bluuebunny/crossref_metadata_2025 huggingface dataset:
Early introduction of cereals into children's diets as a risk‐factor for grass pollen asthma
Authors: Armentia A. , Bañuelos C. , Arranz M. L. , Del Villar V. , Martín‐Santos J.‐M. , Gil F. J. M. , Vega J. M. , Callejo A. , Paredes C.
Published: March 2003

Background The prevalence of asthma has increased from the 1950s to the 1990s. The relationship between diet and asthma is an area of controversy that has never been fully evaluated. Attempts at dietary prevention of asthma have produced conflicting results. We have recently identified allergens from cereals that show cross‐reactivity with proteins in grass pollen. An early intake of cereals in the diet during early life might cause IgE sensitization to cereals. It is not known whether such sensitization predisposes the development of allergy to pollen.

Methods To test this hypothesis, a cross‐sectional study and an observational case‐control analysis of reviewed data were carried out on 16381 patients who had been admitted to our Allergy Unit between 1989 and 1999. All the patients underwent allergy tests to identify asthma risk‐factors. All information in our data base was analysed using the SPSS computer system.

Results There has been an increase of 7.8% in incidences of allergic asthma and a 7.3% increase in asthma due to grass pollen in the last decade. Grass‐pollen asthma was associated with sensitization to cereals. The early introduction of cereals in the diet of children was found to be a risk factor for grass‐pollen asthma (OR = 5.95; 95% CI 3.89–9.10).

Conclusions These findings document the progression of allergic asthma during a decade in a large sample of people who were influenced by similar environmental conditions and studied with the same diagnostic methods. This study represents the largest database of patients in which a common food is shown to be a risk factor for asthma.
Atopic asthma: differential activation phenotypes among memory T helper cells
Authors: Lara‐Marquez M. L. , Moan M. J. , Cartwright S. , Listman J. , Israel E. , Perkins D. L. , Christiani D. C. , Finn P. W.
Published: March 2003

Background T cells have been implicated in the pathogenesis of atopic asthma. We have previously shown that memory T helper cells (CD4+CD45RO+) are preferentially activated relative to naïve T helper cells (CD4+CD45RA+) after bronchial allergen challenge. However, specific T helper subpopulations that are activated in atopy and/or asthma remain undefined.

Objective To determine the T helper subpopulations and activation phenotypes relevant to acute and stable asthma that may be common with or distinct from atopy.

Methods Two groups of atopic asthmatics (ten acute and nine stable asthmatics) and two non‐asthmatic groups (14 non‐asthmatic atopics and eight normal non‐atopic controls) were analysed. Ten acute asthmatics were assessed in the emergency room during an acute episode (FEV1 43.6% ± 18.4). Nine stable asthmatics were assessed during a symptom‐free period (FEV1 85% ± 6). Using multiple colour flow cytometry we analysed T cell subpopulations and the expression of IL‐2‐receptor (IL‐2R) and MHC‐class II antigens (MHC II) on naïve and memory T helper cells in the peripheral blood of asthmatic and non‐asthmatic groups.

Results Atopic asthmatics (acute and stable) had an increased percentage of memory T helper cells expressing IL‐2R compared with normal non‐atopics (mean SD 16.1 ± 6%, 12.4 ± 2% and 7.7 ± 1.8%, P < 0.05) but not compared with non‐asthmatic atopics (10 ± 3.5%). Naïve T helper cells had low expression of IL‐2R and MHC II in all four groups. MHC II antigen expression was increased in memory T helper cells of asthmatics (acute and stable) compared with normal non‐atopics (13.9 ± 7.5, 10.6 ± 5 and 4.9 ± 2.5, P < 0.05) but not compared with non‐asthmatic atopics (7.92 4). A novel finding was that IL‐2R and the MHC II molecules were mainly expressed in non‐overlapping populations and coexpression was found predominantly on memory T helper cells. Asthmatics (acute and stable) had higher proportion of double positive memory T helper cells (IL‐2R+MHC II+) compared with both non‐asthmatic groups (P < 0.05).

Conclusions We demonstrate a differential expression of IL‐2R+ and MCH II+ on CD45RO+ T helper cells that would suggest that there are three subsets of activated memory T helper cells in asthmatics. Two non‐overlapping IL‐2R+ or MHC II+ CD45RO+ T helper cells and a third subpopulation of activated cells that coexpress IL‐2R and MHC II (double positives). This latter subpopulation is significantly higher in asthmatics (acute or stable) compared with both non‐asthmatic groups, suggesting a specific T helper activation phenotype distinct to atopic asthmatics as compared with atopic non‐asthmatics.
Effects of suplatast tosilate, a new type of anti‐allergic agent, on airway cough hypersensitivity induced by airway allergy in guinea‐pigs
Authors: Myou S. , Fujimura M. , Kurashima K. , Kita T. , Tachibana H. , Ishiura Y. , Abo M. , Nakao S.
Published: March 2003

Background Cough receptor hypersensitivity is a fundamental feature of some conditions presenting with chronic non‐productive cough. Suplatast tosilate, an anti‐allergic agent, is a T helper (Th)2 cytokine inhibitor that inhibits the synthesis of interleukin (IL)‐4, IL‐5, immunoglobulin (Ig)E production, and local eosinophil accumulation.

Objective The purpose of this study was to investigate the effect of suplatast on antigen‐induced airway cough hypersensitivity and eosinophil infiltration into the airway.

Methods Number of coughs elicited by inhalation of increasing concentrations of capsaicin (10−8, 10−6 and 10−4 M) was counted 24 h after an antigen challenge in conscious guinea‐pigs and then bronchoalveolar lavage was performed. We investigated the effect of single (before antigen challenge or capsaicin provocation) or repetitive treatment with intraperitoneal suplatast at a dose of 10 or 30 mg/kg on antigen‐induced cough hypersensitivity.

