a reduction in the number of precursor T cells in the bone marrow, and/or to a diminished production of precursor T‐cell chemoattractants.
Th1‐specific Bystander Costimulation Imparts Resistance against Mycobacterium tuberculosis Infection
Authors: Das G. , Vohra H. , Saha B. , Mishra G. C.
Published: March 2003

The protection against Mycobacterium tuberculosis infection is mediated by T helper type‐1 (Th1) cells. Infection of BALB/c mice with M. tuberculosis downregulates expression of a Th1‐specific costimulatory molecule, M150, on the surface of infected macrophages. The proliferation of Th cells and Th1‐cytokine production by these cells are higher in case of M. tuberculosis antigen presentation by uninfected macrophages than by infected macrophages. The difference in inducing interleukin(IL)‐2 and interferon (IFN)‐γ secretion is abolished by providing bystander costimulation through M150 on liposomes.
Macrophage Heterogeneity, Antigen Presentation, and Membrane Fluidity: Implications in Visceral Leishmaniasis
Authors: Sen E. , Chattopadhyay S. , Bandopadhyay S. , De T. , Roy S.
Published: March 2003

Morphological and functional heterogeneity of the splenic macrophage (Mφ) population was studied in Leishmania donovani (LD) infected BALB/c mice. On a discontinuous percoll gradient two distinct Mφ populations were separated. They differed significantly in size as evident from Scanning Electron Microscopy (SEM). Morphologically, the bigger Mφ (LM) showed surface projections, whereas the smaller Mφ (SM) was round. As regards the antigen‐presenting abilities, the LM of infected animals showed defective antigen‐presenting abilities at a later stage of the disease, i.e. 6 months post infection (6I‐LM) but not earlier, whereas the SM population remained functionally intact throughout the course of the infection. Further, the 6I‐LM showed a much enhanced Ad status as compared to their controls. Interestingly, both the 6I‐LM and the control set showed a comparable level of binding of a known Ad restricted peptide. Despite the presence of sufficient Ad molecules and the ability to bind the appropriate peptide, 6I‐LM were unable to stimulate peptide specific T‐cell hybridoma. Further, the 6I‐LM showed an increase in membrane fluidity and distorted morphology with membrane fissure and blebs as evident from SEM. It is possible that an increase in the membrane fluidity may lead to the defective antigen‐presenting ability of 6I‐LM. Thus, the LD infection functionally keep the 6I‐LM out of antigen presentation and this may contribute to the defective cell mediated immune response in leishmaniasis.
IgE‐Mediated Suppression of Primary Antibody Responses In vivo
Authors: Karlsson M. C. I. , Diaz De Ståhl T. , Heyman B.
Published: March 2003

The ability of immunoglobulin (Ig)G to feedback suppress antibody (Ab) responses is a well known property clinically used to prevent haemolytic disease of newborns. We recently found that IgG was able to suppress the primary Ab response to sheep red blood cells (SRBC) in mice lacking the known Fc‐receptors for IgG. In addition, IgE and F(ab′)2 fragments of IgG were able to suppress the response to SRBC in wild‐type mice. These results suggested that the IgG‐mediated suppression can take place independently of the IgG (Fc) portion and that masking of the epitopes is an important mechanism. In the present report we investigated whether the suppression caused by IgE is Fc‐dependent. Monoclonal IgE anti‐2,4,6‐trinitrophenyl (TNP), administered with TNP‐coupled SRBC (SRBC–TNP), can induce an efficient suppression in mice lacking FcγRI + RIII + FcεRI (owing to the lack of the common γ chain, FcRγ), FcγRIIB or FcεRII (CD23). Because the known IgE‐binding receptors are FcεRI, CD23, FcγRIIB and FcγRIII, the results suggest that also the IgE‐mediated suppression can take place independently of the Fc‐receptors. A slightly less efficient suppression in CD23‐deficient animals, suggests a minor involvement of this receptor.
CD40L‐Induced IL‐12 Production is Further Enhanced by the Th2 Cytokines IL‐4 and IL‐13
Authors: Bullens D. M. A. , Kasran A. , Thielemans K. , Bakkus M. , Ceuppens J. L.
Published: March 2003

