key: cord-0042419-o29efdfh
authors: Sullivan, David A.
title: Ocular Mucosal Immunity
date: 2012-12-02
journal: Handbook of Mucosal Immunology
DOI: 10.1016/b978-0-12-524730-6.50052-x
sha: 57fa9544cddc936ebda34a5db0218bdd8768bdfb
doc_id: 42419
cord_uid: o29efdfh

nan

The principal tissues involved in immunological protection of the ocular surface are the lacrimal gland and the conjunctiva. The lacrimal gland, which serves as the predominant source of tear SIgA antibodies (Sullivan and Allansmith, 1984; Peppard and Montgomery, 1987) , is the primary effector tissue in the secretory immune defense of the eye (Franklin, 1989; Friedman, 1990; Sullivan, 1990) . This gland contains a diverse array of lymphocytes, including plasma cells, T cells, B cells, dendritic cells, and macrophages (Table I; Figure 1 ). In humans, plasma cells represent the most numerous lymphocytic population, accounting for more than 50% of all mononuclear cells in lacrimal tissue (Weiczorek et al., 1988) . The vast majority of these plasma cells are IgA positive (Franklins al., 1973; Allansmith et al., 1976a Allansmith et al., ,1985 Brandtzaeg et ai, 1979 Brandtzaeg et ai, ,1987 Crago et ai, 1984; Damato et al., 1984; Brandtzaeg, 1985; Kett et al., 1986; Weiczorek et al, 1988) and express an IgAl/IgA2 subclass distribution that is either different from (Kett et al, 1986) or similar to (Crago etal, 1984; Allansmith etal, 1985) that of other mucosal tissues. In addition, a high percentage of lacrimal IgA plasma cells, which are located in the gland's interstitium, synthesizes both J chain and polymeric IgA (plgA; Brandtzaeg, 1985) that may bind secretory component (SC; Brandtzaeg, 1983) . These cells are complemented by limited numbers of IgG, IgM, IgE, and IgD plasma cells (Franklin et al, 1973; Allansmith et al, 1976; Brandtzaeg et al, 1979 Brandtzaeg et al, ,1987 Gillete et al, 1980; Damato et al, 1984; Wieczorek et al, 1988) , although the IgD-containing subset may increase during IgA deficiency (Brandtzaeg et al, 1979) . The second most frequent lymphocyte population in human lacrimal tissue consists of T cells, which are situated between acinar and ductal epithelial cells, throughout glandular interstitial regions, and within small periductular lymphoid aggregates (Weiczorek ei al, 1988; Pepose ei a/., 1990). The distribution of T cells appears to vary topographically according to specific subclasses, including suppressor/cytotoxic and helper T cells (Weiczorek et al, 1988; Pepose et al, 1990) , and presents with an overall helper: suppressor ratio of approximately 0.56 (Weiczorek et al, 1988) . Minor or rare populations of lacrimal lymphocytes include surface Igbearing B cells, Langerhans-type dendritic cells, monocytemacrophages, and activated IL-2 + T cells, which occur almost exclusively in periductular lymphocyte foci (Weiczorek etal, 1988; Pepose etal, 1990) . These latter lymphoid aggregates, when present, typically appear as primary follicles without germinal center formation and, theoreticaly, may be involved in antigen processing (Weiczorek et al, 1988) .

