Pathophysiological Aspects of PANDO, Dacryolithiasis, Dry Eye, And

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Chapter 2 Pathophysiological Aspects of PANDO Chapter 2 15 Pathophysiological Aspects of PANDO, Dacryolithiasis, Dry Eye, 2 and Punctum Plugs

Friedrich Paulsen

Core Messages! Q Dacryoliths consist partly of secreted mucins that are comparable with the mucin spec- Q Early cases of dacryostenosis are based trum of the epithelium of the healthy on descending inflammation from the eye nasolacrimal ducts. or ascending inflammation from the nose initiating swelling of the mucous membrane Q Besides mucins, TFF peptides are augmented and malfunctions in the subepithelial in dacryoliths and may have a functional role cavernous body with reactive hyperemia, and in dacryolith formation. temporary occlusion of the lacrimal passage. Q It remains unknown whether TFF peptides Q Repeated isolated occurrence of dacryo- per se influence dacryolith formation or cystitis leads to structural epithelial changes whether their secretion as well as the with loss of mucin and TFF peptide produc- secretion of mucins and defense substances ing goblet cells and columnar epithelial cells, is only a secondary phenomenon. remodeling of the helical arrangement of subepithelial connective tissue fibers, and Q Under normal conditions, tear-fluid compo- loss of specialized blood vessels of the nents are constantly absorbed into the blood subepithelial cavernous body. vessels of the surrounding cavernous body. These vessels are connected to the blood Q Structural epithelial and subepithelial vessels of the outer eye and could act as a changes lead either to a total fibrous closure feedback signal for tear-fluid production, of the lumen of the efferent tear duct or to a which ceases if these tear components are non-functional segment in the lacrimal not absorbed. In this way, dry eye could be passage that manifests on syringing. initiated.

Q The first step in dacryolith formation seems Q Punctum plugs could initially function by to be a change in tear fluid rheology with the totally preventing absorption of tear-fluid formation of a still only partly characterized components, thus creating an “empty” amorphous material. tear-fluid system, which may be a strong stimulation signal for tear-fluid production. Q In most cases, the material formed initiates This stimulation signal decreases over time. an epithelial reaction with increased produc- This may explain why nearly all patients tion of secretory components in the nasolac- after insertion of punctum plugs and other rimal passage, based perhaps on mechanical blocking methods – viewed in the long run – irritation or bacterial colonization with require tear substitutes. immigration of granulocytes and production of antimicrobial substances. 16 F. Paulsen

