bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma half-lives and bioavailability of human monoclonal Rh D antibodies BRAD-3 and BRAD-5 following intramuscular injection into Rh D-negative volunteers
Authors: GOODRICK J , KUMPEL B , PAMPHILON D , FRASER I , CHAPMAN G , DAWES B , ANSTEE D 
Published: July 2010

SUMMARY
Two human MoAbs, BRAD-3 (an IgG3 anti-D) and BRAD-5 (an IgG1 anti-D), were produced from Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell lines grown in hollow fibre bioreactors. Six Rh D-negative male volunteers were injected intramuscularly with anti-D; two received BRAD-3 (approx. 1500μg, 2600IU), two were given BRAD-5 (300 μg, 2000 IU), and two had polyclonal anti-D immunoglobulin (500IU, approx. 100μg anti-D). Levels of anti-D in plasma samples taken up to 42 days later were measured by a sensitive AutoAnalyser method. The half life of BRAD-5 (mean 22·2 days) was greater, and that of BRAD-3 (mean 10·2 days) less than that of polyclonal anti-D (mean 15·6 days). The bioavailability (plasma uptake) of the MoAbs (mean 33·9%) was less than that of the polyclonal anti-D (mean 60·3%). BRAD-3 and BRAD-5 may be suitable for use in antenatal and post-natal prophylaxis against Rh D haemolytic disease of the newborn.
Effects of therapy with soluble tumour necrosis factor receptor fusion protein on pulmonary cytokine expression and lung injury following haemorrhage and resuscitation
Authors: ABRAHAM E , COULSON W F , SCHWARTZ M D , ALLBEE J 
Published: July 2010

SUMMARYAcute lung injury frequently develops following haemorrhage, and is characterized by increased proinflammatory cytokine levels and massive neutrophil accumulation in the lung. Blood loss produces rapid increases in tumour necrosis factor-alpha (TNF-α) mRNA expression among pulmonary cell populations which precede the development of lung injury. In order to examine the role of TNP-α in producing acute inflammatory lung injury, we treated mice following haemorrhage and resuscitation with a TNF antagonist, composed of soluble dimeric human p80 TNF receptor linked to the Fc region of human IgG1 (sTNFR:Fc). Therapy with sTNFR:Fc prevented the post-haemorrhage increases in circulating and pulmonary TNF-α levels normally found following blood loss. Administration of sTNFR:Fc also diminished the increase in IL-1/β, IL–6, TNF-α and interferon-gamma (IFN-γ) mRNA normally found in the lungs following haemorrhage. However, therapy with sTNFR:Fc was not associated with improvement in the histologic parameters of post-haemorrhage lung injury, such as neutrophil infiltration and interstitial oedema. In contrast lo the effects of sTNFR:Fc on cytokine mRNA levels among intraparenchymal pulmonary mononuclear cells, such therapy following haemorrhage was associated with increased amounts of mRNA for TNF-α among peripheral blood mononuclear cells, as well as increased IFN-γ titres in serum and bronchoalveolar lavage (BAL) specimens. These results indicate that therapy with sTNFR:Fc in the post-haemorrhage period, although capable of decreasing proinflammatory cytokine expression in the lungs, does not prevent the development of acute lung injury in this setting.
Autoreactive IgG elicited in mice by the non-dominant but pathogenic thyroglobulin peptide (2495–2511): implications for thyroid autoimmunty
Authors: CHRONOPOULOU E , MICHALAK T I , CARAYANNIOTIS G 
Published: July 2010

SUMMARYWe have previously shown that mice challenged with the rat thyroglobulin (Tg) peptide TgP1 (corresponding to aa 2495–2511 of human Tg) develop experimental autoimmune thyroiditis (EAT) and produce IgG antibodies that cross-react with Tg from various species. It was not clear, however, whether such antibodies were TgP1-specific or were induced secondarily—i.e. by autologous Tg released from the destroyed gland—and therefore directed to determinants other than TgP1. In this study we describe that, 5 weeks after priming with TgP1, the binding of serum IgG on native Tg is completely inhibited by free peptide, suggesting lack of recognition of other determinants on mouse Tg (mTg). In addition, TgP1-induced but not mTg-induced IgG bound better to heat-denatured than intact mTg, a result compatible with the recognition of a linear epitope by the peptide-induced antibodies. Comparison of the IgG subclass distribution among mTg-induced versus TgP1-induced IgG did not reveal qualitative differences, since all subclasses were represented in the order IgG1 &gt; IgG2b &gt; IgG2a &gt; IgG3. Finally, TgP1-specific IgG reacted strongly with the follicular colloid in sections of normal thyroids, indicating the potential to bind to native Tg in vivo. These data: (i) highlight TgP1 as the only, so far, Tg sequence known to generate both EAT and Tg-reactive IgG in mice: and (ii) do not provide evidence for an amplification of the Tg-specific IgG response through the involvement of endogenous autoantigen in EAT.
Streptococcal toxic shock-like syndrome: evidence of superantigen activity and its effects on T lymphocyte subsetsin vivo
Authors: MICHIE C , SCOTT A , CHEESBROUGH J , BEVERLEY P , PASVOL G 
Published: July 2010

