ReviewEmerging role of innate B1 cells in the pathophysiology of autoimmune and neuroimmune diseases: Association with inflammation, oxidative and nitrosative stress and autoimmune responses
Graphical abstract
Introduction
In humans, immunity is conventionally divided into innate immunity and adaptive immunity. Innate immunity is always immediately available to recognise and react against foreign antigens but is not specific and does not lead to lasting immunity, whereas adaptive immunity takes time to develop, is highly specific and can lead to immunological memory [1]. In particular, the humoral component of the adaptive immune response involves the secretion of antibodies or immunoglobulins by activated B lymphocytes, which in humans mature in the bone marrow [1]. There are several types of B cells. The largest population are recirculating mature B lymphocytes which develop continuously from bone marrow precursors and populate splenic and lymph node follicles; these are known as B2 (or B-2) cells or follicular B cells [2]. The focus of this paper is on a different class of B lymphocytes, the B1 (or B-1) cells. Baumgarth [2] has summarised key features of B1 cells, including how they differ from B2 cells:
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B-1 cells are innate-like B cells that have features of both the adaptive and innate immune systems.
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The development of B-1 cells is distinct from that of conventional B-2 cells and leads to the establishment of a B cell subset with a B cell receptor (BCR) repertoire which is selected for self- and poly-reactivity and that contains many evolutionarily 'useful' BCR specificities.
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B-1 cells secrete these useful BCR specificities in the steady state as natural IgM (and IgA) antibodies, in the absence of antigenic stimulation.
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B-1 cells do not respond readily to BCR-mediated stimulation by extensive clonal expansion, possibly owing to the expression of inhibitory co-receptors. However, they respond rapidly and vigorously to non-specific inflammatory and pathogen-associated stimuli, by migrating from the body cavities to secondary lymphoid tissues, where they undergo rapid differentiation to antibody-secreting cells.
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Owing in part to their BCR repertoire and their particular response patterns, B-1 cells and the antibodies they secrete function as important regulators of homeostasis. B-1 cells can engulf and clear dead apoptotic cells, produce anti-inflammatory cytokines such as interleukin-10 and secrete IgA in the intestinal mucosa, thereby regulating the local microbiota.
There are two subsets of B1 cells, B1a cells and B1b cells, the latter being capable of memory responses. B1b cells were originally discovered in mice [3]. They play an indispensable role in immune and tissue homeostasis as well as an initial defence against pathogen invasion via the secretion of polyreactive IgM and antigen specific IgM in the spleen and bone marrow as well as being the ultimate source of the bulk of interleukin-10 (IL-10)-secreting regulatory B cells [[4], [5], [6]]. However, accumulating evidence also suggests that B1b cell subsets may have pathogenic potential owing to abnormal homing, the production of high affinity cross-reactive IgM and acting as antigen-presenting cells (APCs) [7]. Interest in this area has blossomed following the confirmation of the existence of B1b cells in humans [3,[8], [9], [10], [11], [12], [13]].
Evidence obtained from human and murine studies suggests that abnormal levels and function of B1b cells play a pathogenic role in systemic lupus erythematosus (SLE) [11,14], rheumatoid arthritis (RA), type 1 diabetes mellitus [15], multiple sclerosis (MS) [16], several neurological diseases [17] and possibly schizophrenia [18,19]. Several authors have also reported that B1 cells play a Janus-faced role in sepsis [20,21] and the development of atherosclerosis [21,22].
Natural IgM (nIgM) may also have either protective or pathogenic properties [6]. The weight of evidence suggests that increased levels, decreased levels or abnormal patterns of IgM production may either contribute to pathology or be a surrogate marker of compartment or tissue specific pathology, most notably in SLE [14,23], RA, sepsis [24,25] and schizophrenia [18,19]. Clearly any treatment aimed at correcting any or all such abnormalities in B1b cell function and/or natural antibody production is dependent on understanding how they arise [4,26,27]. In this context it is important to note that in recent years the research which may be the basis for developing such an understanding has largely been supplied by teams examining the putative roles of B1b cells and natural antibodies in the pathogenesis and pathophysiology of SLE, RA and MS [[27], [28], [29], [30], [31], [32], [33]]. However, more recently several studies have also suggested a role for B1b cells in the pathogenesis and pathophysiology of schizophrenia, which is a notoriously difficult illness to treat [18,19,[34], [35], [36], [37]].