Q TALT may favor the rise of primary low- most cases observed in adults. Pathological studies of grade B-cell lymphoma of the MALT type. the nasolacrimal passage have indicated that PANDO is caused by fibrous obstruction secondary to chronic 2 Q Analysis of TALT, as well as different inflammation [4, 13, 14]. Nevertheless, the patho- epithelial cells of the lacrimal passage, physiology of functional dacryostenosis, i.e., patients are interesting with regard to the induction with epiphora despite patent lacrimal passages on of tolerance in the nasolacrimal ducts and syringing (so-called functional dacryostenosis) has at the ocular surface. still not been understood. Descending pathogens from the conjunctival sac, as well as diverticula of the lacrimal passage, have been suggested to be causal factors. Other specialists claim to have located the origin of idiopathic dacryostenosis in the nose. Here, Contents simple infections of the nasal mucous membrane or diseases of the sinuses have been suggested; however, 2.1 Introduction ...... 16 clinical studies indicate that nasal disease is extreme- 2.2 Primary Aquired Nasolacrimal Duct Obstruction .. 16 ly rare in patients undergoing dacryocystorhinostomy 2.3 Dacryolithiasis ...... 20 (DCR). 2.4 Dry Eye and Punctum Plugs: Interestingly, the mucous membranes of the lacri- Impact of Tear Drainage ...... 23 mal passage and nose reveal morphological differ- 2.5 Primary Low-Grade B-Cell Lymphoma ences between the nasolacrimal epithelial cells with of the MALT Type and Immune Deviation ...... 25 microciliation only and the nasal epithelial cells with 2.6 Conclusion ...... 26 their kinociliae (Fig. 2.1) [24]. This suggests differences in susceptibility to pathogens; however, it has References ...... 27 been shown that ectopia of nasal epithelial cells is a more or less common finding in the nasolacrimal ducts [1, 27]. In addition to descending infection from 2.1 Introduction the eye, ascending infection of these atopical cells during nasal inflammation could thus be the starting Dacryocystitis, dacryostenosis, and dacryolithiasis point of dacryostenosis. In this scenario, the nasal in- are the three major alterations of the human nasolac- flammation has long since abated when the dacryo- rimal ducts the clinican is confronted with in his/her cystitis passes into a chronic state, causing the chang- daily practice. Hardly any malignancies occur in the es characteristic for dacryostenosis (see below). efferent tear-duct system. The leading symptom of Recent findings have indicated that “functional most patients is epiphora. The present chapter sum- obstruction” of the lacrimal passage occurs in many marizes recent advances in the understanding of the more patients than suggested previously (Table 2.1) pathophysiology of dacryostenosis and dacryolithia- [25]. Furthermore, some of these patients report a his- sis. Moreover, it also discusses current considerations tory of acute or chronic dacryocystitis and digital regarding the involvement of the nasolacrimal ducts pressure over the sac also reveals mucopurulent re- with dry eye and the benefit of uncoupling the effer- flux in some cases [25]. ent tear-duct system from the ocular surface by punc- Squamous metaplasia has been observed during tum plugs. recent analyses in cases of functional dacryostenosis with loss of columnar epithelial cells and goblet cells and with that of lacrimal passage specific mucins and 2.2 Primary Aquired Nasolacrimal Duct TFF peptides (see Chap. 1) in the stenotic area Obstruction (Figs. 2.2, 2.3). Moreover, the helically arranged connective tissue fibers undergo remodeling leading to Idiopathic or primary acquired daryostenosis, syn- subepithelial fibrosis (Fig. 2.2) [25]. In addition, a re- onymous with primary acquired nasolacrimal duct duction and even total loss of specialized blood ves- obstruction (PANDO), is a syndrome of unknown sels of the surrounding cavernous body and their re- origin. Of all non-traumatic forms, it accounts for placement by connective tissue occurs (Fig. 2.2) [25]. Pathophysiological Aspects of PANDO Chapter 2 17

Fig. 2.1. Scanning electron micrograph of the epithelial surface of the nasolacrimal duct reveals a single cell with kinociliae (arrows) between cells with microvilli. Bar=6 µm

Fig. 2.2. Histology of dacryosenosis. a Section through a tissue specimen of a patient shows chronic inflammation with epithelial and subepithelial infiltration of defense cells and incipient subepithelial fibrosis with increased occurrence of fibroblasts (arrows). b Section through a subepithelial blood vessel shows chronic fibrosis with wall thickening and intimal proliferation (arrows) c Section through a tissue specimen of a patient shows chronic inflammation with squamous metaplasia, absence of intraepithelial goblet cells, subepithelial fibrosis with basement membrane thickening (arrows), and reduction of wide capillaries. All images are with toluidine blue O staining. a–c Bar=27.5 µm 18 F. Paulsen

Table 2.1. Patient case data of a group of 36 patients undergoing endonasal dacryocystorhinostomy in PANDO at the Department of Otorhinolaryngology, Head and Neck Surgery, Christian Albrecht University of Kiel, Germany. DE duration of epiphora (months), LS lacrimal sac, ND nasolacrimal duct, DC dacryocystitis, MD mucous discharge. (From [25]) 2 Case Gender Age Side DE Patho- Stenosis Degree of DC MD Sinusitis no. (years) logical location obstruction or nasal disease stage

