bluuebunny/crossref_metadata_2025_split huggingface dataset:
Splenic marginal zone atrophy and progressive CD8+ T‐cell lymphocytosis in HIV infection: a study of adult post‐mortem spleens from Côte d'Ivoire
Authors: Wilkins B S , Davis Z , Lucas S B , Delsol G , Jones D B 
Published: March 2003

Aims:  Progressive changes have been reported in lymph nodes in HIV infection, but few accounts describe altered splenic histology at different stages of the disease. Investigation of splenic changes accompanying the progressive CD4+ T‐cell depletion that occurs in HIV infection could shed light on normal immunological interactions in this organ. Therefore, we assessed the amount and distribution of lymphoid tissue in spleens from adults with documented early or advanced HIV disease.Methods and results:  Immunohistochemistry was used to study splenic tissue collected in an extensive autopsy survey of HIV+ adults in West Africa. Compared with post‐mortem spleens from HIV– West African adults and control UK spleens, those from HIV‐infected patients showed severe atrophy of white pulp B‐ and T‐cell compartments. In early and advanced HIV disease, marginal zone atrophy was significant. Peri‐arteriolar lymphoid sheaths contained increased numbers of CD8+/CD45RO+ T‐cells in advanced HIV disease. In red pulp, early and advanced cases showed a lymphocytosis of CD8+/CD45RO– T‐lymphocytes.Conclusions:  Atrophic changes were more extreme in advanced than early HIV infection. Reduced marginal zone function possibly explains the known predisposition of HIV+ patients to infection by encapsulated bacteria. Possible immunological consequences of these CD8+/CD45RO+ (peri‐arteriolar lymphoid sheaths) and CD8+/CD45RO– (red pulp) responses deserve further study. Comparison of West African and UK control spleens indicated that there were no major ethnic differences in spleen structure to prevent extrapolation of our results to European adults.
Soluble Fas mRNA is dominantly expressed in cases with silicosis
Authors: Otsuki T. , Sakaguchi H. , Tomokuni A. , Aikoh T. , Matsuki T. , Kawakami Y. , Kusaka M. , Ueki H. , Kita S. , Ueki A. 
Published: March 2003

Although it is well known that cases with silicosis exhibit various immunological abnormalities, the mechanisms involved in the occurrence of immuno‐dysfunction or dysregulation induced by silica compounds have not yet been determined. Fas is a well‐known cell surface molecule that is involved in the apoptosis pathway that belongs to the tumour necrosis factor‐receptor family. Soluble Fas (sFas) is produced as an alternatively spliced product of the Fas gene and protects cells from apoptosis due to antagonization of the binding between membrane form of the Fas gene (mFas) and the Fas ligand. To determine the role of the Fas/Fas ligand system in silica‐induced immunological abnormalities, we investigated Fas and Fas‐ligand message expression levels using the multiplex reverse transcription–polymerase chain reaction (RT–PCR) method with peripheral blood mononuclear cells from silicosis cases with no clinical symptoms of autoimmune diseases. Although the relative expression levels of the Fas or Fas‐ligand genes were not remarkably altered in these cases, we observed the sFas message was dominantly expressed compared with mFas expression. These results suggest that self‐recognizing clones in cases with silicosis survive for decades, escaping the exclusion mechanisms induced by apoptosis. Then they cause the appearance of autoantibodies and the acquisition of autoimmune diseases sequentially.sFas, soluble Fas PSS, progressive systemic sclerosis RT–PCR, reverse transcriptase–polymerase chain reaction mFas, membrane Fas SLE, systemic lupus erythematosus HV, healthy volunteers SQ‐MPL‐PCR, semi‐quantitative multiplex RT–PCR PR, radiological profusion grades.
Potentiation of antigen‐specific, Th1 immune responses by multiple DNA vaccination with an ovalbumin/interferon‐γ hybrid construct
Authors: Lim Y. S. , Kang B. Y. , Kim E. J. , Kim S. H. , Hwang S. Y. , Kim T. S. 
Published: March 2003

