bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human CD4+ T lymphocytes recognize a highly conserved epitope of human T lymphotropic virus type 1 (HTLV-1)envgp21 restricted by HLA DRB1*0101
Authors: Kitze B , Usuku K , Yamano Y , Yashiki S , Nakamura M , Fujiyoshi T , Izumo S , Osame M , Sonoda S 
Published: March 2003

SUMMARYHTLV-1 causes two distinct human diseases, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T cell leukaemia/lymphoma (ATL). Persistently infected individuals carry a risk of &lt; 1% of developing either disease. These basic epidemiological data imply that virus–host interactions, especially immunogenetic factors, influence the outcome of infection. Several studies showed that the HLA class II DR1 DQ5 haplotype is over-represented in HAM/TSP, but rare in ATL. Therefore, we selected four patients with HAM/TSP and one seronegative control who all carried the HLA DR1 DQ5 haplotype. We analysed the CD4+ T lymphocyte response against eight synthetic peptides of HTLV-1 envelope (env) glycoprotein gp21, a crucial target antigen in HAM/TSP. The first of two immunodominant epitopes corresponded to a domain of the HTLV-1 envelope protein which had previously been shown to be essential for HTLV-1 envelope function. The second immunodominant epitope overlapped a highly conserved sequence of the retroviral transmembrane envelope protein. DR1 (DRB1*0101)-restricted T lymphocytes were activated by the conserved peptide sequence in nanomolar concentrations. In contrast, this conserved sequence can also induce non-specific, cAMP-mediated immunosuppressive effects on T cells when added in micromolar concentrations to culture media, as shown by Haraguchi S, Good RA, James-Yarish M, Cianciolo GJ, Day NK, Proc Natl Acad Sci USA 1995; 92:5568–71. Hence, HTLV-1 env gp21 might exert either stimulating immunological or immunosuppressive effects in HTLV-1-infected individuals, depending on the level of its expression and the presence of HLA DRB1*0101.
Nasal tolerance in experimental autoimmune myasthenia gravis (EAMG): induction of protective tolerance in primed animals
Authors: Shi F-D , Bai X-F , LI H-L , Huang Y-M , Van Der Meide P H , Link H 
Published: March 2003

SUMMARYNasal administration of μg doses of acetylcholine receptor (AChR) is effective in preventing the development of B cell-mediated EAMG in the Lewis rat, a model for human MG. In order to investigate whether nasal administration of AChR modulates ongoing EAMG, Lewis rats were treated nasally with AChR 2 weeks after immunization with AChR and Freund's complete adjuvant. Ten-fold higher amounts of AChR given nasally (600 μg/rat) were required to ameliorate the manifestations of EAMG compared with the amounts necessary for prevention of EAMG. In lymph node cells from rats receiving 600 μg/rat of AChR, AChR-induced proliferation and interferon-gamma (IFN-γ) secretion were reduced compared with control EAMG rats receiving PBS only. The anti-AChR antibodies in rats treated nasally with 600 μg/rat of AChR had lower affinity, reduced proportion of IgG2b and reduced capacity to induce AChR degradation. Numbers of AChR-reactive IFN-γ and tumour necrosis factor-alpha (TNF-α) mRNA-expressing lymph node cells from rats treated nasally with 600 μg/rat of AChR were suppressed, while IL-4, IL-10 and transforming growth factor-beta (TGF-β) mRNA-expressing cells were not affected. Collectively, these data indicate that nasal administration of AChR in ongoing EAMG induced selective suppression of Th1 functions, i.e. IFN-γ and IgG2b production, but no influence on Th2 cell functions. The impaired Th1 functions may result in the production of less myasthenic anti-AChR antibodies and contribute to the amelioration of EAMG severity in rats treated with AChR 600 μg/rat by the nasal route.
B cell-deficient mice do not develop type II collagen-induced arthritis (CIA)
Authors: Svensson L , Jirholt J , Holmdahl R , Jansson L 
Published: March 2003

SUMMARYTo investigate the role of B cells in the development of CIA, a model for rheumatoid arthritis, we investigated susceptibility to CIA in mice lacking B cells due to the deletion of the IgM heavy chain gene (μMT). The μMT deletion was backcrossed into two different CIA-susceptible strains, B10.Q and B10.RIII. Two different variants of the CIA model are inducible in these strains: in B10.Q with rat type II collagen (CII) and in B10.RIII with bovine CII. Homozygous deletion of the IgM gene led to the absence of B cells and dramatically reduced immunoglobulin levels compared with wild-type mice. The deletion of IgM totally abrogated development of CIA in both strains, although the anti-CII T cell response did not differ between the μMT and wild-type controls. We conclude that B cells play a crucial role in the development of CIA.
Anti-ribosomal antibodies bind the Sm proteins D and B/B′
Authors: Caponi L , Bombardieri S , Migliorini P 
Published: March 2003

