Explore the vast range of titles available.

Immunoglobulin E (IgE) antibodies are well known for their role in mediating allergic reactions, and their powerful effector functions activated through binding to Fc receptors FcεRI and FcεRII/CD23. Structural studies of IgE-Fc alone, and when bound to these receptors, surprisingly revealed not only an acutely bent Fc conformation, but also subtle allosteric communication between the two distant receptor-binding sites. The ability of IgE-Fc to undergo more extreme conformational changes emerged from structures of complexes with anti-IgE antibodies, including omalizumab, in clinical use for allergic disease; flexibility is clearly critical for IgE function, but may also be exploited by allosteric interference to inhibit IgE activity for therapeutic benefit. In contrast, the power of IgE may be harnessed to target cancer. Efforts to improve the effector functions of therapeutic antibodies for cancer have almost exclusively focussed on IgG1 and IgG4 subclasses, but IgE offers an extremely high affinity for FcεRI receptors on immune effector cells known to infiltrate solid tumours. Furthermore, while tumour-resident inhibitory Fc receptors can modulate the effector functions of IgG antibodies, no inhibitory IgE Fc receptors are known to exist. The development of tumour antigen-specific IgE antibodies may therefore provide an improved immune functional profile and enhanced anti-cancer efficacy. We describe proof-of-concept studies of IgE immunotherapies against solid tumours, including a range of in vitro and in vivo evaluations of efficacy and mechanisms of action, as well as ex vivo and in vivo safety studies. The first anti-cancer IgE antibody, MOv18, the clinical translation of which we discuss herein, has now reached clinical testing, offering great potential to direct this novel therapeutic modality against many other tumour-specific antigens. This review highlights how our understanding of IgE structure and function underpins these exciting clinical developments.

Chronic lymphocytic leukaemia (CLL), the most frequent type of leukaemia in adults, is a lymphoproliferative disorder that is characterized by the expansion of monoclonal, mature CD5+CD23+ B cells in the peripheral blood, secondary lymphoid tissues and bone marrow. CLL is an incurable disease with a heterogeneous clinical course, for which the treatment decision still relies on conventional parameters (such as clinical stage and lymphocyte doubling time). During the past 5 years, relevant advances have been made in understanding CLL biology. Indeed, substantial progress has been made in the identification of the putative cell of origin of CLL, and comprehensive studies have dissected the genomic, epigenomic and transcriptomic landscape of CLL. Advances in clinical management include improvements in our understanding of the prognostic value of different genetic lesions, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL, and the advent of new therapies targeting crucial biological pathways. In this Review, we discuss new insights into the genetic lesions involved in the pathogenesis of CLL and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease.

A diagnosis of typical chronic lymphocytic leukemia (CLL) requires the presence of ≥5000 clonal B-lymphocytes/μL, the coexistence of CD19, CD20, CD5, and CD23, the restriction of light chain immunoglobulin, and the lack of expression of antigens CD22 and CD79b. Atypical CLL (aCLL) can be distinguished from typical CLL morphologically and immunophenotypically. Morphologically atypical CLL cells have been defined mainly as large, atypical forms, prolymphocytes, or cleaved cells. However, current aCLL diagnostics rely more on immunophenotypic characteristics rather than atypical morphology. Immunophenotypically, atypical CLL differs from classic CLL in the lack of expression of one or fewer surface antigens, most commonly CD5 and CD23, and the patient does not meet the criteria for a diagnosis of any other B-cell lymphoid malignancy. Morphologically atypical CLL has more aggressive clinical behavior and worse prognosis than classic CLL. Patients with aCLL are more likely to display markers associated with poor prognosis, including trisomy 12, unmutated IGVH, and CD38 expression, compared with classic CLL. However, no standard or commonly accepted criteria exist for differentiating aCLL from classic CLL and the clinical significance of aCLL is still under debate. This review summarizes the current state of knowledge on the morphological, immunophenotypic, and genetic abnormalities of aCLL.

