Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 12, Issue 3, 2012

B lymphocytes provide essential protection against infections, and also act as drivers of pathogenesis in some autoimmune diseases. During the recent years, major progress has been made in our understanding of the molecular mechanisms controlling B cell activation, and several novel functions of B cells independent of antibody production have been discovered. The aim of this volume is to present some of these novel findings, with articles on how BCR co-receptors shape B cell responses, how B cells regulate T and innate cells, and how local B cell responses outside of lymphoid organs contribute to frontline immunity. In addition, one review highlights the role of B cells as phagocytes in fish and mammals, and two articles discuss the possibility of using activated B cells for suppressing unwanted immune reactions in adoptive therapy. Altogether, these articles provide an integrated view of B cell responses in the immune system, highlighting their interactive lifestyle, and poly-functionality. Antigen-specific B cell responses start with the recognition of antigen by BCR. Tsubata reviews how BCR co-receptors regulate B cell activation by antigen, with a special focus on CD22 and Fc receptors (1). The cytoplasmic regions of these coreceptors contain immunoreceptor tyrosine-based inhibition motifs (ITIMs), which can recruit phosphatases and inhibit BCR signaling upon engagement. These co-receptors offer multiple possibilities for regulating B cell sensitivity to antigen. For instance, CD22 provides stronger suppression when antigens contain sialic acids, a type of glycan moiety that is abundantly expressed in animals but rarely found in microbes. Thus, CD22 might act as a sensor for self-associated glycosylation patterns, to selectively prevent immunity against autoantigens. Noteworthily, B cells can adjust in a cell-autonomous manner the inhibitory activity of CD22 by modulating the glycosylation pattern of this receptor itself. B cells might therefore change their sensitivity for antigen according to their metabolic status. These new findings are of great interest given the importance of these coreceptors in regulation of immunity in vivo. Polymorphisms in the genes coding for these co-receptors have been associated with increased susceptibility to autoimmune pathologies such as systemic lupus erythematosus (SLE) in human. This link is not fully explained mechanistically but it might involve expression of pathogenic antibody-dependent and -independent functions by B cells....

B lymphocytes (B cells) express a variety of membrane molecules containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region such as FcγRIIB, FCRLs, CD22, mouse Siglec-G/human Siglec-10, PECAM-1, mouse PIR-B/human LIRB1 and LIRB2PD-1 and CD72. When phosphorylated, ITIMs in these molecules recruit and activate phosphatases such as SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1), SHP-2, SH2 domain- containing inositol 5-phosphatase 1 (SHIP1) and SHIP2 depending on receptors. These phosphatases then negatively regulate B cell antigen receptor (BCR) signaling. Because of their ability to inhibit BCR signaling, these ITIMcontaining molecules are called inhibitory BCR co-receptors. Studies on mice deficient in an inhibitory co-receptor have demonstrated that the inhibitory co-receptors regulate B cell development, antibody responses and development of autoimmune diseases. Moreover, polymorphisms in some inhibitory co-receptors such as FcγRIIB, FCRL3 and CD72 are associated with autoimmune diseases, suggesting a crucial role of inhibitory co-receptor polymorphisms in the regulation of autoimmune diseases. The ligands for inhibitory co-receptors regulate their inhibitory activity by inducing co-ligation of the co-receptors with BCR or some other regulatory mechanisms. Inhibitory co-receptors and their ligands are therefore good targets for controlling antibody responses and autoimmune diseases.

The immune system is composed of multiple cell types, which together improve the resistance of the organism against infections. The unfolding of a successful host response ensuring effective protection against pathogens requires an appropriate coordination of the different players of the immune system. Innate cells and T cells extensively communicate during immune reactions, providing multiple opportunities for the mutual coordination of these two defense pathways. Little is known about the functional interactions between B and innate cells, and it is generally assumed that they influence each other indirectly through effects on T cells. However, recent studies highlighted important roles for innate cells in initial presentation of antigen to B cells after immunization, and in long-term maintenance of antibody-producing cells in bone marrow after resolution of immune responses. Furthermore, it was found that activated B cells could regulate the activity of innate cells through production of cytokines. Here, we review how direct interactions between innate and B cells can contribute to orchestration of humoral and cellular immunity.

The evolutionary origins of Ig-producing B cells appear to be linked to the emergence of fish in this planet. There are three major classes of living fish species, which from most primitive to modern they are referred to as agnathan (e.g., lampreys), Chondrichthyes (e.g., sharks), and teleost fish (e.g., rainbow trout). Agnathans do not have immunoglobulin- producing B cells, however these fish contain a subset of lymphocytes-like cells producing type B variable lymphocyte receptors (VLRBs) that appear to act as functional analogs of immunoglobulins. Chondrichthyes fish represent the most primitive living species containing bona-fide immunoglobulin-producing B cells. Their B cells are known to secrete three types of antibodies, IgM, IgW and IgNAR. Teleost fish are also called bony fish since they represent the most ancient living species containing true bones. Teleost B cells produce three different immunoglobulin isotypes, IgM, IgD and the recently described IgT. While teleost IgM is the principal player in systemic immunity, IgT appears to be a teleost immunoglobulin class specialized in mucosal immune responses. Thus far, three major B cell lineages have been described in teleost, those expressing either IgT or IgD, and the most common lineage which co-expresses IgD and IgM. A few years ago, the study of teleost fish B cells revealed for the first time in vertebrates the existence of B cell subsets with phagocytic and intracellular bactericidal capacities. This finding represented a paradigm shift as professional phagocytosis was believed to be exclusively performed by some cells of the myeloid lineage (i.e., macrophages, monocytes, neutrophils). This phagocytic capacity was also found in amphibians and reptiles, suggesting that this innate capacity was evolutionarily conserved in certain B cell subsets of vertebrates. Recently, the existence of subsets of B cells with phagocytic and bactericidal abilities have also been confirmed in mammals. Moreover, it has been shown that phagocytic B-1 B cells have a potent ability to present particulate antigen to CD4+ T cells. Thus, studies carried out originally on fish B cells have lead to the discovery of new innate and adaptive roles of B cells in mammals. This review will concentrate on the evolutionary and functional relationships of fish and mammalian B cells, focusing mainly on the newly discovered roles of these cells in phagocytosis, intracellular killing and presentation of particulate antigen.