Accordingly, this paper will focus on evidence produced by research into these diseases with the aim of highlighting how multiple dimensions of B1b cell-mediated pathology may arise. We begin by providing a summary of B1b cell characteristics, then we will move on to describe the mechanisms underpinning the anti-inflammatory and pro-inflammatory properties of these lymphocytes before reviewing evidence underpinning their potential pathogenic role in SLE, RA, MS and schizophrenia and finally proposing mechanisms which might underpin abnormal B1b cell function and abnormal patterns of IgM production in these illnesses with a focus on elevated oxidative and nitrosative stress seen in all these illnesses [38].
Section snippets
Phenotype
Murine B cells are characterised by sIgMhi, CD23lo/− sIgDlo, CD19hi and CD43+ cells, and may be further subdivided into CD5+ B1a or CD5− B1b. The phenotype of human B1b cells on the other hand may be more variable although CD20+CD27+CD43+CD70− would appear to be the norm [7,11]. There is also some evidence to suggest that B1 cells may also be subdivided on the basis of CD5 and CD11b/Mac1 expression into B1a, which have the CD5 and CD11b/Mac1 phenotype, and B1b, which present as CD19hiCD5loCD11b
Role in early responses to pathogen invasion
The circulating polyreactive pentameric nIgM secreted by B1b cell subsets in the spleen and bone marrow act as a highly versatile and effective and rapid early defence against invading pathogens before the activation of the adaptive immune system. This is underpinned by their capacity to recognise and engage with a multitude of phylogenetically conserved macromolecules such as phospholipids, carbohydrates and nucleic acids [4,65].
Role in tissue homeostasis and clearance of dying cells
A wide range of self-reactive IgM class natural antibodies also
Result of abnormal trafficking
As previously discussed, B1 cells in the peritoneum do not constitutively express nIgM autoantibodies [104] but once activated by the presence of bacteria via ligation of their BCR and/or TLR receptors rapidly egress to the spleen where they differentiate into plasmablasts secreting pathogen-specific IgM, memory B1 lymphocytes and cytokine-secreting cells overwhelmingly, but not exclusively, via T cell independent routes [14,41,105]. Examples of pathogens provoking these responses include
MS
Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating, and neurodegenerative disease of the central nervous system in young adults [127]. MS is a heterogeneous disorder whose pathological hallmark is the formation of demyelinating lesions in the brain and spinal cord. Immune-related mechanisms involving the infiltration of immune cells including T cells, B cells and myeloid cells are thought to play a pivotal role in the formation of focal lesions in this disease [127].
SLE
Several research teams have reported globally low levels of circulating IgM and/or low levels of circulating IgM directed against self-antigens, most notably PC, MDA and oxidised cardiolipin [14,23,149,150]. Importantly, many authors have also reported a strong correlation between low levels of IgM antibodies against PC, MDA, oxidised cardiolipin and phosphatidylserine and the existence of atherosclerosis and atherosclerotic plaques in SLE patients; higher levels of these autoantibodies
Mechanisms governing IL-10 production by Bregs
Several research teams have produced evidence suggesting that the transcription factor signal transducer and activator of transcription 3 (STAT3) and the TLR-MyD88 (myeloid differentiation primary response 88)-STAT3 signalling pathway play an indispensable role in the production of IL-10 by human Bregs [[200], [201], [202]]. The importance of TLR signalling and STAT3 activation was first reported by Liu and fellow workers who showed that TLR signalling, but not CD40 ligation or BCR activation,
Conclusion
In this paper, we have detailed evidence of the important role of innate B1b lymphocytes in the pathophysiology of autoimmune and neuroimmune diseases, including MS, SLE, RA and deficit schizophrenia. Furthermore, we have also shown how abnormal B1b cell function and abnormal patterns of IgM production in these diseases are associated with elevated I&ONS. The results of further research studies in this fledgling area may yield new potential diagnostic and therapeutic approaches.
Declaration of Competing Interest
MB is supported by a NHMRC Senior Principal Research Fellowship (APP1059660) and has received Grant/Research Support from the NIH, Cooperative Research Centre, Simons Autism Foundation, Cancer Council of Victoria, Stanley Medical Research Foundation, MBF, NHMRC, Beyond Blue, Rotary Health, Meat and Livestock Board, Astra Zeneca, Woolworths, Avant and the Harry Windsor Foundation, book royalties from Oxford University Press, Cambridge University Press, Springer Nature and Allen and Unwin, has
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