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Simple Summary: The B cell receptor (BCR) is a membrane-bound protein complex that is required for the normal development of B cells. BCR signalling is also involved in the pathogenesis of B cell cancers. While there is substantial literature on genomic analyses of the BCR, there are limited proteomic studies of receptor structure and its interactions with neighbouring proteins. This is partly due to the location of the BCR in the surface-membrane lipid environment that has limited the ability to enrich the complex for proteomic analysis. Here, we report an enrichment technique that can be used for mass spectrometry analyses of the BCR from live B cells. B cells are central to the adaptive immune response and provide long-lasting immunity after infection. B cell activation is mediated by the surface membrane-bound B cell receptor (BCR) following recognition of a specific antigen. The BCR has been challenging to analyse using mass spectrometry (MS) due to the difficulty of isolating and enriching this membrane-bound protein complex. There are approximately 120,000 BCRs on the B cell surface; however, depending on the B cell activation state, there may be hundreds-of-millions to billions of proteins in a B cell. Consequently, advanced proteomic techniques such as MS workflows that use purified proteins to yield structural and protein-interaction information have not been published for the BCR complex. This paper describes a method for enriching the BCR complex that is MS-compatible. The method involves a Protein G pull down on agarose beads using an intermediary antibody to each of the BCR complex subcomponents (CD79a, CD79b, and membrane immunoglobulin). The enrichment process is shown to pull down the entire BCR complex and has the advantage of being readily compatible with further proteomic study including MS analysis. Using intermediary antibodies has the potential to enrich all isotypes of the BCR, unlike previous methods described in the literature that use protein G-coated beads to directly pull down the membrane IgG (mIgG) but cannot be used for other mIg isotypes. [ABSTRACT FROM AUTHOR]

Head and neck squamous cell carcinoma (HNSCC) is a common malignant tumour. Despite advancements in surgery, radiotherapy and chemotherapy, which have improved the prognosis of most patients, a subset of patients with poor prognoses still exist due to loss of surgical opportunities, postoperative recurrence, and metastasis, among other reasons. The tumour microenvironment (TME) is a complex organization composed of tumour, stromal, and endothelial cells. Communication and interaction between tumours and immune cells within the TME are increasingly being recognized as pivotal in inhibiting or promoting tumour development. Previous studies on T cells in the TME of HNSCC have yielded novel therapeutic possibilities. However, the function of B cells, another adaptive immune cell type, in the TME of HNSCC patients has yet to be determined. Recent studies have revealed various distinct subtypes of B cells and tertiary lymphoid structures (TLSs) in the TME of HNSCC patients, which are believed to impact the efficacy of immune checkpoint inhibitors (ICIs). Therefore, this paper focuses on B cells in the TME to explore potential directions for future immunotherapy for HNSCC. [ABSTRACT FROM AUTHOR]

Immune Thrombocytopenic Purpura ( ITP) is a common autoimmune bleeding disorder characterized by a reduction in peripheral blood platelet counts. In this disease, autoantibodies (Auto-Abs) are produced against platelet GPIIb/ GPIIIa by B cells, which require interaction with T cells. In this review, the importance of B and T lymphocytes in ITP prognosis has been studied. Relevant literature was identified by a PubMed search (1990-2016) of English-language papers using the terms B and T lymphocyte, platelet, CD markers and immune thrombocytopenic purpura. T and B lymphocytes are the main immune cells in the body. Defective function causes disrupted balance of different subgroups of lymphocytes, and abnormal expression of surface markers of these cells results in self-tolerance dysfunction, as well as induction of Auto-Abs against platelet glycoproteins ( PG). Given the role of B and T cells in production of autoantibodies against PG, it can be stated that the detection of changes in CD markers' expression in these cells can be a good approach for assessing prognosis in ITP patients. [ABSTRACT FROM AUTHOR]

Monocytic myeloid-derived suppressor cells (M-MDSCs) were increased during LP-BM5 retroviral infection, and were capable of suppressing not only T-cell, but also B-cell responses. In addition to previously demonstrating iNOS- and VISTA-dependent M-MDSC mechanisms, in this paper, we detail how M-MDSCs utilized soluble mediators, including the reactive oxygen and nitrogen species superoxide, peroxynitrite, and nitric oxide, and TGF-β, to suppress B cells in a predominantly contact-independent manner. Suppression was independent of cysteine-depletion and hydrogen peroxide production. When two major mechanisms of suppression (iNOS and VISTA) were eliminated in double knockout mice, M-MDSCs from LP-BM5-infected mice were able to compensate using other, soluble mechanisms in order to maintain suppression of B cells. The IL-10 producing regulatory B-cell compartment was among the targets of M-MDSC-mediated suppression. [ABSTRACT FROM AUTHOR]

