Regulation of mucosal IgA responses: lessons from primary immunodeficiencies

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: The Year in Human and Medical Genetics: Inborn Errors of Immunity

Regulation of mucosal IgA responses: lessonsfrom primary immunodeficiencies

Andrea Cerutti,1,2,3 Montserrat Cols,3 Maurizio Gentile,1 Linda Cassis,1 Carolina M. Barra,1

Bing He,3 Irene Puga,1 and Kang Chen3

1Municipal Institute for Medical Research (IMIM)-Hospital del Mar, Barcelona, Spain. 2Catalan Institute for Research andAdvanced Studies (ICREA), Barcelona, Spain. 3Department of Medicine, The Immunology Institute, Mount Sinai School ofMedicine, New York, New York

Address for correspondence: Andrea Cerutti, Municipal Institute for Medical Research (IMIM)-Hospital del Mar, BarcelonaBiomedical Research Park, Barcelona, Spain 08003. [email protected] or [email protected]

Adaptive co-evolution of mammals and bacteria has led to the establishment of complex commensal communitieson mucosal surfaces. In spite of having available a wealth of immune-sensing and effector mechanisms capable oftriggering inflammation in response to microbial intrusion, mucosal immune cells establish an intimate dialoguewith microbes to generate a state of hyporesponsiveness against commensals and active readiness against pathogens.A key component of this homeostatic balance is IgA, a noninflammatory antibody isotype produced by mucosal Bcells through class switching. This process involves activation of B cells by IgA-inducing signals originating frommucosal T cells, dendritic cells, and epithelial cells. Here, we review the mechanisms by which mucosal B cellsundergo IgA diversification and production and discuss how the study of primary immunodeficiencies facilitatesbetter understanding of mucosal IgA responses in humans.

Keywords: human; B cells; IgA; mucosa; immunodeficiency

Preferred citation: Cerutti, A., M. Cols, M. Gentile, L. Cassis, C.M. Barra, B. He, I. Puga & K. Chen. 2011. Regulation of mucosalIgA responses: lessons from primary immunodeficiencies. In “The Year in Human and Medical Genetics: Inborn Errors ofImmunity I.” Jean-Laurent Casanova, Mary Ellen Conley & Luigi Notarangelo, Eds. Ann. N.Y. Acad. Sci. 1238: 132–144.

Introduction

The intestinal mucosa is home to trillions of mi-crobes present at densities that greatly exceed thosefound in other habitats, including soil.1 These com-mensal bacteria confer many metabolic capabilitiesthat our mammalian genome lacks, including theability to break down otherwise undigestible dietarycarbohydrates, generate essential vitamins and iso-prenoids, and fill a niche that would otherwise beeasily accessible to pathogens.2 A single layer of in-testinal epithelial cells separates commensals fromthe sterile milieu of our body.3 By recognizing mi-crobial molecular signatures through various fami-lies of pattern recognition receptors, such as Toll-likereceptors (TLRs), intestinal epithelial cells establisha complex dialogue with innate and adaptive cells ofthe intestinal immune system.4 This dialogue leadsto the production of a vast array of immune medi-

ators that generate a state of hyporesponsivenessagainst commensals and active readiness againstpathogens.1

An important component of this homeostaticbalance is IgA, a noninflammatory antibody iso-type generated by follicular B cells from Peyer’spatches, mesenteric lymph nodes, and isolated lym-phoid follicles.5,6 Collectively, these organized lym-phoid structures form the gut-associated lymphoidtissue, which constitutes the major inductive sitefor intestinal IgA responses.5,6 IgA-secreting plasmacells emerging from the gut-associated lymphoidtissue migrate to the effector site of the lamina pro-pria, where they release large amounts of IgA ontothe epithelial surface.5,6 In addition to serving as akey effector site, the lamina propria has a nonor-ganized lymphoid tissue that includes dispersedB cells retaining some IgA-inducing function.5,6

Here, we review the cellular and signaling pathways

doi: 10.1111/j.1749-6632.2011.06266.x132 Ann. N.Y. Acad. Sci. 1238 (2011) 132–144 c© 2011 New York Academy of Sciences.

