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Effects of Acute and Chronic on B-Cell Development and Differentiation Derek Cain1, Motonari Kondo1, Huaiyong Chen1 and Garnett Kelsoe1

Recently, our understanding of hematopoiesis and the development of the immune system has fundamentally changed, leading to significant discoveries with important clinical relevance. Hematopoiesis, once described in terms of irreversible and discrete developmental branch points, is now understood to exist as a collection of alternative developmental pathways capable of generating functionally identical progeny. Developmental commitment to a particular -cell lineage is gradually acquired and reflects both cell intrinsic and extrinsic signals. Chief among the extrinsic factors are the environmental cues of hematopoietic microenvironments that comprise specific ‘‘developmental niches’’ that support hematopoietic stem and progenitor cells. Most of this new understanding comes from the study of normal, steady-state hematopoiesis, but there is ample reason to expect that special developmental and/or differentiative mechanisms operate in response to inflammation. For example, both stem and progenitor cells are now known to express Toll-like receptors that can influence hematopoietic cell fates in response to microbial products. Likewise, proinflammatory mobilize hematopoietic stem cells to peripheral tissues. In this Perspective, we review inflammation’s effects on central and extramedullary B and discuss the potential consequences of peripheral B-cell development in the context of systemic autoimmune diseases. Journal of Investigative Dermatology (2009) 129, 266–277; doi:10.1038/jid.2008.286

INTRODUCTION specific removal of pathogens and/or basis for protective elicited B and are their toxins. Indeed, the generation of by the great majority of contemporary crucial components of both innate and the memory B-cell compartments and . B cells and their development adaptive immunity and provide for the long-lived serum provide the in the primary lymphoid tissues have

Editor’s Note In 1621 Fabricius ab Aquapendente described a sac-like resulted in a heightened interest in B cells as a target for the structure over the terminal gut in birds, known ever since as treatment of autoimmune disease. In this issue Cain and the bursa of Fabricius (Ribatti et al., 2006). In 1954 Glick colleagues report on the role of acute and chronic and Chang found that immunized chickens in which the inflammation in development, Manjarrez-Ordun˜o et bursa of Fabricius was removed early in development did al focus on the role of B cells in the development of not develop antibodies, establishing this structure as critical immunological tolerance, and Nagel et al provide insight to antibody development (Ribatti et al., 2006). These into the potential for B-cell directed therapy of inflammatory observations were followed by the work of Cooper and mediated skin diseases. In one of the first reviews of the Good, who suggested a functional division of immune cells, roles of T and B lymphocytes, Martin Raff wrote that with bursal (B) cells responsible for antibody production and ‘‘yinsight into the functioning of the immune systemy has thymus (T) cells responsible for delayed-type paved the way for rational attempts to manipulate selec- (Cooper et al., 1965). Over the ensuing decades B cells have tively the different cell typesy for the benefit of patientsy’’ been found to play a critical role in antibody formation, T (1973). These Perspectives outline advances towards the cell function and immune regulation (LeBien and Tedder, fulfillment of Raff’s prediction. 2008). Recent development of the rituximab, which is directed against a subset of B cells, has Russell P. Hall, III, Deputy Editor

1Department of , Duke University, Durham, North Carolina, USA Correspondence: Dr Garnett Kelsoe, Department of Immunology, Duke University, Durham, North Carolina 27710, USA. E-mail: [email protected] Abbreviations: BAFF, B-cell activating factor of the TNF family; BCR, B-cell receptor; BM, bone marrow; CLP, common lymphoid progenitor; HSC, ; LTa, lymphotoxin; SCF, stem cell factor; TLR, Toll-like receptors Received 11 March 2008; revised 6 June 2008; accepted 15 July 2008

266 Journal of Investigative Dermatology (2009), Volume 129 & 2009 The Society for Investigative Dermatology D Cain et al. Inflammation and B Lymphopoiesis

