adaptive immune system and the eye: mucosal immunity€¦ · sumed under the prosaic rubric, dry...

Adaptive Immune System and the Eye: Mucosal ImmunityA K Mircheff, University of Southern California, Los Angeles, CA, USA

ã 2010 Elsevier Ltd. All rights reserved.

Glossary

CD80 and CD86 – B7 costimulatory ligands

expressed by antigen presenting cells. They interact

with coreceptors CD28 and CTLA4 on Tcells and are

necessary, but not sufficient for T-cell activation.

MHC class II (major histocompatibility complex

class II molecules) – These molecules typically

acquire autoantigen epitopes in endosomes and

antigen processing compartments of antigen

presenting cells and present them to antigen

receptors of CD4+ T cells.

TGF-b – Pleiotropic cytokine. One critical function in

the mucosal immune system is to favor IgM-to-IgA

isotype class switching; another is to promote

differentiation of immature dendritic cells as

regulatory antigen presenting cells. It may be

mitogenic, antiproliferative, or pro-apoptotic,

depending on target cell or synergistic interactions

with other cytokines and growth factors.

The visual system interfaces with the external world atthe epithelium of the corneal surface. The corneal epithe-lium is part of the convoluted yet topologically continu-ous surface that separates the body’s milieu interieur fromthe external world. Beyond the limbal and conjunctivalepithelia, it ranges in one direction through the lacrimalexcretory ducts and network of ducts to the acini of thelacrimal gland. In the other direction it ranges through thelacrimal drainage system to the oral and pharyngealmucosae; through ducts to the acini of the salivary glands,through the airways to the alveoli of the lungs; throughthe mucosae of the esophagus, stomach, intestine, andcolon; through ducts to the acini of the pancreas; andthrough ducts to the canaliculi of the liver. These moisttissues are linked topologically, via the epidermis, withthe mucosal and glandular epithelia of the urinary tract,the reproductive tracts, and the mammary glands. Theyalso are linked functionally, via the traffic of immune cellsthrough the lymph vessels, secondary lymphoid organs,and vasculature, to comprise a physiological system, themucosal immune system.

The metabolically active epithelial cells that comprisethese surfaces perform diverse functions related to theirroles in the visual, respiratory, gastrointestinal, liver, renal,and reproductive systems. However, they express severalcommon functions. They either produce immense volumes

of fluid, for example, saliva, gastric juice, bile, pancreaticjuice, and occasionally diarrhea, or produce thin, largelyaqueous, but physically and chemically complex, films ashomeostatic milieus exterieurs for themselves. They alsoexecute innate immune functions, and, at specialized in-ductive and effector sites, adaptive immune functions,which protect them, their underlying stromas, and therest of the body from particulate irritants, noxious chemi-cals, and infectious microbes. The central principle of theadaptive immune strategy is to use noncomplement-fixingimmunoglobulins (i.e., dimeric IgA and IgG1) to preventinfection while avoiding inflammatory processes thatwould damage host tissues and compromise their functions.As improved sanitary systems, antibiotics, and vaccinesdecrease morbidity and mortality due to infection, dys-functions of mucosal immune system tissues that result inchronic inflammatory processes join other chronic inflam-matory diseases among the main categories of afflictionsthat burden aging populations. The chronic inflammatorymucosal immune disorders of the visual system are sub-sumed under the prosaic rubric, dry eye disease. Othernames have been suggested, including dysfunctional tearsyndrome and lacrimal keratoconjunctivitis, or, as thisauthor would prefer, dacryokeratoconjunctivitis.

Much of the current understanding of normal mucosalimmune system physiology has come from studies of thegastrointestinal and respiratory systems. The gastrointesti-nal system must not only prevent infection by pathogensbut it must also tolerate, and to a large extent, activelyhost, a rich flora of commensal microbes, which benefitthe organism by processing or producing nutrients thatwould otherwise remain inaccessible or unavailable. Whenthe mucosal immune barrier against infection fails, conven-tional innate and adaptive inflammatorymechanismsmountrobust responses to rescue the host organism, but theseresponses typically induce diarrheal fluid loss, ulcerativedamage to the mucosal and stromal tissues, and malab-sorption of nutrients and electrolytes. The complex rela-tionship the mucosal immune system maintains with itsmicrobiota is paralleled by a nuanced relationshipwith thefoods that the gastrointestinal system processes. Nutrientcarbohydrates and proteins typically are digested to mono-saccharides and amino acids before being absorbed acrossthe intestinal epithelia. Nevertheless, antigen presentingcells continuously surveille the luminal contents, and bothmicropinocytosis and receptor-mediated transcytosis maytransfer intact nutrient macromolecules across the epithe-lium. Clearly, it is in the organism’s interest to avoid inflam-matory responses against them.