Cerutti et al. Mucosal immunity and PID

orchestrating intestinal IgA production and discusshow the analysis of patients with specific formsof primary immunodeficiency (PID) has improvedour understanding of these pathways.

Function of mucosal IgA

The intestinal mucosa has evolved several strategiesto control commensals and neutralize pathogenswithout causing inflammatory damage to the ep-ithelial barrier. One of these strategies involvesthe production of massive amounts of IgA, themost abundant antibody isotype in our body. IgAreaches the intestinal lumen by interacting withthe polymeric Ig receptor on the basolateral sur-face of epithelial cells.5,6 After binding to poly-meric Ig receptor through a joining chain, IgAdimers secreted by intestinal plasma cells translo-cate across epithelial cells onto the mucosal surfaceby undergoing transcytosis.7,8 This process involvesintracellular processing of polymeric Ig receptorinto a polypeptide called secretory component,which remains associated with the joining chain ofthe IgA dimer to form a secretory IgA complex withnoninflammatory protective function.9–11 Indeed,secretory IgA can bind to bacteria without activatingcomplement or stimulating the release of inflamma-tory mediators by innate immune cells.12,13

IgA neutralizes toxins, pathogenic bacteria,and inflammatory microbial molecules, such as,lipopolysaccharide.14–21 IgA also prevents commen-sal bacteria from adhering to the epithelial surfaceby generating steric hindrance, by inducing bac-terial agglutination, by masking adhesion epitopes,and by interacting with mucus through the secretorycomponent.22,23 These processes favor the growth ofcommensal bacteria in biofilms that prevent the out-growth of pathogens through a mechanism involv-ing competition for biological niches and sourcesof energy. Furthermore, IgA facilitates the mainte-nance of homeostasis by decreasing the inflamma-tory tone of the intestine and by favoring the mainte-nance of appropriate bacterial communities withinspecific intestinal segments.21,24,25 Finally, IgA in-teracts with yet poorly defined receptors to facilitatethe sampling of luminal antigen by intestinal den-dritic cells (DCs) and microfold (M) cells, a subset ofantigen-sampling intestinal epithelial cells locatedin the follicular epithelium of Peyer’s patches andisolated lymphoid follicles.17,26–28

Binding modes and reactivity of mucosalIgA

Mucosal IgA antibodies emerge from B cells thatfollow either T cell–dependent (TD) or T cell–independent (TI) pathways (Fig. 1). Intestinal Bcells generate IgA diversification and productionthorugh V(D)J gene somatic hypermutation (SHM)and class switch recombination (CSR) from IgM toIgA.5,6 These processes require the DNA-editing en-zyme activation–induced cytidine deaminase (AID)and predominantly occur in the germinal centerof Peyer’s patches and mesenteric lymph nodes, al-though extrafollicular CSR and SHM have also beendescribed.29–36

In mice, IgA forms both high-affinity andlow-affinity binding systems that originate fromdifferent B cell types and likely serve distinct func-tions.18 High-affinity IgA originates from monore-active and antigen-selected conventional B-2 cellsthat express mutated Ig V(D)J gene sequences andoccupy the follicles of Peyer’s patches and mesen-teric lymph nodes.5,6 Low-affinity IgA would derivefrom polyreactive and nonantigen-selected B-1 cellsthat express unmutated Ig V(D)J gene sequencesand occupy the peritoneal cavity and to some ex-tent the lamina propria.37–42 Additional low-affinityIgA may derive from conventional B-2 cells, such asthose lodged in isolated lymphoid follicles.39,40,43,44

Mutated, antigen-selected, and monoreactive IgAplays an important role in the control of commen-sal bacteria and the neutralization of pathogens andmicrobial toxins.15,16,21,43 Unmutated, low-affinity,and polyreactive IgA would predominantly favorthe exclusion of commensal bacteria from the sur-face of intestinal epithelial cells, but this distinctionis not absolute, as there are examples of unmutatedIgA antibodies that recognize commensal bacteriawith high specificity.2,25,41 Conversely, polyreactiv-ity has been detected in mutated IgA antibodieswith clear traces of antigen selection, at least inhumans.45

In humans, 75% of IgA antibodies from intesti-nal plasmablasts are extensively mutated, have highspecificity for commensal and enteropathogenicantigens, and carry signs of antigen selection.45–47

Some of these antigen-specific antibodies seem todominate the intestinal IgA repertoire in multi-ple individuals, which is remarkable consideringthe enormous diversity of the gut microbiota.45

Ann. N.Y. Acad. Sci. 1238 (2011) 132–144 c© 2011 New York Academy of Sciences. 133

Mucosal immunity and PID Cerutti et al.