Results Twenty‐four hours after antigen challenge, guinea‐pigs developed an increase in cough receptor sensitivity to inhaled capsaicin and eosinophil infiltration in the airways. After a 2‐week treatment with suplatast, but not after only a single treatment before antigen challenge or capsaicin provocation, the antigen‐induced early phase bronchoconstriction, cough hypersensitivity, and airway eosinophilia were inhibited in a dose‐dependent manner.

Conclusion These results indicate that suplatast inhibits airway cough hypersensitivity underlying allergic eosinophilic inflammation.
Antibodies directed against nerve growth factor inhibit the acute bronchoconstriction due to allergen challenge in guinea‐pigs
Authors: De Vries A. , Engels F. , Henricks P. A. J. , Leusink‐Muis T. , Fischer A. , Nijkamp F. P.
Published: March 2003

Background

We have previously demonstrated that the administration of nerve growth factor (NGF) to guinea‐pigs results in airway hyper‐responsiveness within 1 h.

Objective In the present study we document the involvement of NGF in the acute allergic airway response.

Methods Guinea‐pigs that are sensitized to ovalbumin show an acute bronchoconstriction directly after challenge with ovalbumin.

Results Intratracheal application of 10 µg of antibodies directed against NGF (anti‐NGF) 1 h before the challenge reduces the acute severe bronchoconstriction to approximately 40% and the sustained bronchoconstriction to approximately 20% of the reaction in controls. This shows a high potency of anti‐NGF in diminishing the direct bronchoconstriction. Inhibition of the tyrosine kinases of the tyrosine kinase receptor A, the high‐affinity receptor for NGF, has no effect on the bronchoconstriction. Therefore, we postulate that the p75, the low‐affinity receptor for neurotrophins, is responsible for the acute bronchoconstriction. Our findings suggest a role for NGF in the induction of the acute asthmatic reaction.

Conclusion These findings offer a new potential therapeutic strategy for the treatment of allergic asthma.
Coding single nucleotide polymorphism in the high‐affinity immunoglobulin E receptor b chain (Fc"RI‐b) gene is associated with immunoglobulin E receptor‐mediated histamine release from basophils
Authors: Kim Y.‐K. , Oh S.‐Y. , Oh H.‐B. , Chun S.‐Y. , Cho S.‐H. , Koh Y.‐Y. , Min K.‐U. , Kim Y.‐Y.
Published: March 2003

Background  Our previous work on linkage analysis showed that histamine release from basophils to anti‐IgE stimuli was linked to the gene marker of chromosome 11q13, where the β chain of the high‐affinity receptor for IgE (FcεRI‐β) is located.

Objective  To evaluate the association between FcεRI‐mediated histamine release from basophils and four bi‐allelic single nucleotide polymorphisms of the FcεRI‐β gene.

Methods  Phenotypes of asthma, such as maximal histamine release from basophils and atopy, were measured from 80 randomly recruited asthmatic children. Polymorphisms of the FcεRI‐β gene were determined by PCR‐based methods.

Results  The polymorphism in exon 7, resulting in Glu to Gly substitution, was significantly associated with histamine release from basophils to anti‐IgE stimuli, but not with total IgE levels and skin test responses to aeroallergens.

Conclusion This study supports a role for the FcεRI‐β gene in the expression of high affinity IgE receptor‐mediated histamine release from basophils.
Atopic sensitization among children in an Arctic environment
Authors: Krause T. G. , Koch A. , Poulsen L. K. , Kristensen B. , Olsen O. R. , Melbye M.
Published: March 2003

Background Asthma has been reported to be rare among Inuits, but so far total and specific IgE levels have never been determined in arctic populations.

Objective To determine the prevalence of atopy in children living in an arctic environment, and to examine whether atopy and total IgE levels were associated with parental place of birth, as a measure of ethnicity, and travel history.

Material and Methods All schoolchildren in Sisimiut, a community on the West coast of Greenland, were screened for atopy. Blood samples were analysed for total IgE and for specific IgE against inhalant and food allergens. Information on place of birth of children and their parents was obtained from national registries. Information on travel history was obtained from self‐administered questionnaires.

Results A total of 1031 schoolchildren aged 5 to 18 years had a blood sample drawn (85% of available children for the study). Of these, 151 (14.6%) children were sensitized to at least one inhalant allergen and 42 (4.1%) to at least one food allergen. Sensitization to grass was most common, whereas sensitization to mugwort, birch, animal‐dander and house‐dust mite was infrequent. Children whose parents were both born abroad had a higher risk of sensitization to inhalant allergens compared with children born of Greenlandic parents (OR = 8.6, 95% CI 2.8–27.1). Furthermore, children who had been abroad had a higher risk of sensitization towards pollen (OR = 1.6, 95% CI 1.0–2.5) and animal‐dander (OR = 2.1, 95% CI 1.0–4.6) after adjustment for confounders. Both atopic and non‐atopic children demonstrated high levels of total IgE (medians of 251 and 58 kU/L).

Conclusions Compared with European findings Greenlandic children have high levels of total IgE but a low prevalence of allergic sensitization towards inhalant allergens. This may be due to a low genetic susceptibility to atopy and less allergen exposure, as well as to living conditions in an arctic environment.
Effect of ozone exposure on allergic sensitization and airway inflammation induced by dendritic cells
Authors: Depuydt P. O. , Lambrecht B. N. , Joos G. F. , Pauwels R. A.
Published: March 2003

Background Epidemiological studies suggest that ozone exposure is related to increased asthma symptoms. Dendritic cells (DCs) are the principal antigen‐presenting cells in the airways.