33

While a smaller mass and less rich diversity of commen-sal and infectious microbial flora challenge the ocular sur-face tissues, the imperative to avoid inflammatory responseswhile preventing infection is no less urgent than it is inthe gastrointestinal system. The executive decisions largelyare made by antigen presenting cells, but these decisionsare based on information conveyed by paracrine mediatorsthat are produced by parenchymal cells and mesenchymalcells, as well as by neurotransmitters and neuropeptides.

Organized Inductive Sites

New generations of mucosal antigen presenting cells,Tcells, and B cells are introduced to microbes and solublemolecules in organized signaling milieus that amplify Bcells with high-affinity IgM and induce them to undergosomatic hypermutation and immunoglobulin isotype classswitching while continuing to retain expression of theJ chain. Some authors refer to the organized inductivesites generically as mucosa-associated lymphoid tissues(MALTs) and specifically as conjunctiva-associated lym-phoid tissue (CALT), eye-associated lymphoid tissue(EALT), tonsils, adenoids, bronchus-associated lymphoidtissue (BALT), and Peyer’s patches and gut-associatedlymphoid tissue (GALT). Other authors include boththe organized inductive sites and the less organized effec-tor sites together as MALT.

Figure 1 illustrates stereotypical features of mucosalinductive site organization. The epithelial sheet that over-lays an inductive site contains specialized cells with dis-tinctive basal convolutions enfolding superficial dendriticcells. These so-called M cells phagocytose microbes and

engulf soluble molecules at their apical surfaces, transcy-tose them to their basal surfaces, and release them to theunderlying space. Dendritic cells in the immediate sub-epithelial areas again engulf the transcytosed microbesand soluble molecules, which then traffic to acidic endo-somal compartments containing major histocompatibilitycomplex class II (MHC class II) molecules and hydrolyticenzymes. Peptides that are exposed in superficial domainsof the proteins being degraded have the greatest likeli-hood of entering the binding grooves of MHC class IImolecules. Peptides that remain outside the binding groovesare exposed to further degradation. Peptide sequences thatare protected from proteolysis become the dominant epi-topes that theMHC class IImoleculeswill present to CD4+

T cells upon trafficking to the dendritic cells’ surfacemembranes.

Whether or not a dendritic cell redistributes MHCclass II molecules to its surface, upregulates expressionof B7 costimulatory molecules, and migrates the shortdistance to the CD4+ T-cell-rich zone may depend onsignals received early in the encounter with the material ithas internalized. The best understood of these signals areconveyed by lipopolysaccharides and double-strandedDNAs, which activate toll-like receptors (TLRs). TheTLR activation induces a dendritic cell to downregulatechemokine receptors and homing receptors that favorretention in the subepithelial zone and to upregulatereceptors that favor migration to the T-cell-rich zone.Typically, TLR activation also induces dendritic cellsto upregulate surface expression of the costimulatoryB7 ligands, CD80 and CD86, as they redistribute MHCclass II molecule–epitope complexes to their surfacemembranes.

Germinal centerSubepithelial zone T-cell zone B-cell zone

Figure 1 Stereotypical organization of mucosal immune inductive sites. After having taken up microbes or antigens transcytosed byM cells, dendritic cells may traffic directly to the B-cell zone, or they maymigrate to the T-cell zone, where they activate antigen-specific

CD4+ cells to express TH2 cytokines. B cells with antigen receptors of sufficient avidity internalize antigen, then use MHC class II

molecules to present epitopes to activated TH2 cells. Ongoing TH2 activation promotes B-cell division and Ig hypermutation. In this

signaling milieu, TGF-b induces IgM-to-IgA isotype class switching. In combination with B-cell growth factors, TGF-b in germinalcenters promotes plasmablast proliferation and emigration via afferent lymph vessels.