SUMMARYIn order to analyse the specificity of human anti-ribosomal P protein antibodies, anti-ribosomal P protein antibodies were affinity-purified from the sera of lupus patients. Their binding capacity towards recombinant SmD protein and recombinant SmB/B′ protein was evaluated by immunoblot and ELISA. Epitope mapping of SmD was performed by means of synthetic peptides. Anti-ribosomal P protein antibodies bound recombinant SmD (5/10) and SmB/B′ (4/10) on immunoblot; 6/10 showed binding capacity to SmD on ELISA. Inhibition experiments using ELISA confirmed the specificity of this binding. Our data indicate the cross-reactivity of spontaneously developed anti-ribosomal P protein antibodies with the B/B′ and D constituents of the Sm complex. The coexistence of anti-Sm and anti-ribosomal antibodies in lupus sera may therefore be due, at least in part, to the reactivity of a single autoantibody population.
Bystander suppression of murine collagen-induced arthritis by long-term nasal administration of a self type II collagen peptide
Authors: Bayrak Ş , Mitchison N A 
Published: March 2003

AbstractOral and more recently nasal tolerance have attracted attention as potential treatments of autoimmune disease. Arthritis induced by bovine type II collagen (CII) is a widely used animal model of rheumatoid arthritis, which is here used to investigate the efficacy of nasal treatment by a short peptide. The peptide spans residues 707–721 (designated p707), an epitope of mouse CII that is most strongly recognized after immunization of mice with this self-protein. The treatment was partially effective, but almost only when the peptide was administered in large doses over a prolonged period. Mice immunized with bovine CII respond mainly to other peptides, located in the CB11 fragment around amino acid residues 256–270. The tolerance effect therefore results from intramolecular suppression, between epitopes located in different parts of this large protein.
A vigorous virus-specific CD4+ T cell response may contribute to the association of HLA-DR13 with viral clearance in hepatitis B
Authors: Diepolder H M , Jung M-C , Keller E , Schraut W , Gerlach J-T , Grüner N , Zachoval R , Hoffmann R M , Schirren C-A , Scholz S , Pape G R 
Published: March 2003

SUMMARYA strong virus-specific CD4+ and CD8+ T lymphocyte response to hepatitis B virus (HBV) has been associated with viral clearance, but little is known about factors determining the individual's ability to mount such a T cell response. Recently a strong association between the HLA class II allele DR13 and a self-limited course of HBV infection has been described. In the present study of 33 patients with acute hepatitis B we show that individuals carrying HLA-DR13 mount a more vigorous CD4+ T cell response to HBV core (5706 ct/min (25th/75th percentile 3239 ct/min; 10 552 ct/min)) than patients without HLA-DR13 (1365 ct/min (490 ct/min; 5334 ct/min); P = 0.006). However, peptide epitopes aa 50–69, aa 61–85, and aa 81–105 were recognized most frequently by both patient groups. Moreover, among 14 HBV core-specific CD4+ T cell clones from two patients with HLA-DR13, only one T cell clone was HLA-DR13-restricted. Our data suggest that the beneficial effect of the HLA-DR13 alleles on the outcome of HBV infection could be explained by a more vigorous HBV core-specific CD4+ T cell response, which may either be due to more proficient antigen presentation by the HLA-DR13 molecules themselves or a linked polymorphism in a neighbouring immunoregulatory gene.
Endogenous opioids modulate allograft rejection time in mice: possible relation with Th1/Th2 cytokines
Authors: Sacerdote P , Di San Secondo B E M R , Sirchia G , Manfredi B , Panerai A E 
Published: March 2003