been the focus of intense study at the B-cell compartments; and antigen- RAG1/2 expression (Hardy et al., 1991; molecular and cellular level over the dependent differentiation into anti- Lin and Desiderio, 1993; Li et al., 1996) past several decades (for reviews, see body-secreting cells and/or memory B as large pre-B cells; after their arrest in Hardy and Hayakawa, 2001; Defrance cells (Hardy and Hayakawa, 2001; the G1 phase of the cell cycle (Li et al., et al., 2002). These investigations have Carsetti et al., 2004). 1993) the cells are known as small pre-B sharpened our understanding of how B- During their early development in cells. RAG1/2 expression becomes ele- cell antigen receptors are generated and the BM, distinct stages of B-cell devel- vated in small pre-B cells to drive Vk-to- function and the role of B lymphocytes opment can be characterized by the Jk light (L)-chain rearrangements (Reth in the organization and distribution of rearrangement status of immunoglobu- et al., 1987; Schlissel and Baltimore, secondary (Gonzalez et al., 1998) and lin genes (Hartley et al., 1991; Meffre 1989). L-chain expression leads to the tertiary (Lorenz et al., 2003) lymphoid et al., 2000; Hardy and Hayakawa, assembly of mature BCR by the replace- tissues. Similarly, over the past 15 years 2001). Commitment to the B lineage ment of surrogate light chain with Igk or our knowledge of antigen-driven B-cell occurs before the initial rearrange- Igl polypeptide (Alt et al., 1987; differentiation and especially the germ- ments of immunoglobulin gene seg- Rajewsky, 1996). These immature B inal center reaction has grown expo- ments that are necessary to construct a cells are the first in the B lineage to nentially leading to a basic functional B-cell antigen receptor express the BCR on their surfaces and to understanding of just how the humoral (BCR; Hardy et al., 1991; Allman become capable of recognizing exogen- achieves its specifi- et al., 1999) and is identified as the ous (Hardy et al., 1991; Hardy city and affinity (Berek, 1993; Kelsoe, pre-pro-B-cell compartment (Hardy and Hayakawa, 2001). 1996; Bachmann, 1998). et al., 1991). These earliest committed The generation of functional antigen Despite this hard-won, new knowl- progenitors express low levels of the receptors—the BCR—by genetic re- edge, immunologists have held tightly RAG1/2 recombinase (Schatz et al., arrangement and the combinatorial as- to a classic notion that divides B-cell 1989; Oettinger et al., 1990), but have sociation of gene segments ensures a development and differentiation into immunoglobulin gene loci in an un- diverse repertoire of antibody and B-cell distinct phases that are antigen inde- rearranged, germline configuration specificities but also the generation of pendent or dependent. Simply put, (Hardy et al., 1991). Subsequently, self-reactive clones (Nemazee and Wei- antigens are generally not thought to pro-B cells highly express RAG1/2 gert, 2000). Thus, the newly generated affect in any significant way the early (Hardy et al., 1991; Li et al., 1993) pool of immature B cells is purged of phases of B-cell development and and initiate DH-to-JH rearrangements self-reactivity by at least three mechan- maturation in the bone marrow (BM; on both Igh alleles (Alt et al., 1984; isms of immunological tolerance: apop- Defrance et al., 2002). This classic Ehlich et al., 1994). After DHJH rear- totic deletion, inactivation by anergy, - view places the earliest interaction rangement, VH DHJH recombination and receptor editing, the replacement of between B cells and exogenous antigen follows, but this event does not occur autoreactive BCR by secondary V(D)J in the or other peripheral sites simultaneously at both alleles (Alt rearrangement (Nemazee and Weigert, where expansions or contractions of et al., 1984). Initial VHDHJH rearrange- 2000). B cells that survive this negative B-cell populations are induced. This ments that are out-of-frame and selection may enter one of the mature B- view also implies that the tempo of B therefore, nonfunctional, can be com- cell compartments, including the ma- - lymphopoiesis does not respond to pensated by second VH DHJH rear- ture follicular pool that recirculates external cues as does erythropoiesis rangement attempts on the alternative through peripheral tissues (Gray et al., (Mide et al., 2001) and granulopoiesis allele (Sonoda et al., 1997; ten Boekel 1982) and the fixed splenic marginal- (Basu et al., 2000; Hirai et al., 2006). et al., 1998). In-frame VHDHJH rearran- zone compartment (Martin and Kear- However, recent studies indicate that gements lead to the expression of ney, 2002; Lopes-Carvalho and Kear- this view may no longer be tenable and functional mH polypeptides and their ney, 2004; Berland et al., 2006). These that infection, and even sterile inflam- association with the surrogate light mature compartments respond to anti- mation, control the site and rate of B chain, a light-chain-like chaperone gens by distinct pathways of differentia- lymphopoiesis (Ueda et al., 2004, complex comprising the Vpre-B and tion to produce specific antibody and/or 2005). In this review, we shall provide l5 polypeptides (Karasuyama et al., establish pools of high affinity memory a concise overview of B-cell develop- 1990, 1993). This point in B-lineage B cells that persist for long periods of ment and differentiation in the BM and development defines the pre-B cell time. The memory pathway appears to periphery with a focus on the impact stage (Goldsby et al., 2003) and the be largely reserved for the mature that acute and chronic inflammation mH and surrogate light chain polypep- follicular compartment whereas margin- has on these processes. tides associate with the Iga/Igb hetero- al-zone B cells provide rapid but The process of B lymphopoiesis can dimer to form a pre-BCR (Karasuyama transient antibody responses (Oliver be divided roughly into four temporal et al., 1996) that provides constitutive et al., 1999). and spatial phases: early development survival and proliferation signals. Fol- in the BM; maturation of immature/ lowing the assembly of pre-BCR, pre-B EARLY B-CELL DEVELOPMENT transitional B cells during their transit cells undergo several rounds of cell In adult mice and humans, BM is the to the periphery; entry into the mature division and a coincident reduction in primary site of B lymphopoiesis and the

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Self-renewal or Lymphoid or B-lineage Maturation or maturation myeloid T or B commitment neglect

+ – VCAM VCAM Large Small HSC CLP pre-pro-B pro-B pre-BI Imm B MPP MPP pre-BII pre-BII