Figure 1. Cellular networks underlying mucosal IgA responses. Intestinal epithelial cells (IECs) “condition” dendritic cells (DCs)by releasing thymic stromal lymphopoietin (TSLP) and retinoic acid (RA) in response to TLR ligands from commensal bacteria.Different subsets of intestinal DCs release TGF-�, IL-10, RA, and nitric oxide (NO) that promote IgA responses in Peyer’s patches andmesenteric lymph nodes (MLNs) by inducing T regulatory (Treg) and T helper (Th) cells, including Treg-derived T follicular helpercells, which activate follicular B cells via CD40L, TGF-�, IL-4, IL-10, and IL-21. Follicular DCs further enhance IgA production byreleasing B cell–activating factor of the TNF family (BAFF), a proliferation-inducing ligand (APRIL), and TGF-� upon exposure toTLR ligands and RA. Some subsets of intestinal DCs also induce T cell–independent IgA production in mesenteric lymph nodes orthe lamina propria by releasing BAFF, APRIL, RA, and NO in response to TLR ligands from commensals or IFN-� from stromalcells. In humans, these T cell–independent signals would induce switching from IgM or IgA1 to IgA2. The IgA antibodies emergingfrom these pathways undergo transcytosis across IECs via the polymeric Ig receptor.

The remaining 25% of human intestinal IgA an-tibodies show polyreactivity for diverse microbialand autologous antigens, but also these antibod-ies are highly mutated and show traces of antigenselection.45 It has been proposed that polyreactiv-ity may be acquired through the introduction ofsomatic mutations and that selection of mutatedvariants of polyreactive germline gene-encoded an-tibodies may help to narrow down their antigenspecificity.45,48 Consistent with this possibility, somehuman polyreactive IgA antibodies show high reac-tivity to specific commensal bacteria and intestinaltissue structures, but low reactivity to other for-eign or autologous antigens.45 Another possibilityis that mutation-induced polyreactivity enhancesthe binding affinity of human IgA for microbes bysupporting heteroligation between one high-affinitycombining site and a second low-affinity site ona different molecular structure of the microbe.49

Clearly, more studies are needed to further elucidatethe nature and reactivity of intestinal IgA in humans

and to determine whether specific members of themicrobiota elicit different IgA responses.

Although SHM plays a dominant role in the con-trol of intestinal bacteria, CSR from IgM to IgA iscrucial to lower the overall inflammatory tone of theintestine in face of the continuous stimulation ex-erted by the local microbiota.21,25 The mechanismby which C� confers noninflammatory-protectivefunction to IgA remains poorly understood. The in-ability of C� to effectively activate complement andthe relative lack of high-affinity C�-binding Fc� re-ceptors on inflammatory intestinal immune cellslikely play an important role.18 Additional non-inflammatory properties of C� may relate to itsability to interact with the secretory component ofthe polymeric Ig receptor, which delivers regulatorysignals to DCs via an unknown receptor.10,11 C�

may deliver additional regulatory signals via a C-type lectin named DC-SIGN, which tunes down in-flammatory signals from TLRs in antigen-samplingDCs.50,51

134 Ann. N.Y. Acad. Sci. 1238 (2011) 132–144 c© 2011 New York Academy of Sciences.


Table 1. Mucosal cell types involved in IgA class switching and production

Mucosal cell type Mucosal topography Mechanism of IgA induction

Treg cell PP, LP CD40L, TGF-�, possibly IL-10

TFH cell PP, MLN CD40L, IL-21, TGF-�

Th2 cells PP IL-4, IL-10

FDC PP, MLN BAFF, APRIL, TGF-�

Stromal cell ILF, LP BAFF, APRIL, TGF-�

IEC LP BAFF, APRIL, RA, TSLP, IL-10, TGF-�

iNOS+TNF+ DC (tipDC)a PP, LP BAFF, APRIL, nitric oxide

CD11chiCD11bhi DC (TLR5+ DC)a LP RA, IL-6

CX3CR1+ DCa PP, LP Unknown

CD103+ DCa PP, LP, MLN Induction of Treg and possibly TFH cells via RA

CD11c+ DC PP Induction of Th2 cells via IL-10

CD11b+ DCa PP IL-6

aDescribed mostly in mice. TFH, T follicular helper cell.

