“B cells and autoimmunity 2016”

Immunologists have long investigated B lymphocytes as solely antibody-producing cells. With further studies, it became clear that B cells are able to exert a variety of functions within the immune system, and beyond [1,2]. Currently, B cells are considered promising targets for immunotherapy in a variety of disorders, including autoimmune diseases [3,4]. Twenty-five years ago marked the publication of the first report describing the clinical efficacy of depleting B lymphocytes in the autoimmune disease rheumatoid arthritis [5]. It also marked organization of the first “B cells and Autoimmunity” conference in 2001 in Bergen, Norway [6]. For its sixth edition, this conference series settled along the shores of Sun Moon Lake in the heart of Taiwan from 16 to 18 August 2016 to view and discuss recent advances in different facets of B-cell biology and to put them in the prospect of understanding autoimmunity and of designing effective immunointervention strategies [7].

The conference was organized by Betty Diamond (The Feinstein Institute for Medical Research, Manhasset, NY, USA), Gregory Tsay (China Medical University, Taichung, Taiwan), and Moncef Zouali (Inserm and University of Paris). Following the tradition established in 2001, the conference was a forum where basic immunologists and their clinically trained colleagues met to discuss hot topics of autoimmunity research. Speakers from four continents discussed some of their new data and insights and brought considerable excitement to the conference in the refreshingly beautiful and elegant landscape of Sun Moon Lake and its indescribable charm. This special issue of Autoimmunity includes a collection of papers that shows some of the ways in which the many facets of autoimmune research were discussed in Sun Moon Lake.

Secondary lymphoid organs harbor specialized microenvironments, termed germinal centers (GCs), that generate high-affinity, long-lived antibody-forming cells and memory B cells [8]. As discussed by Domeier et al., GCs can spontaneously develop (Spt-GCs) in the absence of deliberate immunization or infection. In autoimmune disease, such as systemic lupus erythematous (SLE), inappropriate maintenance of B-cell tolerance at the GC checkpoint is believed to give rise to autoreactive B cells in Spt-GCs. Identification of a novel B-cell-intrinsic signaling pathway specific to Spt-GC development and autoimmunity should be important to determine whether this pathway that seems to promote aberrantly regulated Spt-GC responses in SLE can be targeted by pharmacological intervention to treat systemic autoimmunity.

Characterization of the isotypes of autoantibodies found in patients with autoimmune diseases has been the focus of much investigation [9]. It can provide not only clues for understanding disease pathogenesis, but also potential biomarkers because autoantibodies can exist in sera of patients several years prior to the onset of clinical manifestations [10]. Early studies disclosed that antinuclear antibodies of the IgE class are present in lupus patients and that they could be of pathogenetic importance. Studies by Ettinger et al. show that, in patients with SLE, the levels of dsDNA-specific IgE autoantibodies correlate with disease severity and that deposits of IgE are also found in the kidneys of patients with lupus nephritis. The experiments reveal that IgE autoantibodies specific for DNA have the capacity to induce potent humoral responses and represent a novel mechanism that could support the generation of pathogenic autoantibodies in lupus patients. They establish a mechanistic link between anti-DNA IgE autoantibodies, plasmacytoid dendritic cells and type-I interferon whose unabated secretion is central to SLE, a concept that has now been clinically validated by blocking the type-I interferon receptor in a phase-2 proof of concept study using the anti-IFNα receptor monoclonal anifrolumab antibody [11].

As has been described in other autoimmune diseases, large-scale genomewide association studies have implicated a number of loci as genetic risk factors for human SLE [12]. In studies of mouse lupus models, backcrossing the lupus-prone NZM2410 genome onto C57BL/6 led to the identification of three genomic intervals, termed sle1, sle2 and sle3, which are associated with lupus susceptibility. Since the highly diverse third hypervariable regions (CDR-H3) of antibodies are key determinants of specificity in antigen recognition, whereas the germline-encoded CDR1 and CDR2 sequences are much more cross reactive, Khass et al. focused on the impact of nonimmunoglobulin genes on the antibody repertoire expressed in different B-cell subsets. The studies suggest that the peripheral CDR-H3 repertoire can be categorically manipulated by the effects of nonantibody genes.

The mechanisms that underlie production of autoreactive B cells and their escape from self-tolerance remain the focus of investigation. Patients with rheumatoid arthritis, type-1 diabetes or SLE show alterations of both central and peripheral B-cell tolerance checkpoints, and a number of signaling abnormalities that can lead to B-cell hyperactivity have been described [13]. Here, Liu et al. discuss the aberrant regulation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathway in SLE B lymphocytes. They propose that defective expression of its upstream and downstream signaling molecules could contribute to failure of depleting autoreactive B cells, and autoantibody production that leads to tissue injury. They suggest that this pathway could be targeted for therapeutic purposes.

