摘要:

AbstractThe most unusual characteristic of myasthenia gravis (MG) is that the thymus has germinal centers (GC). Cultured thymic lymphocytes from MG patients spontaneously produce anti‐acetylcholine receptor antibodies, indicating that autoreactive B cells have escaped negative selection. To investigate the underlying mechanism, we examined the expression of the apoptosis‐related protein Bcl‐2 in GC B cells (defined as CD19+CD38+cells) in the thymus in 14 MG patients using three‐color flow cytometry. GC in MG patients did not show the normal down‐regulation of Bcl‐2 (the frequency of Bcl‐2+GC B cells in the MG thymus and in control tonsils 54.3 ± 16.2% versus 20.6 ± 8.0%; mean ± SD,p<0.0001). In contrast, Bcl‐2 in GC in the mediastinal lymph nodes from four patients was down‐regulated to a relatively normal level. Using the terminal deoxynucleotidyl transferase‐mediated dUTP‐biotin nick end‐labeling (TUNEL) method to detect DNA fragmentationin situ, the frequency of TUNEL+cells in GC in the MG thymus was lower than in control tonsils. These results suggest that autoreactive B cells which normally undergo apoptosis in GC may survive because of Bcl‐2 up‐regul

ISSN:0014-2980    

DOI:10.1002/eji.1830270402

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractInfection withPlasmodium bergheiANKA (PbA) causes fatal cerebral malaria (CM). While a pathogenic role for tumor necrosis factor (TNF) has been established, we asked whether a disruption of interferon‐γ (IFN‐γ) signaling would modulate CM. We demonstrate here that IFN‐γR‐deficient mice are completely protected from CM. PbA‐induced release of TNF and up‐regulation of endothelial intercellular adhesion molecule (ICAM)‐1 expression, recruitment of mononuclear cells, and cerebral microvascular damage with vascular leakage occur only in wild‐type mice. Protected mice die at a later time of severe anemia and overwhelming parasitemia. Resistance to CM in IFN‐γR‐deficient mice is associated with reduced serum TNF levels, reduced interleukin‐12 expression in the brain and increased T‐helper 2 cytokines. In conclusion, IFN‐γ is apparently required for PbA‐induced endothelial ICAM‐1 up‐regulation and subsequent microvascular pathology, resulting in fatal CM. In the absence of IFN‐γ signaling, ICAM‐1 and TNF up‐regulation is reduced; h

ISSN:0014-2980    

DOI:10.1002/eji.1830270403

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractSeveral recent studies have identified eosinophils as a cellular source of various cytokines, indicating that eosinophils play not only an effector role, but also a regulatory role within the allergic inflammatory cell network. In this study, we demonstrate that eosinophils can generate and secrete monocyte chemoattractant protein‐1 (MCP‐1), a prototype of C‐C chemokines. Eosinophils generated immunoreactive MCP‐1 in response to such diverse stimuli as C5a, formylmethionyl‐leucyl‐phenylalanine (FMLP) and ionomycin, but MCP‐1 production was not induced by interleukin (IL)‐1 or tumor necrosis factor‐α. C5a‐ and FMLP‐induced eosinophil MCP‐1 production was absolutely dependent on pretreatment with cytochalasin B. Eosinophils elaborated significantly more MCP‐1 than neutrophils. Immunoreactive MCP‐1 was detected at 6 h of incubation with C5a or FMLP. Expression of MCP‐1 mRNA reached a maximum within the first 3 h after stimulation and then declined rapidly to a very low and stable level by 18 h. Pretreatment with IL‐5 markedly amplified C5a‐induced MCP‐1 production, and the enhancement occurred at the pretranslational level. Eosinophilactive chemokines such as eotaxin failed to induce MCP‐1 generation, even when eosinophils were primed by IL‐5. Since MCP‐1 exerts a potent histamine‐releasing effect on human basophils, our results indicate that eosinophils may regulate basophil mediator release with possible consequent contribution to the pathogenesis of all

