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The random recombination of immunoglobulin V(D)J gene segments produces unique IgM antibodies that serve as the antigen receptor for each developing B cell. Hence, the newly formed B cell repertoire is comprised of a variety of specificities that display a range of reactivity with self‐antigens. Newly generated IgM+ immature B cells that are non‐autoreactive or that bind self‐antigen with low avidity are licensed to leave the bone marrow with their intact antigen receptor and to travel via the blood to the peripheral lymphoid tissue for further selection and maturation. In contrast, clones with medium to high avidity for self‐antigen remain within the marrow and undergo central tolerance, a process that revises their antigen receptor or eliminates the autoreactive B cell altogether. Thus, central B cell tolerance is critical for reducing the autoreactive capacity and avidity for self‐antigen of our circulating B cell repertoire. Bone marrow cultures and mouse models have been instrumental for understanding the mechanisms that regulate the selection of bone marrow B cells. Here, we review recent studies that have shed new light on the contribution of the ERK, PI3K, and CXCR4 signaling pathways in the selection of mouse and human immature B cells that either bind or do not bind self‐antigen. [ABSTRACT FROM AUTHOR]

B cell development is a tightly regulated process dependent on sequential rearrangements of immunoglobulin loci that encode the antigen receptor. To elucidate the role of microRNAs (miRNAs) in the orchestration of B cell development, we ablated all miRNAs at the earliest stage of B cell development by conditionally targeting the enzymes critical for RNAi in early B cell precursors. Absence of any one of these enzymes led to a block at the pro- to pre-B cell transition due to increased apoptosis and a failure of pre-B cells to proliferate. Expression of a Bcl2 transgene allowed for partial rescue of B cell development, however, the majority of the rescued B cells had low surface immunoglobulin expression with evidence of ongoing light chain editing. Our analysis revealed that miRNAs are critical for the regulation of the PTEN-AKT-FOXO1 pathway that in turn controls Rag expression during B cell development.

Resolving the molecular mechanisms of central B cell tolerance might unveil strategies that prevent autoimmunity. Here, using a mouse model of central B cell tolerance in which Forkhead box protein O1 (Foxo1) is either deleted or over-expressed in B cells, we show that deleting Foxo1 blocks receptor editing, curtails clonal deletion, and decreases CXCR4 expression, allowing high-avidity autoreactive B cells to emigrate to the periphery whereby they mature but remain anergic and short lived. Conversely, expression of degradation-resistant Foxo1 promotes receptor editing in the absence of self-antigen but leads to allelic inclusion. Foxo1 over-expression also restores tolerance in autoreactive B cells harboring active PI3K, revealing opposing roles of Foxo1 and PI3K in B cell selection. Overall, we show that the transcription factor Foxo1 is a major gatekeeper of central B cell tolerance and that PI3K drives positive selection of immature B cells and establishes allelic exclusion by suppressing Foxo1. [Display omitted] • Deletion of Foxo1 prevents receptor editing in high-avidity autoreactive immature B cells • Degradation-resistant Foxo1-AAA elicits receptor editing in the absence of self-antigen • Foxo1-AAA reverses defects in central B cell tolerance that are mediated by active PI3Kα • PI3K-dependent regulation of Foxo1 is critical for proper selection of immature B cells McCaleb et al. show that the transcription factor Foxo1 is necessary for central B cell tolerance and that Foxo1 degradation is needed for allelic exclusion at the immunoglobulin loci and for survival and differentiation of nonautoreactive B cells. This explains how PI3K regulates bone marrow selection of B cells. [ABSTRACT FROM AUTHOR]

This paper presents a multi-objective immune memetic algorithm to the challenge of solving the Frequency Assignment Problem (FAP) in cellular networks seeking the minimization of the network's total interference, the maximum interference and the number of used frequencies. The originality of the proposed approach lies in integrating a FAP-specific local search into its evolutionary process instead of crossover and mutation, as well as a guided diversification strategy for better performances. Moreover, the algorithm is supplemented with a clonal selection, inherited from Artificial Immune Systems (AIS), which aims to improve the algorithm exploration and exploitation abilities. Computational experiments performed over COST259 instances show the efficiency of the newly proposed evolutionary multi-objective algorithm and corroborated by the comparisons we did with the most frequently referred algorithm in the related literature. Furthermore, the effect of the main parameters and the interaction between them is analyzed using statistical tools. [ABSTRACT FROM AUTHOR]