IgA induction in Peyer’s patches andmesenteric lymph nodes

Peyer’s patches are the major portal of entry of bac-teria, and together with mesenteric lymph nodes,constitute the major IgA inductive site in the in-testine.28,52 Peyer’s patches develop during fetal lifeindependently of gut colonization by bacteria andconsist of large structures built on a stromal scaf-fold composed of several B cell follicles separatedby areas containing T cells and DCs.5,6 In Peyer’spatches there is an ongoing germinal center reac-tion that continuously drives IgA diversification andproduction.52 This germinal center reaction is op-timized by microbial signals, as mice depleted ofintestinal bacteria have Peyer’s patches with fewerand smaller germinal centers.53,54 In both Peyer’spatches and mesenteric lymph nodes, germinal cen-ter B cells produce IgA through a TD pathwayinvolving activation of CD4+ T cells by antigen-presenting DCs.44,55,56 The phenotype, cytokine ex-pression profile, and immune functions of these andother gut DCs are a matter of intense investigation(Table 1).

In Peyer’s patches, DCs expressing the chemokinereceptor CX3CR1 are found in close contact with thefollicle-associated epithelium and should be equiv-alent to CX3CR1+ DCs present in the lamina pro-pria.57,58 In general, CX3CR1+ DCs originate fromcirculating monocytes, express the DC moleculeCD11c together with the macrophage molecule

CD11b, and extend cellular projections across in-terepithelial junctions to sample antigen from theintestinal lumen, including segmented filamentousbacteria.57,59–64 Although unable to migrate to theinterfollicular areas of Peyer’s patches to presentantigen to T cells,65 CX3CR1+ DCs might con-tribute to TD IgA responses by transferring antigento migratory CD103+ DCs. In Peyer’s patches, DCsexpressing the integrin CD103 have an uncertainlocation but seem phenotypically and functionallysimilar to CD103+ DCs found in the intestinal lam-ina propria.66 In general, CD103+ DCs originatefrom circulating pre-DCs, express CD11c but no orlittle CD11b, and migrate to the interfollicular areaof Peyer’s patches and mesenteric lymph nodes topresent antigen to T cells.62,63,65,67 CD103+ DCs donot seem to form interepithelial projections and,therefore, might acquire antigen from CX3CR1+

DCs or M cells.Peyer’s patches contain additional DC subsets,

including CD11c+ DCs secreting the noninflam-mtory cytokine IL-10 and CD11b+ DCs secretingthe antibody-inducing cytokine IL-6.68,69 An addi-tional DC subset expressing the chemokine recep-tor CCR6 is found in the subepithelial dome, whichlies just underneath the follicle-associated epithe-lium of Peyer’s patches.58,70 Subepithelial CCR6+

DCs can initiate T cell immunity and may give riseto CCR7+ DCs, which are typically detected in theT cell-rich interfollicular area of mesenteric lymphnodes.71 The relationship of all these DC subsets



with CX3CR1+ DCs and CD103+ DCs remains un-clear.

As they sample antigen across epithelial cells, in-testinal DCs receive “conditioning” signals from in-testinal epithelial cells, including thymus stromallymphopoietin (TSLP).72 These signals mitigate DCproduction of IL-12, a cytokine that stimulates theformation of T helper type-1 (Th1) cells producingthe inflammatory cytokine IFN-� .59,72,73 Instead,intestinal DCs, including CD103+ DCs, release IL-10 and retinoic acid (a derivative of vitamin A) topromote the development of Foxp3+ T regulatory(Treg) cells.72–75