Objective We have examined whether ambient doses of ozone (100 ppb for 2 h) enhance allergic sensitization and/or airway inflammation in a mouse model.

Methods C57BL/6 mice were sensitized to inhaled ovalbumin (OVA) by intratracheal instillation of OVA‐pulsed DCs on day 0. Daily exposure to OVA aerosol on days 14–20 resulted in an eosinophilic airway inflammation, as reflected in bronchoalveolar lavage fluid and lung histology. In a first experiment, mice were exposed to ozone or room air immediately prior to and following sensitization. Subsequently, we tested the effect of ozone exposure during antigen challenge in DC‐sensitized mice.

Results Exposure to ozone during sensitization did not influence airway inflammation after subsequent allergen challenge. In contrast, in sensitized mice, challenge with OVA together with ozone (days 14–20) resulted in enhanced airway eosinophilia and lymphocytosis, as compared with mice exposed to OVA and room air (1.91 × 106 ± 0.46 × 106 vs. 0.16 × 106 ± 0.06 × 106 eosinophils/mL lavage fluid; P = 0.015; 0.49 × 106 ± 0.11 × 106 vs. 0.08 × 106 ± 0.03 × 106 lymphocytes/mL lavage fluid; P = 0.004). Ozone exposure without subsequent OVA exposure did not cause airway inflammation.

Conclusion Ozone exposure does not increase allergic sensitization but enhances antigen‐induced airway inflammation in mice that are sensitized via the airways.
Boletus edulis: a digestion‐resistant allergen may be relevant for food allergy
Authors: Helbling A. , Bonadies N. , Brander K. A. , Pichler W. J.
Published: March 2003

Background  Fungal components can cause allergic symptoms either through inhalation, ingestion or contact. Whereas respiratory allergy is thought to be induced by spores, allergic reactions following ingestion are attributed to other parts of the mushroom. Reports of food‐related allergic reactions due to the edible mushroom Boletus edulis have occasionally been reported.

Objective  The aim of the study was to investigate whether separate allergens may be detected in alimentary allergy to Boletus edulis.

Methods  Sera of two subjects, one with recurrent anaphylaxis and the other with a predominantly oral allergy syndrome following ingestion of Boletus edulis, have been analysed by a time‐course digestion assay using simulated gastric fluid and by SDS‐PAGE immunoblotting. Sera of four Boletus edulis skin prick test‐negative subjects and all without clinical symptoms to ingested Boletus edulis served as controls.

Results  In lyophilized Boletus edulis extract, at least four water‐soluble proteins were detected, the most reactive at 55 kDa and at 80 kDa. Following the time‐course digestion assay, IgE binding was found to a 75‐kDa protein, but only if the sera of the subject with recurrent anaphylaxis was used.

Conclusion  The data indicate that Boletus edulis can cause an IgE‐mediated food allergy due to a digestion‐stabile protein at 75 kDa. No IgE immune response to this protein was detected in the serum of a subject with respiratory allergy and oral allergy syndrome to Boletus edulis nor in control sera.
An oral introduction of intestinal bacteria prevents the development of a long‐term Th2‐skewed immunological memory induced by neonatal antibiotic treatment in mice
Authors: Sudo N. , Yu X.‐N. , Aiba Y. , Oyama N. , Sonoda J. , Koga Y. , Kubo C.
Published: March 2003

Background Recent epidemiological studies indicate that antibiotic use in infancy may be associated with an increased risk of developing atopy. Our previous work on animals demonstrated that kanamycin use during infancy promotes a shift in the Th1/Th2 balance towards a Th2‐dominant immunity.

Objective The first purpose of this study is to clarify whether or not the supplementation of intestinal bacteria can reverse such a Th2‐skewed response induced by neonatal antibiotic use. The second objective is to elucidate the contribution of genetic factors to antibiotic‐induced immune‐deviation.

Methods BALB/c or C57BL/6 mice at 3 weeks of age were orally administered 600 µg/day of kanamycin sulphate for seven consecutive days. Thereafter, the mice were inoculated with one type of intestinal bacterial species: Enterococcus faecalis, Lactobacillus acidophilus or Bacteroides vulgatus. Blood samples were collected 10 weeks after the cessation of kanamycin treatment, and the effect of the kanamycin treatment on Th1/Th2 balance was evaluated based on in vivo antibody levels.

Results A kanamycin‐induced elevation of the serum IgE levels was reversed by the supplementation with Enterococcus faecalis, and to a lesser extent by that with Lactobacillus acidophilus. The IgE/IgG2a ratio in the mice supplemented with Enterococcus faecalis significantly decreased in comparison with that in the kanamycin‐treated mice without any bacterial supplementation, while such a ratio was enhanced in the mice inoculated with Bacteroides vulgatus. No antibiotic‐induced Th2‐skewed response was seen in C57BL/6 mice that are genetically biased towards Th1‐dominant immunity.

Conclusion These results suggest that adequate probiotic intervention after antibiotic treatment may improve the intestinal ecosystem, and thereby prevent the Th2‐shifted immunity induced by neonatal antibiotic use. In addition, the difference of genetic backgrounds also contributes to such an antibiotic‐induced Th2‐skewed response.
β‐Lactam allergenic determinants: fine structural recognition of a cross‐reacting determinant on benzylpenicillin and cephalothin
Authors: Zhao Z. , Baldo B. A. , Rimmer J.
Published: March 2003

Background An appreciation of the structural heterogeneity of allergenic determinants on penicillins and cephalosporins reveals the importance of side‐chain groups and their involvement in many allergies to β‐lactam drugs. Although allergenic cross‐reactions between penicillins and cephalosporins are known to occur, the precise molecular bases of such recognitions and cross‐sensitivities have rarely been studied and identified.

