BLyS—an essential survival factor for B cells: basic biology, links to pathology and therapeutic target

Autoimmunity Reviews 3 (2004) 368 – 375 www.elsevier.com/locate/autrev

BLyS—an essential survival factor for B cells: basic biology, links to pathology and therapeutic target Kevin P. Baker * Department of Antibody Discovery and Development, Human Genome Sciences Inc., 14200 Shady Grove Road, Rockville, MD 20850, USA Received 12 February 2004; accepted 21 February 2004 Available online 8 April 2004

Abstract A paradigm shift in our understanding of autoimmune disease pathology is underway; B cells are now considered to play a central role in disease pathogenesis. Targeting B cells may prove to be an effective route for the development of novel therapeutics. BLyS, a member of the TNF family of cytokines, is an essential survival factor for B cells. Constitutive BLyS overexpression in mice leads to an autoimmune phenotype similar to lupus nephritis. Clinically, BLyS is elevated in patients with systemic autoimmune diseases including rheumatoid arthritis and systemic lupus erythematosus. BLyS ablation results in a block of B cell development in which mature B cells are absent. BLyS binds to three receptors, BR3, TACI and BCMA. Analysis of the receptors suggests that the major pro-survival signals are mediated by BR3, while TACI is involved in negative signaling. BCMA is required for survival of long-lived plasma cells. BLyS signaling results in upregulation of antiapoptotic bcl-2 family members. In animal models of autoimmune disease, BLyS antagonists reduce disease severity and delay disease progression. BLyS is an attractive target for antagonism in autoimmune diseases. Multiple approaches are being taken to antagonize BLyS including a fully human antibody and soluble BLyS receptors. These approaches are currently being tested in clinical trials. D 2004 Elsevier B.V. All rights reserved. Keywords: Cytokine; TNF family; Receptor; Signaling

1. Basic activity Immune responses are mediated by distinct families of cytokines that control the proliferation, differentiation and demise of specific cell types. A recent addition to the TNF family of cytokines, B-lymphocyte stimulator (BLyS, also known as BAFF, TALL-1, THANK and zTNF4) has an important role in the

* Tel.: +1-240-314-4400; fax: +1-301-517-8901. E-mail address: [email protected] (K.P. Baker). 1568-9972/$ - see front matter D 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2004.02.001

development of B cells [1] and appears to play a central role in the development of some autoimmune diseases and B cell malignancies. BLyS was initially reported in the literature as a protein that stimulated B cells in vitro [1]. In these assay systems, BLyS imparts a costimulatory signal that alone has little or no proliferative effect except when combined with a second signal such as surface immunoglobulin cross-linking. BLyS is predominantly produced by cells of the myeloid lineage, notably monocytes, macrophages and dendritic cells [2]. Recent data suggest that activated neutrophils and lym-

Table 1 BLyS, BLyS receptors and phenotypic changes associated with these components in animals and man Nature

Expression pattern

Phenotype of overexpression in mice

BLyS

B lymphocyte stimulator

Ligand

Increased B cells, IgG IgM and IgA. Severe deficit of mature B2 Increased levels in RA, SLE Autoantibody production cells, reduced IgG, IgM and and SS, polymorphisms (anti-dsDNA, RF), SLE-like nephritis IgA, B1 cells normal associated with diseasea and Sjo¨gren’s syndrome (SS)

APRIL

A proliferating inducing ligand

Ligand

Monocytes, dendritic cells and activated neutrophils, lymphoid stromal cells, malignant B cells Monocytes, human cancers

BR3

BLyS receptor-3

BLyS specific receptor

TACI

Transmembrane activator and CAML interactor B cell maturation antigen

Receptor for BLyS and APRIL Receptor for BLyS and APRIL

BCMA

Phenotype of mutation in mice

Weak B and T cell phenotype, noneb

Apparently normal, no discernable immune phenotype

B cells

Soluble receptor: depletion of B cells

B cells, small subset of activated T cells

Soluble receptor: depletion of B cells

Mutated in the A/WySnJ mouse; severe B cell deficit similar to BLyS knockout B cells, lymphoproliferative disease Survival of long-lived plasma cells is defective but otherwise normal immune responses