SUMMARY
The continuous infusion of the opioid peptide β-endorphin prolongs skin allograft survival in mice, while the opiate receptor antagonist naloxone, administered together with the opioid at the time of transplantation, abolishes the effect of the opioid. Consistently, naloxone, when given alone at the time of transplantation, but not later, accelerates graft rejection and increases splenocyte IL-2 and interferon-gamma (IFN-γ) production. Splenocyte β-endorphin concentrations are lower in transplanted animals. The effects of exogenous β-endorphin and naloxone suggest that the endogenous opioid peptide β-endorphin exerts a tonic inhibitory effect over early events of T cell-mediated immune responses in vivo. The effects of β-endorphin and naloxone are consistent with the previously shown role of the opioid system in the modulation of the Th1/Th2 cytokine pattern.
mRNA cytokine profile in peripheral blood cells from chronic hepatitis C virus (HCV)-infected patients: effects of interferon-alpha (IFN-α) treatment
Authors: Shapiro S , Gershtein V , Elias N , Zuckerman E , Salman N , Lahat N 
Published: March 2003

SUMMARYNatural immune responses, both cellular and humoral, are not capable of terminating HCV infection in most patients. A role has been suggested for peripheral blood leucocytes (PBL) in viral persistence and clinical implications, as these cells may serve as a viral reservoir and at the same time may be inadequate active participants in antiviral immune reactions. IFN-α administration, although only partially successful, is currently the main therapy available for chronic HCV patients. In addition to its antiviral effects, IFN-α regulates the function of cytokines, their receptors and other molecules of immune importance. The aim of this study was to determine cytokine mRNA expression in PBL derived from chronic HCV patients prior to and at termination of IFN-α treatment. HCV RNA was still observed in sera of most patients (10 out of 14 treated patients) at termination of treatment. In pretreated patients mRNA expression of Th2 (IL-4, IL-6 and IL-10) and Th3 (transforming growth factor-beta (TGF-β)) was observed in only a low percentage of PBL samples from patients, similar to controls. IFN-α treatment led to an elevation in the number of samples expressing these cytokines (significant for IL-4, IL-6, IL-10, tumour necrosis factor-alpha (TNF-α) and TGF-β), accompanied by reduction in liver enzymes but in serum viral load in only ≈ 30% of patients. Expression of TNF-α and TNF-β mRNA was observed in samples from patients but not controls, while no differences were observed for mRNA of classical Th1 cytokines (IL-2 and IFN-γ) between patients before or during treatment as well as controls. The cytokine mRNA profile following IFN-α treatment points to an anti-inflammatory response which does not appear to be involved in termination of the viral infection. The PBL cytokine profile observed in this study may explain the failure of the immune system to eradicate HCV chronic infection and suggests that early treatment in the acute phase of disease with agents that stimulate cytotoxic immune type 1 responses may lead to eradication of HCV infection.
Characterization of NK cells and extrathymic T cells generated in the liver of irradiated mice with a liver shield
Authors: Halder R C , Seki S , Weerasinghe A , Kawamura T , Watanabe H , Abo T 
Published: March 2003

SUMMARYWe previously reported that c-kit+ stem cells which give rise to extrathymic T cells are present in the liver of adult mice. Further characterization of extrathymic T cells in the liver of adult mice is conducted here. When mice with a liver shield were lethally (9.5 Gy) irradiated, all mice survived. All tested organs showed a distribution pattern of hepatic lymphocytes on day 7. The distribution pattern in the liver was characterized by an abundance of NK (CD3− IL-2Rβ+) and extrathymic T cells (CD3int IL-2Rβ+) before and after irradiation. To determine their function, post-irradiation allogeneic bone marrow transplantation (BMT) was performed in mice with or without a liver shield. Allogeneic BM cells were rejected in mice with a liver shield and specific activation of CD8+ CD3int IL-2Rβ+ cells was induced. At that time, potent cytotoxicity of liver mononuclear cells (MNC) against allogeneic thymocytes was induced. Both NK1.1+ and NK1.1− subsets of CD3int cells expanded in these mice. An in vivo elimination experiment of the subsets indicated that the NK1.1+ subset of CD3int cells (i.e. NK T cells) was much more associated with the rejection of allogeneic BM cells. However, even after the elimination of NK T cells, allogeneic BM cells were rejected. In this case, granulocytes expanded in parallel with NK1.1− subsets. Granulocytes may also be associated with the rejection of allogeneic BM cells. These results suggest that the liver is an important haematopoietic organ even in adult life.
Decreased CD4 and increased CD8 counts with T cell activation is associated with chronic helminth infection
Authors: Kalinkovich A , Weisman Z , Greenberg Z , Nahmias J , Eitan S , Stein M , Bentwich R. Z 
Published: March 2003