1 F 64 L 21 Severe LS Functional X 2 F 50 R 120 Severe LS/ND Complete X X 3 M 92 L 12 Severe ND Complete Acute sinusitis 4 F 32 L 6 Mild ND Functional 5 F 75 L 157 Severe ND Complete X X 6 F 48 L 26 Moderate ND Functional X 7 F 69 R 8 Moderate LS/ND Complete X X 8 F 73 R 27 Severe LS/ND Complete X X 9 F 39 R 19 Severe ND Complete 10 F 57 L 9 Moderate ND Complete 11 F 40 R 13 Moderate LS/ND Functional 12 F 45 R 36 Severe ND Complete X X 13 F 67 L 204 Severe ND Functional X X Chronic sinusitis 14 F 63 R 4 Mild LS/ND Functional 15 F 58 L 13 Moderate LS/ND Complete X X 16 M 76 R 27 Severe LS Complete X X 17 F 16 L 20 Moderate ND Complete 18 F 41 R 7 Mild LS Functional X 19 M 32 R 15 Moderate LS Complete 20 M 55 R 24 Severe ND Complete X X 21 F 60 R 120 Severe ND Functional X 22 F 66 L 240 Severe LS Functional X X 23 F 28 L 7 Mild ND Functional 24 F 61 R 240 Severe ND Functional X 25 M 36 R 49 Severe LS/ND Complete X X 26 F 55 L 16 Severe LS/ND Complete X X Nasal sinusitis 27 M 65 L 14 Moderate ND Complete 28 F 79 L 36 Severe ND Complete 29 F 21 L 20 Severe LS Complete X X 30 F 88 R 1 Moderate ND Complete 31 F 61 L 12 Moderate ND Functional Nasal sinusitis 32 F 60 L 10 Mild LS Functional 33 F 51 R 32 Severe ND Complete X X 34 F 45 L 49 Severe LS/ND Complete X X 35 F 70 L 29 Severe ND Complete 36 F 61 L 59 Severe LS/ND Complete Pathophysiological Aspects of PANDO Chapter 2 19

Fig. 2.3. Transmission electron micrograph reveals chronic stage of dacryostenosis. The epithelium shows squamous metaplasia. The metaplastic squamous cells reveal condensed, irregular nuclei (C), reduction of cytoplasm, and reduction of cell organelles. The cell surface shows a loose microciliation projecting into a large extracellular space (E). L lumen of the lacrimal passage. Bar=6 µm

All these changes lead to an interruption of the tear- flow mechanism in the stenotic segment. The follow- 1. In early cases, the rinsing liquid instilled by ing pathogenic concept of primary acquired dacryo- hand pressure into the lacrimal passage is stenosis has been postulated: descending inflammation forced through the segment of the lacrimal pas- from the eye or ascending inflammation from the re- sage obturated by reactive hyperemia and gion of the nose (perhaps by way of inflammation of swelling of the mucous membrane. “ectopical” nasal epithelial cells in the nasolacrimal 2. Structural changes (caused by chronic dacryo- duct; Fig. 2.4) may initiate malfunctions in the cav- cystitis) result in a non-functioning segment ernous body with reactive hyperemia, swelling of the in the lacrimal passage. In this latter case, ob- mucous membrane, and temporary occlusion of the struction is not yet complete, but there is no lacrimal passage [25]. Then, repeated isolated epi- tear transport in the non-functioning segment sodes of dacryocystitis may lead to structural epithe- [25]. lial and subepithelial changes. Loss of typical goblet and epithelial cells, which plays an important role in Ample evidence certainly exists that obstructed naso- the tear-outflow mechanism, as well as fibrosis of the lacrimal systems are colonized by increased numbers helical system of connective tissue fibers in the area of of pathogenic microorganisms. The histopathology the lacrimal sac and nasolacrimal duct and reduction implies that, besides topical or systemic anti-inflam- and destruction of specialized blood vessels of the matory agents, nasal decongestants, such as Afrin, cavernous body, may exacerbate malfunctions of the possibly could also be useful tools in the management tear-outflow mechanism and start a vicious circle of early cases of primary acquired dacryostenosis, [25]; thus, cases of functional dacryostenosis, i.e., pa- since they could counteract the hyperemia and swell- tients with epiphora in spite of patent lacrimal pas- ing of the cavernous body [25]. sages on syringing, are explainable as follows: 20 F. Paulsen

Fig. 2.4. Transmission electron micrograph reveals an early cation of the surface of an epithelial cell demonstrates microvilli stage of dacryostenosis. a Bacteria are visible on the cell surface that are colonized by bacteria. Underneath the surface four of two epithelial cells and in their cytoplasm infiltrating the cell fat vacuoles are visible. L lumen of the lacrimal passage. organelles. Mitochondria indicated by arrows. b High magnifi- a Bar=1.2 µm; b bar=0.4 µm