By expressing the TNF family member CD40 lig-and (CD40L) and releasing IL-10 and TGF-�1, in-testinal Treg cells elicit IgA CSR and production inB cells while inhibiting the formation of inflamma-tory Th1 cells.56,76 Furthermore, intestinal Treg cellsdifferentiate into T follicular helper cells, which in-duce germinal center B cell differentiation as wellas IgA CSR and production via CD40L, IL-21, andTGF-�1.56,77,78 Yet, it is currently unclear whetherintestinal T follicular helper cells arise from naturalor induced Treg cells, and whether Treg and T follic-ular helper cells play specific roles in the generationof commensal-reactive versus pathogen-reactive, orlow-affinity versus high-affinity IgA antibodies. Inaddition to Treg and T follicular helper cells, Th2cells producing IL-4 may further contribute to IgACSR and production in intestinal follicles. CD11b+

DCs appear to be particularly efficient in the induc-tion of Th2 cells in Peyer’s patches.68,79

Together with TGF-�, CD40L is a key elementin the TD pathway for IgA CSR and produc-tion.80–82 Engagement of CD40 on B cells by CD40Lcauses recruitment of TNF receptor–associated fac-tor (TRAF) adaptor proteins to the cytoplasmictail of CD40.83 This event is followed by translo-cation of the transcription factor NF-�B fromthe cytoplasm to the nucleus and by NF-�B–dependent transcription of the AID gene pro-moter.84 In contrast, NF-�B is not required for theactivation of the C� gene promoter, which rather in-volves SMA-homologue mothers against decapenta-plegic (SMAD) transcription factors induced by theTGF-� receptor.84

In spite of requiring CD4+ T cells to develop a ger-minal center reaction, Peyer’s patches can promoteIgA responses in the absence of the B cell antigenreceptor (BCR or Ig receptor).54 The BCR is cen-

tral to antigen-driven cognate T–B cell interactionsand is required for the survival of peripheral B cellsand the development of a germinal center reactionin systemic lymphoid follicles.54,85 This has led tothe proposal that B cells from Peyer’s patches mayundergo IgA diversification and production by uti-lizing a noncanonical TD pathway involving cosig-nals from TLRs instead of cosignals from the BCR.86

Additional BCR-independent signals may originatefrom TNF-inducible nitric oxide synthase (iNOS)-producing DCs, which enhance TD IgA responses byupregulating the expression of the TGF-� receptoron follicular B cells from Peyer’s patches via nitricoxide.87

Follicular B cells from Peyer’s patches can re-ceive additional IgA-inducing signals from follic-ular DCs.88 These cells release CD40L-related fac-tors known as B cell–activating factor of the TNFfamily (BAFF) and a proliferation-inducing lig-and (APRIL) upon “priming” by mucosal sig-nals, such as commensal TLR ligands and retinoicacid.88 Mucosal follicular DCs also release largeamounts of active TGF-�1 and use their dendritesto organize commensal antigens in “periodic” ar-rays.88 By releasing TGF-�1, BAFF, and APRIL andstimulating BCRs and TLRs on B cells, follicularDCs would enhance the IgA-inducing function ofT follicular helper cells in Peyer’s patches.56,88 Asimilar mechanism may enable follicular DCs totrigger IgA production in a TI manner.89,90 Fol-licular B cells from Peyer’s patches and mesen-teric lymph nodes further undergo TI switchingto IgA in response to plasmacytoid DCs.91 Thesecells are “primed” by type-I IFNs from intestinalstromal cells to release large amounts of BAFF andAPRIL.91

IgA induction in isolated lymphoid follicles

Together with Peyer’s patches and mesenteric lymphnodes, isolated lymphoid follicles represent anotherimportant site for IgA induction.92 These lymphoidstructures are scattered throughout the intestine andconsist of solitary B cell clusters built on a scaf-fold of stromal cells with a few interspersed CD4+

T cells and more abundant perifollicular DCs ex-pressing CD11c.56,92 Unlike Peyer’s patches, whichdevelop in the sterile fetal microenvironment, iso-lated lymphoid follicles develop from smaller anla-gen structures called cryptopatches after postnatalbacterial colonization of the intestine.92–94 These



cryptopatches contain lymphoid tissue-inducercells expressing the retinoic acid orphan receptorROR� t and stromal cells that recruit DCs, B, and Tcells in response to bacterial signals, including TLRsignals.92–94