Interaction of the CD40L (CD154) molecule on activated T cells with its receptor, CD40, on macrophages and dendritic cells (DC) provides a strong signal for interleukin (IL)‐12 production. As IL‐12 is the most important factor in driving Th precursor (Thp) cells into T(h)elper 1 cells, CD40–CD40L interactions strongly promote Th1 differentiation. Th2 cytokines (IL‐4, IL‐13, IL‐10) on the other hand, are known to inhibit Th1 differentiation, and to promote either directly or indirectly, Th2 differentiation. Inhibition of lipopolysaccharide (LPS)‐induced IL‐12 production by IL‐4, IL‐13 and IL‐10 is supposed to be one such mechanism. However, we here report that IL‐4 and IL‐13 enhance p70 IL‐12 production and p40 mRNA transcription by human monocytes when the latter are stimulated trough triggering of CD40. This effect on IL‐12 induction is most clear in the presence of interferon (IFN)‐γ, which upregulates CD40 expression. IL‐10 potently inhibits IL‐12 production. The increased IL‐12 production in the presence of IL‐4 and IL‐13 is however, not the indirect result of a reduction in IL‐10 production, but is most likely owing to a direct effect of IL‐4 and IL‐13. We conclude that IL‐4 and IL‐13 enhance rather than decrease the IL‐12 production by human monocytes during interaction with T cells. This effect can potentially contribute in vivo to switching of an ongoing Th2 response towards a Th1 response and the findings also support the dominant effect of CD40/CD40L interaction on Th1 development, even in the presence of Th2 cytokines.
Heat Shock Protein 60 Specific T‐Cell Response in Chlamydial Infections
Authors: Kinnunen A. , Paavonen J. , Surcel H.‐M.
Published: March 2003

Heat shock proteins (HSPs) of most pathogens, including Chlamydia, are major immune targets of both humoral‐ and cell‐mediated immune mechanisms. During the last decade, many investigators have focused their research to elucidate the complex relationship of chlamydial HSPs, especially chlamydial HSP60, and the host immune response. A central issue is whether the pathologic mechanisms in chronic chlamydial diseases are associated with an enhanced immune response to chlamydial HSP60 which can mediate tissue destruction through cytotoxic reactions, or whether they are related to the Th2 type of response that eventually leads to partial or temporary suppression of an effective antichlamydial response. Our review highlights the available knowledge between immune responses to chlamydial HSP60 and chronic chlamydial infections in human.
Endogenous Inhibition of Antimycobacterial Immunity by IL‐10 Varies between Mycobacterial Species
Authors: Roach D. R. , Martin E. , Bean A. G. D. , Rennick D. M. , Briscoe H. , Britton W. J.
Published: March 2003

Interleukin (IL)‐10 is an immunoregulatory cytokine that inhibits both Th1‐like T cell responses and macrophage activation. Deficiency of IL‐10 has been associated with increased Th1‐like CD4+ T‐cell responses and increased clearance of some intracellular pathogens, however, its role in mycobacterial infections is controversial. In order to examine the effects of mycobacterial virulence on the outcome of infection we compared infection with Mycobacterium avium and virulent Mycobacterium tuberculosis in C57Bl/6 IL‐10−/– mice. M. avium infection in IL‐10−/– mice resulted in sustained increases in interferon (IFN)‐γ‐secreting T‐cell responses and was associated with the increased clearance of M. avium from the liver and lung. By contrast, M. tuberculosis infection in IL‐10−/– mice led to a transient increase in IFN‐γ T‐cell responses at 4 weeks postinfection, with reduced bacterial burden in the lungs. This was not sustained so that by 8 weeks there was no difference to wild‐type (WT) mice. In vitro infection of IL‐10−/– macrophages with M. avium, but not M. tuberculosis, led to an increased IL‐12 production. Therefore, endogenous IL‐10 exerts a significant inhibition on specific IFN‐γ T‐cell responses to M. avium infection, however, this effect is short lived during the M. tuberculosis infection, and fails to influence the long‐term course of infection.
Downmodulation of CD18 and CD86 on Macrophages and VLA‐4 on Lymphocytes in Experimental Tuberculosis
Authors: Bonato V. L. D. , Medeiros A. I. , Lima V. M. F. , Dias A. R. , Faccioli L. H. , Silva C. L.
Published: March 2003