34 Adaptive Immune System and the Eye: Mucosal Immunity

While signals from engulfed microbes are decisive indetermining whether the dendritic cell will undergo com-plete functional maturation and activation, the activatedphenotype that the dendritic cell will assume is deter-mined largely by paracrine mediators that are released bythe overlaying epithelium and surrounding mesenchymalcells. The signaling mediators that are known to be pre-dominant are transforming growth factor-beta (TGF-b)and interleukin (IL)-10, and they induce maturing den-dritic cells to also express TGF-b and IL-10. An addi-tional population of dendritic cells are distinguished bythe absence of MHC class II molecule expression andexpression of chemokine and homing signal receptorsthat lead them to bypass the T-cell-rich regions andenter B-cell-rich zones, where there they will release thematerial they had internalized.

Engagement of a naive CD4+ T cell’s antigen receptorsbyMHCclass II molecule–epitope complexes generates theprimary signal necessary, but not sufficient, for activation.Simultaneous engagement of CTLA-4 or CD28 at theT-cell surface byCD80orCD86 at the dendritic cell surfaceprovides the second signal essential for promoting T-cellactivation and differentiation. However, the functional phe-notype the activated CD4+ T-cell expresses is determinedby paracrine mediators in the immediate signaling milieu.These are secreted by dendritic cells, epithelial cells, andmesenchymal cells. They induce CD4+ T cells to differen-tiate as TH2 cells and to change their panel of chemokinereceptors and homing receptors to favor migration from theT-cell-rich zones and into the B-cell-rich zone.

When molecules that dendritic cells have releasedencounter B cells with surface IgM antigen receptors thatbind themwith high enough affinity, they deliver a primaryactivation signal, which induces the B cell to endocytosethe IgM–antigen complex to antigen-processing compart-ments and to begin expressing MHC class II molecules.Thus, CD4+ T cells arriving from the interfollicular zonewill be presented with dominant epitopes that maintainthem in their activated state. They continue secreting theTH2 cytokines needed to induce somatic hypermutationof B-cell immunoglobulin genes and promote selection ofB-cell clones with increasing affinity for the determinant.The signaling milieus within some of the organized induc-tive sites, notably Peyer’s patches, selectively induce IgM-to-IgA class switch recombination. The milieus in theinductive sites in the tonsils, adenoids, and airways mayinduce either IgM-to-IgA or IgM-to-IgG1 class switchrecombination. In cases of IgA deficiency, the numbers ofIgG1+ cells and IgM cells may increase in compensation.Whether induced to express IgA or IgM, the activatedB cells continue to express J chain. The IgA+ B cells willexpress dimeric IgA (dIgA), while IgG1 B cells will expressapparently irrelevant J chain.

The activated B-cell blasts amplify in germinal centers,and they alter their panel of chemokine receptors and

homing receptors, so that they are induced to leave theinductive sites via lymph vessels, enter the circulation viathe thoracic duct, and enter the mucosal immune effectorsites. The IgA+ B cells expressing CCR10, the receptorfor CCL28, traffic to the lamina propria of the oral cavity,lower airways, and colon. The IgA+ B cells expressingCCR9, the receptor for CCL25, traffic to the trachea,stomach, intestine, salivary glands, and mammary gland.The IgG1+ B cells expressing CXCR4, the receptor forCXCL12, traffic to the bone marrow. In each setting, theplasmablasts will take residence and mature to becomelong-lived memory cells or plasmacytes.