Discussion of the antibody repertoire usually emphasizes diversity, but a conspicuous feature of the light chain repertoire is its lack of diversity. The diversity of reported allelic variants of germline light chain genes is also limited, even in well-studied species. In this review, the implications of this lack of diversity are considered. We explore germline and rearranged light chain genes in a variety of species, with a particular focus on human and mouse genes. The importance of the number, organization and orientation of the genes for the control of repertoire development is discussed, and we consider how primary rearrangements and receptor editing together shape the expressed light chain repertoire. The resulting repertoire is dominated by just a handful of IGKV and IGLV genes. It has been hypothesized that an important function of the light chain is to guard against self-reactivity, and the role of secondary rearrangements in this process could explain the genomic organization of the light chain genes. It could also explain why the light chain repertoire is so limited. Heavy and light chain genes may have co-evolved to ensure that suitable light chain partners are usually available for each heavy chain that forms early in B cell development. We suggest that the co-evolved loci of the house mouse often became separated during the inbreeding of laboratory mice, resulting in new pairings of loci that are derived from different sub-species of the house mouse. A resulting vulnerability to self-reactivity could explain at least some mouse models of autoimmune disease.

Discussion of the antibody repertoire usually emphasizes diversity, but a conspicuous feature of the light chain repertoire is its lack of diversity. The diversity of reported allelic variants of germline light chain genes is also limited, even in well-studied species. In this review, the implications of this lack of diversity are considered. We explore germline and rearranged light chain genes in a variety of species, with a particular focus on human and mouse genes. The importance of the number, organization and orientation of the genes for the control of repertoire development is discussed, and we consider how primary rearrangements and receptor editing together shape the expressed light chain repertoire. The resulting repertoire is dominated by just a handful of IGKV and IGLV genes. It has been hypothesized that an important function of the light chain is to guard against self-reactivity, and the role of secondary rearrangements in this process could explain the genomic organization of the light chain genes. It could also explain why the light chain repertoire is so limited. Heavy and light chain genes may have co-evolved to ensure that suitable light chain partners are usually available for each heavy chain that forms early in B cell development. We suggest that the co-evolved loci of the house mouse often became separated during the inbreeding of laboratory mice, resulting in new pairings of loci that are derived from different sub-species of the house mouse. A resulting vulnerability to self-reactivity could explain at least some mouse models of autoimmune disease. [ABSTRACT FROM AUTHOR]

Common variable immune deficiency (CVID) is a heterogeneous disorder characterized by recurrent infections, low levels of serum immunoglobulins, and impaired vaccine responses. Autoimmune manifestations are common, but B cell central and peripheral selection mechanisms in CVID are incompletely understood. Here, we find that receptor editing, a measure of central tolerance, is increased in transitional B cells from CVID patients and that these cells have a higher immunoglobulin κ:λ ratio in CVID patients with autoimmune manifestations than in those with infection only. Contrariwise, the selection pressure in the germinal center on CD27bright memory B cells is decreased in CVID patients with autoimmune manifestations. Finally, functionally, T cell-dependent activation showed that naive B cells in CVID patients are badly equipped for activation and induction of mismatch repair genes. We conclude that central tolerance is functional whereas peripheral selection is defective in CVID patients with autoimmune manifestations, which could underpin the development of autoimmunity. [Display omitted] • Central B cell tolerance is intact in common variable immunodeficiency (CVID) • Peripheral B cell selection is defective in CVID patients with autoimmune disease • The process of somatic hypermutation works suboptimally in CVID • Activated naive B cells only partially induce the mismatch repair genes in CVID Friman et al. show that the central tolerance in patients with common variable immunodeficiency (CVID) is intact whereas the peripheral selection of CD27bright memory B cells is defective, particularly in patients with autoimmune manifestations. This could potentially be one of the underlying reasons of autoimmunity in this patient group. [ABSTRACT FROM AUTHOR]