SUMMARYToxic shock-like syndrome is a serious complication of invasive streptococcal disease. The syndrome is believed to be the consequence of exposure to exotoxins produced by the infecting organisms which behave as superantigens. We describe two patients who fulfilled clinical criteria for this syndrome, one of whom died. Streptococci isolated from both patients were found to produce a mitogen specific for the Vβ2+ T lymphocyte subset in vitro, which had the characteristics of a superantigen. The phenotype and function of lymphocytes collected from both patients during the acute phase of their illness demonstrated a marked reduction in circulating CD4+ (‘helper’) and CD45RA+ (‘naive’) T lymphocytes expressing the Vβ2 chain, and an increase of those expressing CD8, CD45RO and the Vβ2 chain. This effect resolved within 4 weeks in the patient who survived. Proliferation assays demonstrated no T cell anergy in either patient. Stimulation of lymphocytes by superantigen in these clinical situations does not appear to cause permanent deletion of T cell subsets, as has been observed in animal models.
Different growth factor requirements for human Th2 cells may reflectin vivoinduced anergy
Authors: VAN REIJSEN F C , WIJBURG O L C , GEBHARDT M , VAN IEPEREN-VAN DIJK A G , BETZ S , POELLABAUER E-M , THEPEN T , BRUIJNZEEL-KOOMEN C A F M , MUDDE G C 
Published: July 2010

SUMMARYWe previously reported the isolation of allergen-specific Th2 lines and clones from atopy patch test (APT) sites of atopic dermatitis (AD) patients. Upon stimulation with allergen or anti-CD3+phorbol myristate acetate (PMA) IL-4 was released with or without IL-5, while no (or extremely low concentrations of) IL-2 and interferon-gamma (IFN-γ) were detectable. A high IL-4/IFN-γ ratio facilitates production of allergen-specific IgE, of which high levels are observed in AD patients. Here, we show that the above mentioned Th2 cells are notably different from murine Th2 cells. Not IL-4, which is the autocrine acting growth factor for murine Th2 cells, but IL-2 was needed for proliferation of these human APT-derived Th2 lines and clones. Of significance, unless exogenous lL-2 was added, no proliferative response to allergen, presented by Epstein-Barr virus-transformed B (EBV-B) cells, non-T cells or IgE-bearing Langerhans cells (LC), occurred. Lack of proliferation and IL-2 production after full T cell receptor (TCR) triggering is a characteristic first described for in vitro anergized T cells. However, like the clones we describe in this study, anergic T cells may retain production of cytokines other than IL-2. A further resemblance between anergic T cells and the human Th2 clones reported here is that IL-4 can enhance IL-2-driven proliferation, but is not capable of inducing T cell growth by itself. The absence of IL-4-driven proliferation differentiates human Th2 cells from murine Th2 cells. Both produce IL-4 when stimulated in a cognate fashion, but only murine Th2 cells will proliferate. We conclude that the presently reported human Th2 cells are different from murine Th2 cells, in that they need other T cells lo produce IL-2 required for their expansion. Moreover, the Th2 cells phenotypically resemble anergic T cells. As yet, however, we have no clue as to whether these features account for the current Th2 cells only or for human Th2 cells in general. We hypothesize that the Th2 phenotype of AD skin-derived, allergen-specific T cells may be induced in vivo by LC, which lack CD80, and therefore do not provide secondary signals through CD28-CD80 interaction.
Proteolysis of classic anti-neutrophil cytoplasmic autoantibodies (C-ANCA) by neutrophil proteinase 3
Authors: DOLMAN K M , JAGER A , SONNENBERG A , VON DEM BORNEO A E G KR , GOLDSCHMEDING R 
Published: July 2010