ISSN:0014-2980    

DOI:10.1002/eji.1830270404

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractEndotoxin (lipopolysaccharide; LPS) and superantigens (exotoxins) have been identified as potent inducers of lethal shock. While endotoxin primarily interacts with CD 14 receptors on macrophages, superantigens like the staphylococcal enterotoxin B (SEB) preferentially activate T cells. Both cell types are triggered to release pro‐inflammatory cytokines that in turn induce lethal shock. We analyzed whether endotoxin and superantigen interact during the induction phase of lethal shock. We report that LPS and SEB operate synergistically. Lethal doses of both inducers were reduced 100‐fold when given in combination. The induced serum levels of tumor necrosis factor, interleukin‐6, and interferon‐γ (IFN‐γ) were elevated and remained high for a prolonged period. Moreover, synergistic action of LPS and SEB induced lethal toxic shock even without presensitization of mice withD‐galactosamine (D‐GalN). Opposed toD‐GalN‐pretreated mice, mice injected with LPS and SEB showed less liver damage, but rather apoptosis of epithelial cells in the bowel. Cyclosporin A and treatment with anti‐IFN‐γ monoclonal antibody blocked the synergistic action of LPS and SEB, indicating that T cell‐derived IFN‐γ is the mediator of the observed synergism. Concomitant injection of LPS and SEB had no influence on SEB‐induced T cell deletion and anergy induction. Since Gram‐positive and Gram‐negative bacteria can be recovered from septic blood samples, the synergistic action of endotoxin and superantigens might b

ISSN:0014-2980    

DOI:10.1002/eji.1830270405

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractThe assembly of peptide‐major histocompatability class II complexesin vitrois accelerated at low pH, comparable to that found in the intracellular compartments of metabolically active antigen‐presenting cells (APC). Mycobacteria such asMycobacterium tuberculosisreside in phagosomes with only mildly acidic pH. Therefore, we investigated the pH dependency of peptide‐HLA‐DR binding for several T cell epitopes of mycobacterial proteins, focussing particularly on well‐defined, immunodominant HLA‐DR17(3)‐restricted T cell epitopes: peptide (p) 3–13 from the cytoplasmic 65‐kDa heat shock protein ofM. tuberculosis/M. leprae, and peptide 56–65 from the secreted 30/31‐kDa protein fromM. tuberculosis/M. leprae.p3–13 bound to purified, cell‐free DR17 under both acidic and neutral conditions. Four other, unrelated DR17‐binding peptides showed the same pH‐dependent binding characteristics as p3–13. p56–65, however, only bound to purified DR17 at pH 7 but not at all at pH 4.5. These DR17 peptide binding data were confirmed in cell‐bound DR17, in T cell stimulation assays in which fixed APC were peptide‐pulsed at acidic or neutral pH before addition of peptide‐specific DR17‐restricted T cells. As far as we are aware, p56–65 is the only human T cell epitope binding to HLA exclusively at neutral pH. The binding characteristics of p56–65 may reflect dominant processing in alternative, less acidic vacuolar compartments specifically related to the generation of epitopes from (secreted) mycobacterial proteins. The observation that p56–65 is an immunodominant epitope for anti‐mycobacterial T cells suggests the relevance of such novel pr

ISSN:0014-2980    

DOI:10.1002/eji.1830270406

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractIntravenous injection of antigen‐coupled splenocytes has been widely used to induce specific tolerance to a variety of antigens. In this study, we investigated the effects of such a treatment on Th1 and Th2 antigen‐specific immune responses. Using both well‐characterized model antigens and crude homogenates fromLeishmania majorpromastigotes, we found that intravenous injection of antigen‐coupled splenocytes strongly down‐regulated antigen‐specific Th2 responses but had no or only moderate effects on Th1 responses. Because the susceptibility of inbred strains of mice to murine leishmaniasis has been found to be correlated with a strong Th2 response against parasite antigens, we investigated whether administration of splenocytes chemically coupled to parasite antigens could protect susceptible mice from murine leishmaniasis. We found that this was indeed the case and further demonstrated that protection was associated with a strong decrease in the number of parasite‐specific Th2‐like cells. Because administration of antigen‐coupled splenocytes is believed to induce ligation of the T cell receptor complex without inducing a co‐stimulatory signal, our results further suggest that priming of Th1 cells is less dependent on co‐stimulatory signals than the