It has been nearly 15 years since the papers describing the fully systematic epitope mapping approach both for the so-called “continuous” epitopes [Proc. Natl. Acad. Sci. U. S. A. 81 (1984) 3998] and “discontinuous” epitopes [Mol. Immunol. 23 (1986) 709] were published. These seminal papers laid the conceptual foundation for all subsequent developments where a combinatorial approach is applied. Dr. Mario Geysen, the 2000 Kilby Laureate, can certainly lay claim to be the “father of combinatorial chemistry” (http://www.kilby.org/laureates.htm). In this review, I will focus on the aspects of the Multipin technology as they apply to antibody and receptor epitope mapping. Much of what will be presented applies equally well to other applications where peptide libraries (PepSets) and combinatorial approaches are used [Rodda, S.J., 1996. T-cell epitope mapping with synthetic peptides and peripheral blood mononuclear cells. In: Morris, G.E. (Eds.), Methods in Molecular Biology, Vol. 66: Epitope Mapping Protocols. Humana Press, Totowa, NJ, Chap. 30, p. 363; Int. J. Pept. Protein Res. 42 (1993) 384; J. Biol. Chem. 271 (1996) 5603]. Factors and techniques that influence the use of the Multipin method for successful epitope mapping will be presented. [Copyright &y& Elsevier]

T follicular helper (Tfh) cells with the phenotype of mainly expressing surface molecules C-X-C motif chemokine receptor type 5 (CXCR5), inducible co-stimulator (ICOS), secreting cytokine interleukin-21 (IL-21) and requiring the transcription factor B cell lymphoma 6 (BCL-6) have been recently defined as a new subset of CD4+ T cells. They exist in germinal centers (GCs) of lymphoid organs and in peripheral blood. With the ability to promote B cell development, GC formation and antibody production, Tfh cells play critical roles in the pathogenesis of many autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), primary Sjögren's syndrome (pSS), etc. The aberrant proliferation and function of Tfh cells will cause the pathological process like autoantibody production and tissue injury. In this paper, we review the recent advances in Tfh cell biology and their roles in autoimmune diseases, with a mention of their use as therapeutic targets, which will shed more light on the pathogenesis and treatment of certain autoimmune diseases. • Tfh cells are defined as a CD4+ T cell subset that promotes B cell maturation and differentiation, antibody production and GC formation. • The pathogenesis of several autoimmune diseases is associated with Tfh cells. • Targeting Tfh cells represents new insights in the treatment of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Emerging evidence reveals the controversial role of B cells in antitumor immunity, but the underlying mechanisms have to be explored. Three latest articles published in the issue 521 of Nature in 2015 reconfirmed the puzzling topic and put forward some explanations of how B cells regulate antitumor T-cell responses both positively and negatively. This paper attempts to demonstrate that different B-cell subpopulations have distinct immunological properties and that they are involved in either antitumor responses or immunosuppression. Recent studies supporting the positive and negative roles of B cells in tumor development were summarized comprehensively. Several specific B-cell subpopulations, such as IgG(+), IgA(+), IL-10(+), and regulatory B cells, were described in detail. The mechanisms underlying the controversial B-cell effects were mainly attributed to different B-cell subpopulations, different B-cell-derived cytokines, direct B cell-T cell interaction, different cancer categories, and different malignant stages, and the immunological interaction between B cells and T cells is mediated by dendritic cells. Promising B-cell-based antitumor strategies were proposed and novel B-cell regulators were summarized to present interesting therapeutic targets. Future investigations are needed to make sure that B-cell-based pharmacological strategies benefit cancer immunotherapy substantially. [ABSTRACT FROM AUTHOR]