Effector Sites

Specialized Niches

Stereotypical features of the mucosal immune effectorsite are illustrated in the upper panel of Figure 2. LikeIgG+ plasmablasts entering the bone marrow, the dIgA+

plasmablasts that arrive in the mucosal effector sitesreceive signals that induce them to mature into plasma-cytes. One of the critical mediators of maturation signal-ing at the mucosal effector sites is TGF-b. A matureplasmacyte’s ongoing survival depends on the constantpresence of additional signals to suppress the intrinsicapoptotic program. The candidate mediators of the sur-vival signals include IL-6, B-cell activating factor (BAFF),a proliferation-inducing ligand (APRIL), and, perhaps,prolactin. In the rabbit lacrimal gland, which has beenstudied in some detail, epithelial expression of paracrinemediators is compartmentalized according to the epithe-lial histoarchitectural plan and vascular organization.Venules, the vascular elements that plasmablasts cross toenter the stromal space, tend to follow courses that paral-lel interlobular ducts. Epithelial cells of the interlobularducts express TGF-b and prolactin at much higher levelsthan epithelial cells in the acini, and it appears theysecrete these mediators both apically (i.e., into the fluidforming within the duct lumen) by way of their regulatedexocrine secretory apparatus for proteins, and also basally,through either a constitutive paracrine secretory appara-tus or a parallel paracrine apparatus that can be inducedunder certain circumstances. While TGF-b, as noted,induces dIgA+ plasmablast-to-plasmacyte differentiation,it may not be conducive to the plasmacytes’ ongoingsurvival. It appears that TGF-b signaling may be concen-trated in the stromal spaces surrounding the venules andinterlobular ducts. Preliminary findings in the author’slaboratory suggest that transcripts for the extracellularmatrix proteoglycan, decorin, are two orders of magni-tude more abundant than TGF-b transcripts in lacrimalgland epithelial cells. Because decorin binds to the extra-cellular matrix and also binds the latent TGF-b, it maycreate a diffusion barrier that keeps latent TGF-b

Adaptive Immune System and the Eye: Mucosal Immunity 35

concentrated in the periductal stroma. In contrast, pro-lactin may be free to equilibrate through the interstitialfluid, diffusing to plasmablasts throughout the gland’sstromal spaces. Preliminary studies suggest that acinarepithelial cells may be able to express IL-6. In contrast,mRNAs for APRIL and BAFF appear substantially moreabundant in whole gland extracts than in ex vivo acinar

cells. If substantiated, this finding would imply thatAPRIL and BAFF are expressed by infiltrating lympho-cytes, but it cannot exclude significant expression by ductalepithelial cells.

The information so far available about the cytophysio-logical mechanisms that secrete paracrine mediators tothe stroma has come from immunohistochemical studies

IL-10TGF-β

IL-6 α-MSH

ACh

nEpi5-HT

SPNPY

VIP

Enk

Figure 2 Normal (upper panel) and infected (lower panel) mucosal immune effector sites. IgA+ J chain+ plasmablasts, immaturedendritic cells, and T cells enter the lamina propria of the conjunctiva and drainage system, stromal space of the lacrimal gland,

and other effector sites from venules. Paracrine mediators induce plasmablasts to undergo terminal differentiation, then support

their survival as plasmacytes. Of these mediators, TGF-b, IL-10, and IL-6 are provided, at least in part, by epithelial and stromal cells.Sensory, parasympathetic, and sympathetic nerve endings provide neurotransmitters and neuropeptides that may also influence

plasmablasts, plasmacytes, dendritic cells, and lymphocytes. The normal signaling milieu induces dendritic cells that have

taken up soluble proteins and cellular debris to mature as regulatory antigen presenting cells, which exit via afferent lymph vessels

and induce regulatory T cells in the lymph nodes. The TLR activation by microbes that have evaded the immunospecificsIgA barrier induces dendritic cells to mature as immunoactivating antigen presenting cells that will elicit IgG responses in the

lymph nodes.


of TGF-b, epidermal growth factor (EGF), fibroblastgrowth factor (FGF), and prolactin localizations in rabbitlacrimal gland and studies of the intracellular traffic ofprolactin in ex vivo acinar cells from rabbit lacrimal gland.Under normal circumstances, the paracrine mediators arelocalized primarily in the apical cytoplasm, consistentwith secretion into the duct lumen via the regulatedexocrine secretory apparatus. Consistent with this infer-ence, pilocarpine-induced lacrimal gland fluid containshigh concentrations of TGF-b and prolactin. Two-colorconfocal immunofluorescence microscopy of the ex vivomodel indicates that prolactin colocalizes with rab4, rab5,and rab11, which are effectors of traffic to and fromendosomes, and electron microscopic-immunogold stud-ies indicate that prolactin also is localized within maturesecretory vesicles. These findings suggest that lacrimalepithelial cells may maintain two pools of the paracrinemediators they secrete: a large, often static, pool in theregulated exocrine secretory apparatus, and a small, buthigh throughput, pool in the paracrine apparatus.