Proteolysis is an irreversible physiological process that can result in the termination or activation of protein function. Many transmembrane proteins that are involved in the cellular communication between immune cells and structural cells — for example, Notch, CD23, CD44, and membrane-anchored cytokines and their receptors — are cleaved by the ADAM (a disintegrin and metalloproteinase) family of enzymes. Here, we review recent insights into the molecular activation, substrate specificity and function of ADAM proteins in the development and regulation of the immune system, with a particular focus on the roles of ADAM10 and ADAM17.

Background Evident adolescent idiopathic scoliosis (AIS) incurs high treatment costs, low quality of life, and many complications. Early screening of AIS is essential to avoid progressing to an evident stage. However, there is no valid serum biomarker for AIS for early screening. Methods Antibody-based array is a large-scale study of proteins, which is expected to reveal a serum protein signature as biomarker for AIS. There are two segments of the research, including biomarkers screening and validation. In the biomarkers screening group, a total of 16 volunteers participated in this study, and we carried out differentially expressed proteins screening via protein array assay between No-AIS group and the AIS group, through which GeneSet enrichment analysis was performed. In the validation group with a total of 62 volunteers, the differentially expressed proteins from screening group were verified by Enzyme-Linked immunosorbent assay (ELISA), and then multiple regression analysis. Results In our study, there were twenty-nine differentially expressed proteins in AIS, through Protein array assay and GeneSet enrichment analysis in the biomarkers screening group. Then the expression of FAP, CD23 and B2M decreased as the degree of AIS increased via ELISA in validation group (FAP, p  < 0.0001; CD23, p  = 0.0002; B2M, p  < 0.0001). Further, the results of multiple regression analysis showed that FAP, CD23 are linked to Cobb angle, whereas B2M were excluded because of multicollinearity. Conclusions Altogether, we found that serum protein FAP and CD23 are intimately related to AIS, suggesting FAP and CD23 are expected to serve as the serum biomarkers, which significantly facilitate frequent longitudinal monitoring as to keep track of disease progression and tailor treatment accordingly.

Objective Ligelizumab is a humanised IgG1 anti‐IgE antibody that binds IgE with higher affinity than omalizumab. Ligelizumab had greater efficacy than omalizumab on inhaled and skin allergen provocation responses in mild allergic asthma. This multi‐centre, randomised, double‐blind study was designed to test ligelizumab in severe asthma patients not adequately controlled with high‐dose inhaled corticoids plus long‐acting β2‐agonist. Methods Patients received 16 weeks ligelizumab (240 mg q2w), omalizumab or placebo subcutaneously, and ACQ‐7 was measured as primary outcome at Week 16. In addition, the study generated dose‐ranging data of ligelizumab and safety data. Results A total of 471 patients, age 47.4 ± 13.36 years, were included in the study. Treatment with ligelizumab did not significantly improve asthma control (ACQ‐7) and exacerbation rates compared to omalizumab and placebo. Therefore, primary and secondary objectives of the study were not met. The compound was well tolerated, and the safety profile showed no new safety findings. Pharmacokinetic data demonstrated faster clearance and lower serum concentrations of ligelizumab than historical omalizumab data, and exploratory in vitro data showed differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Conclusion Ligelizumab failed to demonstrate superiority over placebo or omalizumab. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high‐affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds. Therefore, the data suggest that different anti‐IgE antibodies might be selectively efficacious for different IgE‐mediated diseases. In this multi‐centre, randomised, double‐blind study, 471 severe asthmatics were treated with the high‐affinity anti‐IgE antibody ligelizumab. Treatment did not significantly improve asthma control and exacerbations compared to omalizumab and placebo. Although ligelizumab is more potent than omalizumab at inhibiting IgE binding to the high‐affinity FcεRI, there is differential IgE blocking properties relative to FcεRI and FcεRII/CD23 between the two compounds, potentially blunting the effect in asthma.