MPP ELP Hardy’s Fr. A Fr. B Fr. C Fr. C′ Fr. D Pr. E CLP2

T, B, MegE, GM T, B, GM T, B B

IgH GL GL ~ D to J V to DJ VDJ IgL GL V to J VJ

Figure 1. B cell development in bone marrow. The step-wise differentiation of hematopoietic stem cells (HSC) into immature B cells in the bone marrow is depicted. Hematopoietic lineage potential gradually decreases as HSC mature through multipotent progenitors (MPP) and early lymphoid progenitors (ELP) to common lymphoid progenitors (CLP). The differentiation potential of each progenitor type to give rise to T cells (T), B cells (B), megakaryocyte/erythroid cells (MegE), and granulocytes/ (GM) is indicated. Cells that commit to the B-lineage progress through a series of additional developmental stages defined by the rearrangement of immunoglobulin genes. The stages at which the immunoglobulin heavy chain genes (IgH) and light chain genes (IgL) rearrange are shown (GL, germline configuration). For reference, Hardy’s nomenclature for murine B-cell development is shown (Hardy et al., 1991).

screening of newly formed B lympho- (Adolfsson et al., 2005; Lai and Kondo, signal transducer, CD19, is not (Hsu cytes for self-reactivity. Many of the 2006). B lineage specification begins as et al., 2006). Presumably, Pax5 levels characteristic events of B-cell develop- early as the VCAM-1À multipotent are insufficient in CLP to induce this ment, including the rearrangement of progenitor stage of development, also critical target and establish B-cell com- the Igh and Igk/l gene loci, correlate known as the early lymphoid progeni- mitment (Hsu et al., 2006). B-cell- with expression of surface markers, tor, where cells express B-cell-specific specific transcription factors form tran- allowing the definition of specific transcription factors together with other scriptional networks along with more stages in B-cell development by multi- lineage-specific molecules (Igarashi generally expressed transcription fac- parameter flow cytometry (Osmond et al., 2002; Lai et al., 2005). The more tors including PU.1 and E2A (Nutt and et al., 1998). That several phenotypic differentiated, common lymphoid pro- Kee, 2007). In pro-B cells, Pax5 and definitions have been used by different genitors (CLPs) give rise to pre-pro-B Stat5 interact and critically regulate the laboratories to describe B-cell develop- cells (also known as CLP-2) and com- accessibility of the Igh gene loci to the ment has led to slightly different pletely lose T- and NK-cell potential RAG1/2 recombinase and thereby con- models/nomenclature for B lymphopoi- upon reaching the pro-B stage (Figure 1; trol the VH-to-DHJH rearrangements esis (Osmond et al., 1998). To avoid Tudor et al., 2000). necessary for the production of mH confusion, and for the sake of simpli- Extracellular factors are necessary polypeptides (Fuxa et al., 2004; Berto- city, in this review we shall focus on for the expression of B-cell-specific lino et al., 2005). Pax5 and E2A are the molecular events that define B-cell transcription factors, including EBF also important in regulating the expres- development. (early B-cell factor), LRF (liver regen- sion of the surrogate light chain poly- B cells derive from multipotent, self- eration factor), and Pax5 (paired box). peptides, Vpre-B and l5 (Melchers, renewing hematopoietic stem cells In mice, IL-7 receptor (IL-7Ra) signaling 2005); in addition, E2A plays a crucial (HSC) and transit through a series of is necessary for the expression of EBF, role in the regulation of Igk rearrange- maturational steps and developmental at least at the transition of CLP to pre- ment (Lazorchak et al., 2006) and checkpoints in the BM (Kondo et al., pro-B cells/CLP-2, as B-cell develop- consequently, the generation of imma- 2003; Hardy et al., 2007). The initial ment is blocked at the pre-pro-B stage ture B cells that express mature BCR developmental checkpoint that defines in IL-7- and IL-7Ra-deficient mice as a capable of interacting with exogenous the B lineage is the lymphoid/myeloid consequence of low EBF expression and self-antigens. branch point which is thought to occur (Dias et al., 2005; Kikuchi et al., 2005). Roughly 90% of the cells that at or after HSC differentiation into Similarly, lack of the transcriptional commit to the B lineage do not reach nonrenewing multipotent progenitors repressor LRF (also known as Pokemon) the immature B-cell stage (Rolink et al., that express the adhesion molecule arrests B-cell development at the pre- 1998). Many, perhaps as many as 75%, VCAM-1 (Figure 1) (Kondo et al., pro-B/CLP-2 stage and results in extra- of developing B cells express BCR that 2003). Functional analyses suggest that thymic T-cell development in BM recognize self-antigens (Wardemann multipotent progenitors first lose the (Maeda et al., 2007), presumably as et al., 2003). Immature B cells that potential for megakaryocyte/erythroid the result of altered Notch signaling encounter their antigen ligands in the differentiation, followed by a dimin- (Pui et al., 1999; Radtke et al., 1999). BM undergo apoptosis (Nemazee and ished capacity to generate granulocytes Another B-lineage transcription factor, Buerki, 1989), or are rendered non- and macrophages, and the eventual Pax5, is also expressed in CLP, even functional by the process known as commitment to the lymphoid lineages though one of its targets, the B-lineage anergy (Goodnow et al., 1988), or