Objectives The unexpected finding of a high incidence of positive IgE antibody reactions with both benzylpenicillin and cephalothin prompted serological and immunochemical studies to identify the chemical basis of antibody recognition of these drugs from the two different families of β‐lactam antibiotics.

Methods Adsorption studies were employed to identify whether or not a single population of antibodies was involved in the recognition of benzylpenicillin and cephalothin. Identification of the fine structural features recognized by IgE antibodies was investigated by quantitative hapten inhibition studies employing carefully selected β‐lactam drugs, analogues and some other structurally related chemicals.

Results Adsorption studies with penicilloic acid‐solid phase clearly established that a single population of cross‐reacting antibodies recognized both benzylpenicillin and cephalothin. Quantitative inhibition findings, especially with phenylacetic acid and 2‐thiopheneacetic acid and with cephaloridine and cefoxitin, which have the same (2‐thienyl)methyl side‐chain as cephalothin, implicated the methylene group as the focus of the allergenic determinant recognized on benzylpenicillin and cephalothin. In addition to the methylene group, recognition graded into neighbouring structures including the amide group and extended weakly to the β‐lactam ring.

Conclusions Results confirmed that structural features as small as a methylene group may be allergenically important. In the present case, this group, making up only part of the different side‐chains on benzylpenicillin and cephalothin, together with neighbouring structures extending toward the β‐lactam ring, accounted for the cross‐reactivity seen between structures that, at first sight, appear to be not closely related. Such subtle, small, common structural features are likely to be immunologically recognized and implicated in allergic reactions to other drugs, including β‐lactam antibiotics.
Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma
Authors: Ozdemir C. , Akkoc T. , Bahceciler N. N. , Kucukercan D. , Barlan I. B. , Basaran M. M.
Published: March 2003

Background Therapeutic modalities of asthma have not been proved to be successful in reversing the already established chronic changes of airways.

Objective We aimed to determine the impact of heat‐killed Mycobacterium vaccae immunization, a potent Th1 stimulant, on chronic changes of asthma.

Methods Newborn BALB/c mice were divided into three groups; mice in M. vaccae group received 107 colony‐forming units (CFU)/50 µL of heat‐killed M. vaccae subcutaneously on days 3, 14 and 42 before the development of chronic asthma model, whereas mice in control and chronic asthma groups received saline. Subsequently, mice in M. vaccae and chronic asthma groups were administered 10 µg/100 µL of ovalbumin (OVA) on days 43, 45, 47, 49, 51, 53 and 55 intraperitoneally, and 20 µg/10 µL of OVA on days 83, 86 and 89 intratracheally. Mice in control group received saline on the same days.

Results Comparison of M. vaccae and chronic asthma groups showed statistically significant differences in goblet cell numbers, thickness of basement membrane and subepithelial smooth muscle of small, medium and large airways and epithelial thickness of medium airways. There was no significant difference between the control and M. vaccae groups except for goblet cell numbers of medium and large airways, and epithelial thickness of medium airways.

Conclusion Results of our study suggested that immunization by M. vaccae of newborn mice would prevent some of the chronic changes of airways due to asthma.
Phosphatidylinositol-specific-phospholipase C cleaves urokinase plasminogen activator receptor from the cell surface and leads to inhibition of pemphigus-IgG-induced acantholysis in DJM-1 cells, a squamous cell carcinoma line
Authors: Asano S. , Seishima M. , Kitajima Y.
Published: March 2003

We showed previously that pemphigus IgG enhanced both the activity of urokinase plasminogen activator (uPA) in cultured cells and the expression of its receptor (uPAR) on uPA-binding keratinocytes. In the present study, to clarify whether uPAR and uPA-activated plasmin are actually involved in the blistering process after pemphigus IgG binding to the cell surface, we examined the effects of the following on uPAR expression and on cell–cell detachment in DJM-1 cells, a squamous cell carcinoma line: (i) phosphatidylinositol-specific phospholipase C (PI-PLC) − which releases uPAR from the membrane surface into the culture medium by cleaving the glycosylphosphatidylinositol anchor thus inhibiting uPAR activity, and (ii) uPA inhibitors (tranexamic acid, aprotinin, p-aminobenzonic acid and dexamethasone). Preincubation with PI-PLC decreased dramatically the pemphigus IgG-induced uPAR expression in a dose-dependent manner, and inhibited pemphigus IgG-induced cell–cell detachment at 10 µg/mL. On the other hand, tranexamic acid (15 mm) inhibited pemphigus IgG-induced cell–cell detachment without reduction of uPAR expression, although aprotinin, p-aminobenzonic acid and dexamethasone failed to alter either of these parameters. Although uPAR expression on the pemphigus IgG-bound cell surface and uPA activation may contribute significantly to the pathogenesis of acantholysis in pemphigus, the mechanisms are complicated and should be defined further.
Potential role of B7-1 and CD28 molecules in immunosuppression in leprosy
Authors: Agrewala J N , Kumar B , Vohra H
Published: March 2003