2.3 Dacryolithiasis partial closure of the lacrimal passage (recognized during syringing by the ophthalmologist). Interest- Dacryoliths (lacrimal stones) or “calculi” of the naso- ingly, dacryoliths occur more often in patients with lacrimal ducts (Fig. 2.5) were described by Cesoni in partial and incomplete closure of the lacrimal passage as early as 1670 [12], and have been reported to occur (i.e., patients with epiphora despite patent lacrimal in between 6 and 18% of patients with nasolacrimal passages on syringing). duct obstruction who undergo dacryocystorhinosto- Scanning electron microscopy has shown that dac- my (DCR). They are one of the causes of PANDO. ryoliths are composed of lobes and lobules built on an Dacryoliths may occur in any part of the nasolacri- amorphous core material (Fig. 2.6; Table 2.2) [18]. mal system, albeit most commonly in the lacrimal Atomic absorption spectrophotometric investigations sac. Several predisposing factors have been suggested, demonstrate that dacryoliths consist almost entirely such as increased occurrence in females, patient age of organic proteins and, to a much lesser extent, of below 50 years, association with cigarette smoking inorganic material [18]. According to Lew et al. [11], and facial-sinonasal trauma, and increased frequency lacrimal fluid from patients with dacryoliths contains subsequent to previous occurrence of dacryocystitis. a reduced amount of lysozyme and a lower calcium However, other studies have indicated increased fre- concentration than normal lacrimal fluid (Table 2.2). quency in males and patients aged above 50 years; It is important to recognize that daryoliths are not therefore, it seems that both genders are involved to calcified or are composed of any other “hard” sub- nearly the same extent. Dacryoliths usually become stances (Table 2.2). Some stones reveal hyphae-like symptomatic when they obstruct the nasolacrimal structures, although no fungi were recovered by cul- system. This can result in epiphora, acute dacryocys- turing (Table 2.2) [18]. titis, protrusion of the lacrimal canthal region, and Pathophysiological Aspects of PANDO Chapter 2 21

Fig. 2.5. Lacrimal sac dacryoliths immediately after dacryocystorhinostomy. a Dacryolith from a 61-year-old man. b Dacryolith of a 64-year-old woman

Table 2.2. Composition of dacryoliths

Lobes and lobules built on an amorphous core material Almost entirely organic proteins Nearly no inorganic material; not calcified; no “hard” substances Reduced amounts of lysozyme and low calcium concentration in tear fluid from patients with dacryoliths Some dacryoliths reveal hyphae-like structures Parts of the amorphous core proteins stain with alcian blue (pH 1) Parts of the amorphous core proteins contain mucins, especially MUC8 seems to be augmented Parts of the amophous core proteins contain TFF peptides; TFF2 is induced in dacryoliths; TFF1 and TFF3 are augmented Few cells are found in the amorphous core material of dacryoliths; these are mainly granulocytes and shredded epithelial cells and single T- and B-lymphocytes as well as macrophages

Fig. 2.6. Microscopic appearance of dacryoliths. a Lacrimal sac cellular material as well as a little amorphous material staining dacryolith reveals scant cellular material and amorphous debris. with alcian blue (pH 2.5) blue. a,b Bar=27.5 µm Hematoxylin–eosin staining. b Part of a dacryolith with scant 22 F. Paulsen

Fig. 2.7. Immunohistochemical detection of neutrophils (a), B-lymphocytes (b), mucin MUC2 (c), TFF1 (d), TFF2 (e), and TFF3 (f). a–f Bar=73 µm Pathophysiological Aspects of PANDO Chapter 2 23