Similar to Peyer’s patches, isolated lymphoid folli-cles have a follicular epithelium comprising antigen-sampling M cells as well as a subepithelial area con-taining CX3CR1+ DCs.92 After capturing bacteriafrom the intestinal lumen or M cells, CX3CR1+

DCs may present TI antigens to local follicular Bcells, thereby, eliciting the activation of TLR andperhaps BCR signaling pathways. CD11c+ DCs as-sociated with isolated lymphoid follicles also ex-press TNF, a powerful inducer of matrix metallo-proteases 9 and 13 that process active TGF-�1 froma latent precursor protein.44 In addition to formingactive TGF-�1, DCs cooperate with stromal cells torelease BAFF and APRIL through a pathway thatis enhanced by microbial TLR signals.44 These cy-tokines induce IgA CSR and production through aTI pathway that does not require germinal centerformation.5,44,95

IgA induction in the lamina propria

The diffuse tissue of the lamina propria can sup-port some IgA CSR and production in the ab-sence of follicular structures.44,96,97 Consistent withthis possibility, some B cells from the lamina pro-pria contain molecular hallmarks of ongoing IgACSR, including AID, H2AX (a nuclear protein as-sociated with AID-induced double-strand DNAbreaks), S�–S� switch circles, and I�–C� switch cir-cle transcripts.34,96,98–101 In general, lamina propriaB cells are scattered and express fewer molecularbyproducts of IgA CSR than Peyer’s patch B cells,which may explain why some groups failed to de-tect IgA CSR in the lamina propria.89,90,102 Dis-crepancies seem particularly evident with regardto AID expression.89,90,102 Yet, this expression hasbeen confirmed in the lamina propria by meansof a green fluorescent protein-AID reporter mousemodel and through the use of in situ hybridizatontechniques.34,96

IgA CSR in the lamina propria likely involvesin situ activation of B cells by DCs.34,44,87,97,103,104 Inthe mouse lamina propria, TNF-iNOS–producingDCs initiate TI IgA CSR and production by releasingBAFF and APRIL through a TLR-dependent mech-anism involving induction of nitric oxide produc-tion by iNOS.87 Another lamina propria DC sub-

set with IgA-licensing function is represented byTLR5+ DCs.97,105 In addition to TLR5, these DCsexpress CD11c, CD11b, and CD103 and induce TIIgA production by releasing retinoic acid and IL-6upon sensing bacteria through the flagellin receptorTLR5.97,105 Also epithelial cells deliver IgA-inducingsignals to lamina propria B cells by releasing BAFFand APRIL after recognizing bacteria via TLRs.34,103

Epithelial cells would further amplify IgA produc-tion by enhancing DC release of BAFF and APRILthrough TSLP.34,103

In humans, APRIL is particularly effective at in-ducing IgA2, an IgA subclass abundant in heav-ily colonized mucosal districts, such as, the distalintestine.34,106,107 Consistent with studies showingthe germinal center–independent origin of IgA2-producing B cells,108 APRIL triggers IgM-to-IgA2CSR independently of CD40L.34 In addition, APRILelicits sequential IgA1-to-IgA2 CSR, thereby, al-lowing hypermutated IgA1-expressing B cells fromPeyer’s patches to acquire a protease-resistant IgA2subclass in the lamina propria.34 This model couldexplain why IgA2 antibodies have mutated V(D)Jgenes in spite of emerging from a seemingly TIpathway.45

BAFF and APRIL trigger IgA CSR by engaginga CD40-related receptor known as transmembraneactivator and calcium modulator and cyclophylinligand interactor (TACI).109,110 In the presence ofcosignals from cytokine receptors and TLRs (Fig. 2),TACI induces AID expression via NF-�B, followedby CSR, antibody production, and plasma cell dif-ferentiation.110,111 An important property of TACIrelates to its ability to establish a close functionalcooperation with B cell-intrinsic TLR signals.110 In-deed, TACI uses the adaptor protein myeloid differ-entiation primary response gene 88 (MyD88) andTRAF6 to activate NF-�B, as TLRs do.110 How-ever, TLRs recruit MyD88 and downstream ki-nases, such as, IL-1 receptor–associated kinase 1(IRAK-1) and IRAK4 through a cytoplasmic Toll-interleukin-1 receptor (TIR) motif, whereas TACIuses a cytoplasmic motif different from TIR.110