Transfer of Immunoglobulins to theMilieu Exterieur

pIgR and dIgA

Several prominent aspects of lacrimal cytophysiologyappear to reflect adaptations to the roles the epitheliumplays in the mucosal immune system: maintaining theunderlying stromal space as a niche for dIgA-secretingplasmacytes and then transferring dIgA from the stromalspace to the fluid within the lumen of the acinus–ductsystem. The fundamental principles of the transcytoticmechanism for dIgA secretion were elucidated in studiesof madin-darby canine kidney (MDCK) cells, derivedfrom a canine kidney, which form continuous epithelialmonolayers when cultured on microporous substrata.Renal tubular epithelial cells do not normally secreteIgA, but when MDCK cells are stably transduced toexpress the polymeric immunoglobulin receptor (pIgR),they gain the ability to internalize dIgA from their basalmedium, which corresponds to the interstitial fluid, andsecrete sIgA into their apical medium, which correspondsto the lumenal fluid of an exocrine gland or the surfacefluid of a mucosal sheet. Figure 3 illustrates the transcy-totic apparatus as it is thought to function in conjunctivalepithelial cells. The pIgR makes its way from the biosyn-thetic apparatus, that is, the endoplasmic reticulum andGolgi complex, through the trans-Golgi network (TGN)and endosomes, to the basal–lateral plasma membranes,hitchhiking in transport vesicles at each step. The pIgRmay or may not bind the J chain and associated immuno-globulin while its ligand-binding domain is exposed at thebasal–lateral membrane. In either case, it is internalized inan endocytotic transport vesicle that will traffic to the

early endosome. Another transport vesicle will trafficpIgR and pIgR–dIgA complex to the recycling endosome,and yet another will traffic pIgR and pIgR–dIgA complexto the apical plasma membrane. Either during its transitthrough the recycling endosome, or upon arriving at theapical plasmamembrane, the pIgRwill encounter a proteasethat cleaves the extracytoplasmic, dIgA-binding domain,referred to as secretory component (SC), from the mem-brane-spanning domain. Thus, the cell releases both free SCand SC–dIgA complexes, that is, secretory IgA (sIgA), intothe milieu exterieur. Consistent with the topological con-straints that preclude traffic of transport vesicles betweenadjoining cells, expression of pIgR is concentrated in theapical-most layer of epithelial cells in the conjunctiva.

Acute Regulation of pIgR Traffic

The traffic of pIgR through lacrimal gland epithelial cellsappears to be somewhat more complex than described intheMDCK cell paradigm. First, it appears that pIgRmightcycle repeatedly to the basal–lateral plasma membranefrom any compartment of the transcytotic apparatus,while free SC is preferentially trafficked from the recy-cling endosome to the apical plasma membrane. Second,some of the pIgR traffic from the TGN to the immaturesecretory vesicle, rather than to the transcytotic apparatus;SC derived from these pIgR remains in mature secretoryvesicles until released into the lumen along with the clas-sical secretory proteins. Interestingly, many of the classiclacrimal secretory proteins, such as b-hexosaminidase,lysozyme, and lactoperoxidase, are innate immune effec-tor molecules. Free SC appears to perform importantfunctions in the ocular surface fluid film, and the abilityto sequester a portion of pIgR away from the transcytoticapparatus ensures that some free SCs always will besecreted, despite the large mass of dIgA that normally ispresent in the stromal space.