In order to understand the mechanism of unresponsiveness towards Mycobacterium leprae antigens in leprosy, we evaluated the role of M. leprae sonicate antigens in regulating the expression of the costimulatory molecules B7-1, CD28, intercellular adhesion molecule-1 (ICAM-1), LFA-1α, LFA-1β and Mac-1 on the lymphocytes of both leprosy patients and healthy subjects. It was observed that the expression of B7-1 and CD28 was significantly decreased but the levels of ICAM-1 and LFA-1α were increased in patients with untreated borderline leprosy (BL)/lepromatous leprosy (LL) disease. No remarkable change was noticed in the case of borderline tuberculoid (BT) leprosy or treated BL/LL patients. Further, a striking finding was that lymphocytes from healthy subjects cultured with a particularly high dose of M. leprae sonicate antigens down-regulated the expression of B7-1 and CD28 molecules, but up-regulated the display of ICAM-1 and LFA-1α. Furthermore, proliferation induced by M. leprae sonicate was inhibited only by anti-B7-1 antibody. Mycobacterium leprae antigen-induced suppression of the proliferation of lymphocytes of healthy volunteers and LL patients was reversed by culturing the lymphocytes with purified protein derivative (PPD). It may be concluded from the findings in this study that down regulation of B7-1 and CD28 in BL/LL leprosy patients may be responsible for a defective T cell signalling by the B7-1/CD28 pathway caused by M. leprae antigens. This may lead to clonal inactivation of M. leprae-reactive T cells, consequently the bacilli grow without restriction in macrophages.
Serum antibodies to HIV-1 are produced post-measles virus infection: evidence for cross-reactivity with HLA
Authors: Baskar P V , Collins G D , Dorsey-Cooper B A , Pyle R S , Nagel J E , Dwyer D , Dunston G , Johnson C E , Kendig N , Israel E , Nalin D R , Adler W H
Published: March 2003

Convalescent sera obtained from patients who were recently recovered from an acute measles virus infection were tested for the presence of anti-HIV-1 antibodies by Western blot analysis. While 16% (17/104) of control sera displayed reactive bands to a variety of HIV proteins, 62% (45/73) of convalescent sera demonstrated immunoreactive bands corresponding to HIV-1 Pol and Gag, but not Env antigens. This cross-reactivity appears to be the result of an active measles infection. No HIV-1 immunoblot reactivity (0/10) was observed in sera obtained from young adults several weeks after a combined measles, mumps, and rubella (MMR) vaccination. Interestingly, examination of anti-HLA typing sera specific for either class I and class II molecules revealed that 46% (19/41) of these sera contained cross-reactive antibodies to HIV-1 proteins. Absorption of measles sera with mixed lymphocyte reaction (MLR)-activated lymphocytes and/or HIV-1 recombinant proteins significantly decreased or removed the presence of these HIV-1-immunoreactive antibodies. Together, these findings suggest that the immune response to a natural measles virus infection results in the production of antibodies to HIV-1 and possibly autoantigens.
Increase of CD57+ T cells in knee joints and adjacent bone marrow of rheumatoid arthritis (RA) patients: implication for an anti-inflammatory role
Authors: Arai K , Yamamura S , Seki S , Hanyu T , Takahashi H E , Abo T
Published: March 2003

The distribution of CD57+ T and CD56+ T cells in patients with RA was examined. In control osteoarthritis patients, these cells exist as a minor population in the peripheral blood. Our data show that in patients with RA, CD57+ T cell levels are elevated in peripheral blood, knee joint fluid, knee synovial membrane and bone marrow (BM), compared with peripheral blood of controls. CD57+ T cells are especially high in knee joint fluid and joint-adjacent BM, while CD56+ T cells show no such increase. CD57+ T cells contain a major population of CD8+ cells and higher proportions of CD4−8− cells and γδ T cells than do CD57−T cells. CD57+T cells in peripheral blood and joint fluid increase with the duration of disease. Erythrocyte sedimentation rate (ESR) is inversely correlated with the proportion of CD57+T cells in the joint fluid. Although RA frequently occurrs in patients with CD3+57+ cell leukaemia, and some CD57+T cells are likely to be involved in the onset of RA, we suggest that CD57+T cells may rather suppress inflammation of RA, and other cellular components (e. g. granulocytes) may govern the severity of the inflammation of RA. These CD57+ T cells are probably generated extrathymically in the adjacent BM or joint space.
The effect of cyclosporin A, FK506 and rapamycin on the murine contact sensitivity reaction
Authors: Salerno A , Bonanno C T , Caccamo N , Cigna D , Dominici R , Ferro C , Sireci G , Dieli F
Published: March 2003

We have evaluated the effects of three potent immunosuppressive agents, cyclosporin A (CsA), FK506 and rapamycin, on the murine contact sensitivity (CS) reaction to the hapten trinitrochlorobenzene. Development of CS reaction requires participation of three distinct T cell subsets: αβ+, CD4+ T lymphocytes, which are the classical effector cell of the CS reaction, γδ+ T lymphocytes, and αβ+, double-negative (CD4− CD8−) T lymphocytes that express the B220 molecule and produce IL-4. We found that all three drugs inhibit the development of the CS reaction, but they affect different target cells. In fact, rapamycin and FK-506 block both αβ+, CD4+ and γδ+ T lymphocytes, while CsA inhibits only the αβ+, CD4+ T lymphocyte. None of the three drugs exerted any inhibitory activity on the αβ+, double-negative (CD4− CD8−) T lymphocytes. Hapten-immune lymph node cells from mice treated in vivo with CsA or FK506 failed to proliferate and to produce IL-2 when re-exposed to the specific antigen in vitro. In contrast, immune lymph node cells from mice that had been treated in vivo with rapamycin gave optimal antigen-specific proliferation and IL-2 production in vitro. The implications of these observations are discussed in relation to the use of these immunosuppressive agents for prevention of allograft rejection.
Expression of macrophage inflammatory protein (MIP)-1α, MIP-1β, and RANTES genes in lymph nodes from HIV+ individuals: correlation with a Th1-type cytokine response
Authors: Trumpfheller C , Tenner-Racz K , Racz P , Fleischer B , Frosch S
Published: March 2003