The preferential differentiation of T helper (Th) cells to Th1 or Th2 subsets is important with respect to susceptibility or resistance to particular infections, or to autoimmune diseases and allergic diseases. To more effectively drive immune responses toward antigen‐specific Th1 responses, we constructed a mammalian expression vector (pOVA/IFN‐γ) carrying a hybrid gene in which the ovalbumin (OVA) (a model antigen) cDNA was covalently linked to murine interferon‐γ (IFN‐γ) cDNA. Intramuscular injection of BALB/c mice with the pOVA/IFN‐γ DNA increased both the production of OVA‐specific IFN‐γ by CD4+ T cells and the ratio of anti‐OVA immunoglobulin G (IgG)2a to IgG1 isotypes, while the injection with the pOVA alone, or with the mixture of the pOVA and pIFN‐γ, caused no or little increase. Furthermore, the OVA‐specific, Th1 immune responses were dramatically augmented by multiple injections with the pOVA/IFN‐γ DNA. These studies indicate that the direct linkage of an OVA gene to an IFN‐γ gene in the expression plasmid is required for efficiently confining the Th1 effects of IFN‐γ to the OVA‐specific cells, and the linkage effect of the OVA/IFN‐γ DNA can be potentiated by multiple vaccination.ELISA, enzyme‐linked immunosorbent assay i.m., intramuscularly KLH, keyhole limpet haemocyanin OVA, ovalbumin.
Rheumatoid factor isotype switch and somatic mutation variants within rheumatoid arthritis synovium
Authors: Williams  , Moyes  , Mageed  
Published: March 2003

SUMMARYThe presence of clonally‐related B‐lymphocyte aggregates within synovial lining tisue of rheumatoid arthritis (RA) patients suggests a germinal centre‐like reaction, which may hold implications for disease pathogenesis and the causes of chronic inflammation. We studied 250 rheumatoid factor (RF) heavy‐chain sequences cloned from the synovium of three patients with RA, to determine whether they undergo both somatic mutation and isotype switching consistent with this hypothesis. Size analysis of immunoglobulin heavy‐chain cDNAs from synovial RF+ B cells revealed oligoclonal RF+ populations and identically‐sized VH‐D‐JH transcripts of different immunoglobulin isotypes. Sequencing of individual inserts selected from cloned immunoglobulin heavy‐chain cDNAs demonstrated a clonal relationship between immunoglobulin M (IgM) RF and IgA RF, suggesting that this isotype switch occurred in synovium. Furthermore, most somatic mutations were found to have occurred after this isotype switch. This finding suggests that the RA synovial microenvironment sustains somatic mutation and isotype switching in RF‐specific B lymphocytes akin to secondary lymphoid organs.
Nitric oxide selectively decreases interferon‐γ expression by activated human T lymphocytes via a cGMP‐independent mechanism
Authors: Roozendaal R. , Vellenga E. , Postma D. S. , De Monchy J. G. R. , Kauffman H. F. 
Published: March 2003

SummaryThe role of exogenous nitric oxide (NO) on the expression of interleukin (IL)‐2, IL‐4, IL‐5 and interferon‐γ (IFN‐γ) by freshly isolated human T lymphocytes was investigated. The presence of NO, generated from any of the NO‐donor compounds, S‐nitroso‐N‐acetyl‐d,
l‐penicillamine (SNAP), DPTA‐nonoate (DPTA) or DETA‐nonoate (DETA), added 15 min prior to T‐cell stimulation (for 24 hr) with anti‐CD3/anti‐CD28 monoclonal antibodies (mAbs), resulted in up to 50% inhibition of IL‐4, IL‐5 and IFN‐γ secretion. In contrast, IL‐2 secretion was not inhibited. Using the guanylate cyclase inhibitor, LY83583, it was shown that the inhibition of IL‐4 and IL‐5 was cGMP dependent, whereas additional mechanisms mediated the inhibition of IFN‐γ. Exposure of T cells to the NO‐donor compounds for 24 hr prior to stimulation resulted in a more pronounced inhibition of IFN‐γ secretion by DPTA and DETA (P < 0·01), despite the fact that NO generation could no longer be detected. Under these conditions, IL‐4 secretion was not inhibited and IL‐5 secretion was inhibited to a lesser extent (P < 0·01 for SNAP and DPTA, P > 0·05 for DETA). IL‐2 secretion was inhibited after 24 hr of preincubation with the NO‐donor compounds, whereas it was not directly affected by NO. The increased inhibitory effects on IFN‐γ and IL‐2 secretion could not be accounted for by the antiproliferative effects of the NO‐donor compounds, which were diminished after 24 hr of preincubation relative to 15 min of preincubation. For IFN‐γ, the inhibition was at least partially effected at the transcriptional level as shown by decreased mRNA accumulation. These data show that NO can modulate the balance between the expression, by human T‐lymphocytes, of T helper 1‐ and T helper 2‐type cytokines, through selective and persistent inhibition of the expression of IFN‐γ via a cGMP‐independent mechanism.
Regulation of B‐1 cell activation and its autoantibody production by Lyn kinase‐regulated signallings
Authors: Ochi H. , Takeshita H. , Suda T. , Nisitani S. , Honjo T. , Watanabe T. 
Published: March 2003