SUMMARY
C-ANCA, which are directed against neutrophil proteinase 3 (PR3), are specific markers for the diagnosis of active Wegener's granulomatosis (WG). The correlation between C-ANCA titre and WG disease activity suggests that these autoantibodies are involved in the development of WG, We have previously observed that C-ANCA interfere with PR3 proteolytic activity and with complexation of PR3 with its major physiologic inhibitor α1-antitrypsin (α1-AT). The possible pathogenic importance of C-ANCA may be related to the stability of C-ANCA IgG PR3 complexes. In the present study we tested proteolysis by PR3 of human IgG and proteolysis of C-ANCA IgG complexed to the enzyme. All human IgG subclass proteins were cleaved by PR3, Digestion products were compared with those obtained by human neutrophil elastase (HNE)-mediated proteolysis of human IgG subclass proteins. Although cleavage products of similar size could be identified, the proteolytic activity of both enzymes towards human IgG differed. Furthermore, inhibiting C-ANCA IgG were cleaved into small peptides when complexed to PR3. The possible pathogenic consequences or these findings will be discussed.
Neutrophil expression of tumour necrosis factor receptors (TNF-R) and of activation markers (CD11b, CD43, CD63) in rheumatoid arthritis
Authors: LOPEZ S , HALBWACHS-MECARELLI L , RAVAUD P , BESSOU G , DOUGADOS M , PORTEU F 
Published: July 2010

SUMMARYIn vitro analysis of polymorphonuclear neutrophils (PMN) has allowed various stages of cell activation to be distinguished, characterized by the expression level of specific membrane markers and of functional receptors. Among those, TNF-α receptors (TNF-R) are modulated by various PMN activators, a mechanism which may be important to control cell responses to TNF in inflammatory reactions such as rheumatoid arthritis (RA). PMN, isolated from the blood of 36 RA patients and from the synovial fluid of 23 of them, were analysed for membrane expression of the two TNF-R (p55 and p75). Soluble p55 and p75 (sTNF-R) and TNF concentrations were measured in the plasma and synovial fluid by specific ELISA assays. Our results show that PMN from the blood of RA patients bear a normal number of TNF-R. with a normal p55/p75 ratio, compared with PMN from normal controls. Soluble TNF-R levels were similar in patients and normal plasma. In spite of high endogenous TNF concentration, patients’ circulating PMN were not activated, as shown by a CD11b/CD18 expression similar to that of control resting cells. In contrast with blood neutrophils, PMN from RA patients’ synovial fluids had an activated phenotype, characterized by increased expression of CD11b, decreased expression of leukosialin, CD43, and the appearance on the plasma membrane of an azurophil granule protein, CD63. High levels of soluble TNF-R were measured in RA synovial fluids. Nevertheless, membrane TNF-R levels and p55 and p75 proportions were similar to those of PMN from normal blood. These results suggest the existence of regulatory mechanisms which maintain a stable neutrophil expression of TNF-R as well as a balance between both types of receptors in inflammatory situations where neutrophils are strongly activated.
Complement receptor expression and activation of the complement cascade on B lymphocytes from patients with systemic lupus erythematosus (SLE)
Authors: MARQUART H V , SVENDSEN A , RASMUSSEN J M , NIELSEN C H , JUNKER P , SVEHAG S-E , LESLIE R G Q 
Published: July 2010

SUMMARYIt has previously been reported that the expression of the complement receptors, CR1 on erythrocytes and blood leucocytes and CR2 on B cells, is reduced in patients with SLE, and that the reduced expression of CR1 on erythrocytes is related to disease activity. We have earlier demonstrated that normal B cells are capable of activating the alternative pathway (AP) of complement in a CR2-dependent fashion. In this study we have investigated whether disturbances in this activity may be related to the altered phenotype of SLE B cells. Flow cytometry was used to measure expression of complement receptors and regulatory proteins on B cells from SLE patients, as well as the deposition of C3 fragments occurring in vivo or after in vitro AP activation. We have confirmed, for a proportion of the patients studied, reduced expression of CR1 and CR2 on B cells, and shown a consistency between low CR2 expression and reduced in vitro AP activation in the presence of homologous, normal serum. In addition, the B cells, like erythrocytes, bear raised levels of in vivo-deposited C3dg, but not C3b fragments, compared with normal B cells. The erythrocytes from SLE patients were unable to inhibit in vitro AP activation by B cells in homologous serum. Finally, we demonstrated an inverse relationship between SLE disease activity index (SLEDAI) and the expression of complement receptor 2 (CR2) on SLE B cells. Thus, determination of CR2 on B cells may emerge as an additional laboratory tool in the assessment of SLE activity.
CDR3 regions in the preimmune VH B cell repertoire oflprmice
Authors: ALARCÓN-RIQUELME M E , FERNÁNDEZ C 
Published: July 2010