It is becoming evident that B-cell responses to particular epitopes or in particular contexts can be highly convergent at the molecular level. That is, depending on the epitope targeted, persons of diverse genetic backgrounds and immuno-logical histories can use highly similar, stereotyped B-cell receptors (BCRs) for a particular response. In some cases, multiple people with immunity to a particular epitope or with a type of B-cell neoplasia will elicit antibodies encoded by essentially identical immunoglobulin gene rearrangements. In other cases, particular VH genes encode antibodies important for immunity against pathogens such as influenza and HIV. It appears that the conserved antibody structures driving these stereotyped responses are highly limited and selected. There are interesting and important convergences in the types of stereotyped BCRs induced in conditions of immunity and B-cell-related pathology such as cancer and autoimmunity. By characterizing and understanding stereotyped B-cell responses, novel approaches to B-cell immunity and in understanding the underlying causes of B-cell pathology may be discovered. In this paper, we will review stereotyped BCR responses in various contexts of B-cell immunity and pathology. [ABSTRACT FROM AUTHOR]

This paper shows a computational approach for quantitative prediction of B cell epitopes. The function was defined, which reflects the average value of B epitopes, according to eight predictors of different B epitopes, as well as structural and energetic considerations of the origin protein. The proposed methodology could be useful to develop both dengue and chikungunya vaccines. [ABSTRACT FROM AUTHOR]

Please cite this paper as: Kersun et al. (2013) A prospective study of chemotherapy immunologic effects and predictors of humoral influenza vaccine responses in a pediatric oncology cohort. Influenza and Other Respiratory Viruses 7(6), 1158-1167. Background: Pediatric oncology patients represent a cohort of individuals uniquely at risk of complications from influenza, yet less likely to respond to the vaccine. It is not yet clear how to best protect this vulnerable population. Methods: We performed a prospective analysis of 177 pediatric oncology patients to define the predictors of influenza vaccine responses. Each variable was examined over three time points and a repeated measure analysis was performed. Results: Patients with ALL vaccinated during induction phase had superior influenza vaccine responses than those subjects vaccinated during post-induction or maintenance phases ( P = 0·0237). Higher aggregate HAI titer responses were associated with a higher baseline B-cell count ( P = 0·0240), and higher CD4 and CD8 influenza-specific T-cell responses, suggesting prior antigen exposure is a significant contributor. The solid tumor cohort had equivalent responses during all time frames of chemotherapy. Discussion: The optimal protection from influenza of pediatric patients on chemotherapy should include vaccination, but it is clear that not all patients produce high titers of antibodies after vaccination. This study identified biomarkers that could be used to individualize vaccine approaches. Immunologic predictors might have a role in targeting resources, as B-cell counts predicted of vaccine responses among the patients with ALL. [ABSTRACT FROM AUTHOR]

Abstract: Hematopoietic progenitors have been shown to retain plasticity and switch lineages by appropriate stimuli. However, mature blood cells hardly showed such differentiation plasticity. In this paper, we tried to reprogram mature B cells into erythroid lineage by expressing various hematopoietic transcription factors. Among various factors, GATA-1, SCL together with CCAAT/enhancer binding protein (C/EBP) α turned out to be a minimal set of factors that efficiently reprogrammed terminally differentiated mature B cells into erythroid lineage, as evidenced by colony forming assays and erythroid-specific gene expressions. This study sets an avenue to generate autologous erythrocytes from peripheral B cells. [Copyright &y& Elsevier]

The article "The bursa of Fabricius and antibody production" by Bruce Glick, Timothy S. Chang, and R. George Jaap first demonstrated the role of the bursa in immune development. Birds, including chickens, possess a peculiar organ, the bursa of Fabricius. The organ was recognized for more than 300 yr before its function was described in 1956. Discovery of the bursa as an essential component of the immune response began by accident. Removal of the bursa, bursectomy, during the rapid growth period diminished the antibody response to Salmonella. A paper describing this exceptional finding was initially rejected by Science and ultimately published in Poultry Science. This revelation triggered sequential events leading to the understanding of the dichotomy of the immune response. Additional work in multiple laboratories over many years revealed fundamental immune mechanisms attributable to the bursa. Understanding those mechanisms advanced agricultural and biomedical science. [ABSTRACT FROM AUTHOR]