SummaryThe src‐family protein tyrosine kinase, Lyn, has been reported to play a crucial role in the regulation of B‐cell antigen receptor (BCR)‐mediated signalling. To elucidate the role of Lyn in the maintenance of immunological tolerance and the prevention of B‐1 cell activation and its autoantibody production, Lyn‐deficient mice were crossed with transgenic mice carrying the immunoglobulin heavy and light chain genes encoding an autoantibody against mouse red blood cells. In the transgenic mice, most peripheral B cells expressed the B‐1 cell phenotype. When the transgenic mice were bred in specific pathogen‐free (SPF) conditions, B‐1 cells were anergic and did not produce any autoantibody. In contrast, Lyn‐deficient transgenic mice kept in the same SPF conditions revealed markedly increased numbers of activated B‐1 cells and developed severe autoimmune haemolytic anaemia. Moreover, the mice had a huge splenomegaly containing a remarkable accumulation of erythroblasts, resulted from extramedullary erythropoiesis, in addition to the increased numbers of lymphoblast‐like cells of the B‐1 cell lineages. The present study demonstrates a crucial role of Lyn kinase in the regulation of B‐1 cell activation and maintenance of tolerance.
Sex hormone levels correlate with the activity of cytokine‐secreting cells in vivo
Authors: Verthelyi D. , Klinman D. M. 
Published: March 2003

SummaryThis work examines the correlation between serum levels of oestrogen, progesterone and dehydroepiandrosterone sulphate (DHEA‐S) and the number of human peripheral blood cells actively secreting interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, tumour necrosis factor‐α (TNF‐α) or interferon‐γ (IFN‐γ) in vivo. Simultaneous assessment of serum hormone levels and cytokine‐secreting cell activity throughout the menstrual cycle showed that the number of peripheral blood mononuclear cells (PBMC) able to secrete IL‐4 in response to stimulation correlated significantly (P < 0·0001) with oestrogen levels and fluctuated with the menstrual cycle in pre‐menopausal women. The activity of IFN‐γ‐secreting cells, on the other hand, varied as a function of serum DHEA‐S levels in pre‐menopausal women (P < 0·0001). Similarly, the number of cells secreting IFN‐γ in men correlated with serum DHEA‐S levels (P < 0·001). In contrast, post‐menopausal women had fewer cells actively secreting cytokines and the activity of these cells did not correlate with sex hormone levels. These results suggest that sex hormones may modulate cytokine production in vivo and contribute to gender‐related differences in normal and pathological immune responses.
T‐cell regulation of peripheral tolerance and immunity: the potential role for  Notch signalling
Authors: Hoyne G. F. , Dallman M. J. , Lamb J. R. 
Published: March 2003

SummaryRecognition of antigen by T cells in the periphery may lead either to the generation of productive immunity or the induction of tolerance. These two functional outcomes are a consequence of distinct pathways of T‐cell differentiation. T cells are selected to become regulatory cells and their function is to maintain homeostasis with the immune system. In this review we discuss the cell‐fate decisions that T cells might make allowing them to promote immunity or induce tolerance in the context of the role that Notch signalling may play in this process.
The Rubino test for leprosy is a β2‐glycoprotein 1‐dependent antiphospholipid reaction
Authors: Panunto‐Castelo A. , Almeida I. C. , Rosa J. C. , Greene L. J. , Roque‐Barreira M.‐C. 
Published: March 2003

