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Do plasma B cells express the BCR or only produce soluble antibodies?

Do plasma B cells express the BCR or only produce soluble antibodies?



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Is the B cell receptor still expressed on a B cell once it has begun to produce soluble antibodies? Is there a gene change that prevents the membrane-bound form from being produced anymore?


B cells can secrete antibody before they are terminally differentiated into plasma cells, so there is a phase during which both membrane-bound and secretory antibodies can be produced by the same cell:

When a naïve or memory B cell is activated by antigen (with the aid of a helper T cell), it proliferates and differentiates into an antibody-secreting effector cell. Such cells make and secrete large amounts of soluble (rather than membrane-bound) antibody, which has the same unique antigen-binding site as the cell-surface antibody that served earlier as the antigen receptor (Figure 24-17). Effector B cells can begin secreting antibody while they are still small lymphocytes, but the end stage of their maturation pathway is a large plasma cell

--Molecular Biology of the Cell. 4th edition.

Plasma cells, generally speaking, have little or no surface immunoglobulin, but it's been claimed that some subsets of plasma cells do have surface Ig:

Surprisingly, although IgG PCs downregulated surface IgG expression, IgA and IgM PCs expressed their respective isotype both intracellularly and on the plasma membrane (Figure 1A, lower panel). Importantly, concordant Ig's were also detected on the plasma membrane of IgA and IgM, but not IgG, PCs isolated from BM or colon LP indicating that this property is a characteristic of PCs present in their physiological niches

--A functional BCR in human IgA and IgM plasma cells


Once B cell starts secreting soluble antibodies, it is no longer a B cell, it is called a plasma cell hence normal B cells do not secrete soluble antibodies before becoming plasma cells. It is the BCR that is secreted. B cells can either differentiate into memory or plasma cells. Plasma cells produce soluble antibody molecules closely modeled after the receptors of the precursor B cell. The plasma cell continuously produces soluble antibodies. I hope this helps since I did not directly answer your questions because they were based on inaccurate information/bases. Please let me know if any other questions based on the information I provided


B cells immunophenotyping

B cells are mediators of the humoral response, or antibody-mediated immunity. By studying this particular cell group we learn more about the inner workings of the immune system, which consequently increases our awareness of the possible causes behind a variety of autoimmune disorders and cancers. Broad immunological research unlocks valuable insight of what future steps might be taken to treat these pathologies.

Development from stem cell to B cell

Generation of the B cell begins in the bone marrow where stem cells give rise to lymphoid cells. Throughout each stage of development the antibody locus— a site where an antigen interacts with the cell— undergoes genetic recombination. This recombination is specific to the developmental stage of the B cell. Development starts with the pro-B cell, which expresses Igα and Igβ. The cell matures further into the pre-B cell that expresses the pre-B cell receptor (Igμ) on its surface. Maturation in the bone marrow ends with the naïve B cell that expresses the B cell receptor (containing IgM and IgD) capable of recognizing an antigen. These cells then leave the bone marrow and enter the periphery (Cambier JC, et al. Nat Rev Immunol. 2007).

Subtypes of conventional B cells

Conventional B cells, also referred to as B-2 cells, terminally differentiate into one of two common subtypes upon activation:

  • Plasma B cells: a plasma cell is the sentry of the immune system. The naïve B cell circulates throughout the body. When it encounters a unique antigen, the plasma cell takes in the antigen through receptor-mediated endocytosis. Antigenic particles are transferred to the cell surface, loaded onto MHC II molecules and presented to a helper T cell. The binding of the helper T cell to the MHC II-antigen complex activates the B cell. The activated B cell goes through a period of rapid proliferation and somatic hypermutation. Selection occurs for those cells that produce antibodies with a high affinity for that particular antigen. Once terminally differentiated, the plasma B cell only secretes antibodies specific for that antigen and can no longer generate antibodies to other antigens.
  • Memory B cells: memory cells are held in reserve, in the germinal centers of the lymphatic system, for when the immune system re-encounters a specific antigen. During any repeat exposure the follicular helper T cell causes the memory cell to differentiate into a plasma B cell that has a greater sensitivity to that specific antigen. This jump-starts the immune system to mount a quicker, more powerful response than was possible previously.

Other B cell subtypes include:

  • B-1 cells: a minor subtype, only about 5% in humans, of self-renewing fetal B cells that act in a similar fashion to plasma cells. B-1 cells are primarily present during fetal and neonatal life.
  • Marginal zone (MZ) B cells: mature memory B cells that are found only in the marginal zone of the spleen. These cells can be activated through toll-like receptor-ligation and not necessarily through the B cell receptor.
  • Follicular (FO) B cells: these are mature, but inactive, B cells. This subset of B cells is primarily found in the follicles of the spleen and lymph nodes. Activation of these cells requires the aid of T cells. FO B cells can differentiate into either plasma or memory B cells.
  • Regulatory B (Breg) cells: Breg cells negatively regulate the strength of the immune response and inflammation by secreting chemical messages called cytokines, such as IL-10. Although these cells make up a small portion of the B cell population (

Immunophenotyping of B cells through flow cytometry

Immature B cells express CD19, CD 20, CD34, CD38, and CD45R, but not IgM. For most mature B cells the key markers include IgM and CD19, a protein receptor for antigens (Kaminski DA. Front Immunol. 2012). Activated B cells express CD30, a regulator of apoptosis. Plasma B cells lose CD19 expression, but gain CD78, which is used to quantify these cells. Memory B cells can be immunophenotyped using CD20 and CD40 expression. The cells can be further categorized using CD80 and PDL-2 regardless of the type of immunoglobulin present on the cell surface (Zuccarino-Catania GV et al. Nat Immunol. 2014.). Globally, cytokines (such as interlukein-10) and chemokines involved with chemokine receptor 3 play an important role in transmitting the biological messages to drive the immune response.

A table of common B cell subtypes with some cell markers which can be useful for flow cytometry:


Autoimmune Polyglandular Syndromes

B-Cell Tolerance

Naïve B cells , during the early stage of development in the bone marrow, express surface immunoglobulin (Ig)M, which serves as B-cell receptors (BCRs). Upon interacting with self-antigens, naïve immature B cells undergo negative selection, either through clonal deletion or anergy, whereby B cells enter a state of unresponsiveness and have a reduced life span. 42 Another process mediating B-cell central tolerance is receptor editing, whereby genetic rearrangement of the Ig chain leads to generation of BCRs with new antigen specificities. B cells with nonautoreactive BCRs are positively selected and continue to the periphery. 43 If self-reactive B cells escape into the periphery, they undergo anergy. Anergized B cells do not die immediately but have a shorter half-life. Naïve mature B cells require T-cell help for realization of their full potential through affinity maturation and class switching. The absence of T-cell help also leads to B-cell tolerance.


Plasma and memory cells

B cells leave the germinal centre response as high-affinity plasma cells and memory B cells (Figure 3). Plasma cells secrete antigen-binding antibodies for weeks after activation. They migrate to the bone marrow soon after formation where they can reside indefinitely, ready to encounter the antigen again and respond. Memory B cells circulate throughout the body on the lookout for antigen with a high-affinity for their BCR and then quickly respond to the antigen, stopping infection. This is how vaccination works. As your body has been previously exposed to the antigen the immune cells can quickly respond to remove the antigen if it is encountered again, stopping you getting sick.

Figure 3: B cell differentiation after activation. When a mature B cell encounters antigen that binds to its B cell receptor it becomes activated. It then proliferates and becomes a blasting B cell. These B cells form germinal centres. The germinal centre B cells undergo somatic hypermutation and class switch recombination. Plasma cells and memory B cells with a high-affinity for the original antigen stimuli are produced. These cells are long lived and plasma cells may secrete antibody for weeks after the initial infection.

Soluble vs. membrane-bound immunoglobulins

Immunoglobulins occur in two main forms: soluble antibodies and membrane-bound antibodies. (The latter contain a hydrophobic transmembrane region.) Alternative splicing regulates the production of secreted antibodies and surface bound B-cell receptors in B cells.

Membrane-bound immunoglobulins are associated non-covalently with two accessory peptides, forming the B-cell antigen receptor complex. The first antigen receptors expressed by B cells are IgM and IgD. The receptor is a prototype of the antibody that the B cell is prepared to produce. The B cell receptor (BCR) can only bind antigens. It is the heterodimer of Ig alpha and Ig beta that enables the cell to transduce the signal and respond to the presence of antigens on the cell surface. The signal generated causes the growth and proliferation of the B cell and antibody production inside the plasma cell.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

We would like to thank the funding from the Swedish Cancer Foundation, the Swedish Childhood Cancer Foundation, Reumatikerfonden, King Gustav V Stiftelse, IngaBritt och Arne Lundbergs Stiftelse, Lundgrens Stiftelse, Amlövs Stiftelser, Swedish Medical Society, Adlerbertska stiftelsen, The Royal Society of Arts and Sciences in Gothenburg, Sigurd och Elsa Golje's mine.