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reactivate Ig gene rearrangement to the TNF family (BAFF) is an important BAFF overexpression allows for the replace the self-reactive BCR (Gay regulator of transitional B-cell matura- survival of T1 B cells that would et al., 1993; Radic et al., 1993; Tiegs tion, and controls the T1-T2 transi- normally be purged by apoptosis (Thien et al., 1993). This last tolerance me- tion. Mice deficient of BAFF have et al., 2004). Consistent with this chanism, receptor editing, is unusual in severely reduced numbers of B cells hypothesis, transgenic B cells bearing that it operates on the autoreactive beyond the T1 stage of development self-reactive receptors are more depen- receptor rather than the autoreactive but have normal numbers of develop- dent on BAFF for survival than are cell (Nemazee and Weigert, 2000). ing B cells in BM (Schiemann et al., alloreactive B cells (Lesley et al., 2004). Once past this initial tolerance check- 2001; Gorelik et al., 2003; Shulga- Elevated serum BAFF has also been point, the residual immature B-cells Morskaya et al., 2004). Three receptors associated with several autoimmune begin a series of maturation steps as for BAFF have been identified, trans- diseases, including lupus, rheumatoid they emigrate from the BM to the membrane activator and calcium-mod- arthritis, and Sjogren’s syndrome spleen or other peripheral lymphoid ulator and cyclophilin-ligand interactor (Cheema et al., 2001; Zhang et al., tissues where they complete their (TACI), B-cell maturation antigen 2001; Groom et al., 2002; Jonsson development. (BCMA), and BAFF receptor (BAFF-R; et al., 2005; Becker-Merok et al., Mackay and Browning, 2002). How- 2006), garnering much attention for PERIPHERAL B-CELL DEVELOPMENT ever, BAFF-R is the principal receptor BAFF as a potential therapeutic target. The final stages of B-cell development for controlling peripheral B-cell devel- Though BAFF production is typically take place in the spleen where transi- opment, as mice deficient in this attributed to myeloid cells, experiments tional B cells (Carsetti et al., 1995), receptor exhibit a phenotype compar- with reciprocal BM chimeras demon- essentially intermediate forms between able to BAFF-deficient mice (Sasaki strated that BAFF production by radia- the immature and mature phenotypes, et al., 2004). BAFF-R signaling activates tion-resistant (presumably nonhemato- undergo selection into the peripheral several transcription factors, including poietic) cells is necessary for peripheral B-cell compartments (Loder et al., NF-kB (Kanakaraj et al., 2001), as well B-cell development and sufficient for 1999). Type 1 transitional (T1) B cells as expression of antiapopototic genes, humoral immune responses (Gorelik continue to mature through the Type 2 including Bcl-2, Bcl-xL, and Mcl-1 (Do et al., 2003). However, BAFF-deficient transitional (T2) B-cell stage, which in et al., 2000; Hsu et al., 2002; Hatada mice reconstituted with BAFF-sufficient turn completes B-cell development/ et al., 2003; Woodland et al., 2008). BM mount antibody responses to im- maturation as mature follicular or Signaling through BAFF-R also upregu- munization with T-cell dependent anti- marginal-zone B cells. Tolerance con- lates the expression of CD21 and gens, indicating that hematopoietic cell- tinues to operate during the T1 and T2 CD23, B-cell associated receptors (for derived BAFF contributes significantly to stages of B-cell development, as the complement and IgE, respectively) that B-cell maintenance and their differentia- frequency of self-reactive clones con- distinguish T1 B cells from more tion to antibody-secreting cells. Hema- tinues to decrease through the imma- mature T2 and mature B cells (Gorelik topoietic sources of BAFF include ture, T1, and T2 stages of B-cell et al., 2004). dendritic cells (Schneider et al., 1999), development (Wardemann et al., A recent study identified a subset of macrophages (Craxton et al., 2003), 2003). However, unlike immature B T2 B cells that are highly sensitive to neutrophils (Scapini et al., 2003), T cells cells, T1 B cells do not appear to be proliferative signals through BAFF-R, (Yoshimoto et al., 2006), and even B able to undergo receptor editing on suggesting that BAFF targets this popu- cells themselves (Chu et al., 2007; exposure to self-antigen ligands (Wang lation as part of the homeostatic Daridon et al., 2007). et al., 2007). Instead, T1 cells undergo regulation of peripheral B-cell devel- BAFF is required for normal periph- apoptosis following BCR ligation opment (Meyer-Bahlburg et al., 2008). eral B-cell development, but is it whereas BCR ligation on T2 B cells Further evidence for BAFF as a homeo- necessary for mature B cells during an induces proliferation and differentia- static regulator of peripheral B lympho- immune response? A role for BAFF in tion to antibody secretion similar to poiesis is based on observations that the maintenance of germinal centers mature B cells (Petro et al., 2002). patients exhibit significant increases in has been proposed based on the Though the mechanism is still unclear, serum BAFF concentrations during B- observation that BAFF-deficient and studies of the frequencies of VH genes cell depletion therapy (Cambridge BAFF-R-deficient mice have attenuated in immature and mature B cell popula- et al., 2006; Pers et al., 2007), suggest- responses (Rahman tions have uncovered biases in VH gene ing that BAFF concentrations mediate et al., 2003; Vora et al., 2003). How- usage, suggesting that positive selec- the size of the peripheral B-cell pool. ever, a recent study found that freshly tion also occurs in the transitional Interestingly, transgenic mice that ex- isolated germinal center B cells have stages of B-cell development (Gu press high levels of BAFF exhibit large no detectable BAFF bound to their et al., 1991; Levine et al., 2000). increases in the numbers of T2 and surface receptors, though they express In addition to tonic BCR signaling, mature B cells, and typically show receptors capable of binding exogen- extracellular factors are required for evidence of systemic autoimmune dis- ous BAFF (Darce et al., 2007). Follicu- transitional B cells to complete their ease (Mackay et al., 1999; Batten et al., lar B cells, on the other hand, have development. B-cell activating factor of 2000; Khare et al., 2000). Presumably, BAFF bound to their surface receptors.