ISSN:0014-2980    

DOI:10.1002/eji.1830270407

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractMajor histocompatibility complex (MHC) restriction of the immune response is established during positive selection of T cells in the thymus. This occurs mainly through interactions of T cell receptor of developing thymocytes with MHC/peptide ligands on cortical thymic epithelial cells (TEC). An ongoing controversy concerns the origin and the role of peptides involved in the positive selection of thymocytes. Evidence provided here shows that processing of MHC class II complexes in cortical TEC differs from that of medullary TEC. Removal of the invariant chain associated with MHC class II complexes was rapid and complete in medullary TEC which present peptides from both exogenous and cytosolic origin. In cortical TEC, a large fraction of class II dimers remained associated with a 10–12‐kDa fragment of invariant chain (Ii). Incomplete removal of Ii correlated with the inability of cortical TEC to present peptides from exogenous origin. However, presentation of peptides from cytosolic proteins by cortical TEC remained possible. Thus, most peptides from exogenous proteins may be excluded from participating in positive selection of CD4+T cells by a mechanism limiting Ii breakd

ISSN:0014-2980    

DOI:10.1002/eji.1830270408

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractThe host response toLeishmaniainfection is regulated by a specific pattern of local cytokine production. We investigated the effect of interleukin (IL)‐10 and IL‐4 on the leishmanicidal activity of human macrophages (Mϕ). As withL. major, intracellular killing ofL. infantumby human Mϕ was obtained following ligation of surface CD23 or cell treatment with Interferon‐γ (IFN‐γ). This leishmanicidal activity required nitric oxide (NO) generation by activated Mϕ, and it was partially mimicked by cell treatment with chemical NO donors. Addition of recombinant human IL‐10 or IL‐4 to CD23 mAb or IFN‐γ decreasedL. infantumandL. majorkilling by infected Mϕ. IL‐10 was more potent than IL‐4 in inhibiting the leishmanicidal activity of human Mϕ. Inhibition ofLeishmaniakilling by IL‐4 and IL‐10 correlated with decreased NO generation from Mϕ, and was reversed when exogenous NO was added to cell cultures. Therefore, IL‐10 and IL‐4 down‐regulate leishmanicidal activity of human Mϕ, in part by in

ISSN:0014-2980    

DOI:10.1002/eji.1830270409

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractResistance and susceptibility to the intestinal parasiteTrichuris murishas been shown to be due to a dominant T helper 2 (Th2) and a dominant Th1 response, respectively. The factors determining the initial polarization of the immune response remain largely unresolved, although the cytokine environment at the time of antigen presentation clearly plays an essential role. Interleukin (IL)‐12, a cytokine produced mainly by macrophages, dendritic cells, and other monocytes has been shown to be important in driving a strong Th1 response by stimulating the production of interferon (IFN)‐γ from natural killer and Th0 cells and therefore forms a link between the innate and adaptive immune system. IL‐12 has been shown to play an important role in resistance to a number of intracellular pathogens, includingListeriaandLeishmania.It has also been proposed as an anti‐tumor agent and for use in the treatment of HIV. Conversely, IL‐12 has been shown to prolong the survival ofNippostrongylus brasiliensisand to accelerate autoimmunity. Our studies demonstrate that by driving a strong Th1 response, IL‐12 promotes chronicT. murisinfection when given to normally resistant BALB/K mice. Parasite‐specific IgG2a, a Th1 parameter of infection, was greatly up‐regulated, whereas some Th2 parameters of infection were down‐regulated. IL‐12 treatment could be delayed until 1 week after infection had started and still promote a strong Th1 response. The actions of IL‐12 in promoting a chronic infection were IFN‐γ dependent as an anti‐IFN‐γ mAb

ISSN:0014-2980    

DOI:10.1002/eji.1830270410

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY

摘要:

AbstractIn this report, we demonstrate stimulation of T cell receptor (TCR) transgenic CD8 T cells by isolated major histocompatibility complex (MHC) class I H‐2Ldcomplexes and antigenic peptide. This is the first demonstration of CD8 T cells activated by MHC and antigenic peptide in the absence of antigen priming. Furthermore, isolated MHC and a potent peptide antigen can stimulate phenotypically naive CD44−T cells to become CTL effectors and to produce interleukin‐2 in nanogram per milliliter amounts. These results demonstrate that particular TCR antigen pairs may overcome the need for specialized antigen‐presenting cells and have implications for mechanisms of autoimmunity and tolerance in

ISSN:0014-2980    

DOI:10.1002/eji.1830270411

出版商:WILEY‐VCH Verlag GmbH    

年代:1997

数据来源: WILEY