B Cells in Autoimmune Diseases

The role of B cells in autoimmune diseases involves different cellular functions, including the well-established secretion of autoantibodies, autoantigen presentation and ensuing reciprocal interactions with T cells, secretion of inflammatory cytokines, and the generation of ectopic germinal centers. Through these mechanisms B cells are involved both in autoimmune diseases that are traditionally viewed as antibody mediated and also in autoimmune diseases that are commonly classified as T cell mediated. This new understanding of the role of B cells opened up novel therapeutic options for the treatment of autoimmune diseases. This paper includes an overview of the different functions of B cells in autoimmunity the involvement of B cells in systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes and current B-cell-based therapeutic treatments. We conclude with a discussion of novel therapies aimed at the selective targeting of pathogenic B cells.

1. Introduction

Traditionally, autoimmune disorders were classified as T cell mediated or autoantibody mediated. However the improved understanding of the complexity of the immune system has significantly influenced the way we view autoimmune diseases and their pathogeneses. Reciprocal roles of T-cell help for B cells during adaptive immune responses and B-cell help in CD4+ T-cell activation are being increasingly recognized. The observation that most autoantibodies in traditionally autoantibody-mediated diseases are of the IgG isotype and carry somatic mutations strongly suggests T-cell help in the autoimmune B-cell response. Likewise B cells function as crucial antigen presenting cells in autoimmune diseases that are traditionally viewed as T cell mediated. This paper will discuss the role of B cells in autoimmune diseases however, it needs to be emphasized that most autoimmune diseases are driven by a dysfunction in the immune network consisting of B cells, T cells, and other immune cells.

2. B-Cell Functions in Autoimmunity

Different functions of B cells can contribute to autoimmune diseases (Figure 1): (1) secretion of autoantibodies (2) presentation of autoantigen (3) secretion of inflammatory cytokines (4) modulation of antigen processing and presentation (5) generation of ectopic GCs.


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(d) (a) B cells in autoimmune diseases. B cells have antibody-dependent and antibody-independent pathogenic functions. Secreted autoantibodies specific to receptors or receptor ligands can activate or inhibit receptor functions. Deposited immune complexes can activate complement and effector cells. Autoantibodies can bind to basic structural molecules and interfere with the synthesis of structural elements and facilitate the uptake of antigen. Independent of antibody secretion B cells secrete proinflammatory cytokines, support the formation of ectopic GCs, and serve as antigen presenting cells. Both secreted autoantibodies and BCR on B cells can modulate the processing and presentation of antigen and thereby affect the nature of presented T-cell determinants. (b) Pathogenic effects of deposited immune complexes. The Fc portion of antibodies in immune complexes can be bound by C1q of the classical complement pathway, which eventually leads to the release of C5a and C3a. These anaphylatoxins promote release of proinflammatory cytokines and serve as chemoattractants for effector cells. Moreover they induce the upregulation of activating FcR on effector cells. Binding of the Fc portion of the antibodies to FcR leads to activation of effector cells and further release of proinflammatory cytokines and proteolytic enzymes, mediators of antibody-dependent cell-mediated cytotoxicity (ADCC). (c) Effect of antibodies and antigen-specific B cells on antigen uptake. Left panel: antigen bound by antibody is taken up via FcR on APCs such as dendritic cells or macrophages. After processing, antigen is presented on MHC molecules. This FcR-mediated antigen uptake is more efficient than antigen uptake by pinocytosis. Right panel: antigen binds to the BCR of antigen-specific B cells and is internalized. B cells are highly efficient APCs in situations of low antigen concentrations. (d) Effect of antibodies and antigen-specific B cells on antigen processing and presentation. BCR-mediated antigen uptake can influence antigen processing and the nature of MHC-displayed T-cell determinants. Likewise, antigen/antibody complexes are bound by the FcR of APCs and processed in a unique fashion dependent on the epitope specificity of the bound antibody. The BCR or antibody can shield certain protein determinants from the proteolytic attack in endocytic compartments (represented as scissors in this figure). Presentation of some determinants may thereby be suppressed, while others are boosted. Thereby cryptic pathogenic peptides may be presented and stimulate autoreactive T cells.

These functions will be discussed in detail below.

2.1. Autoantibodies in Autoimmune Diseases

Autoantibodies can be detected in many autoimmune diseases. Their presence in the peripheral circulation and relative ease of detection makes them preferred markers to aid in diagnosis and prediction of autoimmune disorders. In some autoimmune diseases, the autoantibodies themselves have a pathogenic effect, as will be discussed in the following.

2.1.1. Deposition of Immune Complexes and Inflammation (Figure 1(b))

The deposition of immune complexes composed of autoantibodies and autoantigens is a prominent feature of several autoimmune diseases, including systemic lupus erythematosus, cryoglobulinemia, rheumatoid arthritis, scleroderma, and Sjögren's syndrome. The immune complexes can trigger inflammation through activation of complement and Fc-receptor-dependent effector functions [15]. In the classical complement cascade, the Fc portion of the antibody is bound by complement component C1q, which eventually triggers the activation of the anaphylatoxins C5a and C3a. C5a and to a lesser degree C3a attract effector cells such as neutrophils and NK cells and stimulate the release of proteolytic enzymes and inflammatory cytokines. Activation of complement has been consistently demonstrated in experimental models of immune-complex diseases and in the kidneys of patients with systemic lupus erythematosus and lupus nephritis [16]. The immune complexes can also directly bind to Fc-receptors on effector cells leading to antibody-dependent-cell-mediated cytotoxicity (ADCC).

2.1.2. Stimulation and Inhibition of Receptor Function

Autoantibodies can affect receptor function with different outcomes as illustrated by autoantibodies targeting the thyroid stimulating hormone (TSH) receptor. TSH receptor autoantibodies in Graves’ disease stimulate receptor function, triggering the release of thyroid hormones and development of hyperthyroidism [17], while TSH receptor autoantibodies in autoimmune hypothyroidism block the binding of TSH to the receptor [18]. Inhibitory autoantibodies are also found in Myasthenia gravis, where autoantibodies bind to the nicotine ACh receptors (AChRs) and block neurotransmission at the neuromuscular junction, inducing symptoms such as muscle weakness and fatigue [19], and in multifocal motor neuropathy, where autoantibodies bind to the ganglioside GM1 and cause motor neuropathy with conduction block at multiple sites [20]. Other autoantibodies can bind receptor ligands, preventing their binding to the receptor, as seen in Graves’ disease with anti-TSH autoantibodies [21]. Table 1 summarizes other examples of receptor autoantibodies, their targets, pathogenic mechanisms, and associated diseases.

2.1.3. Facilitation of Antigen Uptake (Figure 1(c))

Autoantibodies facilitate antigen uptake by antigen presenting cells (APCs). Antigen complexed with antibodies is taken up via Fc receptors (FcRs) present on monocytes and dendritic cells [22]. This mechanism is more efficient than pinocytosis and results in 10–100-fold lower necessary antigen concentration for successful T-cell stimulation [23–26]. The importance of this mechanism has been demonstrated in a number of animal studies, where antibodies to various antigens enhanced T-cell responses to the respective antigens [27–29]. Autoantibodies can therefore break tolerance of normal T cells through their capacity to promote uptake of self-antigen by APCs via their FcRs. Indeed, autoantibodies to thyroid self-antigens dramatically enhanced uptake of thyroid peroxidase (TPO) by APCs and subsequent activation of TPO-reactive T cells [30] and blockade of Fc

R markedly reduced this response [31]. Autoantibodies have also been demonstrated to facilitate the uptake of myelin by macrophages, and the removal of the Fc-portion of the antibodies prevented antigen uptake [32]. Moreover, Fc R–deficient DBA/1 mice were protected from myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE), suggesting that FcR-mediated uptake of antibody-bound myelin is involved in the pathogenesis of multiple sclerosis [33]. Autoantibody-mediated antigen uptake may therefore be a critical mechanism in the pathogenesis of T-cell-mediated autoimmune diseases.

Further support for autoantibody-mediated antigen uptake as a pathogenic mechanism in autoimmunity comes from an elegant study by Harbers et al. where transgenic mice expressed ovalbumin (OVA) as “self” in both their thymus and pancreatic beta cells [34]. Presentation of OVA by dendritic cells to diabetogenic CD8+ OVA-reactive T cells was significantly stimulated by administration of antibodies specific to OVA. This response was not observed in mice lacking activating Fc R, indicating that the antibody-driven effector T-cell activation was indeed Fc R dependent.

However, autoantibodies are not always damaging to the organism, but can have protective functions [35, 36], and natural autoantibodies are commonly found in healthy individuals. Most of these antibodies are of the IgM isotype and have been speculated to have protective functions. One of these functions is the clearance of dying and aging cells and in mice natural IgM autoantibodies bind to epitopes specifically expressed on apoptotic cells [37, 38] enhancing the clearance of these cells, which may otherwise elicit a pathogenic autoimmune response [39, 40]. Lack of secreted IgM has been shown to correlate with an increase in pathogenic IgG autoantibodies and autoimmune disease possibly due to the lack of removal of apoptotic cells [41–43].