SUMMARYPrevious studies have suggested that the CDR3 genetic element of the heavy chain variable region of autoantibodies is important in determining reactivity against self antigens, particularly against DNA. The lpr mutation was recently found to encode for a defective form of the fas protein, a molecule important for the transmission of the apoptotic signal into cells. Our aim was to determine whether CDR3 elements similar to those described for autoantibody-producing hybridomas derived from lupus-prone strains could be found in the preimmune repertoire of B cells in mice with the lpr mutation. The analysis of the junctions of the VH -Cμ functional rearrangements derived by polymerase chain reaction (PCR) amplification of RNA obtained from splenic small, resting cells stimulated with lipopolysaccharide (LPS) from male lpr mice showed that a large proportion of them expressed D genes in the unusual reading frames 2 and 3. Two of the lpr joints were formed by D-D fusions. Similarly, nearly half of the lpr sequences had arginines, an amino acid which promotes binding to dsDNA and is seldom observed in normal junctions. Our results show that the preimmune repertoire of lpr animals has abnormal CDR3 elements which may result from a failure at different levels of selection. The antigen-dependent selection of such elements that leads to the expansion of specific, high-affinity anti-dsDNA antibody-producing clones might depend on other genetic factors not found in the C57Bl/6-lpr strains but in the MRL-lpr.
IL-13 results in differential regulation of the complement proteins C3 and factor B in tumour necrosis factor (TNF)-stimulated fibroblasts
Authors: KATZ Y , STAV D , BARR J , PASSWELL J H 
Published: July 2010

SUMMARYIL-13, like IL-4, a product of activated T cells, has multiple biological actions, primarily on B cells and monocytes. The purpose of the present study was to compare the effects of IL-13 with those of IL-4 on the synthesis of complement proteins in fibroblasts. Dermal fibroblasts were developed from skin biopsies. Confluent monolayers were stimulated with the relevant cytokine or combinations of cytokines and biosynthetically labelled with 35S–methionine. The specific proteins were analysed using immunoprecipitation and SDS–PAGE. Addition of IL-13 to fibroblast cultures treated with TNF-α resulted in a dose-dependent increase in C3 protein biosynthesis and a concomitant down-regulation of factor B protein biosynthesis. In TNF-stimulated fibroblasts, the addition of IL-13, 100 ng/ml, induced a 2·45-fold increase in the synthesis of C3, while in the same cells under identical conditions the synthesis of factor B was only 42% of the level without IL-13. Similar effects of IL-13 were noted on IL-1-treated fibroblasts. These effects were specific for C3 and factor B, and no alteration of the constitutive or TNF-induced synthesis of C1s or C1 inhibitor proteins was observed. IL-13 altered the synthesis of C3 and factor B proteins also in fibroblasts stimulated with interferon-gamma (IFN-γ) in addition to TNF, in the same direction as it did in cells stimulated with TNF alone. IL-13 has similar effects to those of IL-4 on the synthesis of C and factor B in TNF- and IL-1-stimulated fibroblasts. The observed effects of IL-13 are IL-4-independent, as anti-IL-4 antibody abrogates IL-4-induced effects, but has no effect on IL-13-induced responses. This interaction between different cytokines on the synthesis of proinflammatory and immunoregulatory proteins may have significance, particularly at local sites of inflammation, and may affect the synthesis of complement proteins in inflamed joint as in rheumatoid arthritis.
Elevation of serum soluble vascular cell adhesion molecule-1 (sVCAM-1) levels in bronchial asthma
Authors: Koizumi A , Hashimoto S , Kobayashi T , Imai K , Yachi A , Horie T 
Published: July 2010