Given that TLR signals are also important to gen-erate the production of TACI ligands by innate im-mune cells,34,103,104 these findings highlight the in-timate cooperation between the innate and adaptiveimmune systems at both cellular and signaling lev-els and provide an additional mechanistic explana-tion for studies linking intestinal IgA responses toMyD88.54,87



Figure 2. Signaling pathways emanating from transmembrane activator and calcium modulator and cyclophylin ligand interactor(TACI). The TGF-� receptor (TGF-�R) initiates germline C� gene transcription by activating the I� promoter via SMA-homologuemothers against decapentaplegic (SMAD) proteins. At the same time, engagement of TACI by BAFF and APRIL triggers therecruitment of myeloid differentiation primary response gene 88 (MyD88) to a TACI highly conserved (THC) motif located in thecytoplasmic domain of TACI receptor. TACI also recruits TNF receptor–associated factor 2 (TRAF2) to a motif located immediatelydownstream of THC. The THC motif is distinct from the Toll-interleukin-1 receptor (TIR) motif, which mediates the recruitmentof MyD88 by Toll-like receptors (TLRs). Recruitment of IL-1 receptor–associated kinase 1 (IRAK-1), IRAK-4, and TRAF6 by TACIand TLRs leads to the activation and nuclear translocation of NF-�B, which initiates transcriptional activation of the AICDA geneencoding activation-induced cytidine deaminase (AID). Together, germline C� gene transcription and AID induction cause classswitch recombination from IgM to IgA in B cells.

Lessons from PID

In addition to neutralizing specific mucosalpathogens, IgA modulates the interaction of com-mensal bacteria with the mucosal immune systemto mitigate the overall inflammatory tone of the in-testine.25 Therefore, it is not surprising that a largeproportion of patients with primary antibody dis-orders, such as selective IgA deficiency (SIgAD),common variable immune deficiency (CVID), and

hyper-IgM (HIGM) syndrome, develop not onlygastrointestinal infections, but also inflammatorybowel disease.112–116 Gastrointestinal inflammationis somewhat less prominent in patients with X-linked agammaglobulinemia (XLA), a primary anti-body disorder in which deleterious substitutions ofthe BCR-associated enzyme Bruton’s tyrosine kinase(Btk) cause developmental arrest of B cell precursorsin the bone marrow and severe depletion of matureB cells in the periphery.117,118 Perhaps, the lack of



functional Btk in XLA attenuates BCR-independentinflammatory signals, such as, TLR signals in mu-cosal DCs, macrophages and epithelial cells.119,120

Alternatively, XLA patients may be protected fromintestinal disease by the lack of heterogeneous T celland DC abnormalities often present in patients withCVID.121–124

Patients with SIgAD or CVID also develop gutnodular lymphoid hyperplasia, a benign lympho-proliferative disorder that consists of multiple nodu-lar lesions made up of lymphoid aggregates usuallyconfined to the lamina propria of the small intes-tine.115,116,123,125 Nodular lymphoid hyperplasia isthought to originate from polyclonal activation ofintestinal B cells by commensal bacteria undergo-ing aberrant expansion in the small intestine.126

Consistent with this interpretation, patients withSIgAD and CVID develop small bowel bacteria over-growth syndrome, which leads to heterogeneousclinical manifestations associated with malabsorp-tion.115,116,123 Nodular lymphoid hyperplasia andsmall bowel bacteria overgrowth syndrome are alsopresent in patients with HIGM syndrome caused bydeleterious AID substitutions that impair both CSRand SHM.127 The molecular basis of impaired mu-cosal IgA responses and gastrointestinal disordersin SIgAD and CVID remain largely unknown, butsome CVID patients have deleterious TACI substi-tutions.128–131