The mouse natural autoantibodies that arise without external antigen exposure are secreted from a subset of B cells, named B1 cells [44, 45], and a similar B-cell subset has been recently identified in humans [46]. In patients with SLE, higher levels of IgM associated with apoptotic cell clearance correlate with lower disease activity [47, 48], and healthy twins of SLE patients often present higher levels of these autoantibodies [49]. Another mechanism of protection by natural autoantibodies is the blockage of pathogenic autoantibodies to react with self-antigen [50], and titers of natural IgM specific to dsDNA correlated inversely with the severity of glomerulonephritis (GN) in SLE [51, 52].

Besides producing antibodies, activated B cells are also fundamental for coordinating T-cell functions as B-cell-depleted mice exhibit a dramatic decrease in numbers of CD4+ and CD8+ T cells, and a significant inhibition of memory CD8+ T cells [53, 54]. There are several antibody-independent mechanisms by which B cells can affect T cells and other immune cells as will be discussed below.

2.2. B Cells as Antigen-Presenting Cells

Especially at low antigen concentrations B cells function as superior APCs [55]. Other APCs (macrophages and dendritic cells) internalize antigen through pinocytosis, while B cells capture antigen through their antigen-specific B-cell receptors (BCRs) (Figure 1(c)). The ability of antigen-specific B cells to serve as efficient APCs has been demonstrated in several in vivo studies [56]. This mechanism is 1,000–10,000-fold more efficient than pinocytosis, and antigens can be successfully presented at very low concentrations, as those present in autoimmune diseases [57–59]. Moreover, the BCR-conferred antigen-specificity enables the B cells to focus the immune response to a specific antigen [60].

B cells serve as APCs in autoimmune diseases including rheumatoid arthritis and type 1 diabetes [61, 62]. Immunoglobulin-deficient mice in a model of autoimmune arthritis (proteoglycan-induced arthritis) did not develop arthritis. The observation that T cells isolated from proteoglycan-immunized transgenic mice that express membrane Ig (mIgM), but lack circulating antibodies, were unable to transfer disease suggested that these T cells were not adequately primed and that antigen-specific B cells may be required for this process. This was confirmed when direct targeting of proteoglycan to the BCR induced T cells competent to transfer arthritis [61].

The role of B cells as APC in type 1 diabetes is discussed in a separate chapter below.

2.3. Proinflammatory Cytokine Secretion

Activated B cells can secrete proinflammatory cytokines like interleukin-6 (IL-6), interferon-gamma (IFN- ), IL-4, and TGF-beta [63–65]. These inflammatory mediators modulate the migration of dendritic cells, activate macrophages, exert a regulatory role on T-cell functions, and provide feedback stimulatory signals for further B-cell activation.

2.4. Modulation of Antigen Processing and Presentation

Besides facilitating antigen uptake, both membrane-bound and soluble antibodies can modulate the processing pattern of the antigen [66–69] (Figure 1(d)). Depending on the antigenic epitope recognized by the antibody or the BCR of the B cell, different T-cell determinants are presented on the MHC molecule [67, 70–73]. Indeed proteolysis of antigen-antibody complexes yielded protein fragments that were not observed in the absence of antibody [74]. This might have consequences for the ensuing T-cell response, in particular when otherwise cryptic T-cell determinants are presented. This bias in processing of antigen complexed with antibody may stem from antibody-mediated protection of distinct peptide sequences from degradation and/or sequestering of peptide sequences and interference with the loading of peptides onto MHC molecules [75].

The relevance of this mechanism in autoimmune diseases was suggested by studies showing that antibodies to thyroglobulin could augment or suppress processing and presentation of pathogenic T-cell determinants [76] and will be discussed further in the T1D chapter.

2.5. Ectopic Germinal Centers

B cells aid in the de novo generation of ectopic germinal centers (GCs) within inflamed tissues that can be observed during periods of chronic inflammation [77]. These ectopic structures are probably not a unique disease-specific occurrence, but a consequence of chronic inflammation. Activated T and B cells that infiltrate the site of chronic inflammation express membrane-bound lymphotoxin

(LT ) [78]. High levels of LT eventually promote the differentiation of resident stromal cells into follicular dendritic cells (FDCs) and the development of ectopic GCs [79, 80]. These structures are similar to the GCs of secondary lymphoid organs and have been described in systemic lupus erythematosus, Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, Sjögren’s syndrome, multiple sclerosis, and type 1 diabetes [81–83]. The function and potential pathogenic role of ectopically formed lymphoid structures within inflamed tissues remains unclear. However, plasma cells residing within the ectopic GCs secrete autoantibodies [84], making it plausible that ectopic GCs have a role in the maintenance of immune pathology [85, 86].

Recent research has demonstrated that B cells are also involved in the inhibition of inflammatory immune responses, a function carried out by a subpopulation of B cells fittingly named regulatory B cells or Bregs.

3. IL-10 Secreting B Cells and Regulatory B Cells

A role of B cells in the inhibitory regulation of immune responses was initially suggested in autoimmune mice, where absence of B cells led to increased inflammation [87–89]. Transfer of wild-type B cells, but not IL10-negative B cells, reversed the inflammatory response [90], and IL-10 producing B cells were shown to suppress inflammation in mouse models of autoimmune diseases [91–93]. The significance of this anti-inflammatory cytokine was further supported by the finding that IL-10-deficient mice showed more severe disease accompanied with an increase in Th1 cytokine levels [88, 94, 95] and lower levels of regulatory T cells [96]. IL-10 is secreted by monocytes, Th2 T cells, regulatory T cells, and a rare subset of B cells. These IL-10 secreting B cells [97–100] can suppress CD4+ T cell responses and prevent autoimmune disease in mouse models and have been fittingly named regulatory B cells or Bregs [98–100]. The involvement of Bregs in human disease was first suggested by the observation that B-cell depletion can exacerbate Th-1-mediated autoimmune conditions such as ulcerative colitis [101] and psoriasis [102], and IL-10 producing B cells have been identified in humans [65]. For detailed discussions of Bregs please refer to other excellent reviews [99, 103].

4. B-Cell Tolerance

B-cell tolerance is established at multiple checkpoints throughout B-cell development, both in the bone marrow and the periphery. It has been estimated that 50% to 75% of newly produced human B cells are autoreactive and must be eliminated by tolerance mechanisms [104]. Induction of B-cell tolerance starts in the bone marrow. The major elimination mechanisms are receptor editing, clonal deletion, and anergy [105–107]. Defects in this early tolerance induction have been observed in subjects with rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes [53, 108–110].

Once autoreactive B cells are removed, the immature B cells leave the bone marrow and migrate to the spleen, where they may encounter autoantigen not present in the bone marrow. B cells with high avidity to autoantigen are deleted, while low-avidity or very-low avidity interactions lead to anergy or ignorance, respectively [111].

An encounter with true foreign antigen triggers the migration of the B cell to the T-cell zone of GCs, and activation by antigen-specific CD4+ T cells. During the ensuing rapid proliferation phase B cells undergo somatic hypermutation predominantly of the variable regions of their immunoglobulins. Only those B cells that express antibodies with increased affinity are selected to survive and exit the GC as antibody producing plasma cells or memory cells (for details see [112]).

4.1. Loss of Tolerance

Any of the above-discussed tolerance checkpoints can be faulted by genetic mutations allowing autoreactive B cells to survive. Some of these mutations have been identified in mouse models of autoimmune diseases with parallel findings in human disease. (1) Faulty negative selection at the immature B cells stage: NZM2410 mice spontaneously develop severe lupus nephritis at an early age. These mice carry the lupus susceptibility locus Sle1 containing at least three subloci, Sle1a, Sle1b, and Sle1c, involved in B-cell tolerance and activation of CD4+ T cells [113]. Using Sle1 congenic C57Bl6 mice, Kumar and colleagues [114] showed that mutations located within the Sle1 induced loss of B-cell tolerance through impaired negative selection of autoreactive B cells at the immature B-cell stage. (2) Increased B-cell signaling by overexpression of BCR signal-enhancing molecules or deficiency of molecules inhibiting BCR signaling: CD19 is a B-cell surface molecule that decreases the threshold for BCR stimulation. Hyperexpression of CD19 in mice led to increased levels of serum antibodies and increased B-cell activation, while the loss of CD19 reversed these phenotypes [115–119]. Deficiency of molecules that inhibit BCR-signaling, such as SHP-1 [120], Lyn [121], or Fc RIIB [122], causes increased B-cell signaling and initiates development of systemic autoimmunity in mice. The inhibitory Fc RIIB is expressed on B cells, where it regulates activating BCR signals. Lack of Fc RIIB expression leads to autoimmunity and autoimmune diseases [122–124]. The importance of Fc RIIB in human autoimmunity is exemplified by the finding that B cells from patients with lupus express lower levels of Fc RIIB on their surface due to polymorphisms in their Fc RIIB promoter [125], or the receptor itself [126, 127]. (3) Generation of autoreactive immunoglobulins during somatic hypermutation: during affinity maturation the massive somatic hypermutations can also cause the inadvertent development of autoreactive immunoglobulins. While normally the resulting autoimmune B cells may either not receive necessary survival signals [128] or be eliminated, they accumulate in autoimmune diseases. (4) Increased survival of autoreactive B cells: B-cell activation factor (BAFF) is a B-cell survival factor and overexpression of BAFF in transgenic mice led to an expansion of peripheral B cells with higher autoantibody levels and the development of a lupus-like disease in the animals [28]. Elevated serum levels of BAFF have been found in patients with rheumatoid arthritis, systemic lupus erythematosus, and primary Sjörgren’s syndrome [129–131]. These observations make BAFF a potential target for therapy [132, 133]. Indeed neutralization of BAFF was shown to be associated with loss of mature B cells [134] and reduced symptoms of autoimmune diseases in animal models [135, 136].