A considerable volume of membrane traffic flowsthrough the lacrimal acinar cell’s transcytotic apparatus.The micropinocytosis associated with endocytotic inter-nalization of transport vesicles from the basal–lateral andapical surface membranes carries fluid phase markers intothe cells, and such markers rapidly equilibrate throughoutthe aqueous phase within the lumena of the early endo-some, recycling endosome, and TGN, as well as the lateendosome, prelysosome, and lysosome. If ex vivo acinarcell models are acutely stimulated with the muscarinicacetylcholine receptor agonist, carbamylcholine (carba-chol, CCh), they increase the rates at which they endocy-tose and exocytose fluid phase markers. If the CChconcentration is increased from 10 mM, which maximallyaccelerates fluid phase endocytosis but half-maximallyaccelerates protein secretion, to 100 mM, a concentra-tion that maximally accelerates protein secretion, fluidphase endocytosis continues at the increased rate, but


the volume of space that the fluid can reach decreases. If amarker is allowed to equilibrate through the fluid phasesof the network of endomembrane compartments underresting conditions, subsequent acute stimulation with100 mM CCh accelerates its release, but release then stopswith a substantial portion of the marker remaining en-trapped within the cell. These findings suggest that whenthe cell is maximally stimulated with CCh, it imposes ablockade of bidirectional traffic between proximal and dis-tal compartments of the endocytotic pathway. Other studiesindicate that the blockade affects traffic to the late endo-some from both the early endosome and the TGN.A possible cytophysiological rationale for this phenomenonis suggested by preliminary studies of the kinetics of CCh-induced SC secretion. The CCh acutely induces a burst ofsecretory vesicle exocytosis, which releases SC along withthe other secretory proteins. Secretory vesicle exocytosis iscomplete within 10 min. However, the cells continue torelease SC at an increased rate for at least 60 min, while

their total content of pIgR plus SC appears to remainunaltered.These phenomena suggest that the cell blockadestraffic to the late endosome in order to divert an increasedproportion of its newly synthesized pIgR from the degrada-tive apparatus to the transcytotic apparatus.

A Mechanism That Constitutively SecretesAutoantigens to the Stroma

A consequence of the strategy of directing a large volumeof transport vesicle traffic from the early endosome to thelate endosome and prelysosome under nonstimulatedconditions is that the reciprocal traffic of transport vesiclesconstitutively secretes lysosomal hydrolases and poten-tial autoantigens that, in other cells, would remain inthe autophagic–lysosomal apparatus and be degraded.Moreover, when traffic to the late endosome is blocked,the lysosomal hydrolases reflux into the compartmentswhich remain accessible (i.e., the TGN), immature

Early endosomeRecycling endosome

Lateendosome

Prelysosome

tgn

Golgier

sIgA SC pIgR dIgA

Lysosomal proteaseMembrane mucin

Figure 3 Transcytotic traffic of sIgA to the milieu exterieur. The apical-most layer of epithelial cells in stratified tissues, like the

epithelial cells of lacrimal acini and ducts, express pIgR. At the basal–lateral surface membrane pIgR mediates endocytosis of dIgA,

which it then chaperones through the early endosome and apical recycling endosome. Either within the apical recycling endosome or atthe apical plasma membrane, the pIgR is cleaved by protease to release either free SC or dIgA–SC complex, that is, sIgA. In lacrimal

gland epithelial cells, pIgR may cycle repeatedly through the TGN and transcytotic apparatus; it may enter immature secretory vesicles

(not shown), where free SC is released and stored for subsequent secretion in response to secretagogue stimulation, or it may traffic

through the late endosome, which is a gateway to the prelysosome and autophagic–lysosomal apparatus. The author proposes that thetraffic of transport vesicles returning from the prelysosome and late endosome to the early endosome accounts for the constitutive

release of an unusually heavy burden of autoantigens to the stromal space.


secretory vesicle, early endosome, and recycling endosome.Of particular interest, at least some of the lysosomal pro-teases are catalytically active andmay process other proteinsthat have accumulated with them in the same compart-ments. This phenomenon might lead to the degradation ofdominant autoantigen epitopes and lead to the eventualpresentation of epitopes that under normal circumstancesare degraded.