By substituting the heavy chain constant region of IgM and IgD with that of IgG, IgA or IgE, immunoglobulin class switching endows antibodies with novel effector functions that enhance the ability of the immune system to effectively clear invading pathogens. Plasmacytoid dendritic cells critically link innate immunity with adaptive immunity by producing massive amounts of type 1 IFN in response to viruses. We have recently found that type 1 IFN triggers class switching by inducing myeloid dendritic cells to upregulate the expression of BAFF and APRIL, two powerful B cell-activating molecules. In this paper, we propose that IFN-producing plasmacytoid dendritic cells modulate class switching by activating B cells through both T cell-dependent and T cell-independent pathways. A better understanding of these pathways may facilitate the development of novel antiviral vaccine strategies and aid in identifying new therapies for antibody-mediated autoimmune disorders, such as lupus. [ABSTRACT FROM AUTHOR]

Antibodies against self-molecules play a significant role in the development and progression of Systemic Lupus Erythematosus, as well as a number of other autoimmune disorders. Immunosuppressive drugs have been used to control this process. However, they are normally not specific to the offending cell, and can actually suppress beneficial immune responses to pathogens. In this paper a genetically engineered targeting molecule is described, which has the capacity to target antigen-specific B cells for inhibition or elimination. The targeting molecule is a fusion of streptavidin subunit to the constant region of human IgG3 (IgG3-Av). It is demonstrated by ELISA and flow cytometry that IgG3-Av binds biotinylated antigen as well as human Fc gamma receptors present on myeloid cells. It is also shown by confocal microscopy and flow cytometry, that IgG3-Av can mediate Fc receptor-dependent phagocytosis of latex microspheres adsorbed with biotinylated antigen. Furthermore, the IgG3-Av construct can modulate Ca^{++} flux, characteristic of B cell inhibition as well as ADCC of B cells in an antigen-specific manner. In summary, these studies describe an approach, which has the potential to be used as a treatment to inhibit or remove antigen-specific (auto-reactive) B cells. [ABSTRACT FROM AUTHOR]

Chimeric Antigen Receptor (CAR) T-cell therapy has demonstrated high rates of response in recurrent B-cell Acute Lymphoblastic Leukemia in children and young adults. Despite this success, a fraction of patients' experience relapse after treatment. Relapse is often preceded by recovery of healthy B cells, which suggests loss or dysfunction of CAR T-cells in bone marrow. This site is harder to access, and thus is not monitored as frequently as peripheral blood. Understanding the interplay between B cells, leukemic cells, and CAR T-cells in bone marrow is paramount in ascertaining the causes of lack of response. In this paper, we put forward a mathematical model representing the interaction between constantly renewing B cells, CAR T-cells, and leukemic cells in the bone marrow. Our model accounts for the maturation dynamics of B cells and incorporates effector and memory CAR T-cells. The model provides a plausible description of the dynamics of the various cellular compartments in bone marrow after CAR T infusion. After exploration of the parameter space, we found that the dynamics of CAR T product and disease were independent of the dose injected, initial B-cell load, and leukemia burden. We also show theoretically the importance of CAR T product attributes in determining therapy outcome, and have studied a variety of possible response scenarios, including second dosage schemes. We conclude by setting out ideas for the refinement of the model. [ABSTRACT FROM AUTHOR]

Adaptive immunity in vertebrates is a complex self-organizing network of molecular interactions. While deep sequencing of the immune-receptor repertoire may reveal clonal relationships, functional interpretation of such data is hampered by the inherent limitations of converting sequence to structure to function. In this paper, a novel model of antibody interaction space and network, termed radial adjustment of system resolution, RAdial ADjustment of System Resolution (RADARS), is proposed. The model is based on the radial growth of interaction affinity of antibodies towards an infinity of directions in structure space, each direction corresponding to particular shapes of antigen epitopes. Levels of interaction affinity appear as free energy shells of the system, where hierarchical B-cell development and differentiation takes place. Equilibrium in this immunological thermodynamic system can be described by a power law distribution of antibody-free energies with an ideal network degree exponent of phi square, representing a scale-free fractal network of antibody interactions. Plasma cells are network hubs, memory B cells are nodes with intermediate degrees, and B1 cells function as nodes with minimal degree. Overall, the RADARS model implies that a finite number of antibody structures can interact with an infinite number of antigens by immunologically controlled adjustment of interaction energy distribution. Understanding quantitative network properties of the system should help the organization of sequence-derived predicted structural data. [ABSTRACT FROM AUTHOR]