Multiple sclerosis (MS) is commonly considered an autoimmune-demyelinating disease, where myelin-reactive T cells enter the central nervous system and drive the inflammatory changes that ultimately create the degenerative MS plaque [14]. Yet, less consideration has been devoted to the role of B cells in the lesional pathogenesis. Investigations by Wekerle and collaborators indicate that B cells are regular components of immune infiltrates in the early-active MS lesion, and raise questions regarding the mechanisms that lead to the recruitment of autoreactive B cells in a spontaneously developing brain disease. Studies performed in two transgenic mouse models that spontaneously develop encephalomyelitis and that are based on the cooperation between autoreactive T and B cells suggest that B cells can play distinct roles, further illustrating the multiple contributions of B cells in this disease.

Having evolved to generate a huge antigen-specific repertoire and to mount T-cell-dependent responses and long-term memory, the B lymphocyte is a central player in the adaptive branch of immune defence. However, accumulating evidence indicates that B-1a cells of the peritoneal cavity and marginal zone B cells of the spleen also can play innate-like immune functions [15]. Their role has been well studied in models of atherosclerosis. As reviewed by Kyaw et al., whereas peritoneal B-1a cells are atheroprotective, conventional B-2 B cells are atherogenic in experimental models. Their reduction by the administration of monoclonal antibody to CD20 or to the BAFF receptor ameliorates atherosclerosis development in mice. By contrast, peritoneal B-1a cells would protect against atherosclerosis development by the secretion of polyclonal, natural IgM that scavenges apoptotic cells and oxidized low-density lipoproteins, thereby reducing apoptosis, necrotic cores and inflammation in atherosclerotic lesions. To further understand the pathophysiology of human atheroma, additional studies are required to define the properties of resident B cells in human arterial lesions [16].

Periodontal disease, or periodontitis, is characterized by the destruction of normal supporting tissues of the dentition by an inflammatory process [17]. Whereas the humoral and cellular immune responses in periodontal inflammation arise as a response to the causative infectious agent(s), they may also target self-antigens liberated during the host tissue breakdown. Given their chief role in innate-like and adaptive immune responses, B cells could exert important functions in periodontitis by producing antibodies able to neutralize bacterial invasion, or to promote inflammation and disease. As discussed by Zouali, although microbial antigens are involved in the induction of the inflammatory responses in human adult periodontitis, endogenous antigens also may contribute to the chronicity of this common disease. Not only antibodies to self-antigens, such as collagen, are locally produced, but the autoreactivities observed in localized aggressive adult periodontitis also are more severe and diverse than those observed in chronic periodontitis, and some putative targets identified in periodontitis include autoantigens that have been implicated in other autoimmune processes, suggesting that autoimmune reactivity could play a role in the tissue destruction of periodontal disease. This novel insight suggests that selective targeting of B cells could represent a future therapeutic avenue for severe periodontal disease.

IgG4-related disease is a rare immune-mediated systemic disease of unknown origin with the capability of involving essentially any organ [18]. The most current investigational treatment approaches have focused on targeting cells of the B-cell lineage, including B-cell-depleting agents that can lead to attenuation of serological biomarkers of the disease. As reviewed by Mattoo et al., IgG4-related patients with active, untreated disease show a marked expansion of plasmablasts in the circulation, as well as at the tissues/organs involved. In addition, CD4⁺cytotoxic lymphocytes have been identified in disease lesions and in the circulation. However, additional work is needed to decipher the potential mechanisms used by activated B cells, plasmablasts and cytotoxic cells to drive the pathology of the disease. Similarly, as discussed by Choi and Morel for lupus pathogenesis, a better understanding of the pathways that govern the interactions between B cells and T cells, as well as dendritic cells could provide clues to better understand the pathogenesis of autoimmune disorders.

As briefly highlighted in this issue, the “B cells and Autoimmunity” conference was, once again, successful in bringing together investigators from the academic and the industrial sectors, and in favoring informal discussion of novel ideas. The traditional Taiwanese hospitality and the tranquility of Sun Moon Lake, with its smaragdin reflections and its sublime panoramas provided a unique setting for this multidisciplinary scientific event to develop various areas related to aspects of B-cell biology and functions. Some of the recently developed approaches have expanded our ability to interrogate B-cell-mediated pathways involved in autoimmune diseases. They are leading to a better understanding of the complexity of autoimmune reactions in animal models and in patients [19–24]. Identification of pathways that take part in the disease process is permitting the introduction of biologics with demonstrable success in clinical trials. It is hoped that the wealth of data that is being gathered and disseminated will lead to new and improved targeting strategies designed to increase objective response rates in patients with autoimmune diseases. It is not unreasonable to conclude that combination of tailored immune targeted therapeutics based on particular immunological alterations will provide patients with more successful drugs [25–29]. The momentum in the field is great, and all look forward to the seventh edition of the “B cells and Autoimmunity” conference.

The organizers wish to thank those companies, societies, institutions, and government agencies that helped to fund the meeting. The guest editor would like to thank the scientists who submitted their papers to this special issue of “Autoimmunity on B cells and Autoimmunity” and to acknowledge the excellent work made by a team of independent reviewers.

Declaration of interest

The author reports no conflicts of interest. The author alone is responsible for the content and writing of this article.