Antibodies made by B cells are critically important for immune protection to a variety of infectious agents. However, it is becoming increasingly clear that B cells do more than make antibodies and that B cells can both enhance and suppress immune responses. Furthermore, there is growing evidence that B cells modulate cellular immune responses by antibody dependent and independent mechanisms. Although we have a good understanding of the roles played by antibody- secreting effector B cells during immune responses, we know very little about the Ab independent “effector” functions of B cells in either health or disease. Given the recent data suggesting that B cells may contribute to autoimmune disease pathogenesis via an antibody independent mechanism and the increasing use of B cell depletion therapy in autoimmune patients, investigators are beginning to reassess the multiple roles for B cells during immune responses. In this article, we review data describing how B cells mediate protection to pathogens independently of antibody production. In particular, we will focus on the role that B cells play in facilitating dendritic cell and T cell interactions in lymph nodes, the importance of antigen-presenting B cells in sustaining effector T cell and T follicular helper responses to pathogens and the relevance of cytokine-producing effector and regulatory B cells in immune responses.

B cells are once again gaining prominence as important programmers of CD4 T cell responses. With widespread use of B cell depletion therapy in the clinic, proving effective in treating diseases previously considered T cellmediated, the time is right for a re-appraisal of the B cell. Though typically considered weak, Th2 driving APC, it is now clear that they are necessary for a robust and long-lived CD4 T cell response in many settings. The sphere of B cell influence extends well beyond that of simply antibody production; antigen presentation, cytokine secretion, costimulation and development of lymphoid tissue architecture are all critical aspects of B cell immunobiology, the absence of which has serious impacts for T cell priming and memory. The aim of this review is to look at non-antibody mediated B cell function and to ask how, where and when do B cells influence the CD4 T cell response?

Viruses form particulate structures possessing high-density B-cell epitopes and viral RNA/DNA, which are ligands for multiple Toll-like receptors (TLRs). B cells are able to sense these viral antigenic signatures through B-cell antigen receptors (BCRs) and TLRs, both of which synergistically shape the magnitude and quality of virus-specific B-cell responses. In many viruses, B-cell recognition of these virus signatures is often hampered by tissue tropisms toward nonlymphoid organs. However, ectopic localizations of B cells at virus replication sites facilitate the efficient recognition of intact virus particles. Following pulmonary infection by influenza virus, virus-specific B-cell responses occur in the tertiary lymphoid organs of lungs near the sites of virus replication as well as in the draining lymph nodes. Lungs then begin to support the germinal center response and the formation of niches for plasma cells and memory B cells, thus potentiating B-cell intrinsic recognition of virus particles at these sites. In this review, we discuss how the anatomical location and virus- sensing properties of B cells coordinate protective B-cell responses against pulmonary virus infection.

The essence of the adaptive immune system is self tolerance, which is maintained by various central and peripheral check points. However, the tolerance mechanisms can be broken in autoimmune disease conditions due to genetic predisposition and environmental triggers. As a consequence, a patient’s tissue is attacked by his/her own adaptive immune system. An ideal therapy for autoimmune diseases should include methods to re-establish tolerance to the underpinning autoantigen(s). During the last 15 years our lab has been dedicated to developing a novel B-cell gene therapy approach for antigen-specific tolerance induction. This approach has been successfully applied to at least five different animal models for human autoimmune diseases. In this article, we will discuss many of our successful preclinical studies using the B-cell gene therapy approach to induce tolerance, as well as similar studies from others. Particular focus will be given to the tolerance induction mechanisms that have been revealed from these studies.

B cells play a pivotal role in host adaptive immunity against pathogenic microorganisms, but may also maladaptively contribute to the pathogenesis of autoimmune diseases. In contrast, distinct B cell subsets have the capacity to regulate host immune response, and suppress inflammation. B regulatory cells are a rare population of endogenous Blymphocytes defined in part by production of the anti-inflammatory cytokine IL-10. Although “natural” B regulatory cells exist in vivo, the low frequency of B regulatory cells may be a limiting factor on their impact in autoimmune ailments. In answer to this unmet need, we have developed a novel strategy for alternate lymphoid activation: fusokines. These wholly engineered chimeric leukines fuse two functionally unrelated cytokines for the purpose of alternate immune modulation. The GM-CSF- and IL-15-derived fusokine: GIFT15, possesses entirely novel and unheralded immune modulating properties mediated through the IL15 receptor which reprograms naive B cells into B regulatory cells (Bregs). In this article, we review the current approaches to generate Bregs in vitro, and highlight gain-of-function mechanisms by which GIFT15- induced Bregs abrogate pathogenic autoimmunity in mice. We also demonstrate that the human equivalent of inducible Bregs may also serve as a new potent therapeutic tool for treatment of autoimmune disease.