Age-dependent production of IgA and IgM autoantibodies against IgG2a in a colony of 129/Sv mice

Although much of the basic immunological work has been done with mice, little is known about anti-IgG autoantibodies in this species. Dresser (1, 2) has reported the occurrence, in CBA mice, of anti-IgG antibody (Ab)(1) detected by a hemolytic-plaque assay after stimulation with endotoxin or immunization against sheep erythrocytes. IgM rheumatoid factor has also been described in various strains of mice with a systemic lupus erythematosus-like disease (3). Recently, we have tried to induce anti-IgG in mice of the 129/Sv strain by inoculating autologous IgG. To our surprise, we found that the sera of all the animals had, before any inoculation, anti-IgG detectable by agglutination of particles coated with autologous IgG. The possibilities to investigate the mechanism of production and the biological role of this kind of Ab prompted us to undertake a study of the nature and specificity of the mouse anti-IgG

Monoclonal anti-IgG autoantibodies derived from lipopolysaccharide-activated spleen cells of 129/Sv mice

In some colonies, 129/Sv mice produce, upon aging, a rheumatoid factor (RF) that is specific for mouse IgG2a but fails to react with IgG2a of the b allotype. It is not known whether this narrow specificity is due to the absence of other RF specificities in the repertoire of these mice or to the selective activation of the production of anti-IgG2a autoantibodies by a specific stimulus. To analyze the RF repertoire of 129/Sv mice, we have derived hybridomas from their spleen cells 3 d after an intraperitoneal injection of lipopolysaccharide. We have obtained 68 hybridomas secreting a monoclonal IgM with RF activity. This represents approximately 3 percent of the total number of hybridomas generated in four hybridizations. In addition, one monoclonal IgA RF was derived from unstimulated 129/Sv spleen cells. The specificities of these monoclonal RF were examined by testing their ability to bind to a panel of homologous and heterologous IgG preparations. The majority of the IgM RF reacted exclusively with a single mouse IgG subclass: 58 with IgG1, and 1 with IgG2a. Eight bound preferentially to IgG1 but cross-reacted to some extent with IgG2a and one was specific for a determinant shared by IgG1, IgG2a, and IgG3. The IgA RF derived from unstimulated spleen cells was primarily directed against IgG2a but cross- reacted somewhat with IgG2b. Identical results were obtained with two different monoclonal IgG1 and IgG2a proteins of the a allotype. No allotypic specificity was found for the anti-IgG1 RF, which all reacted well with IgG1 of the b allotype. In contrast, the IgM anti-IgG2a antibody exhibited such allotypic specificity because it failed to react with IgG2a of the b allotype. When tested on heterologous IgG preparations, all anti-IgG1 RF reacted better with rat IgG1, rat IgG2c, bovine IgG2, goat IgG2, and rabbit IgG than with mouse IgG1, demonstrating a particular homology between these Ig. On the basis of additional cross-reactions with other IgG, including rat IgG2a, rat IgG2b, bovine IgG1, goat IgG1, human IgG, and chicken IgG, seven different anti-IgG1 clonotypes could be identified. However, despite their heterogeneity, nearly all antigenic determinants recognized by anti-IgG 1 RF appeared to be located in the hinge region of the molecule. Total lack of binding to IgG1 Fab fragments was indeed observed, and only one antibody reacted with IgG1 Fc fragments. Unlike the anti-IgG1 RF, the IgM and the IgA anti-IgG2a antibodies did not cross-react with any heterologous IgG of the same panel. Altogether, t 1 different RF clonotypes could be distinguished on the basis of their fine specificity. The anti-IgG2a specificity of the RF spontaneously produced by 129/ Sv mice is thus not due to the absence of other RF specificities in the repertoire of these mice

Iron homeostasis and oxidative stress in idiopathic pulmonary alveolar proteinosis: a case-control study

<p>Abstract</p> <p>Background</p> <p>Lung injury caused by both inhaled dusts and infectious agents depends on increased availability of iron and metal-catalyzed oxidative stress. Because inhaled particles, such as silica, and certain infections can cause secondary pulmonary alveolar proteinosis (PAP), we tested the hypothesis that idiopathic PAP is associated with an altered iron homeostasis in the human lung.</p> <p>Methods</p> <p>Healthy volunteers (n = 20) and patients with idiopathic PAP (n = 20) underwent bronchoalveolar lavage and measurements were made of total protein, iron, tranferrin, transferrin receptor, lactoferrin, and ferritin. Histochemical staining for iron and ferritin was done in the cell pellets from control subjects and PAP patients, and in lung specimens of patients without cardiopulmonary disease and with PAP. Lavage concentrations of urate, glutathione, and ascorbate were also measured as indices of oxidative stress.</p> <p>Results</p> <p>Lavage concentrations of iron, transferrin, transferrin receptor, lactoferrin, and ferritin were significantly elevated in PAP patients relative to healthy volunteers. The cells of PAP patients had accumulated significant iron and ferritin, as well as considerable amounts of extracellular ferritin. Immunohistochemistry for ferritin in lung tissue revealed comparable amounts of this metal-storage protein in the lower respiratory tract of PAP patients both intracellularly and extracellularly. Lavage concentrations of ascorbate, glutathione, and urate were significantly lower in the lavage fluid of the PAP patients.</p> <p>Conclusion</p> <p>Iron homeostasis is altered in the lungs of patients with idiopathic PAP, as large amounts of catalytically-active iron and low molecular weight anti-oxidant depletion are present. These findings suggest a metal-catalyzed oxidative stress in the maintenance of this disease.</p