The in vivo response of the immune system after HIV infection in regard to cytokine production and C-C chemokine synthesis is not well known. Here we have analysed cytokine and chemokine mRNA production in lymph nodes with follicular hyperplasia (FHLN) of HIV-infected patients by in situ hybridization using anti-sense mRNA probes. The synthesis of mRNAs for interferon-gamma (IFN-γ), IL-12p35, IL-12p40, IL-4, and for the C-C chemokines RANTES, MIP-1α, and MIP-1β was compared with that of lymph nodes from non-infected individuals to define HIV-specific events. Only few cells expressing IFN-γ, RANTES, MIP-1α, and MIP-1β mRNAs were detectable in the T-dependent area of lymph nodes from HIV-negatives. In contrast, in FHLN from HIV+ patients a high number of IFN-γ, RANTES, MIP-1α, and MIP-1β mRNA-containing cells were detectable. Remarkably, only single individual IL-12p35 mRNA-producing cells were present in the T-dependent area from both HIV+ and HIV− lymph nodes. Furthermore, the low number of IL-12p40 mRNA-expressing cells did not differ between HIV+ and HIV− lymph nodes. This indicates that IFN-γ is expressed independently of IL-12, possibly by a direct T cell-mediated reaction. IL-4 mRNA-producing cells were hardly detectable in infected and control lymph nodes. The same findings were made in a limited number of samples from patients with advanced disease. Thus, these results demonstrate that a high IFN-γ production is accompanied by a strong expression of MIP-1α, MIP-1β, and RANTES in the lymph node after HIV infection. This favours the idea that a Th1-type immune response correlates with a preferential production of C-C chemokines in FHLN of HIV+ patients.
The human autoantigen La/SS-B accelerates herpes simplex virus type 1 replication in transfected mouse 3T3 cells
Authors: Bachmann M , Deister H , Pautz A , Laubinger J , Schmitz M , Falke D , Podlech J , GRölz D
Published: March 2003

Permanently transfected mouse cell lines which expressed different levels of the human autoantigen La/SS-B were infected with different strains of herpes simplex virus type 1, including the strains ANG, HSZP, 17syn+ and HFEM. During infection the localization of the human La protein was followed using an anti-La MoAb, which recognized only the human La protein but did not cross-react with either the endogenous mouse La protein or any viral encoded protein. After infection La protein was transported from the nucleus to the cytoplasm. The time course of translocation was dependent on the amount of human La protein expressed in the respective cell line. Moreover, acceleration of viral replication was dependent on the level of expression of human La protein, suggesting that La protein is a cellular factor that facilitates virus replication.
Autoimmunity to tropomyosin isoforms in ulcerative colitis (UC) patients and unaffected relatives
Authors: Biancone L , Monteleone G , Marasco R , Pallone F
Published: March 2003

Autoimmunity to cytoskeletal protein tropomyosin (TM) has been demonstrated in UC. However, the TM isoforms involved in this IgG-mediated autoimmune response in UC and the possible presence of serum IgG antibodies against TM (hTMs IgG) in unaffected UC relatives are unknown. The aim of this study was to investigate the human TM (hTM) isoforms recognized by serum IgG from UC and to explore whether hTM IgG antibodies are present in healthy UC relatives. We studied 33 UC patients with 58 unaffected relatives, 31 Crohn's disease (CD) patients with 31 unaffected relatives and 20 controls (C). Serum IgG against four recombinant hTM isoforms (hTM1, 2, 3, 5) were tested by ELISA. p-ANCA were tested by ELISA and immunofluorescence. Serum hTM1 and hTM5 IgG were higher in UC patients than in CD and C (P < 0.005). Among UC patients 52% were seropositive for hTM1 and 64% for hTM5 (P < 0.001 versus CD and C). In UC, hTM5 IgG were higher in p-ANCA+ than in ANCA− patients (P = 0.04). In UC relatives hTM1 IgG were higher than in CD relatives and C (P < 0.01). UC relatives were more frequently seropositive for hTM1 than hTM5 IgG (P = 0.001), while probands were more frequently seropositive for hTM5 IgG (P = 0.008). We conclude that autoimmunity to hTM1 and hTM5 is a feature of UC, while hTM1 IgG differentiate UC relatives from controls. A genetic susceptibility to immune recognition of hTM isoforms in UC is suggested.
Stimulation with thromboxane A2 (TXA2) receptor agonist enhances ICAM-1, VCAM-1 or ELAM-1 expression by human vascular endothelial cells
Authors: Ishizuka T , Kawakami M , Hidaka T , Matsuki Y , Takamizawa M , Suzuki K , Kurita A , Nakamura H
Published: March 2003

A previous study reported that intercellular adhesion molecule-1 (ICAM-1) expression by human vascular endothelial cells (HUVEC) is augmented by intracellular signal transmission mainly through the protein kinase C (PKC) system stimulated by TXA2 receptors. In the present study, we show that a TXA2 receptor agonist, U46619, augments the expression of not only ICAM-1, but also vascular cell adhesion molecule-1 (VCAM-1) or endothelial leucocyte adhesion molecule-1 (ELAM-1) in HUVEC both at protein and mRNA levels. Pretreatment with SQ29,548 (a TXA2 receptor antagonist) or PKC inhibitors greatly diminished the extent of U46619-induced mRNA accumulation and surface expression of the adhesion molecules. An inhibitor of nuclear factor κB (NF-κB) activation, PDTC, diminishes U46619-induced VCAM-1 mRNA accumulation. NAC, which inhibits NF-κB and activation protein 1 (AP-1) binding activity, inhibits the expression of ICAM-1 or ELAM-1 at protein and mRNA levels. These findings suggest that ICAM-1 or ELAM-1 expression of HUVEC stimulated via TXA2 receptors is augmented by induction of NF-κB and AP-1 binding activity through the PKC system, and that VCAM-1 expression is augmented by induction of NF-κB binding activity.
Humoral immune response to mycobacterial heat shock protein (hsp)65 in the cerebrospinal fluid of neuro-Behçet patients
Authors: Taşçi B , Direskeneli H , Serdaroğlu P , Akman-Demir G , Eraksoy M , Saruhan-Direskeneli G
Published: March 2003

