Raised expression of APRIL in Chinese patients with immune thrombocytopenia and its clinical implications

Background: Immune thrombocytopenia (ITP) is an immune-mediated disorder in which destruction of platelets is accelerated by anti-platelet autoimmune antibodies. B-cell-activating factor (BAFF) and a proliferation-inducing ligand (APRIL), essential factors for B cell survival are elevated in systemic autoimmune diseases and correlated with clinical findings. High expression of BAFF has been shown in patients with ITP, but the status of APRIL in ITP is still unknown.

Objective: To determine the expression of APRIL and it receptors, B-cell maturation antigen (BCMA) and trans-membrane activator and calcium modulator and cyclophilin ligand interactor (TACI), in patients with ITP, and evaluate the correlation between plasma APRIL levels and platelet accounts or other clinical parameters.

Methods: Plasma samples from 57 patients with ITP, and 30 normal healthy subjects were assayed for APRIL plasma concentration by enzyme linked immunosorbent assay. Real-time quantitative polymerase chain reaction was performed to determine the mRNA expression of APRIL and its receptors (BCMA and TACI) in peripheral blood mononuclear cells (PBMNCs) in 25 normal controls and 34 untreated ITP patients with active disease.

Results: The APRIL levels in the plasma samples from patients with ITP were significantly higher than those from healthy controls (p = 0.000). PBMNCs may be a source of the excess APRIL. Treated patients with normal platelet count have relatively normal plasma APRIL (p = 0.599). Plasma APRIL levels in active patients were significantly correlated with platelet counts (r = ? 0.387 and p = 0.024).

Conclusion: APRIL is over expressed in untreated active ITP patients and might be a pathogenic factor of this disorder.     

Deleting the BAFF receptor TACI protects against systemic lupus erythematosus without extensive reduction of B cell numbers

B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab (anti-human CD20) in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic mice, SLE development is T cell-independent but relies on innate activation of B cells via TLRs, and TLR expression is modulated by the BAFF receptor TACI. Here, we show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signaling through TACI rather than loss of B cells may underpin the effect of belimumab in the clinic. Therefore, B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.     

Naturally occurring bactericidal antibodies specific for Haemophilus influenzae Lipooligosaccharide are present in healthy adult individuals

Nontypeable Haemophilus influenzae (NTHi), a typical mucosal pathogen largely responsible for respiratory infections and pediatric otitis media, has been increasingly recognized as a significant cause of invasive disease, especially in immunocompromised individuals. Lipooligosaccharide (LOS) is a conserved molecule with an important role in H. influenzae virulence and immune evasion, and it may be considered as a vaccine candidate. However, abilities of H. influenzae LOS to induce protective immune response are poorly understood. The goal of this study was to determine whether antibodies against LOS isolated from H. influenzae strains Eagan, Rd and NTHi 375 are present in the sera of normal individuals. Antigen specific IgG and IgM were studied in sera of 71 and 30 healthy adults, respectively. IgG specific for LOS of all three strains was ubiquitously present in our sample population while IgM specific for Eagan, Rd and NTHi 375 LOS compounds was detected in 37%, 63%, and 40% of samples, respectively. All tested serum samples exhibited bactericidal activity against all three H. influenzae strains; the removal of anti-LOS antibodies from the sera resulted in significant increases in bacterial survival of the corresponding strain. NTHi 375 exhibited the highest serum resistance, whereas the Rd strain was the least resistant. Serum bactericidal activity of anti-LOS antibody was mediated via the classical complement pathway. These findings suggest that in healthy adults, naturally acquired complement-activating anti-LOS antibodies significantly contribute to the overall serum bactericidal activity against both encapsulated and non-encapsulated strains of H. influenzae.     

B cell elimination in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder with a worldwide distribution, potentially life-threatening with considerable morbidity. The elimination of pathogenic B cells has emerged as a rational therapeutic option. Many open label studies have reported encouraging results in which clinical and serological remission have invariably been described, often enabling the reduction of steroid and immunosuppressive treatment. However, the results from randomized controlled studies have been disappointing and several questions remain to be answered. In this review we will focus on results of B cell direct depletion in the treatment of patients with systemic lupus erythematosus.     