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Together these findings suggest that the Normal germinal center is a BAFF-poor envir- BONE MARROW BLOOD SPLEEN onment, consistent with the concept CLP pro-B pre-B Imm B T1 T2 that the survival of germinal center B cells is determined by competition for FO antigen (Kelsoe, 1996). It seems possi- HSC ble, therefore, that attenuated germinal

center responses in BAFF-deficient CMP MB PM PMN PMN mice may be explained better by the indirect effects of BAFF on B-cell development. We note that the few B Inflammation cells that reach maturity in BAFF- DC deficient mice do not express CD21, a pro-B Imm B receptor for the complement activation TLR CLP pro-B pre-B Imm B T2 pre-B products C3d and C3b (Carroll, 2004). The binding of CD21 to C3-decorated T1 FO α antigen strongly amplifies BCR signal- HSC TNF ing (Fearon and Carroll, 2000) and mice deficient in CD21 exhibit de- TLR CMP MB PM PMN PMN PMN creased antibody responses to T-depen- dent antigens (Ahearn et al., 1996; Molina et al., 1996), at least in part Figure 2. Inflammation induces extramedullary B lymphopoiesis. A simplified schematic of due to the inability of CD21-deficient B hematopoiesis during normal and inflamed conditions is depicted, with B-cell development progressing cells to persist in germinal centers from hematopoietic stem cells (HSC) through common lymphoid progenitors (CLP), pro-B cells (pro-B), pre-B cells (pre-B), immature B cells (imm B), transitional 1 B cells (T1), transitional 2 B cells (T2), and (Fischer et al., 1998). mature B cells (Mat B). From HSC, granulocyte differentiation occurs through common myeloid Although a direct role for BAFF in progenitors (CMP), myeloblasts (MB), promyelocytes (PM), and polymorphonuclear neutrophils (PMN). germinal centers can be debated, other Toll-like receptor (TLR) signals induce HSC to develop into myeloid cells and CLP to develop into B-cell compartments may rely on BAFF dendritic cells (DC). TNFa reduces CXCL12 and stem cell factor (SCF) expression by bone marrow to generate effective humoral re- stromal cells, resulting in the mobilization of developing B-lineage cells to peripheral lymphoid tissues sponses. BAFF has been implicated in such as the spleen, where they continue to mature. T-independent antibody responses to infection and has been shown to BM by favoring myelopoiesis, espe- tion is manifest during infections and/or promote class switching independently cially granulopoiesis, over lymphopoi- chronic inflammation is unknown but of T-cell derived CD40 ligand (Litinskiy esis (Nagaoka et al., 2000; Ueda et al., may represent a significant aspect of et al., 2002; Castigli et al., 2005), 2004, 2005; Nagai et al., 2006). Our clinical management. Hopefully, we observations that suggest a direct link current understanding of how inflam- will soon understand how signaling between B cells and innate immune mation affects B lymphopoiesis is through TLR overrides the fate deci- cells in T-independent humoral re- based on three mechanisms: (1) diver- sions that are already established in sponses. Finally, BAFF production by sion of lymphoid progenitors from the CLP, such as the expression of Pax5 blood dendritic cells also appears to be B lineage; (2) induction of apoptosis in and the RAG1/2 recombinase. required for the differentiation of mar- developing B cells; and (3) mobiliza- Hematopoiesis is also affected by ginal-zone B cells into plasmacytes tion of developing B cells to the inflammatory cytokines. TNFa, perhaps secreting low-affinity antibody during periphery. the premiere proinflammatory the early humoral response to bacterial Remarkably, microbial products can (Beutler and Cerami, 1989), is known infections (Balazs et al., 2002). have direct effects on the differentiation to play a major role in modulating B of hematopoietic progenitors. Nagai lymphopoiesis. For example, the BM of INFLAMMATION AND et al. (2006) have demonstrated that mice infected with influenza have BLYMPHOPOIESIS hematopoietic progenitors express at significantly lower numbers of devel- Although infection and inflammation least some Toll-like receptors (TLR) and oping B cells due to the antiprolifera- have long been known to affect leuko- that TLR ligation induces their differ- tive effects of TNFa and lymphotoxin cyte production (Apperley et al., 1989; entiation into innate immune cells. CLP (LTa; Sedger et al., 2002). However, Young et al., 1989; Nagaoka et al., incubated with TLR ligands differenti- this study did not demonstrate whether 2000), it has only been in recent years ate into dendritic cells in vitro. Redir- the proliferative suppression by TNFa that the molecular and cellular details ected differentiation of CLP into and LTa was direct or acted indirectly of inflammatory hematopoiesis have dendritic cells as a result of TLR ligation by altering the BM environment. been explored (Figure 2). Several re- could reduce the B-cell progenitor More recently, TNFa has been cent studies demonstrated that inflam- pool, limiting B lymphopoiesis during shown to affect B lymphopoiesis by mation alters hematopoietic output of infection; whether this potential reduc- regulating the expression of chemo-

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kines and growth factors in BM. The (Waskow et al., 2002), indicating that mobilized to the periphery continue CXCL12/CXCR4 axis is crucial to he- B lymphopoiesis in mice older than 10 their development outside of BM? The matopoiesis (Nagasawa et al., 1996; days requires SCF. Adjuvant immuni- primary implication of extramedullary Nagasawa, 2006) and is a target of zation decreases SCF expression in BM, lymphopoiesis is that B cells could inflammatory signals (Fedyk et al., which, like CXCL12 expression, coin- develop in a ‘‘selection-light’’ environ- 2001). The importance of this chemo- cides with the mobilization of devel- ment (Sandel et al., 2001). Develop- kine in B lymphopoiesis is evident in oping B cells to the circulation (Ueda ment in such an environment might CXCL12-deficient mice, which have et al., 2005). However, the inflamma- allow for the survival of self-reactive B severely reduced B-cell numbers (Na- tory mediator(s) that alters SCF produc- cells that would normally be deleted in gasawa et al., 1996). Similarly, block- tion in BM is not known. the BM, thereby raising the potential for ing CXCR4 with antagonists in vivo The reduction in B-cell production autoimmune pathology. This hypoth- mobilizes B cells from the BM into the during an inflammatory response is esis provides a potential mechanism to circulation (Martin et al., 2003). On a accompanied by increased production explain the strong linkage between finer scale, CXCL12 gradients in the of neutrophils, a process referred to as inflammation and the induction of BM may guide developing B cells to ‘‘emergency granulopoiesis’’ (Basu systemic autoimmune disease. different microenvironments; Martin et al., 2000; Hirai et al., 2006). The On the other hand, the possibility of and colleagues proposed that CXCL12 reciprocal production of B cells and immature B cells playing a role in is a necessary component of the step- granulocytes suggests that the progeni- immune responses to pathogens cannot wise progression of developing B cells tors of each compartment utilize be excluded. Immature B cells are through specialized BM ‘‘niches’’ a common developmental niche prominent in the of adjuvant- (Tokoyoda et al., 2004). They observed (Figure 2). This hypothesis is supported immunized mice, placing them in an that early B lineage cells (pre-pro-B/ by the observation that developing B ideal position to interact with blood- CLP-2 cells) associate with CXCL12- cells and granulocytes colocalize be- borne antigens. Support for this model expressing reticular cells whereas B- neath BM stromal cells in vitro to form was provided in a recent report that lineage cells in the subsequent, more mixed ‘‘cobblestone clusters’’ (Ueda focused on antibody production by mature developmental stage (that is, et al., 2005). Interestingly, the intrave- immature/T1 B cells (Ueda et al., pro-B cells) associate with reticular nous administration of recombinant 2007). In this study, the authors ob- cells that express IL-7 but not CXCL12. TNFa reduces CXCL12 in BM and served that the number of splenic T1 B Mice immunized with sterile adju- mobilizes developing B cells to the cells significantly increased during in- vants such as alum also exhibit sig- periphery, but has only a modest effect flammation as a result of extramedul- nificant decreases in the numbers of on granulopoiesis. On the other hand, lary lymphopoiesis. Though signaling developing B cells in the BM. This loss administration of IL-1 to mice, a proin- through BCR alone induces apoptosis of developing B cells correlates with a flammatory cytokine that has been in T1 B cells (Petro et al., 2002), reduction in BM CXCL12 (Ueda et al., linked to granulopoiesis (Moore and lipopolysaccharide stimulation in vitro 2004); indeed adjuvant-induced reduc- Warren, 1987; Stork et al., 1988; induces proliferation and secretion of tions in CXCL12 expression and the Hestdal et al., 1992; Ueda et al., class-switched antibody, an effect sig- concomitant mobilization of B cells 2005), modestly increases BM neutro- nificantly augmented by the inclusion from BM to blood circulation are phil numbers but does not affect B of BAFF. This observation indicates that attenuated in TNFa-deficient mice, cells. However, co-administration of T1 B cells are competent to respond to demonstrating that TNFa can modulate TNFa and IL-1b recapitulates all of positive BCR signals and participate in B lymphopoiesis by reducing the ability the effects of adjuvant-induced inflam- T-independent humoral responses. The of the BM to retain developing B cells. mation, mobilizing BM B cells to the production of class-switched antibody This premature emigration may reflect periphery and significantly enhancing requires the activity of activation- the physiologic process for removing granulopoiesis, suggesting that these induced cytosine deaminase (AID). transitional B cells into the periphery two proinflammatory cytokines syner- Surprisingly enough, T1 B cells, but (Fedyk et al., 1999) but results in a gize to redirect hematopoiesis in favor not T2 B cells, have been found to transient loss of central B lymphopoi- of granulopoiesis (Ueda et al., 2005). express functional levels of AID as part esis (Ueda et al., 2004, 2005). Inflammation-induced reductions in of their developmental program, rather Inflammation also affects the expres- BM B cells are accompanied by in- than in response to TLR ligation or T- sion of stem cell factor (SCF) in BM. creases in the number of developing B cell help (Ueda et al., 2007). In The receptor for SCF, c-Kit, is expressed cells in the spleen, indicating that addition, T1 B cells express low but by HSC (Ikuta et al., 1991; Ogawa inflammation mobilizes developing B significant amounts of Blimp-1 (B- et al., 1991), myeloid progenitors cells from BM to the periphery (Nagaoka maturation promoting), a (Akashi et al., 2000), CLPs (Kondo et al., 2000; Ueda et al., 2004, 2005). transcription factor required for differ- et al., 1997), and early B-cell progeni- The fact that inflammation mobilizes entiation into antibody secreting cell tors (Hunte et al., 1998). Mice with developing B cells instead of inducing (Turner et al., 1994; Angelin-Duclos inactive c-Kit exhibit age-dependent apoptosis leads to an important ques- et al., 2000). Together, these observa- blockades in B-cell development tion: do developing B cells that have tions suggest that T1 B cells, like

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marginal-zone B cells, may be poised self-limiting, healing process, allowing et al., 1991), and LAT (Zhang et al., to respond rapidly to antigens as part of for the clearance of the initiating 1999)) known to be important in the the ‘‘innate’’ humoral response. This stimuli via localized recruitment of development and organization of sec- notion is supported by the recent immune effector cells. However, when ondary lymphoid tissues. Remarkably, observation that human transitional B the inflammatory stimulus persists, the the mutation with the strongest effect cells differentiate into plasmacytes resulting chronic inflammation can be on oil granuloma formation was mMT, upon encounter with TLR ligands (Ca- protective or pathogenic depending on an IgCm mutation that prevents com- polunghi et al., 2008). the circumstances. For example, gran- plete B-cell development (Kitamura What is the physiologic role of ulomas can wall off persistent inflam- et al., 1991). The mMT mutation is antigen-responsive T1 B cells? As T1 B matory agents when the normal effective in interfering with the devel- cells have not completed developmen- mechanisms of antigen clearance fail opment of secondary lymphoid tissues, tal selection, they are enriched for self- or are otherwise insufficient (Chatto- but these tissues normally contain large reactive clones compared to mature padhyay, 1994). numbers of B cells (Ngo et al., 2001; follicular B cells (Wardemann et al., We and many others have used Tumanov et al., 2004). We note that 2003). Normally, the production of pristane (2,6,10,14-tetramethylpenta- the mMT mutation also blocks the low-affinity, polyreactive antibody dur- decane), a natural, saturated 19-C formation of oil granulomas even ing the early immune responses is alkane, to induce chronic peritoneal though very few B cells are present in attributed to B-1 and marginal-zone B inflammation (Richards et al., 1999; the granuloma structure (manuscript in cells (Martin et al., 2001) but the ability Potter, 2003). When injected into the preparation). TNFaÀ/À mice exhibit of T1 B cells to respond quickly to peritoneal cavity, pristane is either modestly impaired granuloma forma- antigen (Ueda et al., 2007) suggests phagocytosed by macrophages or sur- tion after pristane whereas oil granulo- that these developmentally immature rounded by infiltrating leukocytes to ma development in LTa-deficient mice cells may also contribute to early form oil–cell complexes. These com- is comparable to normal controls humoral defense. plexes adhere to peritoneal surfaces (manuscript in preparation). From these The observation that lipopoly- and preferentially to the mesenteric observations, we conclude that pris- saccharide-stimulated T1 B cells are membranes (Potter and Maccardle, tane-induced granulomas likely repre- dependent on BAFF for survival (Ueda 1964). With time, the infiltrating leuko- sent an inflammatory tissue that is et al., 2007) raises the possibility that cyte complexes expand to form struc- organized, at least in part, by the BAFF serves as the limiting factor in the tures known as oil granulomas. genetic pathways that also organize recruitment of T1 B cells into immune Chronic inflammation induces ter- secondary and tertiary lymphoid tis- responses. In this model, the amount of tiary lymphoid tissues via the same sues. B cells, though rare in the oil BAFF available in normal, uninfected cellular and molecular signals that granulomas of C57BL/6 mice, appear individuals would be sufficient for B- direct the organization and formation to exert a powerful effect on the cell development, maturation, and of secondary lymphoid tissues (Drayton development of these tissues. homeostasis, but not high enough to et al., 2006). Mice deficient of TNFa Chronic inflammation may also allow the survival of T1 B cells that (TNFaÀ/À), LTa (LTaÀ/À), or mature B contribute to the development of B-cell encounter self- or exogenous antigens. cells (mMT) exhibit impaired abilities to tumors. Pristane-induced oil granulo- Conversely, increased BAFF production form normal secondary lymphoid tis- mas contain macrophages and fibro- during infection would promote the sues including lymph nodes and blasts that secrete IL-6 (Fagarasan et al., survival of T1 cells that encounter Peyer’s patches (De Togni et al., 2000; Potter, 2003), an inflammatory antigen, allowing their participation in 1994; Pasparakis et al., 1996; Fu cytokine that promotes the differentia- immune responses. Indeed, the obser- et al., 1998; Gonzalez et al., 1998). tion of B cells into plasmacytes (Roldan vation that dendritic cells upregulate The generation of organized oil granu- and Brieva, 1991). Mice that over- BAFF production in response to inflam- lomas under conditions of chronic express IL-6 develop spontaneous mye- matory cytokines suggests that modu- inflammation led us to question lomas and lymphomas at much higher lated BAFF production during infection whether these granulomas might be rates than control mice (Kovalchuk may represent a physiological and considered a sort of tertiary lymphoid et al., 2002). Plasmacytes bearing the protective response to abet humoral tissue (Potter and Maccardle, 1964; chromosomal translocations t(12;15) or immunity (Litinskiy et al., 2002). Nacionales et al., 2006). If so, muta- t(6;15) proliferate and survive within tions that affect the development of the IL-6-rich environment of pristane- CHRONIC INFLAMMATION AND B secondary lymphoid tissues might also induced oil granulomas, resulting in LYMPHOPOIESIS be expected to interfere with oil gran- the development of plasmacyte tumors If acute inflammation, even the modest uloma development and/or organiza- called plasmacytomas or myelomas inflammation that results from immu- tion. To investigate this potential (Fagarasan et al., 2000; Potter, 2003). nization with adjuvant, affects central relationship, we injected C57BL/6 mice Thus, granulomatous tissues associated hematopoiesis, what are the effects of that were genetically deficient of genes with chronic inflammation promote persistent inflammation? Generally, in- (TNFa (Pasparakis et al., 1996), LTa specific B-cell tumors by providing an flammation is regarded as a beneficial, (De Togni et al., 1994), mMT (Kitamura environment where neoplastic B cells