Although systemic immune reactivity to 65-kD mycobacterial hsp65 (m-hsp65) has been shown previously in Behçet's disease (BD), local immune response was not investigated. We studied anti-m-hsp65 IgG, IgM and IgA antibodies in the serum and cerebrospinal fluid (CSF) of 25 BD patients with cerebral parenchymal involvement (p-NBD), seven BD patients with intracranial hypertension (ih-NBD), eight BD patients without central nervous system (CNS) involvement, 30 patients with multiple sclerosis (MS) and 24 patients with non-inflammatory CNS disorders (NIC). Significantly higher CSF IgG responses were detected in p-NBD patients (ELISA ratio 1.3 ± 0.9) compared with NIC (0.7 ± 0.4, P < 0.01). In p-NBD patients' IgG, IgM or IgA CSF anti-m-hsp65 positivity rate was 48% (12/25); this was significantly higher when compared with MS (3/30; P < 0.03) and NIC (3/24; P < 0.01). CSF anti-m-hsp65 IgG ratios correlated with the duration of BD (r = 0.4, P < 0.04) but not with the duration of neurological involvement. Serum IgM and IgA responses were elevated in ih-NBD, suggesting a different type of involvement than p-NBD. These results implicate an increased local humoral response to m-hsp65 in the CSF of p-NBD patients, which might be related to the pathogenesis of neurological involvement.
Immune complex-like moieties in immunoglobulin for intravenous use (IVIg) bind complement and enhance phagocytosis of human erythrocytes
Authors: Shoham-Kessary H , Naot Y , Gershon H
Published: March 2003

Treatment with IVIg can, on rare occasions, lead to detrimental effects such as enhanced erythrocyte sequestration and an increase in serum immune complexes with inflammatory sequellae such as exacerbation of glomerular nephritis. In this study, IVIg (Sandoglobin) was examined for complement binding moieties which resemble immune complexes and can mediate the binding of IgG and C′3b to human erythrocytes via CR1 and enhance erythrocyte susceptibility to sequestration. Sephacryl S-200 HR separated IVIg into two fractions: monomeric IgG (74%) and larger complexes of the molecular weight of an IgG dimer or greater (≥ 300 kD) (26%). In the presence of complement, the ‘dimers’ bound to human erythrocytes, rendering them susceptible to phagocytosis in vitro. Removal of erythrocyte-specific isoantibodies from the IVIg had no effect on ‘dimer’ binding to the erythrocytes. Monomeric IgG contained virtually no complement-activating, erythrocyte-binding activity. Erythrocyte binding of complement-bearing IgG ‘dimers’ and subsequent phagocytosis resembles the binding of complement-bearing immune complexes to erythrocyte CR1. Exposure to Factor I leads to the release of complement-bearing IgG ‘dimers’ from erythrocyte CR1 and to the abrogation of erythrophagocytosis. Binding of complement-bearing IgG ‘dimers’ to the erythrocyte is blocked by To5, a CR1-specific monoclonal antibody.
Increased spontaneous apoptosis in T lymphocytes in DiGeorge anomaly
Authors: Gupta S , Aggarwal S , Nguyen T
Published: March 2003

The aim of this study was to determine whether increased apoptosis in peripheral blood lymphocytes plays a role in T cell deficiency associated with DiGeorge anomaly. T cell subsets from a patient with DiGeorge anomaly were examined for the expression of Fas, FasL, Bcl-2 and Bcl-XL at the protein level with monoclonal antibodies, using dual-colour flow cytometry, and at the mRNA level in mononuclear cells by quantitative reverse transcriptase-polymerase chain reaction. In vitro spontaneous apoptosis was examined by propidium iodide staining and DNA fragmentation, using flow cytometry and gel electrophoresis, respectively. Fas and FasL expression, both at the level of protein and of mRNA, was increased, whereas Bcl-2 expression was decreased both at the level of protein and of mRNA. However, no difference in Bcl-XL expression was observed between the patient and an age-matched control. A significant proportion of both CD4+ and CD8+ T cells from the patients underwent spontaneous apoptosis, whereas almost no spontaneous apoptosis was observed in the age-matched control. These data suggest that spontaneous apoptosis in T lymphocytes, at least in part, may be responsible for T cell deficiency in DiGeorge anomaly.
Characteristics ofPrevotella intermedia-specific CD4+ T cell clones from peripheral blood of a chronic adult periodontitis patient
Authors: Wassenaar A , Reinhardus C , Abraham-Inpijn L , Snijders A , Kievits F
Published: March 2003