Mature B cells/plasma Soluble receptor: depletion cells of B cells

Link to human pathology

Increased expression in human cancer lines and tissues, polymorphisms associated with SLE None reported

Polymorphisms associated with SLE and RAc Polymorphisms reported but no link to autoimmunity

K.P. Baker / Autoimmunity Reviews 3 (2004) 368–375

Component Name

a

J. Gottenberg et al., ACR 2003 meeting, Abstract 1461. S. Wojcik and K.P. Baker, unpublished. c A. Kawasaki et al., ACR 2003 meeting, Abstract 938. b

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K.P. Baker / Autoimmunity Reviews 3 (2004) 368–375

phoid stromal cells may also contribute active BLyS [3]. Presumably BLyS is produced under normal circumstances to bolster an immune response; it is upregulated by interferon gamma and other cytokines [2]. BLyS has a trimeric structure and is produced as a 285 amino acid membrane bound precursor which is cleaved by a furin-like protease to produce a 152amino-acid soluble protein. The structure of soluble BLyS has been solved both alone and co-crystallized with its receptors [4].

The soluble form of BLyS appears to be the major contributor of activity in in vitro assays where macrophages and dendritic cells are co-cultured with B cells; similar activities are observed whether the cells are separated by a semi-permeable membrane or directly co-cultured together [5]. The in vivo role, if any, of uncleaved, membrane-bound BLyS remains enigmatic but it may be important within lymphoid microenvironments where cell – cell contacts may dictate immune responsiveness. Alternate splicing of the

Fig. 1. The role of BLyS in B cell development. The life of a conventional B cell is depicted from stem cells in the bone marrow, through the spleen and peripheral lymphoid tissues. The pathway reflects a composite of several defined steps from murine and human B cell development. The sites of BLyS action are shown as determined by in vitro activity or in vivo from the phenotypes of numerous mouse strains that carry mutations in BLyS, APRIL, or BLyS receptors. Cells emerge from the bone marrow having undergone heavy and light chain rearrangement to produce functional immunoglobulin. Cells travel from one tissue to another either through the blood or through the lymphatic system. Maturation of the B cells occurs in the spleen. As noted in the text, BLyS is essential for the T1 to T2 transition during splenic development; mice lacking BLyS have few B cells beyond this point of development. BLyS has been shown to be involved in several further maturation steps by in vitro activity (see text for details). BCMA is upregulated during plasma cell differentiation and BCMA deficient animals have normal immune responses but the long-term survival of antibody-secreting plasma cells is impaired. A BCMA ligand (BLyS and/or APRIL) is therefore necessary for the survival of long-term plasma cells. Some important markers used for immunophenotyping the different cell types are depicted, although for the sake of clarity this is not an exhaustive list, and not all cells are fully phenotyped for every marker. PreBcR, pre-B cell receptor.

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BLyS mRNA can result in a variant protein, DBLyS, which has been shown to be present in cell lines and appears to downregulate the secretion of functional BLyS from cells [6]. BLyS administration to mice results in increased B cell representation as well as increased total serum immunoglobulins. BLyS also stimulates the production of specific antibody responses to both T-independent (TI) and T-dependent (TD) antigens [7]. These observations were confirmed and extended by longerterm studies utilizing transgenic animals that constitutively overexpress BLyS [8,9]; see Table 1. BLyS transgenic animals have B cell hyperplasia, increased immunoglobulins and, with prolonged BLyS overexpression, produce autoantibodies including antidsDNA antibodies and rheumatoid factor (RF). The transgenic animals have immunoglobulin deposition in the kidneys, develop autoimmune glomerulonephritis with proteinuria, have shortened lifespans and, as they age, develop a Sjo¨gren’s syndrome (SS)-like phenotype [10]. The essential requirement for BLyS in B cell development was shown by the phenotype of BLyS knockout mice, which have a severe deficit of mature B2 (conventional) cells, and reduced immunoglobulins but have normal B1 (peritoneal) cell populations [11]. These mice contain immature B cells including normal marrow precursors and T1 transitional immature cells but few mature B2 cells. The point at which B cell development is arrested in these mice must represent the first step at which BLyS is essential for survival (Fig. 1). There are subsequent steps in B cell development where BLyS is also important, if not essential. In vitro analysis of human splenocytes has demonstrated that BLyS is involved in the memory B cell to plasmablast development step; it has been reported that BLyS enhances the survival of plasmablasts without enhancing proliferation [12]. Additionally, analysis of the remaining germinal center (GC) responses in BLyS knockout mice or the BLyS receptor BR3 defective mouse strain, A/WySnJ (see below), suggest that BLyS is not required for the initiation of a GC reaction but is required for maintenance of the response [13,14]. As discussed below, the three BLyS receptors are differentially regulated during B cell development and the effect that BLyS has on individual subsets of B cells will be a function of the receptor expression pattern of that subset. Further studies are needed to dissect the