人TACI-linker-BR3双受体融合基因真核表达载体构建及其在COS-7细胞中的表达

目的:构建人双受体融合基因真核表达载体--pcDNA3.1( )-TACI-linker-BR3-IgGFc,观察其在COS-7细胞中的表达.方法:应用基因工程技术构建重组载体,脂质体转染COS-7细胞,通过Western印迹、ELISA以及免疫组化方法,检测目的蛋白的表达及其与BAFF、APRIL蛋白相互作用情况.结果:融合基因在瞬时转染的真核细胞中获得表达,并分泌至上清,转染效率能达到48%,融合蛋白能与BAFF、APRIL蛋白有效结合而且融合蛋白中分子标签IgGFc未影响双受体融合蛋白的结构及其生物学活性.结论:人TACI-linker-BR3双受体基因与IgGFc融合基因载体构建成功,表达的融合蛋白具有生物学活性,为进一步探讨SLE等自身免疫疾病的发病机制和生物学治疗方法奠定了基础.     

Emerging roles of basophils in allergic inflammation

Basophils have long been neglected in immunological studies because they were regarded as only minor relatives of mast cells. However, recent advances in analytical tools for basophils have clarified the non-redundant roles of basophils in allergic inflammation. Basophils play crucial roles in both IgE-dependent and -independent allergic inflammation, through their migration to the site of inflammation and secretion of various mediators, including cytokines, chemokines, and proteases. Basophils are known to produce large amounts of IL-4 in response to various stimuli. Basophil-derived IL-4 has recently been shown to play versatile roles in allergic inflammation by acting on various cell types, including macrophages, innate lymphoid cells, fibroblasts, and endothelial cells. Basophil-derived serine proteases are also crucial for the aggravation of allergic inflammation. Moreover, recent reports suggest the roles of basophils in modulating adaptive immune responses, particularly in the induction of Th2 differentiation and enhancement of humoral memory responses. In this review, we will discuss recent advances in understanding the roles of basophils in allergic inflammation.     

Regulation of proliferation, survival and apoptosis by members of the TNF superfamily

Tumor necrosis factor (TNF) was first identified in 1984 as a cytokine with anti-tumor effects in vitro and in vivo. Extensive research since then has shown that there are at least 18 distinct members of the TNF super family and they exhibit 15-25% amino acid sequence homology with each other. These family members bind to distinct receptors, which are homologous in their extracellular domain. These cytokines have been implicated in a wide variety of diseases including tumorigenesis, septic shock, viral replication, bone resorption, rheumatoid arthritis, diabetes, and other inflammatory diseases. TNF blockers have been approved for human use in treating some of these conditions in the United States and other countries. Various members of the TNF super family mediate either proliferation, survival, or apoptosis of cells. Although distinct receptors, all members share a common cell signaling pathway that mediates the activation of nuclear factor-kappaB (NF-kappaB) and mitogen-activated protein kinases (e.g. c-jun N-terminal kinase). Regulation of cell growth and activation of NF-kappaB and of c-jun N-terminal kinase by the TNF super family is mediated through sequential activation/association of a set of cell signaling proteins named TNF receptor-associated factors, Fas-associated death domain and FADD-like ICE, caspases, receptor-interacting protein, NF-kappaB-inducing kinases, and IkappaBalpha kinases. Both apoptotic and antiapoptotic signals are activated simultaneously by the same cytokine in the same cell. Together these cytokines regulate cell growth/survival/apoptosis in a complex dance of changing partners and overlapping steps.     

TACI‐Ig prevents the development of airway hyperresponsiveness in a murine model of asthma

Background Increased levels of serum IgE are associated with greater asthma prevalence and disease severity. IgE depletion using an anti‐IgE monoclonal antibody has met with success in the treatment of moderate‐to‐severe and severe persistent allergic asthma. Objective To test whether B cell‐targeted therapy is a more effective treatment for airway hyperresponsiveness (AHR) in a murine model compared with IgE‐depletion. Methods We delivered soluble mTACI‐Ig, a receptor for the B cell survival factors BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation‐Inducing Ligand), or anti‐IgE to allergen‐sensitized mice before airway challenge with allergen. Results mTACI‐Ig treatment reduced circulating mature B cell levels in the blood, while anti‐IgE treatment had no effect on B cell counts. Both mTACI‐Ig and anti‐IgE decreased the levels of total and allergen‐specific IgE in the serum. Histopathologic analysis of lungs showed a reduction in disease severity scores for both treatment groups, but results were more pronounced in mTACI‐Ig‐treated mice. Neutrophil and eosinophil numbers in the bronchoalveolar lavage (BAL) were significantly reduced following mTACI‐Ig treatment, but not after anti‐IgE delivery. BLyS and APRIL blockade also resulted in a significant decrease in IL‐4 and eotaxin mRNA and IL‐4 and KC protein levels in total lung homogenates and BAL fluid, respectively. Finally, mTACI‐Ig treatment was more effective than anti‐IgE treatment in reducing AHR to inhaled antigen. Conclusions Our data demonstrate that delivery of mTACI‐Ig is a more effective treatment than anti‐IgE mAb in a murine model of AHR.