Development and evaluation of new vaccines and immunotherapy against tuberculosis demand a better understanding of the immune mechanisms in this disease. Costimulatory signals and intercellular contact seem to be pivotal in determining whether recognition of antigen by T cells leads to activation or anergy. In this paper, we show that virulent M. tuberculosis H37Rv downmodulates the ex vivo expression of CD18 and CD86 on peritoneal macrophages and VLA‐4 on lymphocytes but does not disturb the in vitro production of interleukin (IL)‐12 and interferon (IFN)‐γ after intraperitoneal infection. In addition, splenocytes from infected mice produce IL‐10, while the expression of cell surface receptors is unchanged. The interplay among IL‐12, IFN‐γ and IL‐10 in vivo and the downmodulation of cell‐surface receptors during the infection at the inflammatory site may contribute to the explanation of the maintenance of infection.
NK1.1+ Cells and T‐Cell Activation in Euthymic and Thymectomized C57Bl/6 Mice during Acute Trypanosoma cruzi Infection
Authors: Cardillo F. , Cunha F. Q. , Tamashiro W. M. S. C. , Russo M. , Garcia S. B. , Mengel J.
Published: March 2003

Natural killer (NK) cells may provide the basis for resistance to Trypanosoma cruzi infection, because the depletion of NK1.1 cells causes high levels of parasitemia in young C57Bl/6 mice infected with T. cruzi. Indeed, NK1.1 cells have been implicated in the early production of large amounts of interferon (IFN)‐γ, an important cytokine in host resistance. The NK1.1 marker is also expressed on special subpopulations of T cells. Most NK1.1+ T cells are of thymic origin, and their constant generation may be prevented by thymectomy. This procedure, by itself, decreased parasitemia and increased resistance in young mice. However, the depletion of NK1.1+ cells by the chronic administration of a monoclonal antibody (MoAb) (PK‐136) did not increase the parasitemia or mortality in thymectomized C57Bl/6 mice infected with T. cruzi (Tulahuen strain). To study the cross‐talk between NK1.1+ cells and conventional T cells in this model, we examined the expression of activation/memory markers (CD45RB) on splenic CD4+ and CD8+ T cells from young euthymic or thymectomized mice with or without depletion of NK1.1+ cells and also in aged mice during acute infection. Resistance to infection correlated with the amount of CD4+ T cells that are already activated at the moment of infection, as judged by the number of splenic CD4+ T cells expressing CD45RB−. In addition, the specific antibody response to T. cruzi antigens was precocious and an accumulation of immunoglobulin (Ig)M with little isotype switch occurred in euthymic mice depleted of NK1.1+ cells. The data presented here suggest that NK1.1+ cells have important regulatory functions in euthymic, but not in thymectomized mice infected with T. cruzi. These regulatory functions include a helper activity in the generation of effector or activated/memory T cells.
Receptor Revision and Systemic Lupus
Authors: Monestier M. , Zouali M.
Published: March 2003