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specific BLyS requirements at various stages of B cell development and the role of the different receptors in each of these steps.

2. BLyS receptors BLyS has potent effects on B cells but has few direct effects on other cell types. This specificity is achieved at the molecular level by binding to three different receptors, namely TACI, BCMA [15] and BR3 [16] (also known as BAFF-R [17]) that are almost exclusively expressed on cells of the B cell lineage. It appears that BR3 is the major driver of B cell development since a mutation in this receptor is present in the A/WySnJ mouse strain and the phenotype of these mice is remarkably similar to the BLyS knockout mouse. BR3 expression is upregulated following activation through the B cell receptor [18] and is downregulated as cells mature from B cells into plasma cells [12]. BCMA, conversely, is upregulated during plasma cell development [19] and is implicated in playing a role in plasma cell survival [20]. The specific roles of each of the three receptors is still unclear but much has been learned from the phenotypes of mice that are mutated in either the receptors or ligands (Table 1). The BLyS receptors are not only differentially regulated during B cell development [18,21], they also send qualitatively different signals to the cells. TACI knockout mice have increased B cell populations and with age the animals develop a lymphoproliferative disorder suggesting that TACI is a negative regulator of B cells [22]. BCMA knockout mice were originally described as having no apparent defects in B cell development and immune responses, and BCMA was considered to be functionally redundant. Subsequently, BCMA has been shown to be important for long-term survival of plasma cells in the bone marrow and for prolonged antibody production [20]. The BLyS receptor system displays an intriguing biological complexity in that two of the receptors, TACI and BCMA, also interact with a related TNF family ligand known as APRIL (A p roliferating i nducing l igand). A full description of APRIL is outside the scope of this article but it is important to note that the function of APRIL is not fully

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understood. Recombinant APRIL protein or APRIL derived from macrophages does not possess robust in vitro B cell stimulatory activity [5]. APRIL knockout animals have no apparent immune defects [23]. Importantly, APRIL transgenic animals [24] do not exhibit a major B cell phenotype, nor do they develop autoimmune-like disease like the BLyS transgenic animals. BLyS and APRIL are also capable of forming heterotrimers, although the physiological significance of these remains unclear, heterotrimers may act to modulate BLyS activity posttranslationally [25].

3. Signal transduction The signal transduction pathways initiated by BLyS binding to its receptors remain to be fully delineated. The analysis of BLyS signaling pathways is complex because of the three different BLyS receptors. It is clear that BLyS can activate NFnB and cJun NH2-terminal kinase (JNK). TNF receptor-associated factors (TRAF) 5 and 6, NFnB inducing kinase (NIK) and InB kinase (IKK) have been shown to be involved in BCMA signaling [26] while TACI has been shown to interact with TRAF 2, 5 and 6 [27]. TRAF 3 has been implicated in BR3 signaling [28]. BLyS has also been shown to signal via a NEMO (NFnB essential modulator)independent mechanism by NFnB2 [29], although it has also been proposed that the canonical NFnB pathway is rapidly and transiently engaged following BLyS stimulation and the non-canonical pathway is utilized with delayed kinetics [30]. The B cell deficit that results from the loss of BLyS signaling (via BR3) in A/WySnJ mice can be suppressed by the overexpression of BclXL which supplies a survival signal, suggesting that a major consequence of BLyS signaling is the prevention of apoptosis by upregulation of anti-apoptotic factors or the downregulation of pro-apoptotic factors [31]. In agreement with this, BLyS treatment of defined (mature or immature; resting or CD40L stimulated) murine B cell populations results in differential upregulation of gene expression; mature B cells survive by upregulation of Bcl-2 family members BclXL and Bfl1/A1, while immature B cells do not upregulate these genes [7,21]. These studies suggest