FcgRn and IgG1

While the plasmacytes that produce dIgA reside in thestromal spaces of exocrine glands and the lamina propriaof mucosal sheets, the plasmacytes that produce IgG1typically reside in the bone marrow, and IgG1 must travelthrough the circulation to reach the epithelia that willsecrete it. The same subcellular apparatus that transportsSC and pIgR–dIgA complexes through epithelial cellslikely also mediates the secretion of IgG1. However,IgG1 does not associate with J chain, and its traffic ismediated not by pIgR but by the neonatal Fcg receptor,FcgRn. The association between IgG1 and FcgRn isregulated by pH, such that binding affinity is highest inrelatively acidic endosomal compartments and lower atthe pH of the interstitial fluid. In the tissues where it hasbeen studied, the IgG1–FcgRn complex tends to bypassthe late endosome in favor of the early endosome andrecycling endosome. Because dissociation of IgG1 fromFcgRn does not require proteolytic processing, FcgRncan mediate multiple cycles of IgG1 absorption as wellas secretion. The FcgRn can also mediate absorption andsecretion of IgG1-immune complexes, in some cases secret-ing opsonized microbes and immune complexes and inothers absorbing them in a physical state that minimizesthe risk of infection but perpetuates T-cell and B-cellresponses. The extent to which FcgRn might be expressedin the lacrimal glands and drainage system has not beeninvestigated; recently, however, it has been found to bepresent in epithelial cells of rat conjunctiva.

Mucosal Tolerance and Response toInfection

Commensal microbes in the gut are coated with sIgA,which normally prevents them from entering the epitheliallining. Notably, dendritic cells as well as dIgA-secretingplasmacytes populate the mucosal effector sites. They arepresent within the lamina propria and the epithelia andmay extend processes that interdigitate between adjoiningcells to surveille the milieu exterieur. As in the organizedinductive sites, immature dendritic cells are endocytoticallyactive, and under normal circumstances the material theyinternalize consists of soluble molecules and cellular debris.

The robustness of the phenomenon of oral tolerance sug-gests that the TGF-b- and IL-10-rich milieu directs themto mature as regulatory antigen presenting cells, which,when they arrive in lymph nodes, induce food antigen-and, presumably, autoantigen-specific CD4+ T cells tomature as TH3 and TR1 regulatory cells. The regulatorycells might function in both the effector sites and the lymphnodes to prevent inflammatorymediators or activated effectTcells from redirecting dendritic cells toward expression ofimmunoactivating phenotypes.

As illustrated in the lower panel of Figure 2, TLR onimmature dendritic cells in the epithelium or laminapropria recognizes microbes that have evaded the immu-nospecific sIgA barrier, and TLR activation induces phago-cytosis, redistribution of MHC class II molecules to thedendritic cell surface, and upregulation of surface CD80and CD86. Certain microbes induce maturing dendriticcells to remain in the lamina propria and release antigendirectly to B1 cells, stimulating activation independently ofT-cell help. Typically, however, dendritic cells are activatedto switch chemokine receptor and homing receptor expres-sion to favor emigration via afferent lymph vessels. In thelymph nodes, they will induce activation of naive, antigen-specific CD4+ T cells as TH2 cells and generation of IgG-producing B cells.

Implications for Ocular SurfacePathophysiology

Contemporary paradigms hold that dry eye disease resultsfrom insufficiency of the ocular surface fluid film. Suchmight be the consequence of impaired lacrimal gland fluidproduction, excessive evaporation of water from the ocularsurface fluid due to deficient production of lipids in theMeibomian glands, and excessive breakup of the fluid filmdue to deficiencies of the normally hydrophilic substratumprovided by the apical surfaces of corneal and conjunctivalepithelial cells. There is a general consensus that, whateverthe etiology, the principal feature of pathophysiologicalstate is inflammation of the ocular surface tissues. Inflam-matory processes plausibly account for much of the cytopa-thology that occurs within the lacrimal gland and leads toquiescence of impairment of its exocrine functions. Thisseems to be the case, not only in Sjogren’s syndrome, butalso in graft-versus-host disease, sarcoidosis, Wegener’sgranulomatosis, and diffuse infiltrative lymphocytosis syn-drome associated with HIV infection. A histopatholog-ical syndrome distinct from the familiar diagnoses anddescribed primarily through postmortem studies is charac-terized by lymphocytic infiltration, acinar atrophy, ductaldilatation, and periductal fibrosis. Its underlying patho-physiological mechanisms have not been studied, althoughthey appear not to involve production of autoantibodies.