SUMMARYWe have previously reported the presence of marked immune dysregulation with a dominant Th2 profile, in a population of Ethiopian immigrants (ETH) in Israel heavily infected with helminths. In order to characterize better this immune dysregulation we studied by flow cytometry the expression of several activation markers on peripheral T cell populations, and lymphocyte apoptosis, in blood samples obtained from 63 ‘new’ ETH (recently arrived), 18 ‘old’ ETH (&gt; 5 years since immigration) and 34 non-Ethiopian Israelis. The main findings in the ‘new’ ETH group in comparison with the non-Ethiopian controls were: (i) decreased CD4 and increased CD8 lymphocyte counts; (ii) elevated levels of activated T cells (CD3, CD4 and CD8) expressing HLA-DR; (iii) decreased levels of ‘naive’ CD4+ cells (CD45RA+), with increased levels of ‘memory’ CD4+ cells (CD45RO+); (iv) decreased numbers of CD28+ CD8+ lymphocytes; (v) marked increase in lymphocyte apoptosis. These T cell alterations and activation profile remained unchanged in 10 ‘new’ ETH in whom the helminth infections persisted for 6–11 months. In contrast, in 18 ‘old’ ETH, without helminth infections, the T cell activation profile was within the normal range. These findings suggest that chronic helminth infections may have a profound effect on the immune system of the host that disappears after eradication of these infections and adjustment to the new environment. It should therefore be taken into consideration for every immunomodulation therapy and especially in vaccine design and trials, in regions endemic for helminth infections.
Argininosuccinate lyase: a new autoantigen in liver disease
Authors: Pelli N , Fensom A H , Slade C , Boa F , Mieli-Vergani G , Vergani D 
Published: March 2003

SUMMARYAnti-liver cytosol 1 autoantibody (LC1) characterizes a severe form of autoimmune hepatitis (AIH), staining the cytoplasm of periportal hepatocytes and targeting an unidentified 60-kD liver cytosolic antigen. To identify its target, we used high-titre anti-LCI+ sera from two patients with AIH to screen 18 cytoplasm enzymes with periportal location by double immunodiffusion (DDI). Both sera gave a broad precipitin line against human liver cytosol, suggesting that they may recognize two distinct antigens, a possibility confirmed by the appearance of two precipitin lines when DDI conditions were optimized (0.8% agarose and 3% polyethylene glycol (PEG)). Experiments by DDI and Western blot (WB) identified a liver cytosolic autoantigen of 50 kD, different from LC1, giving a line of identity with argininosuccinate lyase (ASL). Reactivity to ASL was then investigated by DDI and WB in 57 patients with AIH, 17 with primary biliary cirrhosis (PBC), 15 with chronic hepatitis B virus (HBV) infection, 13 with αl-antitrypsin deficiency, 17 with Wilson's disease, 18 with extrahepatic autoimmune disorders, and in 48 healthy controls. Anti-ASL was found in 16% of AIH and 23% of PBC patients by DDI and in 14% of AIH, 23% of PBC and 20% of HBV patients by WB. No argininosuccinate was present in the urine of four anti-ASL+ patients tested, excluding an inhibition of enzymatic activity by anti-ASL. The addition of anti-ASL+ serum to human fibroblast cultures induced a significant increase in ASL activity. ASL is a new autoantigen in liver disease and its clinical relevance warrants further investigation.
Methotrexate specifically modulates cytokine production by T cells and macrophages in murine collagen-induced arthritis (CIA): a mechanism for methotrexate-mediated immunosuppression
Authors: NEURATH M F , HILDNER K , BECKER C , SCHLAAK J F , BARBULESCU K , GERMANN T , SCHMITT E , SCHIRMACHER P , HARALAMBOUS S , PASPARAKIS M , MEYER ZUM BÜSCHENFELDE K-H , KOLLIAS G , MÄRKER-HERMANN E 
Published: March 2003