SUMMARYWe have previously shown the elevation of serum soluble intercellular adhesion molecule-1 (sICAM-1) and soluble E-selectin (sE-selectin) in patients with bronchial asthma during asthma attacks. In the present study, we extended our earlier study by measuring serum sVCAM-1 levels by ELISA in 45 patients with bronchial asthma (23 atopic and 22 non-atopic) during asthma attacks and in stable conditions in order to assess further the state of adhesion molecules in allergic inflammation of bronchial asthma. The levels of sVCAM-1 in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. These findings were observed regardless of atopic status. To examine the regulatory mechanism in the elevation of serum sVCAM-1 levels, serum tumour necrosis factor-alpha (TNF-α) levels were measured by ELISA. TNF-α levels in sera obtained during bronchial asthma attacks were higher than those in sera obtained in stable conditions. The nature of change in serum TNF-α levels correlated with the nature of change in serum sVCAM-1 levels, but serum TNF-α levels did not correlate with serum sVCAM-1 levels. These results suggest that higher levels of sVCAM-1 during asthma attacks may reflect the up-regulation of VCAM-1 expression in allergic inflammation, and that a soluble form of VCAM-1 molecules may be useful markers for the presence of allergic inflammation. TNF-α is shown to enhance the expression and release of VCAM-1 in vitro, however; the regulatory mechanism in the elevation of serum sVCAM-1 levels remains to be clarified.
A prospective controlled crossover trial of a new heat-treated intravenous immunoglobulin
Authors: Zuhrie S R , Webster A D B , Davies R , Fay A C M , Wallington T B 
Published: July 2010

SUMMARYTwenty-one patients with primary immunoglobulin deficiency were enrolled in a crossover study to test the efficacy and safety of Alphaglobin in comparison with the licensed preparations Sandoglobulin and Gamimune. There was no statistical difference in these parameters between Alphaglobin and Sandoglobulin/Gamimune. The level of total serum IgG and specific IgG to pneumococcal polysaccharides was similar in individual patients when they were receiving Alphaglobin or one of the other products. Transient increases in serum alanine transferase occurred in five patients on Sandoglobulin/Gamimune and two patients on Alphaglobin. Some patients showed a rise in total serum IgM afterwards, indicating a response to infection. However, serum hepatitis C virus (HCV) RNA was not found during the alanine transferase (ALT) rises, and IgM antibody to hepatitis A virus (HAV) was negative afterwards. We conclude that Alphaglobin is a safe, well tolerated and clinically efficacious treatment for patients with primary antibody deficiency.
Anti-p57: a novel association with neonatal lupus
Authors: Maddison P J , Lee L , Reichlin M , Sinclair A , Wasson C , Schemmer G , Reichlin M 
Published: July 2010

SUMMARYIgG antibodies to a 57-kD protein (p57) present in various human and bovine extracts were detected by immunoblotting in the serum of the mother of a baby with congenital heart block, but not in the corresponding cord blood, suggesting specific antibody consumption in the baby. Since this indicates a possible functional role for these antibodies, the antigen target was characterized and the association of the antibodies to heart block was further studied. A human K562 λgt11 cDNA library was screened and two clones were identified whose products reacted with the prototype serum. Antibody affinity-purified by use of the cloned gene products reacted on immunoblot with the 57-kD band. Partial sequences of both inserts were identical, but differed from DNA encoding the Ro(SSA) and La(SSB) antigens. Antibodies to the p57 were detected in 10% of systemic lupus erythematosus (SLE) sera, almost exclusively in association with anti-Ro(SSA). Furthermore, they were present in 38% (8/21) mothers of babies with neonatal lupus expressing either cardiac or cutaneous manifestations. Antibodies to this 57-kD protein may be an additional risk factor for neonatal lupus in anti-Ro-positive women. Moreover, disappearance of antibody from cord blood suggests that they may have a role in disease manifestations.
Lack of cytotoxic activity againstMycobacterium leprae65-kD heat shock protein (hsp) in multibacillary leprosy patients
Authors: De La Barrera S , Fink S , Finiasz M , Minnucci F , Valdez R , BaliÑA L M , Sasiain M C 
Published: July 2010

SUMMARYCytotoxic T cells play an important role in host defence mechanisms, as well as in the immunopathology of leprosy. In this study, we evaluated whether Mycobacterium leprae hsp18, hsp65 and Myco. tuberculosis hsp71 could induce cytotoxic T cell activity against autologous macrophages pulsed with these hsp. Paucibacillary (PB) patients and normal controls generated more effector cells than multibacillary (MB) patients with all three hsp tested. There was no cross-reactivity between any of the hsp tested. Mycobacterium leprae hsp65 induced cytotoxic responses only in those MB patients undergoing an erythema nodosum leprosum (ENL) episode. Although hsp65 and hsp18 induced similar proliferation in MB patients, a high proportion of these patients did not generate cytotoxic effector cells in response to hsp65. Hence, those T cells reacting to hsp65 may play an important role in the control of Myco. leprae infection.