In the following the role of B cells in autoimmune diseases will be discussed in the context of systemic lupus erythematosus, rheumatoid arthritis, and type 1 diabetes. Systemic lupus erythematosus is a classic B-cell-mediated autoimmune disease, while rheumatoid arthritis and type 1 diabetes were initially considered to be predominantly T cell mediated. However recent studies suggest a role of B cells in the pathogenesis of these autoimmune diseases, as will be discussed in detail below.

Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease, characterized by hyperglobulinemia, immune complex deposition, and end organ damage. B cells have been identified as major contributors to SLE, and B-cell depletion in SLE animal models abrogated the development of disease [54, 137]. Indeed, generalized B-cell hyperactivity has been documented in several murine models of lupus [138] and is also evident in patients with lupus [139, 140], where the number of B cells at all stages of activation is increased during active disease [141]. Both the decrease in proapoptotic genes and the increase in prosurvival gene expression have been suggested to cause this prolonged half-life of B cells in SLE (see also above).

A pathogenic role of autoantibodies in SLE is supported by the observation that the passive transfer of anti-DNA antibodies induces distinct features of lupus nephritis in healthy animals [142, 143]. Autoantibodies in SLE contribute to end organ damage in glomerulonephritis (glomerular antibodies and anti-DNA antibodies) [144–146], congenital heart block (anti-Ro antibodies) [147], and thrombosis (anticardiolipin antibodies) [148]. Other autoantibodies are directed to diverse self-molecules, most notably antinuclear antibodies directed to double stranded DNA (dsDNA) [149], and small nuclear ribonucleoprotein (snRNP). However, B cells also have antibody-independent effects on the SLE pathogenesis. These functions include antigen presentation, costimulation of T cells, and secretion of proinflammatory cytokines. This role was evaluated in a set of experiments conducted by Chan and colleagues, where B cells in a SLE mouse model carried a mutation that prevented the secretion of antibodies [54]. Thus these animals had B cells but were devoid of circulating antibodies. Despite the absence of autoantibodies, the mice developed nephritis, indicating an antibody-independent effect of B cells. B-cell-deficient MRL/lpr mice remain disease-free and fail to develop activated CD8+ and CD4+ T cells found in B-cell-sufficient mice, a finding attributed to loss of B cell-CD4 T cell interactions [150].

The dual effect of IL-10 as a B-cell stimulator and inhibitor of T-cell activation is exemplified in SLE [151]. In mice models for SLE, IL-10 appears to exert mainly its above-discussed anti-inflammatory effect and IL-10-deficient mice develop a more severe disease with increased proinflammatory cytokine levels [152], while transfer of IL-10 producing B cells induced the expansion of regulatory T cells [96]. However, in human SLE IL-10 promotes disease, IL-10 serum levels are significantly elevated and correlate with disease activity [153] and IL-10 induced a significant increase of anti-DNA antibody secretion in cultured PBMCs from SLE patients [154]. This antibody secretion was significantly reduced in the presence of neutralizing IL-10-specific antibodies [155] and treatment with IL-10-specific monoclonal antibodies led to marked improvement in participants of a small clinical trial [156]. The protective effect of IL-10 in mice appears to be mediated through T-cell regulation, as IL-10 overexpression in a mouse model for lupus resulted in reduced T-cell activation, while B-cell phenotypes remained unaffected [151]. In SLE patients immune cells that normally suppress B-cell activation are defective and do not counteract the IL-10-mediated stimulation of B cells resulting in the subsequent secretion of autoantibodies [157].

Rheumatoid Arthritis (RA) is a chronic inflammation of the joint capsule (synovium) and synovial membranes, associated with proliferation of synovial fibroblasts and macrophages, leading eventually to cartilage injury and bone erosion [158]. While T cells are a major component in the pathogenesis, several observations suggest that B cells are necessary for the development of the disease, as B-cell deficiency in RA animal models abrogates disease [159, 160], and autoimmune T cells alone are not sufficient to induce disease [161]. At least two mechanisms of B-cell involvement are currently considered: the production of autoantibodies and antigen presentation. Autoantibodies in patients with RA typically target several autoantigens, including rheumatoid factor (RF), type II collagen (CII), and citrullinated proteins (ACPA). A model for the pathological role of RA-associated autoantibodies will be discussed for autoantibodies directed to CII. These autoantibodies are found in

70% of patients with early RA [162–164] both in their serum and synovial fluids. A pathogenic role of CII-specific antibodies was indicated in an animal model termed collagen-induced arthritis (CIA), where immunization of animals with CII induced the development of CII antibodies [165] and triggered arthritic symptoms [166–168]. Moreover, arthritic symptoms were also observed after passive transfer of CII-reactive serum obtained from CIA animals [169], patients with RA [170], or monoclonal antibodies specific to CII [165, 171] to healthy recipient animals, further supporting a pathological role of CII antibodies. CII autoantibodies are thought to mediate the formation of immune complexes in the joint, followed by complement activation and inflammatory cell recruitment. After Fc R ligation, the activated cells secrete proinflammatory cytokines, further activating an immune reaction consisting of synovial macrophages and infiltrating mononuclear cells with the eventual release of tissue-degrading enzymes that cause cartilage damage [172]. CII autoantibodies may also have a direct pathogenic function, which occurs in the absence of inflammatory mediators [173]. Here the antibodies modify the synthesis of collagen fibrils effecting cartilage synthesis and stability [174–176], possibly through steric hindrance of collagen epitopes that are important for the formation of collagen fibrils [177–179].

Type 1 Diabetes (T1D) is an organ specific autoimmune disease, characterized by the destruction of the insulin-producing beta cells in the pancreas. During progression towards T1D the pancreatic islets are infiltrated by mononuclear cells consisting of CD4+ and CD8+ T cells, B cells, macrophages, and dendritic cells [180, 181]. Both CD4+ and CD8+ T cells contribute to the ultimate attack on the beta cells [182], but in recent years the pathogenic role of B cells is beginning to emerge [183, 184]. A major hallmark of the autoimmunity leading to T1D is the presence of autoantibodies to beta cell antigens. At the time of clinical diagnosis more than 90% of patients present at least one of the T1D-associated autoantibodies [185]. The four beta cell antigens most frequently targeted by autoantibodies are insulin [186], the smaller isoform of glutamate decarboxylase (GAD65) [187], protein-tyrosine-phosphatase-like protein IA-2 [188], and the zinc transporter 8 (ZnT8) [189]. These autoantigens are also targeted by autoreactive T cells, suggesting a collaborative interaction between T and B cells [190]. No direct pathogenic role has been assigned to these autoantibodies and they are generally viewed as markers only. However a potential role of GAD65Ab in enhanced antigen uptake has been suggested [191]. Stimulation of GAD65-specific T-cell clones with human recombinant GAD65 was tested in the presence of sera obtained from GAD65Ab-positive T1D patients and GAD65Ab-negative T1D patients. Only sera from GAD65Ab-positive patients significantly enhanced T-cell stimulation. Moreover, this effect was inhibited by monoclonal antibodies to the FcR, suggesting Fc-mediated uptake of GAD65 complexed with GAD65Ab as the underlying mechanism.