that BLyS enhances survival of cells at distinct stages within B cell development through stagespecific receptor expression and distinct signal transduction mechanisms.

4. Links to disease—a therapeutic target Two major avenues of evidence link BLyS to autoimmunity, namely studies in animal models and the measurement of BLyS levels in patients with systemic autoimmune diseases. BLyS is elevated in autoimmune-prone mice, notably NZB/WF1 and MRL lpr strains [15]. As mentioned above, BLyS transgenic animals develop a lupus-like disease followed by a Sjo¨gren’s-like disease, characterized by immune infiltration of salivary tissue, as they age [10]. Thus excess BLyS is sufficient to induce an autoimmune state in mice. BLyS levels are elevated in patients with SLE, RA, SS and other systemic autoimmune diseases [32]. BLyS levels also fluctuate during the course of SLE [33], and BLyS has been proposed to be a biomarker for SLE disease activity (M. Petri et al., abstract 1712, ACR 2003 meeting). BLyS levels in RA patients were found to be higher in the synovium than in the corresponding serum, suggesting that local production of BLyS in the synovium [34] drives the maturation of B cells to produce the ectopic lymphoid-like tissue in the pannus of the RA joint. While any one of the above pieces of information is suggestive of a link between BLyS and development of autoimmunity, en mass these observations implicate BLyS in the etiology and progression of autoimmune disease pathogenesis. As such, antagonism may provide a novel therapeutic approach to the treatment of autoimmune diseases. Such agents should modulate BLyS activity and ultimately restore immune homeostasis within autoimmune patients. Two types of antagonists are currently in development. A fully human monoclonal antibody against BLyS, (LymphoStat-Bk antibody), has entered clinical trials (see below). Soluble forms of the BLyS receptors in which the extracellular domain of a BLyS receptor is fused to the Fc domain of immunoglobulin are also in various stages of development. These proteins retain the ability to neutralize BLyS while gaining the

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extended half-life normally associated with an immunoglobulin. The benefit of antagonizing BLyS has been shown in animal models using soluble receptors; TACI-Fc and BR3-Fc administration to lupus prone NZB/W-F1 mice reduced the glomerulonephritis, proteinuria and increased the survival of the animals [15,35]. Interestingly, only the BLyS specific reagent, BR3-Fc, reduced the titer of antidsDNA antibodies in this experimental system. TACI-Fc was effective at reducing inflammation and preventing joint damage in the murine collagen-induced arthritis model of RA [36]. TACI-Fc is currently in Phase 1 clinical testing. A fully human monoclonal antibody directed against BLyS has been shown to bind to BLyS with high affinity and inhibit the biological activity of BLyS in vitro and in vivo. Administration of LymphoStat-B to cynomolgus monkeys for 4 weeks resulted in depletion of B cell populations from the spleen and lymph nodes [37], while long-term (6 month) administration resulted in a reversible depletion of B cells in tissues and peripheral blood down to 30% of normal (W. Halpern et al., abstract 1537, ACR 2003 meeting). LymphoStat-B has completed a Phase I clinical trial in SLE patients and was shown to be safe and biologically active, resulting in depletion of peripheral CD20+ B cell (R. Furie et al., abstract 922, ACR 2003 meeting). LymphoStat-B is currently in two Phase II clinical trials in SLE and RA patients. Changes in BLyS expression have also been linked to the development of several other B cell pathologies. While this review has focused on the role of BLyS in autoimmune disease, there is mounting evidence that BLyS also plays a key role in promotion and/or progression of malignant B cells [38]. BLyS may represent a link between autoimmunity and the increased frequency of B cell neoplasms observed in autoimmune conditions. Conversely, BLyS may play a role in the increased frequency of autoimmune manifestations observed in such B cell malignancies such as CLL.