SummaryWe describe the isolation and identification of three components required for the Rubino reaction (RR), which is the rapid sedimentation of formalinized sheep red‐blood cells (SRBC) initiated by serum from leprosy patients with defective Mycobacterium leprae‐specific cell immunity. The Rubino reaction factor (RRF) required for this phenomenon, previously identified as an immunoglobulin M (IgM), was purified from leprosy patient serum by adsorption to formalinized SRBC. Purified RRF IgM, when added to formalinized SRBC, did not produce a positive RR. However, when the contact was carried out in the presence of normal human serum (NHS), cells rapidly sedimented. The purified cofactor from NHS contained two components of 70 000 and 50 000 molecular weight (MW), as determined by sodium dodecyl sulphate–polyacrylamide gel electrophoresis (SDS–PAGE). The latter was recognized by the RRF IgM on immunoblot and its N‐terminal sequence indicated that it was β2‐glycoprotein 1 (β2‐GP1), an anionic phospholipid‐binding protein. Methanol‐treated formalinized SRBC did not support the RR. Thin‐layer chromatography of an extract of membranes indicated that the SRBC ligand was a cell‐surface phospholipid. Cardiolipin inhibited the RR. These data demonstrate that the RR involves a trimolecular interaction in which IgM, β2‐GP1 and an SRBC phospholipid participate. By analogy with the antiphospholipid antibodies (anti‐PL) that occur in autoimmune processes, serum samples from 29 systemic lupus erythematosus patients with high levels of anticardiolipin antibodies were submitted to the RR. A positive RR was obtained for 45% (13 of 29 patients). These results modify the paradigm of the absolute specificity of the RR for leprosy and demonstrate that RRF IgM is a β2‐GP1‐dependent anti‐PL.
Granulocyte–macrophage colony‐stimulating factor regulates cytokine production in cultured macrophages through CD14‐dependent and ‐independent mechanisms
Authors: Bergamini A. , Bolacchi F. , Bongiovanni B. , Cepparulo M. , Ventura L. , Capozzi M. , Sarrecchia C , Rocchi G. 
Published: March 2003

SummaryGranulocyte–macrophage colony‐stimulating factor (GM‐CSF) has multiple effects on the antigen phenotype and function of macrophages. In this study we investigated the effect of GM‐CSF on cytokine production by macrophages. We found that GM‐CSF may modify the tumour necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6) response to lipopolysaccharide (LPS) through two different mechanisms. Relatively early in culture, GM‐CSF increases the amount of cytokines synthesized by responding cells; this effect appears to be unrelated to modulation of CD14 expression and LPS‐binding capacity. After prolonged incubation, GM‐CSF up‐regulates both CD14 expression and LPS‐binding capacity, and the frequency of cytokine‐producing cells. Release of CD14 in the culture supernatant was decreased in the presence of GM‐CSF, suggesting that a reduced shedding was responsible for the effect of GM‐CSF on CD14 expression. Enhancement of cytokine production was also observed in GM‐CSF‐treated macrophages after stimulation by phorbol 12‐myristate 13‐acetate (PMA), thus indicating that GM‐CSF affects both CD14‐dependent and ‐independent cytokine production. Finally, GM‐CSF did not modulate the LPS‐ and PMA‐induced production of IL‐10 and IL‐12. We conclude that GM‐CSF may play a role in manipulating the activation‐induced expression of pro‐inflammatory cytokines by macrophages. Enhanced production of these cytokines could play an important role in the pathogenesis of Gram‐negative septic shock syndrome and in defence against infectious agents.
Virulence of Sporothrix schenckii conidia and yeast cells, and their susceptibility to nitric oxide
Authors: Fernandes K. S. S. , Coelho A. L. J. , Bezerra L. M. Lopes , Barja‐Fidalgo C. 
Published: March 2003

SummaryThe involvement of nitric oxide (NO) in macrophage (Mφ) fungicidal activity against Sporothrix schenckii, and the relationship between NO susceptibility and the differential virulence of conidia and yeast cells, were investigated. Confirming a previously reported correlation between the length of time in culture and virulence of S. schenckii, conidia isolated from 12‐day mycelial cultures (Ss‐12) were less virulent to mice than conidia from 7‐day cultures (Ss‐7) or yeast cells. Indicative of NO production, infected animals showed a significant increase in serum levels of nitrite that was lower in mice infected with Ss‐12 than in mice infected with Ss‐7 or yeast. Stimulation of murine Mφ with interferon‐γ (IFN‐γ) induced NO production and inhibition of fungal growth. The cytotoxic activity of Mφ against Ss‐12 was significantly greater than against Ss‐7 or yeast cells, the highly virulent fungal forms. The addition of NO synthase inhibitors abrogated Mφ cytotoxic activity against all fungal forms. The phagocytic activity of Mφ against Ss‐7 was significantly lower than against Ss‐12 or yeast cells. Although the ingestion of fungal cells triggered the oxidative burst in Mφ, the fungicidal activity was not altered in the presence of superoxide dismutase (SOD) and catalase. In addition, Ss‐12 and yeast cells were more susceptible than Ss‐7 to the direct fungicidal activity of the NO donors S‐nitroso‐N‐acetyl‐dl‐penicillamine (SNAP), S‐nitrosoglutathione (GSNO) and 3‐morpholinosydnonimine (SIN‐1). The results of this study indicate that NO is a key cytotoxic mediator involved in the murine Mφ defence against S. schenckii, and that the virulence of Ss‐7, Ss‐12 and yeast cells may be related to a differential susceptibility to NO.
Differential expression of ovine CD1
Authors: Rhind S. M. , Hopkins J. , Grant E. S. 
Published: March 2003