Studies over the past 10 years have shown that B cells can undergo secondary heavy‐ or light‐chain immunoglobulin (Ig) rearrangements at various stages of their normal development, a process termed receptor editing. In the bone marrow, this mechanism is important to maintain tolerance because it can extinguish a self‐reactive specificity without having to physically eliminate a potentially autoreactive B cell. In the periphery, secondary rearrangements may also play a role in the diversification and maturation of an immune response, although conclusive evidence for this process is still required. Individuals with systemic autoimmune diseases, such as lupus, show evidence of intricate abnormalities in receptor editing. On the one hand, decreased editing may not eliminate the self‐reactive specificities that emerge during B‐cell development in the bone marrow. Conversely, excessive secondary rearrangements, especially in the periphery where tolerance mechanisms are less effective, can result in the production of autoantibodies by edited B cells. It will be important to assess whether the complex editing defects observed during lupus are a primary susceptibility factor to this disease or if they are secondary to other abnormalities of lymphocyte development in these autoimmune patients.
Cross‐Priming is Under Control of the relB Gene
Authors: CASTIGLIONI P. , JANSSEN E. M. , PRILLIMAN K. R. , GERLONI M. , SCHOENBERGER S. , ZANETTI M.
Published: March 2003

Cross‐priming is an important mechanism of intercell transfer of antigenic material leading to the specific activation of cytotoxic T lymphocytes. Dendritic cells (DCs) are considered the central antigen‐presenting cell in cross‐priming. Here we decided to probe the role of the relB gene, a regulator of DC differentiation, in the in vivo cross‐priming of a model tumour antigen, TAP(–/–) murine embryo cells (MEC), expressing human adenovirus type 5 early region 1. To this end, we used relB(–/–) mutant mice to generate bone marrow (BM) chimeras as these possess few residual DC but are capable of initiating CD4+ and CD8+ T‐cell responses in vivo. Our results show that relB(–/–) BM chimeras are unable to cross‐prime CD8+ T cells, suggesting that the relB gene regulates cross‐priming.
Evidence of Clonotypic Pattern of T‐Cell Repertoire in Synovial Fluid of Children with Juvenile Rheumatoid Arthritis at the Onset of the Disease
Authors: Chini L. , Bardare M. , Cancrini C. , Angelini F. , Mancia L. , Cortis E. , Finocchi A. , Riccardi C. , Rossi P.
Published: March 2003

Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are characterized by chronic inflammation, synovial cell proliferation and progressive joint damage. It has been speculated that T cells play an important role in the pathogenesis of RA and JRA in the early stage of the disease. Previous studies have demonstrated discrepant results regarding the significance of T‐cell clonality in RA or JRA lesions. It can be postulated that the heterogeneity of these data may be linked to the stage of the disease, as the relative importance of selective immunological events is different during the time from onset to established disease. To avoid this problem, we conducted the present study in nine children affected by JRA at the onset of the disease and before treatment. We analysed the T‐cell receptor beta chain variable (TCRBV) of CD4+ and CD8+ lymphocytes in peripheral blood (PBL) and synovial fluid (SFL), by a panel of monoclonal antibodies (MoAbs). Furthermore, to assess the clonotypic pattern of T‐cell repertoire, the CDR3 length distribution was evaluated by spectratyping analysis. Our results showed no significant expansion of distinct TCRBV subset in either synovial or peripheral compartments. Conversely, when we studied the CDR3 length distribution, an oligoclonal pattern was found in the SFL of six patients, suggesting the presence of a clonotypic restriction of T cells in SFL, which is not detectable in PBL. These findings are consistent with an antigen driven T‐cell expansion sequestered at the inflammatory site.
Interstratal dewatering origin for polygonal patterns of sand‐filled cracks: a case study from late Proterozoic metasediments of Islay, Scotland
Authors: Tanner
Published: March 2003

Sand‐filled cracks from the Lower Fine‐grained Quartzite of Dalradian (late Proterozoic) age on the Island of Islay, western Scotland, may be divided into two main types, both of which form orthogonal and non‐orthogonal closed patterns on bedding surfaces. Type 1 cracks are short and lenticular in cross‐section, contain sand which had been injected downwards, and are found on the bottoms of cross‐laminated sandstone beds. Type 2 cracks cut several beds and preserve evidence of upward flow of water‐saturated sand. Both types of crack developed through the interstratal intrusion of water‐saturated sand into shrinkage cracks in mud or muddy sand, not, as previously thought, as a result of sub‐aerial desiccation, or sub‐aqueous cracking of the sediment surface (synaeresis). These cracks likely resulted from layer‐parallel contraction caused by compaction of mudstone layers during burial. Seismic shock may have provided the trigger for the preferential development of polygonal crack patterns in these layers instead of the more usual small‐scale dewatering structures. From a detailed comparison with published descriptions of filled cracks from a number of different geological environments, it is concluded that interstratal cracking is a mechanism which rivals sub‐aerial desiccation in importance, and is more common in the geological record than is currently realized.
Massive dolomitization of a late Miocene carbonate platform: a case of mixed evaporative brines with meteoric water, Nijar, Spain
Authors: Lu Feng H. , Meyers William J.
Published: March 2003