SUMMARYImmunosuppressive therapy with methotrexate (MTX) has been established as effective treatment for patients with rheumatoid arthritis. To analyse the therapeutic potential and mechanisms of action of MTX, we determined serum cytokine levels and cytokine production by splenic T cells and macrophages in untreated and MTX-treated mice. Furthermore, we assessed the role of MTX in a murine model of experimental arthritis induced by collagen type II (CIA). MTX reduced spontaneous and IL-15-induced tumour necrosis factor (TNF) production by splenic T cells but not by macrophages from healthy mice in vitro in a dose-dependent manner. In contrast, interferon-gamma (IFN-γ) production was less strikingly reduced and IL-4 production was virtually unaffected. In addition, treatment of healthy mice with MTX in vivo led to reduced TNF serum levels and diminished TNF production by splenic T cells and macrophages. Intraperitoneal administration of MTX prior to the onset of arthritis completely prevented clinical and pathological signs of CIA. This was associated with a striking reduction of TNF production by spleen cells from MTX-treated mice. The role of TNF in MTX-mediated effects on cytokine production was further underlined by the finding that MTX effects on IFN-γ production were augmented in TNF-transgenic mice but abrogated in mice in which the TNF-α gene had been inactivated by homologous recombination. Thus, MTX specifically modulates spontaneous and IL-15-induced TNF-α production in mice and prevents experimental murine CIA. These data suggest that TNF production by T cells is an important target of MTX and may serve as a basis to understand and further analyse MTX-mediated mechanisms of immunosuppression in patients with RA.
Ro/SS-A- and La/SS-B-reactive B lymphocytes in peripheral blood of patients with Sjögren's syndrome
Authors: HALSE A-K , WAHREN-HERLENIUS M , JONSSON R 
Published: March 2003

SUMMARYThe aim of this study was to investigate the production of anti-Ro/SS-A and anti-La/SS-B antibodies in peripheral blood (PB) of patients with Sjögren's syndrome (SS). The ELISPOT method was performed to quantify the frequency of PB lymphocytes spontaneously secreting anti-Ro/SS-A and/or anti-La/SS-B antibodies. The total number of IgG-, IgA- and IgM-producing cells was also quantified. The recombinant Ro 52-kD, Ro 60-kD and La 48-kD proteins were used as target antigens. Three of 18 SS patients had PB lymphocytes secreting IgG antibodies against the recombinant Ro 52-kD protein. The same three patients had high serum titres of anti-Ro 52-kD antibodies. In addition, these patients were classified as having severe disease, and all three had focus scores of ≥ 8 in biopsies of the labial salivary glands (LSG). The correlation between the number of PB cells producing IgG antibodies against the recombinant Ro 52-kD protein and the focus score was significant (P &lt; 0.01). The results indicate that only SS patients with severe disease and high degree of local inflammation in LSG have B cells producing anti-Ro/SS-A antibodies in PB. Thus, most of the spontaneous autoantibody production must take place in other body compartments, e.g. in exocrineglands and probably also in the lymphoid organs and/or other mucosal sites.
Genetic markers in clinically well defined patients with ulcerative colitis (UC)
Authors: BOUMA G , CRUSIUS J B A , GARCÍA-GONZÁLEZ M A , MEIJER B U G A , HELLEMANS H P R , HAKVOORT R J , Th. SCHREUDER G M , KOSTENSE P J , MEUWISSEN S G M , PEÑA A S 
Published: March 2003

SUMMARY
Results of genetic association studies in UC are conflicting. We propose that the power of candidate gene studies will increase when disease heterogeneity is taken into account. Phenotype frequencies of molecularly defined HLA-DR alleles, polymorphisms in the tumour necrosis factor-alpha (TNF-α), lymphotoxin-alpha (LT-α), IL-1 receptor antagonist (IL-1Ra) and IL-1β genes were determined in 98 clinically well characterized UC patients with a mean period of follow up of 10 years, and ethnically matched healthy controls (HC). The alleles HLA-DRB1*0103 (phenotype frequency 6% versus 0.2%; P = 0.0002; odds ratio (OR) 27.6) and DRB1*15 (41% versus 26%; P = 0.001; OR = 2.0, compared with HC) were associated with overall disease susceptibility. Subgroup analysis revealed that DRB1*15 was only increased in females (53% versus 24%; P &lt; 0.0001; OR = 3.5), but not in males. With regard to disease localization, all DRB1*0103+ patients had extensive disease (P &lt; 0.002; OR = 33.5), and DRB1*15 was found in 59% of females with extensive colitis (P &lt; 0.0001; OR = 4.4). DRB1*0103 was significantly increased in patients undergoing colectomy (P &lt; 0.0002; OR = 84). No association between overall disease susceptibility and the cytokine gene polymorphisms were found. Subgroup analysis revealed several significant associations, but most did not retain significance when corrected for multiple comparisons. However, a noticeable finding was that haplotype TNF-C was significantly associated with progression in extent of disease (P = 0.003, OR = 20.4). This study provides additional evidence for the role of DRB1 alleles in the susceptibility to UC, and supports the hypothesis that these alleles may determine the severity of the disease. The cytokine gene polymorphisms evaluated in this study do not seem to be strong risk factors for the overall disease susceptibility in UC, but may be involved in determining the severity of the disease.