Differentiation and Recruitment of Th9 Cells Stimulated by Pleural Mesothelial Cells in Human Mycobacterium tuberculosis Infection

Newly discovered IL-9–producing CD4+ helper T cells (Th9 cells) have been reported to contribute to tissue inflammation and immune responses, however, differentiation and immune regulation of Th9 cells in tuberculosis remain unknown. In the present study, our data showed that increased Th9 cells with the phenotype of effector memory cells were found to be in tuberculous pleural effusion as compared with blood. TGF-β was essential for Th9 cell differentiation from naïve CD4+ T cells stimulated with PMA and ionomycin in vitro for 5 h, and addition of IL-1β, IL-4 or IL-6 further augmented Th9 cell differentiation. Tuberculous pleural effusion and supernatants of cultured pleural mesothelial cells were chemotactic for Th9 cells, and this activity was partly blocked by anti-CCL20 antibody. IL-9 promoted the pleural mesothelial cell repairing and inhibited IFN-γ-induced pleural mesothelial cell apoptosis. Moreover, pleural mesothelial cells promoted Th9 cell differentiation by presenting antigen. Collectively, these data provide new information concerning Th9 cells, in particular the collaborative immune regulation between Th9 cells and pleural mesothelial cells in human M. tuberculosis infection. In particular, pleural mesothelial cells were able to function as antigen-presenting cells to stimulate Th9 cell differentiation

A nationwide analysis of incidence and outcome of breast cancer in the country of Surinam, during 1994-2003

In this study, we describe the incidence, treatment, and outcome of breast cancer (BC) during the period 1994-2003 in the South-American country of Surinam and compare these with those of BC in the Netherlands. Pathology reports and hospital charts from all BC cases diagnosed between 1994 and 2004 were retrieved from Surinam's single pathology laboratory and its five hospitals. Data on demographics, tumor characteristics, treatment, and follow-up were gathered. We compared our data to BC statistics of first generation immigrants from Surinam to the Netherlands. 421 patients were diagnosed with BC during the study period. The age-adjusted incidence rate was 26 per 100,000 compared to 65/100,000 in first generation Surinamese women in the Netherlands. The majority had a fairly advanced stage at presentation, with 60% of tumors larger than 2 cm, and 41.6% with lymph node involvement. Because of the absence of radiotherapy facilities, local treatment in most patients was radical mastectomy. Adjuvant hormonal therapy (51.6%) was administered more frequently than adjuvant chemotherapy (20.3%). A significant number of patients were lost to follow-up, resulting in a median follow-up duration of only 23 months. The 5-year overall survival was 79%. BC incidence in Surinam is low compared to that in the western world, but the advanced stage at diagnosis, the low utilization of systemic adjuvant therapy, and the inadequate follow-up may lead to poor outcomes. A number of steps are underway to improve the level of cancer care in Surina

Dietary Blue Pigments Derived from Genipin, Attenuate Inflammation by Inhibiting LPS-Induced iNOS and COX-2 Expression via the NF-κB Inactivation

The edible blue pigments produced by gardenia fruits have been used as value-added colorants for foods in East Asia for 20 years. However, the biological activity of the blue pigments derived from genipin has not been reported.The anti-inflammatory effect of blue pigments was studied in lipopolysaccharide (LPS) stimulated RAW 264.7 macrophage in vitro. The secretions of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) were inhibited in concentration-dependent manner by blue pigments. Real-time reverse-transcription polymerase chain reaction (Real-time RT-PCR) analyses demonstrated that the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin (IL)-6, and tumor necrosis factor alpha (TNF-α) was inhibited, moreover, ELISA results showed that the productions of IL-6 and TNF-α were inhibited. Cell-based ELISA revealed the COX-2 protein expression was inhibited. The proteome profiler array showed that 12 cytokines and chemokines involved in the inflammatory process were down-regulated by blue pigments. Blue pigments inhibited the nuclear transcription factor kappa-B (NF-κB) activation induced by LPS, and this was associated with decreasing the DNA-binding activity of p65 and p50. Furthermore, blue pigments suppressed the degradation of inhibitor of κB (IκB) α, Inhibitor of NF-κB Kinase (IKK) α, IKK-β, and phosphorylation of IκB-α. The anti-inflammatory effect of blue pigments in vivo was studied in carrageenan-induced paw edema and LPS-injecting ICR mice. Finally, blue pigments significantly inhibited paw swelling and reduced plasma TNF-α and IL-6 production in vivo.These results suggest that the anti-inflammatory properties of blue pigments might be the results from the inhibition of iNOS, COX-2, IL-6, IL-1β, and TNF-α expression through the down-regulation of NF-κB activation, which will provide strong scientific evidence for the edible blue pigments to be developed as a new health-enhancing nutritional food for the prevention and treatment of inflammatory diseases

Polymorphisms of −174G>C and −572G>C in the Interleukin 6 (IL-6) Gene and Coronary Heart Disease Risk: A Meta-Analysis of 27 Research Studies

OBJECTIVE: Elevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The -174 G>C and -572 G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the -174 G>C and -572 G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD. METHODS AND RESULTS: PubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the -174 C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the -174 G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the -572 C allele was associated with a decreased risk of CHD when compared with the -572 G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis. CONCLUSIONS: The -174 G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The -572 G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed