Immunoglobulin Responses at the Mucosal Interface€¦ · IY29CH11-Cerutti ARI 4 February 2011 16:46 Immunoglobulin Responses at the Mucosal Interface Andrea Cerutti,1,2,3 Kang Chen,3

IY29CH11-Cerutti ARI 4 February 2011 16:46

Immunoglobulin Responsesat the Mucosal InterfaceAndrea Cerutti,1,2,3 Kang Chen,3

and Alejo Chorny3

1ICREA, Catalan Institute for Research and Advanced Studies, 2Municipal Institute forMedical Research-Hospital del Mar, Barcelona Biomedical Research Park, Barcelona 08003,Spain; email: [email protected], [email protected] of Medicine, The Immunology Institute, Mount Sinai School of Medicine,New York, New York 10029

Annu. Rev. Immunol. 2011. 29:273–93

First published online as a Review in Advance onDecember 21, 2010

The Annual Review of Immunology is online atimmunol.annualreviews.org

This article’s doi:10.1146/annurev-immunol-031210-101317

Copyright c© 2011 by Annual Reviews.All rights reserved

0732-0582/11/0423-0273$20.00

Keywords

mucosal immunity, B cells, IgA, IgD, class switching

Abstract

Mucosal surfaces are colonized by large communities of commensalbacteria and represent the primary site of entry for pathogenic agents.To prevent microbial intrusion, mucosal B cells release large amountsof immunoglobulin (Ig) molecules through multiple follicular and ex-trafollicular pathways. IgA is the most abundant antibody isotype in mu-cosal secretions and owes its success in frontline immunity to its abilityto undergo transcytosis across epithelial cells. In addition to translocat-ing IgA onto the mucosal surface, epithelial cells educate the mucosalimmune system as to the composition of the local microbiota and in-struct B cells to initiate IgA responses that generate immune protectionwhile preserving immune homeostasis. Here we review recent advancesin our understanding of the cellular interactions and signaling pathwaysgoverning IgA production at mucosal surfaces and discuss new findingson the regulation and function of mucosal IgD, the most enigmaticisotype of our mucosal antibody repertoire.

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MALT: mucosa-associated lymphoidtissue

Peyer’s patch (PP):organized lymphoidaggregate of the smallintestinal mucosa thatfunctions as a majorIgA inductive site(about 30 in humans)

Mesenteric lymphnode (MLN): lymphnode lying betweentwo sheets of theperitoneal membraneconnecting varioussegments of the smallintestine to theabdominal cavity

LP: lamina propria

INTRODUCTION

Mucosal membranes provide a dynamic inter-face that separates the sterile milieu of our bodyfrom the external environment. A key compo-nent of this interface is the mucosal epithelium,which blocks invasion by pathogenic and com-mensal bacteria by forming multiple layers ofphysical and immune protection (1). Epithelialprotection is particularly sophisticated in theintestine, which contains large communities ofcommensal bacteria that process otherwise in-digestible polysaccharides, synthesize essentialvitamins and isoprenoids, stimulate the mat-uration of the immune system, and form anecological niche that prevents the growth ofpathogenic species (2). Conversely, the intes-tine provides commensals with a stable habitatrich in energy derived from ingested food.

A fine line exists between the homeostaticbalance required to maintain commensals andthe destructive response required to repelpathogens (3). Such a balance involves anintimate dialogue between prokaryotic andeukaryotic cells of our body that ultimatelygenerates finely tuned signaling programs thatensure a state of hyporesponsiveness againstcommensals and a state of active readinessagainst pathogens (4). In this dialogue, ourepithelial cells function as interpreters thatcontinuously translate prokaryotic messages toeducate the mucosal immune system as to thecomposition of the local microbiota (5).

Although needed by the host, commensalsrepresent a potential threat of infection andunrestrained inflammation (6). A major defen-sive mechanism that excludes commensals fromthe mucosal surface involves immunoglobulinA (IgA) (7). This antibody class works togetherwith nonspecific protective factors such as mu-cus to block microbial adhesion to epithelialcells without causing a tissue-damaging inflam-matory reaction (8). By doing so, IgA estab-lishes a state of armed peace in the homeostaticinteraction between the host and noninvasivecommensal bacteria. When invasive pathogenicbacteria trespass the epithelial border, a stateof open war breaks out and IgA receives help

from IgG to repel the invaders. In this life-threatening situation, IgG provides a secondline of defense that controls microbial dis-semination by eliciting a robust inflammatoryreaction (9).

Remarkably, different mucosal districts arecharacterized by distinct antibody signatures.The intestinal tract contains IgA and someIgM but virtually no IgG, whereas the respi-ratory and urogenital tracts contain equivalentamounts of IgA and IgG in addition to someIgM (10). In humans, the intestinal and uro-genital tracts produce large amounts of an IgAsubclass known as IgA2, whereas the respiratorytract contains IgD, the most enigmatic class ofour mucosal antibody repertoire (10). This re-view discusses recent advances in our under-standing of the regulation and function of mu-cosal IgA and IgD.

MUCOSA-ASSOCIATEDLYMPHOID TISSUES

General Features

Mucosal surfaces comprise various lymphoidstructures collectively referred to as mucosa-associated lymphoid tissue (MALT) (8). Thissecondary lymphoid organ can be further di-vided in functionally connected subregions,including the gut-associated lymphoid tissue(GALT), nasopharynx-associated lymphoid tis-sue (NALT), and bronchus-associated lym-phoid tissue (BALT) (11–13). In the MALT,functionally distinct inductive and effector sitescan be recognized. Intestinal Peyer’s patches(PPs) and mesenteric lymph nodes (MLNs) ex-emplify mucosal inductive sites, which containT and B cells undergoing clonal expansion anddifferentiation upon activation by antigen (14).The intestinal lamina propria (LP) exemplifiesmucosal effector sites, whose main function isto recruit effector T and B cells emerging frominductive sites (15).

Antibodies released by effector B cells,including plasma cells, provide the first line ofprotection at mucosal surfaces. In the intesti-nal tract and other mucosal districts, the vast

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Microfold cell (Mcell): an intestinalepithelial cell typedevoid of microvilliand specialized inantigen sampling

CSR: class switchrecombination

Somatichypermutation(SHM): a process thatintroduces pointmutations in thevariable portion of Iggenes and provides astructural correlate forantibody affinitymaturation

Activation-inducedcytidine deaminase(AID): a DNA-editing enzymerequired for theinduction of classswitching and somatichypermutation in Bcells

majority of mucosal plasma cells secrete dimericor oligomeric IgA and to a lesser extent pen-tameric IgM, both of which interact with thepolymeric Ig receptor (pIgR) expressed on thebasolateral surface of epithelial cells througha joining ( J) chain (16). This interaction isfollowed by endocytosis of IgA and IgM, pro-teolytic cleavage of pIgR, and basolateral-to-apical transcytosis of secretory IgA (SIgA) andSIgM, which comprise a pIg-derived secretorycomponent (SC) providing mucophilic prop-erties to the SIg complex (16). As for IgG, thisantibody class gains access to respiratory andurogenital secretions through both nonspecificand specific mechanisms, the latter involvinginteraction with an antibody transporter knownas neonatal Fc receptor (nFcR) (10, 17). Themechanism by which IgD enters respiratorysecretions remains unknown (10, 18, 19).

GALT and NALT

Although equipped with a general architectureresembling that of systemic lymphoid organs,the MALT has several unique features, includ-ing absence of afferent lymphatics, which re-quires sampling of antigen directly from theepithelial surface (8). In the GALT, antigensampling involves specialized microfold (M)cells lodged in the follicle-associated epithelium(20). M cells filter bacteria through a complexglycocalix and sample some of these bacteriavia poorly defined receptors (21). IgA receptorsallow M cells to sample IgA-coated commen-sals (22), whereas glycoprotein 2 receptor sam-ples IgA-free commensals as well as pathogens(23). Sampled antigen is eventually transferredto dendritic cells (DCs), which occupy largebasolateral invaginations of M cells (21). Al-ternatively, DCs directly sample antigen fromthe lumen through transepithelial projections(24). These antigen-loaded DCs migrate to theperifollicular area of PPs to present antigen toCD4+ T cells and initiate antigen-specific Tand B cell responses (8).

The NALT has antigen-sampling strategiessimilar to those present in the GALT, includingM cells (11). In humans, the NALT consists

of a set of lymphoid aggregates known asWaldeyer’s ring that occupy strategic areas ofthe oropharynx and nasopharynx and includepharyngeal tonsils (or adenoids) as well astubal, palatine, and lingual tonsils (10). NALTorganogenesis markedly differs from GALTorganogenesis in terms of both kinetics andcytokine requirements (11, 25). For example,PPs begin their development during embry-onic life and require signals from interleukin-7(IL-7) and lymphotoxin receptors, whereastonsils initiate their development shortly afterbirth and require signals from environmentalantigens (11, 25). Another important differencebetween GALT and NALT is that NALT-targeted immunization preferentially inducesantigen-specific immunity in the respiratoryand genital tracts, whereas GALT-targeted im-munization mainly elicits protective responsesin the gastrointestinal tract (11, 26).

NATURE AND FUNCTIONOF MUCOSAL ANTIBODIES

Genesis and Functionof Antibody Diversity

Diversification is essential for the mucosalimmune system to mount protective responses.Antibodies diversify through three majorDNA-modifying processes known as V(D)Jrecombination, class switch recombination(CSR), and somatic hypermutation (SHM).Bone marrow B cell precursors generateantigen recognition diversity through V(D)Jrecombination, an antigen-independent pro-cess mediated by recombination-activatinggene (RAG) endonucleases that assembleantigen-binding Ig variable regions from indi-vidual V (variable), D (diversity), and J (joining)gene segments (27). Mature B cells emergingfrom the bone marrow colonize peripherallymphoid organs, where they undergo a secondwave of Ig gene remodeling through SHM andCSR, two antigen-dependent processes thatrequire the DNA-editing enzyme activation-induced cytidine deaminase (AID) and mediateantibody affinity maturation and antibody

www.annualreviews.org • Frontline IgA and IgD Production 275

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Class switching: anIg gene–modifyingprocess that occursthrough class switchrecombination andprovides antibodieswith novel effectorfunctions

TD: T cell–dependent

TI: T cell–independent

class (or isotype) switching, respectively(28, 29).

SHM introduces point mutations withinV(D)J exons, thereby providing the structuralcorrelate for selection of high-affinity Ig mu-tants by antigen, whereas CSR replaces con-stant μ (Cμ) and Cδ exons encoding IgM andIgD with Cγ , Cα , or Cε exons encoding IgG,IgA, or IgE, thereby providing antibodies withnovel effector functions without changing theirantigen-binding specificity (30, 31). In humans,a noncanonical form of CSR from Cμ to Cδ

also exists and generates B cells specialized inIgD production (18, 32). As already discussed,IgA mediates its effector functions by inter-acting with pIgR on the basolateral surface ofmucosal epithelial cells (16). In addition, IgAbinds to a high-affinity IgA receptor known asFcαRI (or CD89), which is expressed on gran-ulocytes, monocytes, macrophages, DCs, natu-ral killer (NK) cells, and mast cells (33). Theseinnate immune cells generate activating or reg-ulatory signals upon FcαRI receptor engage-ment by IgA, depending on the degree of IgAoligomerization (34).

Additional IgA receptors include transfer-ring receptor (CD71), Fcα/μR (which alsobinds IgM), and asyaloglycoprotein receptor,but their functions remain poorly understood(33). As for IgG and IgE, these antibody classesinitiate multiple innate and adaptive immuneresponses by activating high- or low-affinityFcγR and FcεR on various innate immune cells(35). In addition, IgG undergoes bidirectionaltranscytosis across epithelial cells by bindingto nFcR (17, 36). In IgE-mediated allergicdisorders, IgE undergoes transcytoses acrossepithelial cells by utilizing a low-affinity IgEreceptor known as FcεRII (or CD23) (37–39).The receptors mediating IgD effector functionsand IgD transcytosis remain elusive. Althoughexpressing abundant J chain, IgD-secretingplasma cells seem to release monomeric IgDonly, which does not bind to pIgR (10). Consid-ering that the hinge region of IgD has a heparinligand–like site, heparin and other heparansulfate proteoglycans may play an importantrole in at least some IgD effector functions (18).

Antibody Compositionof Mucosal Sites

Differences in epithelial cell expression ofspecific antibody transporters and plasmacell–recruiting chemokines contribute todetermining the antibody class composition ofa given mucosal site. In general, IgA is the mostabundant antibody isotype in mucosal secre-tions. Yet, IgA is somewhat less abundant thanIgG in the urine, bile, and genital and bron-choalveolar secretions. IgD can be detected innasal, salivary, lacrimal, and bronchoalveolarsecretions (10, 18, 19), whereas IgE is measur-able in nasal, bronchoalveolar, and intestinalsecretions, at least when allergy is present (37).

Unlike mouse B cells, human B cells pro-duce two IgA subclasses, IgA1 and IgA2, whichhave a similar receptor-binding profile but dif-ferent topography from each other (40). IgA1 ispresent in both systemic and mucosal districts,whereas IgA2 is mostly present in mucosal dis-tricts colonized by a large microbiota, includingthe distal intestinal tract and the urogenital tract(40). This circumstance could reflect the factthat IgA2 is more resistant than IgA1 to degra-dation by bacterial proteases because IgA2 hasa shorter hinge region than IgA1 does (41, 42).

Function of Mucosal IgA

Mucosal IgA comprises antibodies that rec-ognize antigen with high- and low-affinitybinding modes (8). In general, high-affinityIgA neutralizes microbial toxins and invasivepathogens, whereas low-affinity IgA confinescommensals in the intestinal lumen. Yet thisdistinction is not absolute, as growing evidenceindicates an important role for high-affinityIgA in the control and regulation of the com-mensal microbiota (43). Conversely, additionalevidence shows that low-affinity IgA protectsagainst some pathogens (44, 45). High-affinityIgA is thought to emerge from follicular B cellsstimulated via T cell–dependent (TD) path-ways, whereas low-affinity IgA likely emergesfrom extrafollicular B cells stimulated via Tcell–independent (TI) pathways (14). However,this view is rapidly changing. Indeed, recent


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Germinal center: aspecialized lymphoidstructure fosteringimmunoglobulin classswitching and somatichypermutation

B cell antigenreceptor (BCR):a term that refers totransmembraneimmunoglobulinmolecules on B cells

findings document the existence of TI pathwaysof IgA production in follicular B cells (46).

IgA also promotes the maintenance of ap-propriate bacterial communities in specific in-testinal segments (47). Indeed, IgA modulatesthe gene-expression profile of commensal bac-teria, selecting species with less inflammatoryactivity on the host’s tissues (48). By prevent-ing overstimulation of mucosal B cells, thisIgA-mediated selection process may impedebacteria-induced expansion of autoreactive, in-flammatory, proallergic, and neoplastic B cellclones (7, 14, 40). Furthermore, IgA facilitatesthe establishment of specific symbiotic relation-ships not only in the mucosal lumen, but alsoin PPs (49). As discussed above, IgA also fa-cilitates sampling of luminal antigens by bind-ing to poorly defined receptors on M cells (22,50). Moreover, IgA neutralizes inflammatorymicrobial products inside epithelial cells (51).Finally, if bacteria trespass the epithelial bar-rier, IgA transports these bacteria back into thelumen via pIgR or promotes their phagocytosisthrough FcαRI (34, 52).

The in vivo relevance of IgA can be bestseen in patients with SIgAD, common variableimmunodeficiency (CVID), and hyper-IgM(HIGM) syndrome. In these primary im-munodeficiencies, impaired IgA productionis associated with recurrent respiratory andgastrointestinal infections as well as allergy andautoimmunity (53, 54). Some IgA-deficientpatients also develop intestinal inflammationand small intestinal nodular lesions, possiblyresulting from excessive B cell stimulationby aberrantly expanded commensals (14, 55).Yet SIgAD, CVID, and even some cases ofHIGM syndrome can be asymptomatic ormildly symptomatic, possibly because of com-pensatory increases of unaffected antibodiessuch as IgM and IgD (10, 18, 53, 54).

Function of Mucosal IgD

The function of IgD has puzzled immunolo-gists over the past several decades. Originallythought to be a recently evolved isotype, IgD isnow recognized to be an ancestral molecule that

has been conserved throughout evolution tocomplement the functions of IgM (18, 56). IgDwould afford protection to the respiratory mu-cosa by binding to pathogenic bacteria such asMoraxella catarrhalis and Haemophilus influenzaeas well as to their virulence factors (32, 57). Inaddition to crossing epithelial cells, IgD bindsto circulating basophils, monocytes, and neu-trophils as well as to mucosal mast cells throughunknown receptors (18, 58).

Consistent with recently published datashowing the important role of basophils in Thelper type 2 (Th2) cell responses and antibodyproduction (59–63), IgD cross-linking inducesbasophil release of B cell–activating cytokinessuch as interleukin (IL)-4 and IL-13, which inturn facilitate IgM as well as IgG and IgA pro-duction (32). Furthermore, IgD cross-linkingtriggers basophil release of antimicrobialpeptides such as cathelicidin, inflammatorycytokines such as IL-1β and TNF, and var-ious chemokines such as CXCL10 (32, 58).Therefore, IgD may contribute to mucosalimmunity not only by neutralizing pathogensand excluding commensals, but also by recruit-ing basophils as well as other immune cellswith antimicrobial and immune-augmentingfunctions (18).

PATHWAYS INDUCINGMUCOSAL IgA RESPONSES

T Cell–Dependent Pathways

Most antigens initiate mucosal IgA responsesthrough a TD reaction that takes place inmucosal lymphoid follicles (8, 15), such asintestinal PPs and MLNs (Figure 1a,b). Theseorganized structures comprise a germinalcenter that fosters antibody diversification andaffinity maturation, including SHM and CSR,through antigen-specific cognate interactionsbetween B cells that express the CD40 receptorand CD4+ Th cells expressing CD40 ligand(CD40L) (13, 40). Together with cytokinereceptors and B cell antigen receptor (BCR),CD40 is critical for the induction of AIDexpression and the initiation of SHM and CSR


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L A M I N AP R O P R I A

L U M E N

’Y E R ’PP SSY E RYEEP ’T C HT CTP A T HCCT C HTAP A

CD4+

T cell

TGF-β

TGF-β

TGF-β1

RA

TACI

APRIL

APRIL

APRIL BAFF

BAFFCSR, SHM

TSLP RA

RA

Foxp3+

Largeintestine

Smallintestine

Small intestine (normal)

IgA AID DAPISmall intestine (normal)

IgA APRIL DAPI

Small intestine (AIDS)

IgA AID DAPISmall intestine (HIGM3)

IgA AID DAPI

PP

LP

PP

LP

LP

LP

a

c

b

DC

Bacteria

TLRs

TLRDC

tipDC B

Th2

TFH

B

IgA1+

B cell

IgA1

IgA1

IgA1 IgA2 IgM IgD

IgA1

IgA1 IgA2

IgA2IgA2IgA2

IgM+IgD+

B cell

IgA2+

plasmablast

IgA1+

plasmablast

CD40CD40L

MHC

MHCIL-10

IL-10

IL-21

IL-4

TCR

TCRFDC


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Toll-like receptors(TLRs): a family ofinnate antigenreceptors thatrecognize highlyconserved microbialpatterns

ILF: isolatedlymphoid follicle

(40, 64). Engagement of CD40 by CD40Lleads to (a) the recruitment of TNF receptor-associated factor (TRAF) adaptor proteins tothe cytoplasmic tail of CD40 (65), followed by(b) activation of an NF-κB inhibitory protein(IκB) kinase (IKK) complex, which triggers(c) phosphorylation and degradation of IκBthat retains NF-κB in an inactive state (66,67). The resulting IκB-free NF-κB proteinstranslocate from the cytoplasm to the nucleusto initiate transcription of the AICDA genepromoter that encodes AID (40, 68). In con-trast, NF-κB is not required for the activationof the intronic α (Iα) promoter upstream ofthe Cα gene and therefore has little or no rolein germ-line Cα gene transcription (40, 69).This circumstance may explain why additionalsignals from cytokines such as transforminggrowth factor-β (TGF-β) are needed to elicitIgA CSR, at least in mice (13).

T Cell–Independent Pathways

The conventional TD pathway requires 5 to7 days to initiate protective antibody responsesin systemic lymphoid tissues (70, 71). Such ki-netics may not be appropriate to afford optimalmucosal protection because mucosal surfacesare constantly exposed to dietary and bacterialantigens. In addition, the TD pathway is oftenassociated with an inflammatory reaction thatcould disrupt the mucosal epithelial barrier. Tocompensate for these limitations, the intestinalmucosa has developed a faster TI pathway thatgenerates IgA in response to highly conserved

microbial signatures recognized by Toll-likereceptors (TLRs) (14, 40), a family of germ-linegene-encoded antigen receptors involved inthe activation of both innate and adaptive armsof the immune system (72, 73). In mice, TIIgA production involves B-1 cells from theperitoneal cavity and intestinal LP as well asconventional B-2 cells from isolated lymphoidfollicles (ILFs) (13). These B cells releaselow-affinity IgA (and IgM) in the absence ofhelp from CD4+ T cells via CD40L (74–76).The human counterpart of mouse B-1 cellsremains unknown.

TLRs facilitate TI IgA responses either byactivating B cells directly or by inducing releaseof the B cell–activating factor of the TNF family(BAFF, also known as BLyS) and its homologa proliferation-inducing ligand (APRIL) frominnate immune cells (7, 40). Engagement ofTLRs by microbial ligands triggers activationof NF-κB (72, 73). This activation requires re-cruitment of the adaptor protein MyD88 to acytoplasmic Toll-interleukin-1 receptor (TIR)domain that subsequently elicits formation ofan IKK-activating signaling complex composedof IL-1 receptor–associated kinase (IRAK)1,IRAK4, TRAF6, and TGF-β-activated kinase(TAK)-1 (73).

In addition to inducing AID expression in Bcells (77, 78), TLR signaling via NF-κB elicitsBAFF and APRIL expression in DCs, mono-cytes, macrophages, granulocytes, and epithe-lial cells, including intestinal epithelial cells(IECs) (79–84). In the presence of appropri-ate cytokines, BAFF and APRIL initiate Cα

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−Figure 1IgA responses in the intestinal mucosa. (a) Scheme of human MALT, including intestinal mucosa. (b) Immunofluorescence analysis ofgut mucosa from healthy, HIGM3, and AIDS donors stained for IgA ( green), AID or APRIL (red ), and nuclei (DAPI staining, blue).Left panels show Peyer’s patches (PPs) and lamina propria (LP); right panels show only LP. Original magnification, x20. (c) Scheme ofmucosal IgA responses. Antigen-sampling DCs receive conditioning signals from TLR-activated intestinal epithelial cells (IECs) viathymic stromal lymphopoietin (TSLP) and retinoic acid (RA). Various DC subsets releasing TGF-β, IL-10, RA, and nitric oxideinitiate IgA responses in PPs by inducing Th2, Treg, and Treg-derived T follicular helper (TFH) cells that activate follicular B cells viaCD40L, TGF-β, IL-4, IL-10, and IL-21. In addition, DCs activate some B cells in the LP via BAFF, APRIL, and RA. Thesemolecules are also used by TLR-activated IECs to induce local IgA production, including sequential switching from IgA1 to IgA2, aswell as plasma cell differentiation and survival. (Additional abbreviations used in figure: AID, activation-induced cytidine deaminase;APRIL, a proliferation-inducing ligand; BAFF, B cell–activating factor; CSR, class switch recombination; DC, dendritic cell; HIGM3,hyper-IgM 3; MALT, mucosa-associated lymphoid tissue; SHM, somatic hypermutation; TGF-β, transforming growth factor-β;TLR, Toll-like receptor.)


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germ-line expression and Cμ-to-Cα CSR byengaging a CD40-related receptor known astransmembrane activator and calcium modula-tor and cyclophylin ligand interactor (TACI)(84–88). One important property of this recep-tor is to establish a close cooperation with Bcell–intrinsic signals from TLRs (85).

IgA RESPONSES INMUCOSAL FOLLICLES

Role of CD4+ T Cells

Growing evidence indicates that TD IgA re-sponses involve a heterogeneous population ofCD4+ T cells (Figure 1c), including T follic-ular helper (TFH) cells, Th2 cells, and T reg-ulatory (Treg) cells (13, 40). These CD4+ Tcell subsets express CD40L and release largeamounts of IgA-inducing cytokines (89–92).But how do IgA-inducing TFH, Th2, and Tregcells differentiate from naive CD4+ T cells? Akey role is played by DCs strategically posi-tioned in the subepithelial area (21). In additionto receiving antigen from M cells, these DCs di-rectly sample antigen in the intestinal lumen byemanating transepithelial projections througha process controlled by signals from TLRs inIECs (24, 93). Overall, M cells and DCs captureonly small amounts of bacteria because intesti-nal IgA responses have a much higher inductionthreshold (108–109 bacteria) than do systemicIgG responses (43).

Antigen sampling through transepithelialprojections involves nonmigratory gut-residentDCs expressing the fractalkine receptorCX3CR1 (94) developmentally distinct frommigratory DCs expressing the αE integrinCD103 (95, 96). As they sample antigen inthe lumen, DCs receive powerful conditioningsignals from IECs, thereby becoming primedfor the induction of noninflammatory CD4+

T cells with an IgA-inducing function (7,92, 97). Antigen-loaded DCs migrate fromsubepithelial to perifollicular areas, where theyinduce Treg and Th2 cell differentiation (95,96, 98, 99). Although Th2 cells may elicitCD40-dependent IgA CSR and production by

releasing IL-4, IL-5, IL-6, and IL-10 (89, 92,100, 101), Treg cells would do so by releasingTGF-β (90, 91). Some Treg cells would furtherdifferentiate into TFH cells, which induce IgACSR and production via IL-21 and TGF-β1(91, 102). In general, CD4+ T cells thatprovide help to B cells in PPs are clearly func-tionally different from their counterparts thatinitiate IgG responses in systemic lymphoidfollicles, which may explain why intestinal IgAresponses have a slower onset than systemicIgG responses (>14 days versus 5–7 days) (43).

IgA-producing B cells generated via TDpathways further differentiate into IgA-secreting plasma blasts in the intestinal LP (7).Here, Th17 cells might facilitate transepithelialrelease of SIgA through an IL-17-dependentmechanism involving upregulation of pIgRexpression (103), although thus far this mecha-nism has only been described in the respiratorymucosa. Despite requiring CD4+ T cells forgerminal center formation, PPs are capableof producing IgA independently of canonicalT-B cell interactions (104). Indeed, PPs retainTD IgA responses in the absence of BCR,which is instead required by systemic folliclesto initiate TD IgG responses (104). Thus, PPsmay generate IgA through an alternative TDpathway that involves activation of B cells bymicrobial TLR ligands (105). Supporting thismodel, lack of MyD88 impairs IgA productionin intestinal PPs (46, 106).

Role of Conventional Dendritic Cells

Intestinal DCs maintain homeostasis not onlyby inducing noninflammatory IgA responses,but also by dampening inflammatory Th1 andTh17 cell responses (7, 13, 99, 107–109). Strik-ingly, both processes implicate DC-induceddifferentiation of antigen-specific Th2, Treg,and TFH cells (90–92, 98). Intestinal DCs areparticularly skilled in eliciting these homeo-static CD4+ T cell responses (Figure 1c) be-cause they receive conditioning signals fromIECs (97, 107). One of these signals is providedby thymic stromal lymphopoietin (TSLP), anIL-7-like epithelial cytokine that shifts the


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Th1/Th2 balance toward Th2 polarization byattenuating DC production of IL-12 but not ofIL-10 (92, 110).

Importantly, IECs release TSLP in responseto TLR-mediated signals from bacteria (111).Accordingly, genetic disruption of TLR sig-naling via NF-κB reduces TSLP expression byIECs and augments IL-12 production by DCs(112). In addition to TSLP, IECs release TGF-β and retinoic acid, which stimulate the devel-opment of CD103+ DCs, at least in vitro (113).These DCs promote the formation of Treg cellsvia TGF-β and retinoic acid and suppress thedevelopment of inflammatory Th1 and Th17cells (99, 114, 115). As discussed earlier, Tregcells emerging from this pathway could in-duce IgA CSR and production through TGF-β(90, 91).

It must be noted that thus far no DC subsethas been formally assigned to the induction ofIgA responses in PPs. One notable exceptionis a TNF-α-inducible nitric oxide synthase–producing DC (tipDC) subset that enhancesIgA CSR and production by upregulating theexpression of TGF-β receptor on B cells fromPPs via nitric oxide (106). The ontogenetic andfunctional relationships of tipDCs with otherintestinal DC subsets remain unclear.

Role of Follicular Dendritic Cells

Germinal centers from PPs and MLNs containa meshwork of antigen-trapping folliculardendritic cells (FDCs) ontogenetically differ-ent from DCs. Indeed, FDCs originate fromnonhematopoietic precursors that may includemesenchymal cells (116). One of the main func-tions of FDCs is to facilitate the positive selec-tion of high-affinity follicular B cells by antigen(117). During this process, antigen arrays onthe surface of FDCs activate B cells by exten-sively cross-linking BCR (118). As shown byrecent studies (46), FDCs from PPs and MLNsefficiently induce IgA CSR and production(Figure 1c). This response occurs in a TImanner and involves TLR-mediated sensingof bacteria by FDCs, followed by FDC releaseof TGF-β, BAFF, and APRIL (46).

Role of Lymphoid TissueInducer Cells

Together with PPs and MLNs, IFLs representanother important site for IgA induction(14). These lymphoid structures are scatteredthroughout the intestine and consist of solitaryB cell clusters built on a scaffold of stromalcells with interspersed CD4+ T cells andabundant perifollicular DCs (119). Unlike PPs,ILFs appear after birth in response to bacteriacolonization (119). Recent findings indicatethat TLR signals from commensal bacteriainitiate a crosstalk centered on RORγt+

lymphoid tissue inducer (LTi) cells (74). Thesecells recruit DCs and B cells through variouschemokines and stimulate release of activeTGF-β, BAFF, and APRIL by activating DCsand stromal cells via a signaling loop involvinglymphotoxin (74). Together with microbialTLR ligands, TGF-β, BAFF, and APRILinduce IgA CSR in the absence of help fromCD4+ T cells (74). Of note, LTi cells alsorelease the IEC-activating cytokine IL-22 andthe B cell–attracting chemokine CXCL13,which may enhance IgA production in additionto promoting homeostasis (120).

Homing of IgA-Expressing B Cells

IgA-producing B cells generated in PPs andMLNs upregulate the expression of critical gut-homing receptors such as the α4β7 integrin aswell as CCR9 and CCR10 chemokine recep-tors upon being primed by retinoic acid thatis released by local DCs (121). These retinoicacid–primed B cells enter the general circula-tion via the thoracic duct and thereafter gainaccess to the LP by binding mucosal addressin-cell adhesion molecule-1 (MadCAM-1) ex-pressed on LP-based high endothelial venulesthrough α4β7 (122). Retinoic acid–primed Bcells further respond to CCL25 and CCL29,two IEC chemokines that bind to CCR9 andCCR10, respectively (122). Once in the LP,IgA-expressing B cells terminally differenti-ate into IgA-secreting plasma cells, possiblythrough the help of local signals from IECs,DCs, and macrophages (40). Similar cells would


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S region: switchregion, a highlyrepetitive intronicDNA sequence thatguides recombinationbetween activelytranscribed CH genes

also provide robust activation and survival sig-nals to B cells emerging from PPs and MLNs,which may explain why intestinal IgA responsesdo not always correlate with a florid germinalcenter reaction in PPs and yet show a sustainedhalf-life (>16 weeks) (43).

IgA RESPONSES IN MUCOSALEXTRAFOLLICULAR AREAS

IgA CSR in the IntestinalLamina Propria

The diffuse tissue of the LP is an additionalsite for IgA production and diversification(Figure 1c), although it is less importantthan PPs and MLNs (123). Consistent withthis possibility, genetically engineered micelacking PPs, MLNs, and even ILFs retain someantigen-specific IgA plasma cells, which aremostly located in the LP (124, 125). In bothmice and humans, a fraction of B cells fromthe intestinal LP contain molecular hallmarksof ongoing IgA CSR, including AID, H2AXprotein (a nuclear protein associated withdouble-strand DNA breaks generated by AIDwithin S regions), excised Sα-Sμ switch circles,and switch circle Iα-Cμ transcripts (111, 126–128). Of note, AID and IgA remain detectablein LP B cells from mice and humans lackingCD4+ T cells or CD40L (74, 111, 129). Ingeneral, LP B cells are less activated and morescattered than PP B cells, and therefore LP IgACSR can pass unrecognized unless highly sensi-tive and accurate methodologies are used (126,130, 131). In this regard, a green fluorescentprotein–AID reporter mouse model has provenvery helpful (129). The mechanisms underlyingIgA CSR in the LP remain poorly understoodbut likely involve DCs and IECs (111, 132).

Role of DCs

Abundant evidence demonstrates that DCs caninitiate TI CSR and antibody production by ac-tivating B cells through antigen and cytokines,including BAFF and APRIL (84, 133–138).In the intestine, antigen-sampling CX3CR1+

DCs or CD103+ DCs may activate LP B cellsthrough similar mechanisms (Figure 1c). A LP

DC subset with clearer B cell–stimulating func-tion is that of tipDCs (106). These DCs initi-ate TI IgA production by releasing BAFF andAPRIL through a mechanism involving TLR-induced iNOS-mediated nitric oxide produc-tion (Figure 1c). In the LP, another DC sub-set with B cell–licensing functions is that ofCD11chiCD11bhi DCs (139). These DCs in-duce TI IgA production upon sensing bacteriathrough TLR5, a process that elicits release ofretinoic acid and IL-6 (Figure 1c).

Role of Intestinal Epithelial Cells

IECs and respiratory epithelial cells can deliverIgA-inducing signals to LP B cells by releas-ing BAFF, APRIL, and IL-10 in response toTLR signals (79, 111, 127, 140). Similar ep-ithelial cells can also amplify DC production ofBAFF, APRIL, and IL-10 by stimulating DCsthrough TSLP (79, 111). In humans, APRIL isparticularly effective at inducing IgA2, an IgAsubclass particularly abundant in the distal in-testine (111). In addition to triggering directIgM-to-IgA1 CSR (111), APRIL elicits sequen-tial IgA1-to-IgA2 CSR in the LP of the distalintestine (Figure 1c). This process would allowB cells arriving from PPs to acquire an IgA2subclass more resistant than IgA1 to degrada-tion by bacterial proteases (42).

IgD RESPONSES IN THERESPIRATORY MUCOSA

Geography of IgD Production

IgD constitutes a significant fraction of theantibodies produced in the upper segmentsof the human respiratory and digestive tracts(Figure 2a). The mucosal IgD class originatespredominantly from IgD+IgM− B cells bearingmorphologic and immunophenotypic featuresof plasmablasts (32). Indeed, IgD+IgM− B cellsdisplay canonical plasma cell traits such as aneccentric nucleus, a large basophilic cytoplasmfilled with IgD (Figure 2b), and J chain as wellas IgD-secreting activity, in addition to featurestypical of mature B cells such as expressionof surface IgD and CD19 (32, 141–143). Ofnote, IgD+IgM− plasmablasts originate from a


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process of Cμ-to-Cδ CSR that leads to the lossof IgM expression (142). This process takesplace in the aerodigestive mucosa becausethis site contains various molecular hallmarksof ongoing Cμ-to-Cδ CSR (32). In general,the respiratory mucosa expresses chemokinesand vascular adhesion molecules capable ofpromoting the recruitment of IgD+IgM−

plasmablasts from the periphery (144). In thisregard, the peripheral blood contains someIgD+IgM− plasmablasts, which may be intransit to reach distant mucosal effector sites(32, 145). IgD+IgM− plasmablasts are rarelyfound in the GALT, probably because these Bcells express little or no gut homing receptorssuch as α4β7 and CCR9 (144).

Regulation of IgD ProductionIn humans and other higher mammals suchas cows, a rudimentary S-like intronic DNAregion known as σδ is present upstream ofthe Cδ exon (18). Like canonical S regions,σδ contains guanosine-cytosine repeats andserves as an acceptor DNA region for donorSμ to mediate nonhomologous Cμ-to-Cδ CSR(18). Alternatively, virtually identical Iμ and�μ intronic DNA regions located 5′ of Cμ

and Cδ exons, respectively, could mediatehomologous Cμ-to-Cδ CSR (18). Sμ-to-σδ

CSR requires AID because HIGM2 patientswith AID deficiency are completely devoid ofIgD+IgM− plasmablasts (32). In addition, naiveB cells from HIGM2 patients are unable toundergo Sμ-to-σδ CSR when stimulated withappropriate stimuli in vitro (32). HIGM1 andHIGM3 patients with deleterious substitutionsof CD40L and CD40, respectively, and CVIDpatients with deleterious substitutions of TACIhave a reduced and yet detectable fractionof IgD+IgM− plasmablasts in mucosal sites(32), suggesting that IgD CSR and productionproceed through both TD and TI pathways(Figure 2c). Consistent with this possibility,CD40L, BAFF, or APRIL can induce IgDCSR and production when combined withIL-15 plus IL-21 or IL-2 plus IL-21 (32).

IgD+IgM− plasmablasts are biased towardthe use of Igλ light chain, harbor hypermu-

tated V(D)J genes, and release polyreactive aswell as monoreactive IgD (32, 142, 143). Se-creted IgD would exert its protective functionnot only by binding to antigen, but also by in-teracting with innate immune cells, includingbasophils (18, 32). By arming basophils withIgD highly reactive against respiratory bacteria,mucosal IgD+IgM− plasmablasts may educateour immune system as to the antigenic compo-sition of the upper respiratory tract (18). Uponsensing respiratory antigen, IgD-activated ba-sophils would initiate or enhance innate andadaptive immune responses both systemicallyand at mucosal sites of entry (18). This possi-bility is consistent with recent evidence show-ing that activated basophils can migrate to sec-ondary lymphoid organs to initiate Th2 and Bcell responses (59, 61, 63, 146).

Hyper-IgD syndrome (HIDS) is an inherited autoinflammatoryperiodic fever syndrome caused by partial deficiency of meval-onate kinase (MVK), an enzyme of the cholesterol biosyntheticpathway. HIDS causes recurrent attacks of fever and inflamma-tion that are often accompanied by cervical lymphadenopathy,abdominal pain, vomiting, and diarrhea. Hepatosplenomegaly,headache, arthralgias, arthritis, maculopapular rash, and purpuraare also common together with continuously elevated IgD.Complete MVK deficiency causes mevalonic aciduria (MA),which is characterized by hyper-IgD production, periodic fever,and inflammation as well as developmental delay, failure tothrive, hypotonia, ataxia, myopathy, cataracts, uveitis, and blooddisorders. Hyper-IgD production is also present in periodicfever-aphthous stomatitis-pharyngitis-adenitis (PFAPA) syn-drome and a series of hereditary inflammasome defects, includingfamilial Mediterranean fever (FMF) and cryopyrin-associatedperiodic syndromes (CAPS). This latter comprises neonatal onsetmultisystem inflammatory disease, Muckle-Wells syndrome, andfamilial cold autoinflammatory syndrome. Like HIDS and MA,PFAPA, FMF, and CAPS cause periodic antibiotic-resistant feverand inflammation that often targets the upper respiratory, uro-genital and intestinal mucosae. The pathogenesis of hyper-IgDproduction and the role of IgD in periodic fever syndromes areunknown, but recent studies suggest that IgD may enhance feverand inflammation by triggering basophil release of IL-1β (32).


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L A M I N A

P R O P R I A

L U M E N

F O L L I C LF O L L I C L E

APRILBAFF

BAFF, IL-4,IL-1β, TNF,

etc.

IgD

IgD

IgM

IgD

Antimicrobialfactors

CSR,SHM

Salivaryglands

Tonsil

Nasal mucosa (normal)

IgD DAPITonsil (normal)

IgD AID BAFF

Tonsil (HIGM1)

IgD DAPITonsil (PFAPA)

IgD DAPI

a

c

b

Bacteria

DC

DCIgM+IgD+

B cell

IgM+IgD+

B cell

IgDplasmablast

IL-2

IL-2

IL-21

IL-21

IL-15

CD40

CD40L

MHC

TCR

Lachrymalgland

Nasalmucosa

FDC

IgM– IgD+

B cell Circulatingbasophil

IgM– IgD+

B cell

TH

TH

Migration toupper aerodigestive

mucosa and blood

Mucosalinfiltration

IgDR

IgM IgD


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COMPLEXITY OF MUCOSALHUMORAL IMMUNITY

Despite a wealth of sensing and effector mech-anisms capable of triggering inflammation inresponse to microbial sensing and intrusion,our mucosal immune system establishes home-ostatic conditions based on a fine discrimina-tion between commensals and pathogens (3).Epithelial cells play a key role in this processby sensing bacteria through a complex arse-nal of pattern-recognition receptors, includingTLRs (1). These innate antigen receptors edu-cate the immune system as to the compositionof the local microbiota and thereafter instructthe generation of effector and regulatory lym-phocytes whose main function is to dampen in-flammation and elicit massive IgA production(5).

A key aspect of this response relates to theintertwined nature of the signaling networks in-volved in the induction of mucosal IgA. In thesenetworks, the adaptor protein MyD88 seems toform a critical hub because its deletion leadsto a profound impairment of intestinal IgA re-sponses, at least in mice (46, 106). This findinglikely relates to the fact that TLRs are criticalfor the activation and differentiation of multipleimmune and nonimmune cells involved in theproduction and release of IgA, including B cells,

T cells, DCs, FDCs, and IECs. Yet some studiessuggest that mucosal signaling pathways may beeven more interconnected and integrated thancurrently thought.

As discussed earlier, TLR signaling viaMyD88 induces IEC, DC, and FDC produc-tion of BAFF and APRIL, two innate factorsthat deliver IgG and IgA CSR signals by en-gaging TACI on B cells (40). In addition togenerating TACI ligands, TLRs cooperate withTACI to optimize IgA and IgG CSR and pro-duction (79, 111, 147). Such cooperation in-volves upregulation of TACI expression on Bcells (148). However, TLRs and TACI furthercooperate at the signaling level (Figure 3). In-deed, TACI engagement triggers recruitmentof MyD88 to a highly conserved cytoplasmicdomain of TACI distinct from the cytoplas-mic TIR domain of TLRs (85). Interaction ofTACI with MyD88 is followed by activationof a TLR-like pathway that elicits AID expres-sion and CSR via NF-κB (85). These findingscould provide an alternative explanation to pre-viously published in vivo data demonstrating anessential role of MyD88 in systemic TI IgG re-sponses induced by BAFF (148) and, togetherwith other studies (46, 106, 149, 150), suggestthat TACI and TLRs may converge on MyD88to generate mucosal IgA.

←−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−Figure 2IgD responses in the aerodigestive mucosa. (a) Scheme of human NALT, including tonsillar mucosa. (b) Immunofluorescence analysisof nasal and tonsillar mucosal surfaces from healthy, HIGM1, and PFAPA (periodic fever-aphthous stomatitis-pharyngitis-cervicaladenitis) donors stained for IgD ( green), AID (red ), and BAFF or nuclei (DAPI staining, blue). Dashed lines demarcate follicles.Original magnification, ×10. (c) Scheme of mucosal IgD responses. Antigen-sampling DCs initiate IgD CSR by activating follicular orextrafollicular B cells through T cell–dependent (CD40L, IL-2, IL-15, IL-21) or T cell–independent (BAFF, APRIL, IL-15, IL-21)pathways, respectively. The resulting plasmablasts secrete IgD reactive against respiratory bacteria that exert protective functions eitherlocally or systemically by interacting with an elusive IgD receptor (IgDR) on circulating basophils. In the presence of IgD-bindingantigens, basophils migrate to systemic or mucosal lymphoid tissues, where they enhance immunity by releasing antimicrobial factors aswell as B cell–stimulating and proinflammatory mediators such as BAFF, IL-4, IL-1β, and TNF. As compared to tonsil tissues ofhealthy subjects, there are decreased (and yet detectable) numbers of IgD class switched (IgD+IgM−) plasmablasts in follicular andextrafollicular areas in tonsils of patients with Hyper-IgM syndrome type 1 (HIGM1) caused by loss-of-function mutations in theCD40L gene. Increased numbers of IgD class switched (IgD+IgM−) plasmablasts are found in tonsils of a patient with PFAPAsyndrome, with increased levels of IgD in tonsillar epithelium. (Additional abbreviations used in figure: APRIL, a proliferation-inducing ligand; BAFF, B cell–activating factor; CSR, class switch recombination; NALT, nasopharynx-associated lymphoid tissue;SHM, somatic hypermutation; TNF, tumor necrosis factor.)


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C Y TC Y T O S OO S O LL

B C E L L

N U C L E U S

APRIL

?

TBS

THC

TBS

THCTACI

TACI

BAFF

APRILBAFF

DC

TLRligand

TLRCytokine

Cytokinereceptor TIR

Jak

STAT

TIR

MyD88 MyD88

CAML

P

P

STATP STAT P

STATP STAT P

STATP STAT P

STATP STAT P

STATP

TRAF6

IRAK1 IRAK4

TAK1

TRAF6

TAK1

TR

AF

5

TR

AF

6

TR

AF

2

IKKcomplex

CH AICDA

I-κB

NF-κB

NF-κB

κB

NF-κB

κB

NF-κB

κB

NF-κB

κBGAS

STATP STAT P

GAS

I-κB

NF-κB

P

II-κκBBP

NF-κB

NF-κBNF-κB

Figure 3Interconnectivity of signaling pathways emanating from TLRs and TACI. DCs activate B cells by releasingBAFF, APRIL, and cytokines upon sensing microbial TLR ligands. Engagement of TACI by BAFF and/orAPRIL triggers association of the adaptor MyD88 to a TACI highly conserved (THC) domain that activatesNF-κB via IRAK-1, IRAK-4, TAK-1, and IKK-mediated degradation of IκB. Additional NF-κB activationinvolves binding of TRAF2, TRAF5, and TRAF6 to a TRAF-binding site (TBS) in the cytoplasmic domainof TACI and calcium modulator and cyclophilin ligand (CAML), a transmembrane TACI-interactingprotein. NF-κB initiates class switch recombination (CSR) by binding to κB motifs on AICDA and CH genepromoters. Engagement of TLRs by microbial ligands enhances CSR through a TIR-dependent pathwaythat shares MyD88 with the TIR-independent pathway emanating from TACI. Further CSR-inducingsignals are provided by cytokines via signal transducer and activator of transcription (STAT) proteins thatbind to γ-interferon-activated site (GAS) motifs on AICDA and CH gene promoters. (Additionalabbreviations used in figure: APRIL, a proliferation-inducing ligand; BAFF, B cell–activating factor;DC, dendritic cell; IKK, IκB kinase; IRAK, IL-1 receptor–associated kinase; TACI, transmembraneactivator and calcium modulator and cyclophylin ligand interactor; TAK, TGF-β-activated kinase; TIR,Toll-interleukin-1 receptor; TLR, Toll-like receptor.)


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CONCLUSIONS

The past decade has seen copious new discov-eries regarding the regulation and functionof mucosal antibodies and on the lineage,functional heterogeneity, and plasticity ofmucosal cell types with B cell–modulating andantibody-inducing function. In addition, it isbecoming increasingly clear that mucosal anti-body responses follow dynamics quite differentfrom those characterizing systemic IgG re-sponses. For instance, intestinal IgA responsesshow additive increases after each antigenicchallenge instead of prime-boost synergisticincreases typical of systemic IgG responses(43). In addition, intestinal IgA responses to agiven bacterial species are rapidly attenuatedby colonization with a different species (43).Such IgA attrition could reflect the need ofthe gut immune system to rapidly adapt itselfto the dominant microbial species present inthe lumen at any given time (43). The lack of

cardinal IgG memory characteristics in intesti-nal IgA responses has important implicationswith respect to the development of effectivemucosal vaccines. One prediction is that induc-tion of long-lasting IgA-mediated protectionwill require the development of creative vaccinedelivery strategies capable of ensuring sus-tained stimulation of mucosal B cells, includingthe embedding of appropriate immunogens instable components of our microbiota, edibleprobiotic bacteria, or genetically modifiedfoods such as transgenic plants. Another crit-ical step toward the generation of an effectivemucosal vaccine is to acquire more detailedknowledge of the multiple pathways involvedin mucosal antibody responses. A better under-standing of these pathways will be critical in de-vising mucosal vaccines that can provide rapid,robust, and sustained protection without caus-ing excessive inflammation or inappropriatetolerance.

DISCLOSURE STATEMENT

The authors are not aware of any affiliations, memberships, funding, or financial holdings thatmight be perceived as affecting the objectivity of this review.

ACKNOWLEDGMENTS

The authors are supported by U.S. National Institutes of Health grants R01 AI-05753 and R01AI-074378 (to A. Cerutti), Ministerio de Ciencia e Innovacion grant SAF 2008-02725 (to A. Cerutti),funds from Catalan Institute for Research and Advanced Studies (to A. Cerutti), funds from theMunicipal Institute of Medical Research Foundation (to A. Cerutti), and a Sara Borrell fellowship(to A. Chorny).

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IY29-Frontmatter ARI 4 February 2011 21:56

Annual Review ofImmunology

Volume 29, 2011Contents

Innate Antifungal Immunity: The Key Role of PhagocytesGordon D. Brown � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1

Stromal Cell–Immune Cell InteractionsRamon Roozendaal and Reina E. Mebius � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �23

Nonredundant Roles of Basophils in ImmunityHajime Karasuyama, Kaori Mukai, Kazushige Obata, Yusuke Tsujimura,

and Takeshi Wada � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �45

Regulation and Functions of IL-10 Family of Cytokinesin Inflammation and DiseaseWenjun Ouyang, Sascha Rutz, Natasha K. Crellin, Patricia A. Valdez,

and Sarah G. Hymowitz � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �71

Prevention and Treatment of Papillomavirus-Related CancersThrough ImmunizationIan H. Frazer, Graham R. Leggatt, and Stephen R. Mattarollo � � � � � � � � � � � � � � � � � � � � � � � � 111

HMGB1 Is a Therapeutic Target for Sterile Inflammation and InfectionUlf Andersson and Kevin J. Tracey � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 139

Plasmacytoid Dendritic Cells: Recent Progress and Open QuestionsBoris Reizis, Anna Bunin, Hiyaa S. Ghosh, Kanako L. Lewis, and Vanja Sisirak � � � � � 163

Nucleic Acid Recognition by the Innate Immune SystemRoman Barbalat, Sarah E. Ewald, Maria L. Mouchess, and Gregory M. Barton � � � � � � 185

Trafficking of B Cell Antigen in Lymph NodesSantiago F. Gonzalez, Søren E. Degn, Lisa A. Pitcher, Matthew Woodruff,

Balthasar A. Heesters, and Michael C. Carroll � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 215

Natural Innate and Adaptive Immunity to CancerMatthew D. Vesely, Michael H. Kershaw, Robert D. Schreiber,

and Mark J. Smyth � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 235

Immunoglobulin Responses at the Mucosal InterfaceAndrea Cerutti, Kang Chen, and Alejo Chorny � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 273

HLA/KIR Restraint of HIV: Surviving the FittestArman A. Bashirova, Rasmi Thomas, and Mary Carrington � � � � � � � � � � � � � � � � � � � � � � � � � � � 295

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IY29-Frontmatter ARI 4 February 2011 21:56

Mechanisms that Promote and Suppress Chromosomal Translocationsin LymphocytesMonica Gostissa, Frederick W. Alt, and Roberto Chiarle � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 319

Pathogenesis and Host Control of Gammaherpesviruses: Lessons fromthe MouseErik Barton, Pratyusha Mandal, and Samuel H. Speck � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 351

Genetic Defects in Severe Congenital Neutropenia: Emerging Insights intoLife and Death of Human Neutrophil GranulocytesChristoph Klein � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 399

Inflammatory Mechanisms in ObesityMargaret F. Gregor and Gokhan S. Hotamisligil � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 415

Human TLRs and IL-1Rs in Host Defense: Natural Insightsfrom Evolutionary, Epidemiological, and Clinical GeneticsJean-Laurent Casanova, Laurent Abel, and Lluis Quintana-Murci � � � � � � � � � � � � � � � � � � � � 447

Integration of Genetic and Immunological Insights into a Model of CeliacDisease PathogenesisValerie Abadie, Ludvig M. Sollid, Luis B. Barreiro, and Bana Jabri � � � � � � � � � � � � � � � � � � � 493

Systems Biology in Immunology: A Computational Modeling PerspectiveRonald N. Germain, Martin Meier-Schellersheim, Aleksandra Nita-Lazar,

and Iain D.C. Fraser � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 527

Immune Response to Dengue Virus and Prospects for a VaccineBrian R. Murphy and Stephen S. Whitehead � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 587

Follicular Helper CD4 T Cells (TFH)Shane Crotty � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 621

SLAM Family Receptors and SAP Adaptors in ImmunityJennifer L. Cannons, Stuart G. Tangye, and Pamela L. Schwartzberg � � � � � � � � � � � � � � � � � 665

The Inflammasome NLRs in Immunity, Inflammation,and Associated DiseasesBeckley K. Davis, Haitao Wen, and Jenny P.-Y. Ting � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 707

Indexes

Cumulative Index of Contributing Authors, Volumes 19–29 � � � � � � � � � � � � � � � � � � � � � � � � � � � 737

Cumulative Index of Chapter Titles, Volumes 19–29 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 744

Errata

An online log of corrections to Annual Review of Immunology articles may be found athttp://immunol.annualreviews.org/errata.shtml

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