Recent findings have indicated that parts of the of mucous gels. Given the increased production of amorphous core proteins stain with PAS and alcian TFFs in dacryolithiasis, it is likely that TFFs may cou- blue (Fig. 2.6) and react with antibodies to mucins ple with MUC5AC and MUC2, and possibly with and TFF peptides (Fig. 2.7) [20]. Moreover, these find- other mucins (MUC8) as well, and contribute to in- ings show that most dacryoliths contain single cells creased tear-film viscosity of the mucins drained and cellular debris. Most of these cells seem to be neu- through the nasolacrimal passage [8, 31]. trophils that produce alpha defensins 1–3. Also, the The first step in dacryolith formation could be a calcium-dependent enzyme secretory phospholipase change in tear-fluid rheology with the formation of a A2 is present in many dacryoliths, indicating a host yet uncharacterized amorphous material (hypotheti- defense reaction against Gram-positive pathogens. A cally the amorphous material might consist of de- few T and B lymphocytes and macrophages have been graded substances of the ocular tear-film components detected, too (Table 2.2). It was demonstrated that a and develops based on water extraction by the epithe- changed production of mucins and TFF peptides oc- lium of the nasolacrimal ducts from causes as yet un- curs in dacryoliths [20]. Mucins and TFF peptides are known). In most cases, the material formed initiates distributed as smaller or larger conglomerations in an epithelial reaction with increased production of dacryoliths [20]. This distribution pattern is mostly in secretory components (TFF peptides, distinct mu- conformity with the mucin and TFF peptide reper- cins) in the nasolacrimal passage, based perhaps on toire of the healthy epithelium of the lacrimal sac and mechanical irritation or bacterial colonization with nasolacrimal duct. Production of MUC1, 2, 4, 5AC immigration of granulocytes and production of anti- and 5B was observed in most dacryoliths, but not all, microbial substances. Fungal colonization also seems whereas reactivity for MUC3, 6, and 7 was only de- to occur in some cases. In this scenario, differences in tected in a few cases. Interestingly, MUC8 was visible the composition of dacryoliths with regard to mucins in nearly all investigated dacryoliths and revealed and defense cells may be explained by colonization strong staining intensity [20]. with distinct bacteria; however, it is not clear yet The most interesting finding in dacryolithiasis, whether dacryolith formation occurs as a reaction to however, was the strong staining of TFF peptides in previous inflammation of the nasolacrimal ducts or dacryoliths, suggesting upregulation of TFF peptides whether other factors, such as drugs (perhaps differ- in dacryolithiasis [32]. RT-PCR and immunohisto- ent eye drops), changes in the hormonal status, or im- chemistry revealed expression and production of all munmodulation (allergy), may lead to the initiation three TFF peptides, whereas in the healthy situation of dacryolith formation with recurrent dacryocystitis only TFF1 and TFF3 are expressed and produced, as a secondary phenomenon. indicating that induction of TFF2 occurs in dacryoli- Finally, the question remains whether TFF pep- thiasis. Analysis by real-time PCR revealed increased tides and mucins per se influence dacryolith forma- expression levels of TFF1 and TFF3 [20]; thus, TFF2 tion, or whether their secretion is only a secondary seems to be induced in dacryolithiasis, whereas TFF1 phenomenon. A full understanding of the molecular and TFF3 are augmented (Table 2.2). A comparable function of TFF peptides and mucins at the mucosal finding has just recently been published in the biliary surface of the efferent tear duct passage will provide tract where it was shown that all three TFF peptides further insight into the occurrence of dacryolithiasis, are augmented in hepatolithiasis. which often leads to residual functional impairment The increased TFF peptides may play a role in dac- with epiphora. ryolithogenesis together with oversecreted mucins. The TFFs alter the physiological properties of the secreted mucin, leading to an increase in the optical 2.4 Dry Eye and Punctum Plugs: density and viscosity of purified mucin preparations Impact of Tear Drainage when added in vitro. TFF1 interacting proteins are MUC2 and MUC5AC. The binding regions are The Dry Eye Workshop 2004, at the Puerto Rico VWFC1 and VWFC2 cysteine-rich domains, possibly TFOS (Tear Film and Ocular Surface Society) confer- raising the viscosity of the mucin. It has also been ence, defined dry eye (also termed sicca syndrome or suggested that TFF2 and TFF3 may act as link pep- keratoconjunctivitis sicca) as a multi-factorial disor- tides and thereby influence the rheological properties der of tears and the ocular surface, associated with 24 F. Paulsen