However, the major mechanism by which B cells contribute to T1D development is the antibody-independent presentation of beta cell antigens [190, 192, 193]. Nonobese diabetic (NOD) mice deficient of mature B cells do not develop T1D [193–199]. In the absence of B cells, NOD mice showed significantly lower numbers of CD4+ and CD8+ T cells in their insulitic lesions [62, 195, 198–200], suggesting a role of B cells in the activation of autoreactive T cells. The function of B cells as APCs was illustrated in NOD mice whose B cells were rendered MHC class II deficient [201]. Although these animals retained their ability to present antigen via dendritic cells and macrophages, they were protected from diabetes development. However, the presence of insulitis in B-cell-deficient mice [62] and the report of at least one B-cell-deficient T1D patient [202] indicate that B cells may not be absolutely essential for the development of T1D and can be substituted by other APCs. As discussed above, B cell can focus the immune response towards a specific antigen. NOD mice that expressed only B cells specific to an irrelevant antigen (Hen Egg Lysosome) did not develop an autoantigen-specific T-cell response and remained healthy, indicating that only autoantigen-specific B cells enhance the development of T1D in the NOD mouse [203]. We will discuss the role of autoantigen-specific B cells exemplified by GAD65-specific B cells. Although GAD65 levels in murine pancreatic beta cells are very low, it is a major autoantigen in the pathogenesis of T1D in the NOD mouse [204]. GAD65-specific T cells have been demonstrated in both T1D patients and the NOD mouse [205–209]. Adoptive transfer of GAD65-reactive T cells isolated from NOD mice caused recipient animals to develop T1D [207, 210], supporting the concept of diabetogenic GAD65-specific T cells in the pathogenesis of T1D. Importantly, the development of these GAD65-specific T cells depends on the presence of B cells [190, 192, 203]. The finding that reconstitution of B-cell-depleted NOD mice with B cells reinstated T1D only if the repopulating B cells were primed with GAD65 [190] suggests that B-cell-mediated presentation of GAD65 stimulates GAD65-reactive T effector cells to target pancreatic beta cells. It is however not only the antigen specificity, but also the epitope specificity of the B cells that affects the T-cell response. GAD65-specific B-cell hybridomas with different epitope specificities were tested for their capacity to stimulate GAD65-specific T-cell clones. Those T-cell clones whose epitope lays outside of the BCR epitope showed increased T-cell responses, while T-cell clones whose epitope lays inside the BCR epitope showed suppressed responses, suggesting that the BCR epitope specificity can promote the presentation of some T-cell determinants, while suppressing that of others [211, 212].

Based on the promising results of B-cell depletion in the prevention of T1D in NOD mice, the effect of B-cell depletion on human T1D was tested in a phase II multicenter clinical trial on newly diagnosed human T1D patients [213]. One year after treatment a delay in the loss of beta cell function as shown by the preservation of C-peptide was demonstrated. Moreover, patients required less insulin and had better overall blood glucose control. These results confirm that B cells contribute also to human T1D.

Gathering the current understanding of B cells in T1D, the following mechanisms have been suggested (Figure 2). Beta cell antigen is taken up via BCR by antigen-specific B cells (1) and presented on MHC class II molecules to CD4+ T cells (2). Activated CD4+ T cells provide help to B cells (3). B cells differentiate to plasma cells and secrete autoantibodies (4). These autoantibodies form autoantigen-autoantibody complexes that bind to the Fc R on other APCs (5). This enhanced antigen presentation eventually triggers both natural killer cells and CD8+ T cells to attack the pancreatic beta cell.


Model of pathogenic function of B cells in type 1 diabetes. Islet cell antigen released from the pancreatic beta cells is being taken up at low antigen concentrations by antigen-specific B cells, which present the antigen determinants to CD4+ T cells. T cells provide help to the B cells to eventually differentiate into antibody secreting plasma cells. Autoantibodies can now bind to the autoantigen and the resulting autoantibody/autoantigen complexes are efficiently taken up via FcR present on other APCs. This enhanced autoantigen uptake and presentation finally activates cytotoxic CD8+ T cells, which carry out the killing of the beta cells.

5. B-Cell Depletion

The growing understanding that B cells play a pathological role also in autoimmune diseases that are traditionally viewed as T cell mediated led to B-cell depletion treatment not only in diseases that are clearly B cell dominated, but also in autoimmune diseases that are traditionally viewed as T cell mediated, such as T1D.

B-cell depletion can target a number of different B-cell molecules, either with the goal of B-cell elimination, or the suppression of survival. Four major classes of B-cell targeting drugs have been evaluated for the treatment of autoimmune diseases: neutralization of survival factors BAFF and APRIL [214], killing of B cells using monoclonal antibodies directed to CD19, CD20, and CD22 [215–217], induction of apoptosis using reagents targeting the BCR itself or BCR associated transmembrane signaling proteins such as CD79 [193, 218], and ablation of the formation of ectopic GCs by antibodies against lymphotoxin- receptor (LT R) [219].

B-cell depletion for treatment of human autoimmune diseases is often accomplished through antibodies targeting the surface molecule CD20 (e.g., Rituximab and Ofatumumab). Treatment with these antibodies depletes B cells by a combination of antibody-mediated cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and antibody-triggered apoptosis [220] (Figure 3). The CD20 density on B cells appears to be important for CDC, since it is highly correlated with CDC [221]. CD20mAb/CD20 immune complexes aggregate in microdomains, where the antibodies’ Fc regions are bound by C1q, leading to complement activation [222]. CD20 may also act as a signaling molecule to trigger apoptosis when engaged with CD20mAb [223, 224].


B-cell depletion with CD20 (Rituximab). Anti-CD20 mAb can direct the killing of B cells by antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), or apoptosis. ADCC is triggered by the interaction between the Fc region of the antibody and the FcR on effector cells of the immune system. In CDC the Fc region is bound by the complement component C1q, which triggers a proteolytic cascade. Apoptosis occurs when CD20 molecules are cross-linked by anti-CD20 mAb in lipid rafts and activate signaling pathways leading to cell death.

B-cell depletion using Rituximab has been used for the treatment of a number of autoimmune and chronic inflammatory diseases [213, 225, 226]. Rituximab treatment results in nearly undetectable circulating B-cell levels one month after therapy and B cell counts remain low for 6–12 months [227]. Because the drug targets B cells expressing surface CD20, mature and memory CD20+CD27+ B cells in blood and primary lymphoid organs are effectively depleted, while long-lived plasma cells are not directly depleted [228], and Rituximab treatment appears not to affect circulating IgG levels [229], while reducing circulating IgM levels [230]. This effect of Rituximab is illustrated by the observation that immunization within the first 9 months after Rituximab treatment results in significantly reduced antibody responses, which develop from IgM-positive B cells [231, 232]. It is therefore of interest that for some autoimmune diseases B-cell depletion was reported to be associated with a decrease in IgG autoantibody titers [77] and specific depletion of autoreactive B cells by CD20mAb was demonstrated in mice [233]. As bone marrow stem cells and early B-cell precursors (pro-B cells) do not express CD20 [234], the new naïve B cells repopulate the B-cell compartment once the drug has cleared the system, allowing the immune response to return to normal. Disease relapses in about 50% of patients either at the time that B-cell numbers increase to pretreatment levels or within 3 months, while in other cases clinical relapse can be delayed for years [235]. Additional Rituximab courses can induce subsequent remission [236]. Multiple Rituximab courses are often associated with progressive decrease in circulating IgM [237] and IgG levels [238].

The antibody-independent effect of Rituximab treatment may be due to the elimination of B cells as APC and subsequent reduced stimulation of T cells [239, 240]. However, not all CD20+ B cells are equally affected by Rituximab treatment. B cells located in the peritoneal cavity are surprisingly resistant to depletion [241]. While these B cells express normal CD20 densities and are bound by CD20mAb, only about 50% of these cells are depleted. These location-dependent sensitivities to CD20mAb-mediated depletion could have significant consequences for therapy and may be the reason of the heterogeneity of results in human clinical trials. Other factors such as gender, age, and weight [242] and immunological profile [243] affect the outcome of Rituximab treatment. The major side effect of B-cell depletion is the risk of severe infections, which needs to be taken into consideration when evaluating the risks and benefits of B-cell depletion [244, 245].

In summary, B-cell depletion offers a promising therapy for the treatment of a variety of autoimmune diseases. The treatment is usually well tolerated however, adverse events include infusion reactions, infections, and hypogammaglobulinemia.

6. Conclusions and Future Directions

The traditional concept of T-cell-mediated and autoantibody-mediated autoimmune diseases needs to be adjusted to reflect the interaction of different immune cells in autoimmune pathogenesis. The recognition of the contribution of B cells in the pathogenesis of autoimmune diseases, which are traditionally viewed as T cell mediated, led to promising immune-modulating therapies.

Global B-cell depletion eliminates both protective and pathogenic B cells. The success of B-cell depletion is therefore dictated by the extent of depletion of protective versus pathogenic B cells. The hopes that B-cell depletion would allow the restoration of immunological tolerance with long-term remission were not fulfilled, as is evident from the recurrence of autoimmune disease after the B-cell compartment is replenished. Selective depletion of antigen-specific B cells may provide an alternative to global B-cell depletion. This approach has the additional advantage that unlike Rituximab treatment it may also eliminate CD20-long-lived autoreactive plasma cells.

Several mechanisms are currently investigated in different in vitro and in vivo models of autoimmune diseases, a few of which will be discussed here.