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or plasmacytes escape normal regula- the BM environment to favor myelo- glein profile. J Am Acad tory cues. poiesis and by mobilizing developing B Dermatol 40:167–70 Interestingly, the development of cells to the blood and peripheral Angelin-Duclos C, Cattoretti G, Lin KI, Calame K pristane-induced plasmacytomas is lymphoid sites, where exposure to (2000) Commitment of B lymphocytes to a fate is associated with Blimp-1 strain dependent; BALB/c mice are antigens and inflammatory agents are expression in vivo. J Immunol 165:5462–71 susceptible whereas C57BL/6 mice are common. The utility, consequences, Apperley JF, Dowding C, Hibbin J, Buiter J, resistant, indicating that the genetic and potential dangers of extramedul- Matutes E, Sissons PJ et al. (1989) The effect differences between the strains affect lary B lymphopoiesis are not yet known of cytomegalovirus on hemopoiesis: in vitro both granuloma development and pre- but deserve additional study and con- evidence for selective infection of marrow stromal cells. Exp Hematol 17:38–45 disposition for plasmacytomas. Indeed, sideration, especially in the light of the Bachmann MF (1998) The role of germinal centers oil granulomas in C57BL/6 and BALB/c persistent inflammation associated with for antiviral B cell responses. Immunol Res mice differ in their anatomical location chronic infection and . In 17:329–44 on the mesentery; in C57BL/6 mice, the periphery, B-cell tolerance may be Balazs M, Martin F, Zhou T, Kearney J (2002) pristane elicits oil granulomas at the less efficient and the capacity of Blood dendritic cells interact with splenic gut/mesentery boundary whereas in activation-induced cytosine deami- marginal zone B cells to initiate T-indepen- dent immune responses. Immunity BALB/c mice granulomas are centripe- nase-positive T1 B cells to respond to 17:341–52 tally distributed on the mesentery antigenic stimuli suggests a pathway for Basu S, Hodgson G, Zhang HH, Katz M, Quilici (Potter and Maccardle, 1964 and generating and expanding clones of B C, Dunn AR (2000) ‘‘Emergency’’ granulo- manuscript in preparation). The identi- cells reactive with self-antigens. A poiesis in G-CSF-deficient mice in response fication of genes that regulate oil particularly attractive test of this to Candida albicans infection. Blood 95:3725–33 granuloma formation is required to hypothesis may be found in the understand better the differential sus- Batten M, Groom J, Cachero TG, Qian F, spreading associated with the desmo- Schneider P, Tschopp J et al. (2000) BAFF ceptibilities to pristane-induced plasma- glein antibodies responsible for pem- mediates survival of peripheral immature B cytomas. At least two genes that confer phigoid disease (Ishii et al., 1997; lymphocytes. J Exp Med 192:1453–66 resistance to plasmacytomas elicited by Amagai et al., 1999; Miyagawa et al., Becker-Merok A, Nikolaisen C, Nossent HC pristane have been identified (Potter 1999; Futei et al., 2000; Tsunoda et al., (2006) B-lymphocyte activating factor in et al., 1994), but their roles in oil 2002). systemic lupus erythematosus and rheuma- toid arthritis in relation to autoantibody granuloma development are unknown. levels, disease measures and time. Lupus Chronic inflammation is also asso- CONFLICT OF INTEREST 15:570–6 ciated with the induction or exacerba- The authors state no conflict of interest. Berek C (1993) Somatic mutation and memory. tion of autoimmunity. Pristane-induced Curr Opin Immunol 5:218–22 autoimmunity is observed in many Berland R, Fernandez L, Kari E, Han JH, Lomakin strains of mice (Satoh et al., 2000, REFERENCES I, Akira S et al. 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