Late Miocene platform carbonates from Nijar, Spain, have been extensively dolomitized. Limestones are present in the most landward parts of the platform, in stratigraphically lower units and topographically highest outcrops, suggesting that dolomitizing fluids were derived from the adjacent Nijar Basin. The dolomite crystals range from <10 to ≈100 μm existing as both replacements and cements. Na, Cl and SO4 concentrations in the dolomites range from 200 to 1700 p.p.m., 250–650 p.p.m., and 600–7000 p.p.m., respectively, comparable with other Tertiary and modern brine dolomite values, and also overlapping values from mixing‐zone dolomites. Sr concentrations range between 50 and 300 p.p.m., and the molar Sr/Ca ratios of dolomitizing fluids are estimated to range between 7× seawater brine to freshwater ratios. The δ18O and δ13C of the dolomites range from −1·0 to +4·2‰ PDB, and −4·0 to +2·0‰ PDB, respectively. 87Sr/86Sr values (0·70899–0·70928) of the dolomites range from late Miocene seawater to values greater than modern seawater.

Mixtures of freshwater with seawater and evaporative brines probably precipitated the Nijar dolomites. Modelled covariations of molar Sr/Ca vs. δ18O and Na/Ca vs. δ18O from these mixtures are consistent with those of the proposed Nijar dolomitizing fluids. Complete or partial dolomite recrystallization is ruled out by well preserved CL zoning, nonstoichiometry and quantitative water–rock interaction modelling of covariations of Na vs. Sr and δ18O vs. δ13C. The possibility of multiple dolomitization events induced by evaporative brines, seawater and freshwater, respectively, is consistent with mineral‐mineral mixing modelling.

The basin‐derived dolomitizing brines probably mixed with freshwater in the Nijar Basin or mixed with fresh groundwater in the platform, and were genetically related either to deposition of the Yesares gypsum or the Feos gypsum. Dolomitization occurred during either the middle Messinian or the early upper Messinian. Nijar dolomitization models may be applicable to dolomitization of other late Miocene platform carbonates of the western Mediterranean. Moreover, the Nijar models may offer an analogue for more ancient evaporite‐absent platform carbonates fringing evaporite basins.
Biofilm‐related calcification, sediment trapping and constructive micrite envelopes: a criterion for the recognition of ancient grass‐bed environments?
Authors: Perry Christopher T.
Published: March 2003

Micrite envelopes are a common feature in carbonate sediments and are typically associated with the micrite filling of borings produced by microendolithic organisms. These are referred to as ‘destructive micrite envelopes’ and have long been recognized as reflecting an important early diagenetic process. Recent analysis of sediments collected from back‐reef environments at Discovery Bay, north Jamaica, however, has demonstrated ‘envelope’ formation on the surfaces of carbonate grains, clearly distinct from the micrite filling of microborings. Such constructive envelopes occur almost exclusively in sediments from grass‐bed environments and are always intimately associated with ‘biofilms’ comprising abundant mucilage, cyanobacteria, bacteria and diatoms. It is suggested that these envelopes represent a product of both biologically mediated micrite precipitation (occurring within the biofilm mucilage and around the biofilm components, i.e. cyanobacteria and diatoms) and associated trapping of carbonate mud and fine‐grained sediment. Their recognition only within grass‐bed sediments may enable their use as a diagnostic feature of grass‐bed environments or vegetation‐stabilized substrates in the rock record.