Autoantigens can be fused to the IgG1 Fc domain to activate complement and FcR-dependent effector cell responses. This approach has been successfully evaluated in vitro and in vivo for the treatment of multiple sclerosis by autoantigen fused to Fc, which induced the effective and specific effector lysis of autoantigen-specific B cells [246]. An inhibitory B-cell signal can be induced by cross-linking of the autoantigen-specific BCR with the inhibitory Fc RIIb. Autoantigen fused to an Fc RIIb-binding mAb successfully reduced autoantibody levels and disease symptoms in lupus-prone MRL/lpr mice [247–249]. Autoantigen can also be coupled to an antibody specific to complement receptor 1 (CR1). CR1 negatively regulates the proliferation and differentiation of activated B cells after binding C3b [250]. In a small clinical trial SLE patients treated with dsDNA coupled to a CR1-specific monoclonal antibody showed a significant reduction of dsDNA autoantibody titers [251]. In an early study, Blank et al. employed anti-idiotypic antibodies directed to a pathogenic anti-DNA idiotype. Administration of this anti-idiotypic antibody alone or coupled to the cytotoxin saporin induced a significant reduction in anti-DNA antibody titer and diminished clinical manifestation in lupus-prone mice [252]. In a similar approach we demonstrated that GAD65Ab-specific anti-idiotypic antibodies protected NOD mice from development of T1D [253]. In addition to the direct elimination of antigen-specific B cells, autoantigen-fusion proteins can also bind pathogenic autoantibodies and route them to clearance.

Recently Bollmann proposed the targeted elimination of autoantigen-specific B cells using artificial antigens linked to magnetic nanoparticles. Here the autoantigen-specific B cells would be removed in an extracorporeal filtration method in an attempt to suppress or cure the autoimmune response [254].

The feasibility of these specific B-cell depletion approaches needs to be further evaluated however, they offer new therapeutic options for the treatment of autoimmune diseases.

Abbreviations

AChR: ACh receptor
ACPA: Citrullinated proteins
ADCC: Antibody-dependent-cell-mediated cytotoxicity
APCs: Antigen presenting cells
BAFF: B-cell activation factor
BCR: B-cell receptors
Bregs: Regulatory B cells
CII: Type II collagen
CDC: Complement-dependent cytotoxicity
FcR: Fc receptor
Fc R: Fc gamma receptor
FDCs: Follicular dendritic cells
GAD65: 65 kD isoform of glutamate decarboxylase
GC: Germinal centers
IA-2: Protein-tyrosine-phosphatase-like protein
IFN- : Interferon-gamma
LT : Membrane-bound lymphotoxin
LT R: Lymphotoxin- receptor
MHC: Major histocompatibility complex
mIgM: Membrane IgM
NOD: Nonobese diabetic
OVA: Ovalbumin
RA: Rheumatoid arthritis
RF: Rheumatoid factor
SLE: Systemic lupus erythematosus
T1D: Type 1 diabetes
TPO: Thyroid peroxidase
TSH: Thyroid stimulating hormone
ZnT8: Zinc transporter 8.

Acknowledgments

This work was supported by the National Institutes of Health (DK26190) and the Juvenile Diabetes Research Foundation.

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Copyright

Copyright © 2012 Christiane S. Hampe. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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137. Kang ZH, Bricault CA, Borducchi EN, Stephenson KE, Seaman MS, Pau M, et al. Similar epitope specificities of IgG and IgA antibodies elicited by Ad26 vector prime, Env protein boost immunizations in rhesus monkeys. J Virol. (2018) 92:e00537�. doi: 10.1128/JVI.00537-18

138. Mei HE, Frolich D, Giesecke C, Loddenkemper C, Reiter K, Schmidt S, et al. Steady-state generation of mucosal IgA+ plasmablasts is not abrogated by B-cell depletion therapy with rituximab. Blood. (2010) 116:5181�. doi: 10.1182/blood-2010-01-266536

139. Iversen R, Snir O, Stensland M, Kroll JE, Steinsbo O, Korponay-Szabo IR, et al. Strong clonal relatedness between serum and gut IgA despite different plasma cell origins. Cell Rep. (2017) 20:2357�. doi: 10.1016/j.celrep.2017.08.036

140. Neu KE, Guthmiller JJ, Huang M, La J, Vieira MC, Kim K, et al. Spec-seq unveils transcriptional subpopulations of antibody-secreting cells following influenza vaccination. J Clin Invest. (2018). doi: 10.1172/JCI121341

141. Patricia D'souza M, Allen MA, Baumblatt JAG, Boggiano C, Crotty S, Lymph Node Webinar C, et al. Innovative approaches to track lymph node germinal center responses to evaluate development of broadly neutralizing antibodies in human HIV vaccine trials. Vaccine. (2018) 36:5671�. doi: 10.1016/j.vaccine.2018.07.071

142. Linterman MA, Hill DL. Can follicular helper T cells be targeted to improve vaccine efficacy? F1000Res. (2016) 5:88. doi: 10.12688/f1000research.7388.1

143. Bart PA, Meuwly JY, Corpataux JM, Yerly S, Rizzardi P, Fleury S, et al. Sampling lymphoid tissue cells by ultrasound-guided fine needle aspiration of lymph nodes in HIV-infected patients. Swiss HIV Cohort Study AIDS. (1999) 13:1503𠄹. doi: 10.1097/00002030-199908200-00010

144. Havenar-Daughton C, Carnathan DG, Torrents De La Pena A, Pauthner M, Briney B, Reiss SM, et al. Direct probing of germinal center responses reveals immunological features and bottlenecks for neutralizing antibody responses to HIV env trimer. Cell Rep. (2016) 17:2195�. doi: 10.1016/j.celrep.2016.10.085

145. Cirelli KM, Crotty S. Germinal center enhancement by extended antigen availability. Curr Opin Immunol. (2017) 47:64𠄹. doi: 10.1016/j.coi.2017.06.008

146. Haynes BF, Kelsoe G, Harrison SC, Kepler TB. B-cell-lineage immunogen design in vaccine development with HIV-1 as a case study. Nat Biotechnol. (2012) 30:423�. doi: 10.1038/nbt.2197

147. Xiao X, Chen W, Feng Y, Dimitrov DS. Maturation Pathways of Cross-Reactive HIV-1 Neutralizing Antibodies. Viruses. (2009) 1:802�. doi: 10.3390/v1030802

148. Xiao X, Chen W, Feng Y, Zhu Z, Prabakaran P, Wang Y, et al. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem Biophys Res Commun. (2009) 390:404𠄹. doi: 10.1016/j.bbrc.2009.09.029

149. Bonsignori M, Hwang KK, Chen X, Tsao CY, Morris L, Gray E, et al. Analysis of a clonal lineage of HIV-1 envelope V2/V3 conformational epitope-specific broadly neutralizing antibodies and their inferred unmutated common ancestors. J Virol. (2011) 85:9998�. doi: 10.1128/JVI.05045-11

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151. Abbott RK, Lee JH, Menis S, Skog P, Rossi M, Ota T, et al. Precursor frequency and affinity determine B cell competitive fitness in germinal centers, tested with germline-targeting HIV vaccine immunogens. Immunity. (2018) 48:133� e136. doi: 10.1016/j.immuni.2017.11.023

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157. Talaat KR, Luke CJ, Khurana S, Manischewitz J, King LR, Mcmahon BA, et al. A live attenuated influenza A(H5N1) vaccine induces long-term immunity in the absence of a primary antibody response. J Infect Dis. (2014) 209:1860𠄹. doi: 10.1093/infdis/jiu123

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Keywords: B cell memory, vaccination, mouse vs. human, influenza virus, infection

Citation: Palm A-KE and Henry C (2019) Remembrance of Things Past: Long-Term B Cell Memory After Infection and Vaccination. Front. Immunol. 10:1787. doi: 10.3389/fimmu.2019.01787

Received: 14 June 2019 Accepted: 16 July 2019
Published: 31 July 2019.

Michael Vajdy, EpitoGenesis, United States

Johannes Tr࿌k, University Children's Hospital Zurich, Switzerland
Claude-Agnes Reynaud, Institut National de la Santé et de la Recherche Mຝicale (INSERM), France

Copyright © 2019 Palm and Henry. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

† Present address: Anna-Karin E. Palm, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden


BIO 140 - Human Biology I - Textbook

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Chapter 26

The Adaptive Immune Response: B-lymphocytes and Antibodies

  • Explain how B cells mature and how B cell tolerance develops
  • Discuss how B cells are activated and differentiate into plasma cells
  • Describe the structure of the antibody classes and their functions

Antibodies were the first component of the adaptive immune response to be characterized by scientists working on the immune system. It was already known that individuals who survived a bacterial infection were immune to re-infection with the same pathogen. Early microbiologists took serum from an immune patient and mixed it with a fresh culture of the same type of bacteria, then observed the bacteria under a microscope. The bacteria became clumped in a process called agglutination. When a different bacterial species was used, the agglutination did not happen. Thus, there was something in the serum of immune individuals that could specifically bind to and agglutinate bacteria.

Scientists now know the cause of the agglutination is an antibody molecule, also called an immunoglobulin . What is an antibody? An antibody protein is essentially a secreted form of a B cell receptor. (In fact, surface immunoglobulin is another name for the B cell receptor.) Not surprisingly, the same genes encode both the secreted antibodies and the surface immunoglobulins. One minor difference in the way these proteins are synthesized distinguishes a naïve B cell with antibody on its surface from an antibody-secreting plasma cell with no antibodies on its surface. The antibodies of the plasma cell have the exact same antigen-binding site and specificity as their B cell precursors.