In this article, an improved immune algorithm (IIA), based on the fundamental principles of the biological immune system, is proposed for optimizing the pulse width modulation (PWM) control sequence of a single-phase full-bridge inverter. The IIA takes advantage of the receptor editing and adaptive mutation mechanisms of the immune system to develop two operations that enhance the population diversity and convergence of the proposed algorithm. To verify the effectiveness and examine the performance of the IIA, 17 cases are considered, including fixed and disturbed resistances. Simulation results show that the IIA is able to obtain an effective PWM control sequence. Furthermore, when compared with existing immune algorithms (IAs), genetic algorithms (GAs), a non-traditional GA, simplified simulated annealing, and a generalized Hopfield neural network method, the IIA can achieve small total harmonic distortion (THD) and large magnitude. Meanwhile, a non-parametric test indicates that the IIA is significantly better than most comparison algorithms. Supplemental data for this article can be accessed athttp://dx.doi.org/10.1080/0305215X.2016.1250894. [ABSTRACT FROM AUTHOR]

A vaccine that can effectively prevent HIV-1 transmission remains paramount to ending the HIV pandemic, but to do so, will likely need to induce broadly neutralizing antibody (bnAb) responses. A major technical hurdle toward achieving this goal has been a shortage of animal models with the ability to systematically pinpoint roadblocks to bnAb induction and to rank vaccine strategies based on their ability to stimulate bnAb development. Over the past 6 years, immunoglobulin (Ig) knock-in (KI) technology has been leveraged to express bnAbs in mice, an approach that has enabled elucidation of various B-cell tolerance mechanisms limiting bnAb production and evaluation of strategies to circumvent such processes. From these studies, in conjunction with the wealth of information recently obtained regarding the evolutionary pathways and paratopes/epitopes of multiple bnAbs, it has become clear that the very features of bnAbs desired for their function will be problematic to elicit by traditional vaccine paradigms, necessitating more iterative testing of new vaccine concepts. To meet this need, novel bnAb KI models have now been engineered to express either inferred prerearranged V(D)J exons (or unrearranged germline V, D, or J segments that can be assembled into functional rearranged V(D)J exons) encoding predecessors of mature bnAbs. One encouraging approach that has materialized from studies using such newer models is sequential administration of immunogens designed to bind progressively more mature bnAb predecessors. In this review, insights into the regulation and induction of bnAbs based on the use of KI models will be discussed, as will new Ig KI approaches for higher-throughput production and/or altering expression of bnAbs in vivo, so as to further enable vaccine-guided bnAb induction studies. [ABSTRACT FROM AUTHOR]

The ultimate cause of follicular lymphoma (FL) remains unknown. Remarkably, almost nothing is known about immunological tolerance mechanisms that might contribute to FL development. Immunological tolerance mechanisms, like other stimuli, also induce persistent changes of B cell receptors that induce genetic instability and molecular aberrations promoting the development of a neoplasm. Using the same method as Burnet, we provide a new perspective taking advantage of the comparison of a normal linear B cell differentiation process and FL development within the framework of clonal selection theory. We propose that FL is a malignancy of cells that acquire both translocation t(14;18) and self-BCR, inducing them to proliferate and mature, resistant to negative selection. Additional genetic damage induced by non-apoptotic tolerance mechanisms, such as receptor editing, may transform a self-reactive B cell with t(14;18) into an FL. The result of tolerogenic mechanisms and genetic aberrations is the survival of FL B cell clones with similar markers and homogenous gene expression signatures despite the different stages of maturation at which the molecular damage occurs. To antagonize further growth advantage due to self-antigen recognition and chronic activation of tolerance mechanisms in the apoptosis-resistant background of FL B cells, inhibitors of BCR signaling may be promising therapeutic options. [ABSTRACT FROM AUTHOR]

The cell formation problem is one of the first issues faced in the designing of cellular manufacturing systems. In this paper, a new solution approach based on the artificial immune system algorithm is presented for the problem with the aim of maximizing the grouping efficacy. To intensify the search, the proposed method is refined by a tabu search algorithm. Numerical results confirm the effectiveness of the method since it can reach the best known solutions of 30 most widely used benchmark problems in short computational time. Compared with different methods collected from the literature, the proposed algorithm performs well on all test problems. [ABSTRACT FROM AUTHOR]

VH replacement is a type of antibody gene rearrangement in which an upstream heavy chain variable gene segment (VH) invades a pre-existing rearrangement (VDJ). In this Hypothesis and Theory article, we begin by reviewing the mechanism of VH replacement, its developmental timing and its potential biological consequences. Then we explore the hypothesis that specific sequence motifs called footprints reflect VH replacement vs. other processes. We provide a compilation of footprint sequences from different regions of the antibody heavy chain, include data from the literature and from a high throughput sequencing experiment to evaluate the significance of footprint sequences. We conclude by discussing the difficulties of attributing footprints to VH replacement.