Table 2.3. Summary of dry eye disease diseases that are related to tear-outflow disturbances lead to dry eye? And why do punctum plugs and other Multifactorial disorder of tears and the ocular surface methods that interrupt the connection between the Associated with symptoms of discomfort ocular surface and the nasolacrimal ducts sometimes 2 and/or visual disturbance show very good results in the therapy of dry eye? Pathological features include increased epithelial These questions can be answered as follows: stratification and proliferative index and abnormal differentiation with maintenance of a basal phenotype 1. Currently, little is known about whether dis- Reduced expression of secretory and membrane-bound mucins by the superficial ocular-surface epithelial cells eases of the drainage system coincide with changes in tear-fluid production, although pa- Worsened severity as aqueous tear secretion decreases and as the ability to reflex tears in response to sensory tients with diseases of the nasolacrimal ducts stimulation is lost suffer from tear overflow. On the other hand, it Disease results in a vicious cycle has been reported that patients with acquired obstruction of the efferent tear ducts rarely The normally constant absorption of tear-fluid components into the blood vessels of the surrounding cavernous body have symptoms of epiphora [5, 7], and lack of could come to halt if these tear components significant epiphora has also been reported in are not absorbed, and thus could initiate dry eye patients with congenital absence of lacrimal puncta [2]. Moreover, as already mentioned, there are patients who suffer from functional dacryostenosis, i.e., patients with epiphora in spite of patent lacrimal passages on syringing. symptoms of discomfort and/or visual disturbance 2. Both dry eye and diseases of the efferent tear (Table 2.3). Much is known about the pathogenesis of ducts occur with high frequency in women of the keratoconjunctivitis sicca that occurs in dry eye middle to advanced age [15]. disease (Table 2.3). The pathological features of this 3. Considering the results after insertion of punc- condition include increased epithelial stratification tum plugs and other blocking methods, one and proliferative index and abnormal differentiation can ascertain that patients, in the long run, re- with maintenance of a basal phenotype (Table 2.3) quire tear substitutes. Punctum plugs could [9]. Furthermore, the expression of secretory and initially function by totally preventing absorp- membrane-bound mucins by the superficial ocular tion of tear-fluid components, thus creating an surface epithelial cells is reduced (Table 2.3) [3, 6, 26]. “empty” tear-fluid system, which may be a An exact mechanism for the development of these strong stimulation signal for tear-fluid produc- pathological changes has not yet been elucidated. The tion. This stimulation signal decreases with severity of keratoconjunctivitis sicca worsens as aque- passing of time. Ocular surface sensation and ous tear secretion decreases and as the ability to reflex tear production also decrease after temporary tear in response to sensory stimulation is lost. The punctual occlusion in normal subjects [30]. disease results in a vicious cycle. These effects are more pronounced in subjects Clinical reports have suggested that tear produc- with both upper and lower puncta occluded; tion and outflow of tears from the ocular surface are however, in normal subjects, there appears to linked [16, 17]. As described in Chap.1, the human be an autoregulatory mechanism that returns nasolacrimal ducts have absorptive functions. Based tear production and tear clearance to preocclu- on this, hypothetically it could be suggested that the sion levels 14–17 days after punctual occlusion, normally constant absorption of tear-fluid compo- a mechanism that seems to be lacking in dry- nents into the blood vessels of the surrounding cav- eye patients [30]. ernous body, which are connected to the blood vessels of the ocular surface, could provide a signal for tear- The apparently contradictory findings raised above fluid production, which ceases when these tear com- under point 1 above can be explained as follows: Cas- ponents are not absorbed [23]. es of acquired obstruction of the lacrimal drainage If this hypothesis is true, the question remains: system or congenital absence of lacrimal puncta re- Why do not all possible forms of efferent tear-duct sult from fibrous obstruction secondary to chronic Pathophysiological Aspects of PANDO Chapter 2 25