Targeting of immunoglobulin E (IgE) represents an interesting approach for the treatment of allergic disorders. A high-affinity monoclonal anti-IgE antibody, ligelizumab, has recently been developed to overcome some of the limitations associated with the clinical use of the therapeutic anti-IgE antibody, omalizumab. Here, we determine the molecular binding profile and functional modes-of-action of ligelizumab. We solve the crystal structure of ligelizumab bound to IgE, and report epitope differences between ligelizumab and omalizumab that contribute to their qualitatively distinct IgE-receptor inhibition profiles. While ligelizumab shows superior inhibition of IgE binding to FcεRI, basophil activation, IgE production by B cells and passive systemic anaphylaxis in an in vivo mouse model, ligelizumab is less potent in inhibiting IgE:CD23 interactions than omalizumab. Our data thus provide a structural and mechanistic foundation for understanding the efficient suppression of FcεRI-dependent allergic reactions by ligelizumab in vitro as well as in vivo. Immunoglobulin E (IgE) plays a central role in allergic responses, yet therapeutic targeting of IgE with antibodies such as omalizumab is met with various limitations. Here the authors characterize the molecular properties and crystal structure of a new anti-IgE antibody, ligelizumab, for mechanistic insights related to its enhanced suppression activity.

The aim of this study was to assess the relationship between the expression of the CD23 molecule on B-cells and the levels of specific IgE against allergens and molecular components of storage mites (Gly d 2, Lep d 2), dog (Can f 1, Can f 2), cat (Fel d 1), shrimp (Pen m 2), molds (Asp f 6, Mala s 11, Alt a 6, Alt a 1, Mala s 6, Cla h), and German cockroach (Bla g 9) in atopic dermatitis (AD) patients (with and without dupilumab therapy). Here, 46 patients with AD were included (26 without dupilumab treatment, 20 with dupilumab treatment). Serum levels of specific IgE were measured using the component-resolved diagnostic microarray ALEX2 Allergy Xplorer, and the expression of the CD23 molecule on B-cells was evaluated using flow cytometry. For statistical analysis, a Spearman's rank correlation was used. The data indicated there was a higher correlation between CD23 expression on B-cells and specific IgE against molecular components of storage mites Bla g 9 (up to 27%), cat Fel d 1 (22.7%), and allergen extract Cla h ( ) up to 38.9% in AD patients treated with dupilumab. These results regarding the higher association suggested a significant role in the non-inflammatory clearance and uptake of these specific IgE antibodies.

evaluate the association between expression of CD23 molecule on B-lymphocytes and the level of specific IgE to molecular components of birch, Bermuda grass, hazel pollen, timothy, and rye grass in atopic dermatitis (AD) patients (with and without dupilumab therapy). A total of 46 patients suffering from AD were included: 26 without dupilumab treatment and 20 with dupilumab treatment. Serum levels of specific IgE were measured by the components resolved diagnostic assay ALEX2 Allergy Xplorer, the expression of CD23 molecule on B-lymphocytes was evaluated with flow cytometry. For the statistical analysis, the Spearman's rank correlation coefficient was used. In patients treated with dupilumab, the higher association was observed between the expression of CD23 on B-lymphocytes and specific IgE to molecular components Bet v 1, Cor a 1.0103, Cor a 1.0401, and Phl p 1. This study demonstrated that the relationship between CD23 expression on B-lymphocytes and specific IgE to pollen molecular components varies depending on whether the patient was treated with dupilumab and the type of molecular component involved.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease that affects the function of exocrine glands, such as the lacrimal and the salivary glands. Extraglandular lesions and malignant lymphoma also occur during the progressive stage of pSS. We have, herein, focused on the pulmonary lesions of pSS and have aimed clarifying their pathophysiological mechanism by comparing the glandular with the extraglandular lesions observed in a mouse model of pSS. The histopathological analysis of lung tissues obtained from NFS/ mice that have undergone neonatal thymectomy was performed. Moreover, and experiments were conducted along with immunological analyses in order to characterize the unique phenotypes of the pulmonary lesions identified in these pSS model mice. Inflammatory lesions with a bronchus-associated lymphoid tissue-like structure were identified in the lungs of pSS model mice. In addition, relative to salivary gland lesions, pulmonary lesions showed increased CD23 follicular B (FB) cells. and pulmonary B cells were more readily driven to CD23 FB cell phenotype than salivary gland B cells in pSS model mice. Furthermore, the CD23 FB cell differentiation was found to be enhanced in a CD4 T-cell-dependent manner under a Th2-type condition in the lungs of herein examined pSS model mice. A Th2-type response in the pSS lung may promote the progression of autoimmune lesions through an enhanced abnormal differentiation of B cells.