There are five different classes of antibody found in humans: IgM, IgD, IgG, IgA, and IgE. Each of these has specific functions in the immune response, so by learning about them, researchers can learn about the great variety of antibody functions critical to many adaptive immune responses.

B cells do not recognize antigen in the complex fashion of T cells. B cells can recognize native, unprocessed antigen and do not require the participation of MHC molecules and antigen-presenting cells.

B Cell Differentiation and Activation

B cells differentiate in the bone marrow. During the process of maturation, up to 100 trillion different clones of B cells are generated, which is similar to the diversity of antigen receptors seen in T cells.

B cell differentiation and the development of tolerance are not quite as well understood as it is in T cells. Central tolerance is the destruction or inactivation of B cells that recognize self-antigens in the bone marrow, and its role is critical and well established. In the process of clonal deletion , immature B cells that bind strongly to self-antigens expressed on tissues are signaled to commit suicide by apoptosis, removing them from the population. In the process of clonal anergy , however, B cells exposed to soluble antigen in the bone marrow are not physically deleted, but become unable to function.

Another mechanism called peripheral tolerance is a direct result of T cell tolerance. In peripheral tolerance , functional, mature B cells leave the bone marrow but have yet to be exposed to self-antigen. Most protein antigens require signals from helper T cells (Th2) to proceed to make antibody. When a B cell binds to a self-antigen but receives no signals from a nearby Th2 cell to produce antibody, the cell is signaled to undergo apoptosis and is destroyed. This is yet another example of the control that T cells have over the adaptive immune response.

After B cells are activated by their binding to antigen, they differentiate into plasma cells. Plasma cells often leave the secondary lymphoid organs, where the response is generated, and migrate back to the bone marrow, where the whole differentiation process started. After secreting antibodies for a specific period, they die, as most of their energy is devoted to making antibodies and not to maintaining themselves. Thus, plasma cells are said to be terminally differentiated.

The final B cell of interest is the memory B cell, which results from the clonal expansion of an activated B cell. Memory B cells function in a way similar to memory T cells. They lead to a stronger and faster secondary response when compared to the primary response, as illustrated below.

Antibody Structure

Antibodies are glycoproteins consisting of two types of polypeptide chains with attached carbohydrates. The heavy chain and the light chain are the two polypeptides that form the antibody. The main differences between the classes of antibodies are in the differences between their heavy chains, but as you shall see, the light chains have an important role, forming part of the antigen-binding site on the antibody molecules.

Four-chain Models of Antibody Structures

All antibody molecules have two identical heavy chains and two identical light chains. (Some antibodies contain multiple units of this four-chain structure.) The Fc region of the antibody is formed by the two heavy chains coming together, usually linked by disulfide bonds (Figure 1). The Fc portion of the antibody is important in that many effector cells of the immune system have Fc receptors. Cells having these receptors can then bind to antibody-coated pathogens, greatly increasing the specificity of the effector cells. At the other end of the molecule are two identical antigen-binding sites.

Figure 1: The typical four chain structure of a generic antibody (a) and the corresponding three-dimensional structure of the antibody IgG2 (b). (credit b: modification of work by Tim Vickers)

Five Classes of Antibodies and their Functions

In general, antibodies have two basic functions. They can act as the B cell antigen receptor or they can be secreted, circulate, and bind to a pathogen, often labeling it for identification by other forms of the immune response. Of the five antibody classes, notice that only two can function as the antigen receptor for naïve B cells: IgM and IgD (Figure 2 ). Mature B cells that leave the bone marrow express both IgM and IgD, but both antibodies have the same antigen specificity. Only IgM is secreted, however, and no other nonreceptor function for IgD has been discovered.

IgM consists of five four-chain structures (20 total chains with 10 identical antigen-binding sites) and is thus the largest of the antibody molecules. IgM is usually the first antibody made during a primary response. Its 10 antigen-binding sites and large shape allow it to bind well to many bacterial surfaces. It is excellent at binding complement proteins and activating the complement cascade, consistent with its role in promoting chemotaxis, opsonization, and cell lysis. Thus, it is a very effective antibody against bacteria at early stages of a primary antibody response. As the primary response proceeds, the antibody produced in a B cell can change to IgG, IgA, or IgE by the process known as class switching. Class switching is the change of one antibody class to another. While the class of antibody changes, the specificity and the antigen-binding sites do not. Thus, the antibodies made are still specific to the pathogen that stimulated the initial IgM response.

IgG is a major antibody of late primary responses and the main antibody of secondary responses in the blood. This is because class switching occurs during primary responses. IgG is a monomeric antibody that clears pathogens from the blood and can activate complement proteins (although not as well as IgM), taking advantage of its antibacterial activities. Furthermore, this class of antibody is the one that crosses the placenta to protect the developing fetus from disease exits the blood to the interstitial fluid to fight extracellular pathogens.

IgA exists in two forms, a four-chain monomer in the blood and an eight-chain structure, or dimer, in exocrine gland secretions of the mucous membranes, including mucus, saliva, and tears. Thus, dimeric IgA is the only antibody to leave the interior of the body to protect body surfaces. IgA is also of importance to newborns, because this antibody is present in mother&rsquos breast milk (colostrum), which serves to protect the infant from disease.

IgE is usually associated with allergies and anaphylaxis. It is present in the lowest concentration in the blood, because its Fc region binds strongly to an IgE-specific Fc receptor on the surfaces of mast cells. IgE makes mast cell degranulation very specific, such that if a person is allergic to peanuts, there will be peanut-specific IgE bound to his or her mast cells. In this person, eating peanuts will cause the mast cells to degranulate, sometimes causing severe allergic reactions, including anaphylaxis, a severe, systemic allergic response that can cause death.

Clonal Selection of B Cells

Clonal selection and expansion work much the same way in B cells as in T cells. Only B cells with appropriate antigen specificity are selected for and expanded (Figure 3). Eventually, the plasma cells secrete antibodies with antigenic specificity identical to those that were on the surfaces of the selected B cells. Notice in the figure that both plasma cells and memory B cells are generated simultaneously.

Figure 3: During a primary B cell immune response, both antibody-secreting plasma cells and memory B cells are produced. These memory cells lead to the differentiation of more plasma cells and memory B cells during secondary responses.

Primary versus Secondary B Cell Responses

Primary and secondary responses as they relate to T cells were discussed earlier. This section will look at these responses with B cells and antibody production. Because antibodies are easily obtained from blood samples, they are easy to follow and graph (Figure 4). As you will see from the figure, the primary response to an antigen (representing a pathogen) is delayed by several days. This is the time it takes for the B cell clones to expand and differentiate into plasma cells. The level of antibody produced is low, but it is sufficient for immune protection. The second time a person encounters the same antigen, there is no time delay, and the amount of antibody made is much higher. Thus, the secondary antibody response overwhelms the pathogens quickly and, in most situations, no symptoms are felt. When a different antigen is used, another primary response is made with its low antibody levels and time delay.

Figure 4: Antigen A is given once to generate a primary response and later to generate a secondary response. When a different antigen is given for the first time, a new primary response is made.

Active versus Passive Immunity

Immunity to pathogens, and the ability to control pathogen growth so that damage to the tissues of the body is limited, can be acquired by (1) the active development of an immune response in the infected individual or (2) the passive transfer of immune components from an immune individual to a nonimmune one. Both active and passive immunity have examples in the natural world and as part of medicine.

Active immunity is the resistance to pathogens acquired during an adaptive immune response within an individual ( Table ). Naturally acquired active immunity, the response to a pathogen, is the focus of this chapter. Artificially acquired active immunity involves the use of vaccines. A vaccine is a killed or weakened pathogen or its components that, when administered to a healthy individual, leads to the development of immunological memory (a weakened primary immune response) without causing much in the way of symptoms. Thus, with the use of vaccines, one can avoid the damage from disease that results from the first exposure to the pathogen, yet reap the benefits of protection from immunological memory. The advent of vaccines was one of the major medical advances of the twentieth century and led to the eradication of smallpox and the control of many infectious diseases, including polio, measles, and whooping cough.

Table 1: Active versus Passive Immunity

Natural Artificial
Active Adaptive immune response Vaccine response
Passive Trans-placental antibodies/breastfeeding Immune globulin injections

Passive immunity arises from the transfer of antibodies to an individual without requiring them to mount their own active immune response. Naturally acquired passive immunity is seen during fetal development. IgG is transferred from the maternal circulation to the fetus via the placenta, protecting the fetus from infection and protecting the newborn for the first few months of its life. As already stated, a newborn benefits from the IgA antibodies it obtains from milk during breastfeeding. The fetus and newborn thus benefit from the immunological memory of the mother to the pathogens to which she has been exposed. In medicine, artificially acquired passive immunity usually involves injections of immunoglobulins, taken from animals previously exposed to a specific pathogen. This treatment is a fast-acting method of temporarily protecting an individual who was possibly exposed to a pathogen. The downside to both types of passive immunity is the lack of the development of immunological memory. Once the antibodies are transferred, they are effective for only a limited time before they degrade.