Fig. 2.8. The normally constant absorption of tear-fluid com- signal for tear-fluid production (2; left) that comes to a halt if the ponents into the blood vessels of the surrounding cavernous nasolacrimal system has been occluded by punctum plugs body of the nasolacrimal ducts and their transport to the lacri- (right) mal gland by blood vessel connections (1) could be a feedback inflammation, with total obstruction of the whole gland/ocular surface/efferent tear duct integrated lacrimal sac and nasolacrimal duct [4, 13, 14]. This unit, new paradigms may emerge regarding which scenario is comparable to the insertion of punctum patients with dry-eye disease may benefit from punc- plugs, as absorption of tear-fluid components is to- tual occlusion and which patients may suffer conse- tally prevented and the production of tear fluid is quences. downregulated by the lacrimal gland, leading to symptoms of epiphora (Fig.2.8). In the second case (patients with epiphora in spite of patent lacrimal pas- 2.5 Primary Low-Grade B-Cell Lymphoma sages on syringing), a non-functioning segment in of the MALT Type and Immune the lacrimal passage results from advanced structural Deviation changes with loss of specialized blood vessels of the cavernous body, with changes in the helical organiza- The occurrence of mucosa-associated lymphoid tis- tion of connective tissue, and with epithelial metapla- sue (MALT) is not a ubiquitous finding in the naso- sia caused by chronic dacryocystitis (see section 2.2) lacrimal ducts (although it is a feature commonly [25]. In this latter case, obstruction is not yet com- found in symptomatically normal nasolacrimal ducts) plete, but no tear transport takes place in the non- [19] and is acquired in response to antigenic stimula- functioning segment. In this scenario, there is ab- tion. Loss of tear-duct-associated lymphoid tissue sorption of tear-fluid components in the area lying in (TALT) seems to be associated with the scarring of front of the non-functioning segment [25], leading to symptomatic dacryostenosis, suggesting that the normal tear-fluid production; however, as tear fluid is presence per se of TALT does not lead to scarring [21]. not drained, or is only minimally drained, a tear over- Whether special types of bacteria, viruses, allergic re- flow results. actions, or other factors, such as some type of immune Disturbances in one part of the “lacrimal func- deviation (see below), are responsible for the develop- tional unit” (see Chap. 1, section 1.2.4) can have ef- ment of TALT in humans is not clear at present; how- fects on all participant structures. As greater knowl- ever, the occurrence of TALT may favor the rise of edge is gained about the regulation of the lacrimal primary low-grade B-cell lymphoma of the MALT 26 F. Paulsen

Fig. 2.9. Possible meaning of tear- duct (TALT) or conjunctiva (CALT) associated lymphoid tissue in the 2 pathogenesis of dry eye

type, as has been shown by Kheterpal et al. [10], White 2.6 Conclusions et al. [29], and Tucker et al. [28]. Within the scope of this chapter it is impossible to review special immunological features of the eye; W however, it should be mentioned that the anterior eye As described, the human nasolacrimal ducts must chamber (comparable to brain, placenta, testicle) has be included in the considerations concerning dry a special immunological state of reduced activation of eye. Areas of interest include analyses of normal the specific and non-specific immune system. This tear components, such as mucins, TFF peptides, and condition of local immune suppression, termed the freely water-soluble small molecules (e.g., urea or immune privilege, is expressed in delayed or totally amino acids), or perhaps smaller molecular tear pro- suppressed rejection of allogenic transplantations in teins such as lysozyme. Moreover, analysis of such these organs. This is illustrated in the survival of cor- molecules in certain diseases, such as dacryosteno- neal and lens transplants in the anterior eye chamber sis, are of interest. Such investigations would be and is called immune tolerance. It is known that such useful for extrapolation to the human situation, as tolerance is transferable by injection into a second the exact mechanism of absorption and regulation animal of splenocytes from an animal that was primed of these processes at the mucosa of the lacrimal by inoculation of an antigen, demonstrating that an- passage is still not understood. Current investiga- tigens from the anterior eye chamber receive a signal tions of epithelial transporter systems of the human that produces immune deviation and that regulatory nasolacrimal ducts will give deeper insights into T-cells have developed. possible routes of absorption and also the substanc- Recent analysis indicates that defective stimulation es that are able to be absorbed. Possibly, some of of TALT (Fig. 2.9) could result in abnormal immune these transporters are regulated by hormones in deviation at the ocular surface leading to an autoim- the efferent tear ducts, similar to the action of the munological response that causes dry-eye pathology. water transporter aquaporine (AQP) 2 in the kidney, For more and detailed explanation see work by where AQP2 is only present in the apical membrane Paulsen et al. [22]. of collecting duct main cells under the influence of adiuretic hormone. Moreover, current analysis of TALT and also conjunctiva-associated lymphoid tissue (CALT), as well as different epithelial cells of the lacrimal passage, are interesting with regard to the induction of tolerance in the nasolacrimal system and at the ocular surface. Pathophysiological Aspects of PANDO Chapter 2 27

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