Periodontitis is a chronic destructive inflammatory disease associated with periodontopathic bacteria. In addition, autoantigens such as collagen and heat shock proteins (hsp) have been suggested to play a role. Established periodontal lesions are characterized by dense infiltrations of immune cells such as cytokine-producing CD4+ and CD8+ T cells. CD4+ T cells specific for Prevotella intermedia can be isolated from lesional gingiva, suggesting an active role for CD4+ T cells in the response to this bacterium. We therefore investigated the characteristics of a panel of 13 P. intermedia-specific CD4+ T cells generated from the peripheral blood of a patient with chronic adult periodontitis. All 13 P. intermedia-specific CD4+ T cells recognized the antigens in the context of HLA-DR. The T cell clones were mainly classified as Th0, producing comparable amounts of interferon-gamma (IFN-γ) and IL-4, and Th2, producing high amounts of IL-4 and almost no IFN-γ. None of the P. intermedia-specific T cell clones recognized antigens of the periodontopathic bacteria Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis and of the autoantigens collagen and hsp. The reactivity profile of the T cell clones to size-fractionated cell envelope antigens of P. intermedia indicated that P. intermedia-specific CD4+ T cell clones recognize probably five different antigen specificities in the context of the MHC class II molecules, DR7 or DR15. These results suggest that a broad panel of cell-associated protein antigens play a role in the induction of P. intermedia-specific CD4+ T cell response.
IL-10 up-regulates nitric oxide (NO) synthesis by lipopolysaccharide (LPS)-activated macrophages: improved control ofTrypanosoma cruziinfection
Authors: Jacobs F , Chaussabel D , Truyens C , Leclerq V , Carlier Y , Goldman M , Vray B
Published: March 2003

We examined the effects of IL-10 on tumour necrosis factor-alpha (TNF-α) and NO production by LPS-activated macrophages and on the ability of these cells to control Trypanosoma cruzi infection. We first observed that the addition of rIL-10 to macrophages of the J774 cell line decreased their synthesis of TNF-α but increased their release of NO in a dose-dependent manner. In parallel, treatment of J774 cells with rIL-10 resulted in a better control of T. cruzi infection involving up-regulation of NO synthesis, as it was not observed in presence of N-nitro- l-arginine methyl ester (l-NAME), a competitive inhibitor of NO synthase. The enhancing effect of rIL-10 on NO production was not observed on peritoneal macrophages from wild-type C57Bl/6 mice, but well on macrophages from IL-10 knock-out mice. The control of NO production by endogenous IL-10 was confirmed by the demonstration that neutralization of IL-10 secreted by LPS-activated macrophages from wild-type mice inhibited their production of NO and, in parallel, their ability to control T. cruzi infection. Taken together, these data demonstrate that both exogenous and endogenous IL-10 up-regulate the production of NO by LPS-activated macrophages and improve thereby their ability to clear T. cruzi infection.
Cytokine expression in squamous intraepithelial lesions of the uterine cervix: implications for the generation of local immunosuppression
Authors: Giannini S L , Al-Saleh W , Piron H , Jacobs N , Doyen J , Boniver J , Delvenne P
Published: March 2003

We have addressed the notion that the progression of cancer of the uterine cervix is associated with a preferential constraint on the development of a type 1 cellular mediated response, which is necessary to efficiently eliminate (pre)neoplastic cells. Based on the importance of cytokines in the regulation of an appropriate immune response, we have evaluated the expression of IL-12p40, IL-10 and transforming growth factor-beta 1 (TGF-β1). Using reverse transcriptase-polymerase chain reaction (RT-PCR), the expression of these three cytokines was evaluated in both low-grade (LG) and high-grade (HG) cervical squamous intraepithelial lesions (SIL) and in normal exocervix and transformation zone biopsies. Our results show that the average level of IL-12 increases within both the LG and HG SIL, compared with both control groups. Interestingly, the percentage of HG SIL expressing IL-12p40 was lower compared with LG SIL. In contrast, the expression of IL-10 increased in parallel with the severity of the lesion to a maximal level in HG SIL. Using immunohistochemistry, we ascertained the presence of IL-12 protein in SIL and IL-10 protein in the transformation zone and SIL biopsies. Both IL-12- and IL-10-producing cells were localized in the stroma, not within the SIL. Furthermore, in this study we also observed that the region of the cervix the most sensitive to lesion development, the transformation zone, was associated with higher average levels of the immunosuppressive cytokines IL-10 and TGF-β1.
Compartmentalized transgene expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mouse lung enhances allergic airways inflammation
Authors: Lei X-F , Ohkawara Y , Stämpfli M R , Gauldie J , Croitoru K , Jordana M , Xing Z
Published: March 2003

To investigate the role of GM-CSF in asthmatic airways inflammation, we have targeted GM-CSF transgene to the airway cells in a mouse model of ovalbumin (OVA)-induced allergic airways inflammation, a model in which there is marked induction of endogenous IL-5 and IL-4 but not GM-CSF. Following intranasal delivery of a replication-deficient adenoviral gene transfer vector (Ad), transgene expression was found localized primarily to the respiratory epithelial cells. Intranasal delivery of 0.03 × 109 plaque-forming units (PFU) of AdGM-CSF into naive BALB/c mice resulted in prolonged and compartmentalized release of GM-CSF transgene protein with a peak concentration of ≈ 80 pg/ml detected in bronchoalveolar lavage fluid (BALF) at day 7, but little in serum. These levels of local GM-CSF expression per se resulted in no eosinophilia and only a minimum of tissue inflammatory responses in the lung of naive mice, similar to those induced by the control vector. However, such GM-CSF expression in the airways of OVA-sensitized mice resulted in a much greater and sustained accumulation of various inflammatory cell types, most noticeably eosinophils, both in BALF and airway tissues for 15–21 days post-OVA aerosol challenge, at which times airways inflammation had largely resolved in control mice. While the levels of IL-5 and IL-4 in BALF and the rate of eosinophil apoptosis were found similar between different treatments, there was an increased number of proliferative leucocytes in the lung receiving GM-CSF gene transfer. Our results thus provide direct experimental evidence that GM-CSF can significantly contribute to the development of allergic airways inflammation through potentiating and prolonging inflammatory infiltration induced by cytokines such as IL-5 and IL-4.