T cell-dependent versus T cell-independent Antigens

As discussed previously, Th2 cells secrete cytokines that drive the production of antibodies in a B cell, responding to complex antigens such as those made by proteins. On the other hand, some antigens are T cell independent. A T cell-independent antigen usually is in the form of repeated carbohydrate moieties found on the cell walls of bacteria. Each antibody on the B cell surface has two binding sites, and the repeated nature of T cell-independent antigen leads to crosslinking of the surface antibodies on the B cell. The crosslinking is enough to activate it in the absence of T cell cytokines.

A T cell-dependent antigen , on the other hand, usually is not repeated to the same degree on the pathogen and thus does not crosslink surface antibody with the same efficiency. To elicit a response to such antigens, the B and T cells must come close together (Figure 5). The B cell must receive two signals to become activated. Its surface immunoglobulin must recognize native antigen. Some of this antigen is internalized, processed, and presented to the Th2 cells on a class II MHC molecule. The T cell then binds using its antigen receptor and is activated to secrete cytokines that diffuse to the B cell, finally activating it completely. Thus, the B cell receives signals from both its surface antibody and the T cell via its cytokines, and acts as a professional antigen-presenting cell in the process.

Figure 5: To elicit a response to a T cell-dependent antigen, the B and T cells must come close together. To become fully activated, the B cell must receive two signals from the native antigen and the T cell&rsquos cytokines.

Chapter Review

B cells, which develop within the bone marrow, are responsible for making five different classes of antibodies, each with its own functions. B cells have their own mechanisms for tolerance, but in peripheral tolerance, the B cells that leave the bone marrow remain inactive due to T cell tolerance. Some B cells do not need T cell cytokines to make antibody, and they bypass this need by the crosslinking of their surface immunoglobulin by repeated carbohydrate residues found in the cell walls of many bacterial species. Others require T cells to become activated.


A Summary of B Cells

The immune system as a whole can be broadly separated into two main branches: the innate immune response and the adaptive immune response. The innate immune response is performed by a system that is always present across the body, while the adaptive immune response appears only in response to an infection and is always specific to a particular infectious agent. B cells are a part of the adaptive immune system.

B cells are one of the two types of lymphocytes, the other kind being T cells. Like most immune cells, B cells have a very specific function: the production of antibodies, which play a major role in immunity. However, in order for a B cell to produce antibodies it must first become activated.

How is a B cell activated?

In order for a B cell to start producing antibodies, a very specific sequence of events must happen. First, an infectious agent, such as a bacterium, must enter the body. Next, a piece of the infectious agent’s machinery, such as a protein, must be visible on the surface of the infectious agent this is where major histocompatibility complex (MHC) class molecules come in.

MHC class molecules come in two primary forms, MHC1 and MHC2, which are found on the cell surface of all nucleated cells in the human body.

In the case of viruses, these stick to a cell’s MHC1 receptor. Some viruses inhibit production of MHC1, which has led the human body to destroy any cell that does not show MHC1 on its surface.

At this point, the protein detected on the surface of the infectious agent can be called an antigen. If the infectious agent is killed by the innate immune response, the protein can be recovered in a number of ways macrophages, for instance, can grab the antigens after consuming an infectious agent and present them on their surface MHC2 receptors.

Some antigens become free-floating after infectious agents have been destroyed. Dendritic cells can ‘taste’ these free-floating antigens and latch onto them, ready to present them. Dendritic cells can also phagocytose (engulf) infectious agents and destroy them particularly slowly, ensuring that they can collect antigens without destroying them[1]. With viruses, the protein stuck to the infected cell’s MHC1 receptor is automatically presented. Cells that present antigens on their surfaces are known as ‘Antigen Presenting Cells’.

Next, to cause activation, the antigen on the MHC of the antigen presenting cell must be detected by a T cell using the T cell’s TCR receptor, while the T cell’s CD28 receptor must detect a B7 receptor on the antigen-presenting cell’s surface, which allows the T cell to realize that the antigen-presenting cell is native to the body.

Either a memory T cell (which stores information vital to immunity) or a naive T cell (which is used for new threats) can be activated in this way. Because all T cells are specific to a single surface protein, only some T cells can be activated by any one antigen these activated cells have been ‘clonally selected’.

The selected T cells become active T helper cells before they begin to massively replicate in a process called clonal expansion. At the same time, a B cell is similarly activated by detecting an antigen on its surface through use of a specific, pre-prepared antibody. However, this will have no effect until a T helper cell brushes against the B cell and binds to its MHC, along with the usual CD28 – B7 binding to recognize the B cell as ‘self’. At this point, the T helper cell releases cytokines – chemical messengers (IL4 specifically) – which are detected by the B cell, causing its activation.

Once a naive B cell is activated, it begins to clonally expand as well, dividing multiple times and specializing (differentiating) the resulting ‘daughter cells’ into either plasma cells or B memory cells. The B memory cells are kept in order to maintain immunity, while the plasma cells begin to produce antibodies, releasing them into surrounding tissues and the blood.

What are antibodies?

Antibodies, otherwise known as immunoglobulins, are water-soluble proteins that the human body uses to fight large, external threats, such as parasites and bacteria, that cannot hide within our own cells.

There are five main types of antibody:

IgE: Defense against helminth worms (and cause of the side effect of allergies)

IgA: General, found in mucus, saliva, breast milk, blood, and tears

IgG: Anti-bacterial and anti-virus, found in all tissues of the body. These are some of the few antibodies that can cross a mother’s placenta without causing damage to the offspring. There are multiple types of this kind.

IgM: Found in blood and lymph, first to be made in response to infection, involved in the B cell activation process

IgD: Involved in the B cell activation process

What are the uses of antibodies?

Antibodies can weaken or kill harmful pathogens (infectious agents) directly, but there are other uses for them.

They can be used to clump pathogens together in a process known as agglutination, which makes it easier for macrophages and other immune cells to target them. This ability to clump pathogens together has a valuable scientific and diagnostic use as well. If a cell is infected by a virus or has a specific receptor on its surface, an antibody specific to that virus or receptor can be used to bind these cells together.

Normally, if you take a group of cells suspended in water and leave them for a while, they will sink to the bottom of their container, leaving a ‘dot’. If they are bound together through enough antibodies, they will instead form a ‘matrix’ within the water, essentially remaining floating within the water to the perception of the human eye. Through this method, a scientist can estimate the concentration of viruses in any sample by detecting how much antibody is needed to prevent the formation of a ‘dot’.

Antibodies are a key method by which the body maintains immunity to specific diseases. Immunity against bacteria mainly relies on antibodies and can be seen through the primary and secondary immune response. The primary immune response is the immune response to the first infection from a specific pathogen, while the secondary immune response is the immune response to an infection by the same pathogen a second time.

During the secondary immune response, the concentration of antibodies in the bloodstream increases much more rapidly after an infection compared to the primary immune response. This is due to the presence of T and B memory cells that remember the pathogen and activate the immune response more quickly this is of major significance to the immune system and how it responds to threats.

The plasma cells know what kind of antibody to make through exposure to particular chemical messengers[2]. Interleukins (ILs), interferons (IFN), transforming growth factor (TGF), and these factors do the following:

IL4 signals the creation of IgE and IgG1

IL4, 2 and 5 signal the creation of IgM

IFN gamma signals the creation of IgG2a and IgG3

TGFbeta signals the creation of IgA and IgG2b

IL4 and IL10 signal the creation of IgD, though IgD can be made spontaneously

In summary, B cells (the precursors to plasma cells) are the source of antibodies within the body. These antibodies have immunological, scientific, commercial, and industrial uses and are a major part of our ability to carry immunity. They are a part of the adaptive immune system and can only impact extracellular threats, which are outside of our cells.

There are many types of antibodies, each with different purposes, which are created in response to chemical signals. Finally, T cells are required to activate B cells, which interconnects two major parts of the immune response.


Gamma/Delta (&gamma&delta) T Cells

  • Their TCR is encoded by different gene segments. [Link]
  • Their TCR binds to
    • antigens that can be intact proteins (just as antibodies do) as well as a variety of other types of organic molecules (often containing phosphorus atoms).
    • antigens that are not "presented" within class I or class II histocompatibility molecules
    • antigens that are not presented by "professional" antigen-presenting cells (APCs) like dendritic cells.

    What is the Function of &gamma&delta T cells?

    Situated as they are at the interfaces between the external and internal worlds, they may represent a first line of defense against invading pathogens. Their response does seem to be quicker than that of &alpha&beta T cells.

    Curiously, many of the antigens to which &gamma&delta T cells respond are found not only on certain types of invaders (e.g., Mycobacterium tuberculosis, the agent of tuberculosis) but also on host cells that are under attack by pathogens.

    Knockout mice that cannot make &gamma&delta T cells are slower to heal injuries to their skin. They are also much more susceptible to skin cancers than normal mice. Perhaps immune surveillance is one of the functions of &gamma&delta T cells.