Nodular lymphoid hyperplasia and bacterialovergrowth have also been observed in AID knock-out mice and in mice with deleterious AID substi-tutions that abrogate the induction of SHM but notCSR.21,24 The small intestine of these mice showsuncontrolled expansion of segmented filamentousbacteria as well as a prominent antibiotic-sensitivehyperplasia of isolated lymphoid follicles.21,24 To-gether, these observations indicate that specificrecognition of commensals by somatically hyper-mutated IgA plays an important role in the controlof the composition and compartimentalization ofthe intestinal microbiota. The lack of this functionwould lead to increased bacterial growth in the smallintestine, with subsequent polyclonal hyperactiva-tion of local as well as systemic B cells. Over time,this process may lead to the aberrant expansion ofallergen-reactive, autoreactive, and clonal B cells,which could contribute to the increased frequencyof allergy, autoimmunity (celiac disease, hemolyticanemia, immune thrombocytopenic purpura), and

B cell tumors (mostly non-Hodgkin lymphoma) ob-served in individuals with SIgAD, CVID, or HIGMsyndrome.

In cases characterized by specific gene defects,PIDs can be regarded as an “experiment of na-ture” that may help immunologists to better un-derstand the regulation of mucosal IgA responses.In HIGM syndrome caused by deleterious CD40substitutions,132 the intestinal lamina propria in-cludes IgA-producing B cells and plasmablasts thatcontain AID, a hallmark of ongoing CSR.34,101,133

Consistent with the key role of CD40 in the ger-minal center reaction,134 AID expression and IgACSR are virtually abolished in germinal center Bcells from mucosal follicles of individuals withHIGM syndrome.104,132 In contrast, subepithelialB cells from the intestinal and respiratory mu-cosal surfaces of these patients show AID expres-sion and active IgA CSR.104,132 IgA CSR is alsoconserved in subepithelial B cells from chronicallyinfected HIV-infected patients with massive deple-tion of intestinal CD4+ T cells.100 These patientsalso show a profound impairment of the germinalcenter reaction.100 Overall, these findings suggestthat human B cells can produce IgA through a ger-minal center–independent pathway that does notrequire help to B cells by CD4+ T cells expressingCD40L.

In humans, CD40-independent IgA productionmay mostly rely on APRIL signaling to B cells viaTACI.110 Accordingly, IgA production is decreasedin CVID patients with deleterious TACI substitu-tions, whereas patients with deleterious BAFF-Rsubstitutions have normal IgA, at least in the circu-lation.128,129,135 Additional studies show that B cellsfrom patients with MyD88 or IRAK4 deficiency, twoPIDs associated with invasive bacterial infections,are less responsive to CSR signals from BAFF andAPRIL, indicating a possible role of MyD88 andIRAK-4 in the generation of class-switched anti-bodies to bacterial TI antigens, such as, polysac-charides.110,136,137 Consistent with this possibility,MyD88-deficient mice have defective intestinal IgAproduction, and their B cells do not effectively un-dergo CSR in response to TACI engagement by BAFFor APRIL.5,54,87,95 Of note, patients lacking MyD88or IRAK-4, a kinase downstream of MyD88, havenormal levels of total IgA in the serum.136–138 How-ever, mucosal IgA responses have never been mea-sured in these patients.



Conclusions

IgA is the predominant antibody isotype of thegut-associated lymphoid tissue that has been se-lected throughout evolution to provide protectionagainst mucosal microorganisms. IgA has long beenknown for its importance in the protection againstpathogens, but its role in the selection and mainte-nance of a spatially diversified bacterial communityin the gut has become clear only in recent years. Anumber of studies have revealed that IgA responsesinvolve B cells from both follicular and extrafollicu-lar districts and follow multiple TD and TI pathways.Yet, the precise cellular and signaling componentsof these pathways, and their relative contributionto mucosal immunity and homeostasis remain tobe fully elucidated. Further studies are also neededto characterize the mechanisms by which IgA con-trols the inflammatory tone of the intestine and reg-ulates the composition and compartimentalizationof the intestinal microbiota. PIDs with genetic alter-ations affecting known B cell–regulating pathwaysmay provide excellent models to address some ofthese questions in humans.

Acknowledgments

This study was supported by National Institutesof Health Grants R01 AI-074378, U01 AI-095613,P01 AI-096187, and P01 AI-061093, and by Ministe-rio de Ciencia e Innovacion Grant SAF 2008-02725to A.C.

Conflicts of interest

The authors declare no conflicts of interest.

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Regulation of mucosal IgA responses: lessons from primary immunodeficiencies