5. The role of B cells in autoimmunity While autoimmune disease pathologies are considered to be ‘‘driven’’ by T cells, emerging data

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suggest that B cells play a more important role in these diseases than previously considered. While it has long been known that levels of autoantibodies such as RF correlate with disease severity and progression in RA and anti-dsDNA antibodies are often elevated prior to a disease flare in lupus, it is little appreciated that B cells have more than a passive role in these diseases. B cells are able to present antigens and play important immunomodulatory roles by secreting numerous cytokines. Perhaps the strongest evidence for a key role for B cells in autoimmune disease is from clinical studies evaluating the effects of B cell depletion using an antiCD20 monoclonal antibody (rituximab). B cell depletion appears to have benefits, at least in small studies of ITP, SLE and RA patients [39]. The complex nature of autoimmune disease pathogenesis and the differential effects that current therapeutics have within patient populations (e.g., the differential effects of anti-TNFa-based therapeutics in RA patients) suggest that the molecular etiology of autoimmunity is diverse. BLyS levels may be elevated and have a causative role in disease pathogenesis in only a portion of autoimmune patients, nevertheless, the essential role of BLyS in B cell development makes BLyS antagonism an attractive approach in all patients in light of the apparent therapeutic benefits of B cell depletion by targeting CD20. Thus by blocking B cell development and preventing the survival of autoreactive B cells, BLyS antagonism may have therapeutic benefits regardless of whether BLyS levels are normal or elevated. Excess BLyS may cause autoreactive B cells to escape the normal regulatory mechanism and mature into antibody-secreting B cells and plasma cells. At what stages of B cell development are elevated BLyS levels skewing the B cell population to influence the normal depletion of self-reactive clones? It seems likely that excess BLyS promotes survival of selfreactive B cell clones during the normal negative selection process. One of the key checkpoints for negative selection is believed to occur as cells transition the T1 –T2 stages of development and control of BLyS exposure this stage may be a key regulatory component of negative selection [40]. It is at or near this point where B cell development is ‘‘arrested’’ in BLyS knockout mice.

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6. Conclusions

Acknowledgements

While much has been unveiled about BLyS in the last few years, there is still much more to learn on the basic biology of BLyS and its role in normal and abnormal B cell development: at how many steps of B cell development is BLyS required; what are the precise signaling pathways used by each of the three receptors; and what, if any, is the role of APRIL in B cell homeostasis? Despite these remaining questions, it is clear that with the discovery of BLyS, an important regulator of B cell activity has been identified that appears to have a key role in B cell development and antibody production. Antagonism of BLyS is an attractive target for therapeutic intervention of systemic autoimmune diseases where B cells and/or autoantibodies are thought to play a central role in the pathology. Clinical trials are currently underway to study any potential therapeutic benefits resulting from suppression of BLyS function in the autoimmune patient.

I am indebted to Drs. D. Hilbert, V. Albert, A. Bell, W. Freimuth and Mr. R. Haynes for critical comments on the manuscript.

Take-home messages 





 

BLyS is an essential survival factor for B cells. Three BLyS receptors are differentially expressed on B cells as they differentiate from an immature stage to antibody-secreting plasma cells. The absence of BLyS in mice results in loss of mature B cells. BLyS is elevated in patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjo¨gren’s syndrome (SS), and other systemic autoimmune diseases. Overexpression of BLyS in mice results in an autoimmune disease phenotype similar to SLE. BLyS is elevated in mice that are prone to lupuslike disease and antagonism of BLyS in these mice slows disease progression and reduces disease severity. B cell depletion is emerging as a treatment modality for several autoimmune diseases. BLyS is an attractive target for development of antagonists. BLyS antagonism should reduce BLyS levels and subsequently deplete B cells. Several BLyS antagonists are in development; a fully human monoclonal antibody is currently in Phase 2 clinical trials.

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