The author suggests that these inflammatory processesnormally are prevented by the same strategy that preventsimmune responses to food antigens, soluble autoantigens,and cellular debris. There may be particular challenges tomaintaining immunoregulation in the lacrimal glands,where vigorous traffic through the transcytotic apparatusreleases an exceptionally heavy burden of potential auto-antigens into the stromal space, and in the ocular surfacetissues, where environmental stresses may induce releaseof inflammatory mediators that abrogate the local signal-ing milieu’s ability to generate regulatory antigen pre-senting cells. Additional challenges may result from theepithelia’s dependence on systemic hormones to maintainexpression of the local signaling milieu.

See also: Adaptive Immune System and the Eye: T Cell-

Mediated Immunity; Conjunctiva Immune Surveillance;

Defense Mechanisms of Tears and Ocular Surface;

Lacrimal Gland Overview; Tear Film; Tear Film Overview.

Further Reading

Brandtzaeg, P. and Johansen, F.-E. (2005). Mucosal B cells:Phenotypic characteristics, transcriptional regulation, and homingproperties. Immunological Reviews 206: 32–63.

Cain, C. and Phillips, T. E. (2008). Developmental changes inconjunctiva-associated lymphoid tissue of the rabbit. InvestigativeOphthalmology and Visual Science 49: 644–649.

Evans, E., Zhang, W., Jerdeva, G., et al. (2008). Direct interactionbetween Rab3D and the polymeric immunoglobulin receptorand trafficking through regulated secretory vesicles in lacrimalgland acinar cells. American Journal of Physiology. Cell Physiology294: C662–C674.

Franklin, R. M, Kenyon, K. R., and Tomasi, T. B. (1973).Immunohistologic studies of human lacrimal gland: Localization of

immunoglobulins, secretory component and lactoferrin. Journalof Immunology 110: 984–992.

Kaetzel, C. S. (2005). The polymeric immunoglobulin receptor: Bridginginnate and adaptive immune responses at mucosal surfaces.Immunological Reviews 206: 83–99.

Kim, H., Fariss, R. N., Zhang, C., et al. (2008). Mapping of theneonatal Fc receptor in the rodent eye. Investigative Ophthalmologyand Visual Science 49: 2025–2029.

Knop, E., Knop, N., and Claus, P. (2008). Local production of secretoryIgA in the eye-associated lymphoid tissue (EALT) of the normalhuman ocular surface. Investigative Ophthalmology and VisualScience 49: 2322–2329.

Macpherson, A. J., McCoy, K. D., Johansen, F.-E., and Brandtzaeg, P.(2008). The immune geography of IgA induction and function.Mucosal Immunology 1: 11–22.

Meagher, C. K., Liu, H., Moore, C. P., and Phillips, T. E. (2005).Conjunctival M cells selectively bind and translocate Maackiaamurensis leukoagglutinin. Experimental Eye Research80: 545–553.

Mircheff, A. K.,Wang, Y., de Saint Jean,M., Ding, C., and Schechter, J. E.(2007). Lacrimal epithelium mediates hormonal influences on APCand lymphocyte cycles in the ocular surface system. In: Zierhut, M.,Rammensee, H.G., andStreilein, J.W. (eds.)Antigen Presenting Cellsand the Eye, pp. 93–119. New York: Informa.

Rose, C. M., Qian, L., Hakim, L., et al. (2005). Accumulation ofcatalytically active proteases in lacrimal gland acinar cellendosomes during chronic ex vivo muscarinic receptor stimulation.Scandinavian Journal of Immunology 61: 36–50.

Seder, R. A., Marth, T., Sieve, M. C., et al. (1998). Factors involved inthe differentiation of TGF-beta-producing cells from naive CD4+T cells: IL-4 and IFN-g have opposing effects, while TGF-b positivelyregulates its own production. Journal of Immunology 160:5719–5728.

Spiekermann, G. M., Finn, P. W., Ward, E. S., et al. (2002).Receptor-mediated immunoglobulin G transport acrossmucosal barriers in adult life: Functional expression of FcRn inthe mammalian lung. Journal of Experimental Medicine196: 303–310.

Wang, Y., Chiu, C. T., Nakamura, T., et al. (2007). Traffic ofendogenous, over-expressed, and endocytosed prolactin in rabbitlacrimal acinar cells. Experimental Eye Research 85: 749–761.

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adaptive immune system and the eye: mucosal immunity€¦ · sumed under the prosaic rubric, dry...

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