SummaryDifferential expression of ovine CD1 was examined using a combination of reverse transcription–polymerase chain reaction (RT–PCR) with sequence‐specific primers and Northern and in situ hybridization techniques. The aim of the study was to establish the patterns of CD1 expression at the molecular level and address questions posed by previous studies in other species regarding expression patterns of CD1. A ‘pan‐CD1’ probe based on the exon 4 (alpha 3) region was used in addition to isotype‐specific probes for SCD1B (the exon 3 region of clone SCD1B42) and SCD1D (the exon 3 region of clone SCD1D). Widespread expression of CD1 (including thymus, peripheral blood lymphocytes, lung and intestine) was identified using both the exon 4 and SCD1D probe. SCD1B expression was more restricted, being identified in equivalent levels only in the thymus and in scattered populations of dendritic cells. These results highlight the difference in expression patterns between group 1 and group 2 CD1 family members and establish SCD1D as the CD1 family member with the widest pattern of expression, consistent with a differential role for the different CD1 family members.
Modulatory effect of prostaglandins on human monocyte activation for killing of high‐ and low‐virulence strains of Paracoccidioides brasiliensis
Authors: Soares A. M. V. C. , Calvi S. A. , Peraçoli M. T. S. , Fernandez A. C. , Dias L. A. , Dos Anjos A. R. 
Published: March 2003

SummaryThe effect of indomethacin (Indo), a cyclo‐oxygenase inhibitor, on the monocyte‐mediated killing of a low‐ (Pb265) and a high‐ (Pb18) virulence strain of Paracoccidioides brasiliensis was examined. The Pb18 strain was not killed by either non‐activated or interferon‐γ (IFN‐γ) ‐activated human monocytes but these cells did show fungicidal activity if pretreated with Indo. In contrast with IFN‐γ, tumour necrosis factor‐α (TNF‐α) was very effective at stimulating the fungicidal activity of monocytes. While the low‐virulence strain, Pb265, could not be killed by monocytes, cells preincubated with IFN‐γ demonstrated fungicidal activity. The killing of this strain was also induced by pretreatment of monocytes with Indo. The results suggest a negative role for prostaglandins, which are synthesized via the cyclo‐oxygenase pathway, in the regulation of monocyte‐mediated killing of virulent and avirulent strains of P. brasiliensis and that TNF‐α generation during the fungus–monocyte interaction is more important in the killing of Pb265 than Pb18.
Metalloprotease inhibitor‐mediated inhibition of mouse immunoglobulin production
Authors: Kilmon M. A. , Mayer R. J. , Marshall L. A. , Conrad D. H. 
Published: March 2003

SummaryHigh levels of membrane CD23 have been shown to decrease immunoglobulin E (IgE). CD23 is a very labile molecule and is cleaved from the cell surface by an unknown metalloprotease. Two metalloprotease inhibitors, compound A (N‐[4‐hydoxyamino‐2‐(R)‐isobutyl‐3‐(S)propargylthiomethylsuccinyl]‐(S)‐phenylalnine‐N′‐methyl‐amide) and compound B (N‐[3‐(S)‐hydroxy‐4‐hydroxyamino‐2‐(R)‐(2‐naphthylmethyl) succinyl]‐(S)‐tert‐leucinamide), were chosen for their ability to inhibit human CD23 cleavage and selectively inhibit IgE production. The ability of these inhibitors to block cleavage of murine CD23 and immunoglobulin production in an in vitro system was examined. The inhibitors blocked sCD23 release from B cells. The inhibitors also decreased IgE production by B cells; however, 20–30 times more inhibitor was needed to give a similar amount of inhibition as compared with sCD23 release. The effects on immunoglobulin production did not require the presence of CD23 in that these inhibitors also blocked in vitro immunoglobulin production when B cells from CD23–/– mice were used. The inhibitors decreased production of all other immunoglobulin isotypes examined and reduced the number of IgE antibody‐forming cells (AFC) while having no effect on cell proliferation or viability. The level of Iε transcripts in cells treated with compounds A and B were not different as compared with control cells. These results suggest that while these inhibitors effectively inhibit IgE production in a CD23‐specific manner in the human, these compounds, in the mouse, inhibit immunoglobulin production by an unknown mechanism that is unrelated to CD23.