The human lacrimal gland also Franklin et al. (1973) ; Allansmith et al. (1976a Allansmith et al. ( ,1985 ; Brandtzaeg et al. (1979 ; ; Crago et al. (1984) ; Damato et al. (1984) ; Brandtzaeg (1985) ; Kett et al. (1986) ; Wieczorek et al. (1988) Shimada and Silverstein (1974) ; Franklin et al. (1979) ; Jackson and Mestecky (1981) Gudmundsson et al. (1984 Gudmundsson et al. ( ,1985a Gudmundsson et al. ( , 1988 ; Sullivan et al. ( ,1990a Sullivan et al. ( , 1990 /91); Allansmith et al. (1987) ; Hann et al. (1988) ; Pappo et al. (1988) ; Montgomery et al. (1989 Montgomery et al. ( ,1990 ; Sullivan and Hann (1989a) McGee and ; Montgomery et al. (1985) ductule epithelium (Weiczorek et al., 1988) and certain acini (Mircheff et al., 1991) 4. contains lymphatic channels that drain into local cervical and preauricular lymph nodes (Iwamoto and Jakobiec, 1989) With respect to human accessory lacrimal tissue, its immunological characteristics appear to be identical to those of the major lacrimal gland (Gillette et al, ,1981 Sacks et al, 1986) . Lacrimal tissues of rats, rabbits, cows, and mice also seem to share the immune features of the human gland (Table I) . Thus, rat lacrimal glands contain a pronounced population of IgA plasma cells (Gudmundsson et al., 1985a; Sullivan et al, ,1990a Sullivan et al, ,1990 Hann etal, 1988; Sullivan and Hann, 1989) , which undergo a striking age-related increase in density from infancy to adulthood Sullivan et al, 1990a) . These cells are accompanied by IgG and IgM plasma cells (Gudmundsson et al, 1985a; Allansmith et al, 1987; Hann et al, 1988; Sullivan et al, 1990a) , immature suppressor/cytotoxic and helper T cells (Gudmundsson et al, 1988; Pappo et al, 1988; Montgomery et al, 1989 Montgomery et al, ,1990 , surface Ig-bearing B cells (Pappo et al, 1988; Montgomery et al, 1989 Montgomery et al, ,1990 ) that proliferate in response to mitogen exposure (Pappo et al, 1988) , phagocytic macrophages that express Fc receptors and la antigens (Pappo et al, 1988) , and rare mast cells (Gudmundsson et al, 1984) . Moreover, acinar cells from rat lacrimal tissue synthesize and secrete SC (Sullivan et al, 1984b (Sullivan et al, , 1990b Gudmundsson et al, 1985a; Hann et al, 1989 Hann et al, , 1991 Kelleher et al, 1991; Lambert et al, 1993) which appears to transport plgA into tears against an apparent concentration gradient Sullivan and Hann, 1989b) . Similarly, lacri-mal glands of cows (Butler et al, 1972) , rabbits (Shimada and Silverstein, 1975; Franklin et al, 1979) , and mice (McGee and Franklin, 1984) either produce IgA or harbor plasma cell populations that are predominantly IgA positive and, at least in rabbits, contain acinar and ductal cells that produce SC (Franklin et al, 1979) . However, periductular lymphoid aggregates appear to be very uncommon in lacrimal tissues of these species, except under pathological conditions (e.g., autoimmune disorders; Kessler, 1968; Mizejewski, 1978; Hoffman et al, 1984; Jabs et al, 1985; Liu et al, 1987; Jabs and Prendergast, 1988; Ariga et al, 1989; Liu, 1989; Vendramini et al, 1991; Sato et al, 1991) .

The primary origin of IgA-containing lymphocytes and T cells in the lacrimal gland remains to be determined, but may, in part, be local cervical (Brandtzaeg et al, 1979; Ebersole et al, 1983) , distant peripheral (Montgomery et al, 1985; O'Sullivan and Montgomery, 1990) , and gut-associated lymphoid tissue (Montgomery et al, 1983; O'Sullivan and Montgomery, 1990) , as well as the thoracic duct (O' Montgomery, 1990), spleen (McGee and , and mammary gland (Montgomery et al, 1985) . The migration of lymphocytes into the lacrimal gland appears to be random (McGee and Franklin, 1984) , yet the selective retention and heterogeneous distribution of IgA-containing cells within lacrimal tissue is not random (Sullivan et al, 1990/ 91) and may be stimulated by antigenic challenge (Jackson and Mestecky, 1981; Allansmith et al, 1987) and regulated by microenvironmental (Franklin, 1981; /91a), endocrine Sullivan and Hann, 1989a) , neural (Walcott et al, 1986; Franklin et al, 1988 Franklin et al, ,1989 Oeschger et al, 1989; Sullivan et al, 1990/91) , T-cell (Franklin et al, 1985; Franklin, 1989; Franklin and Shepard, 1990/91) , or acinar epithelial-cell (Franklin et al, 1985) signals. The lymphocytic accumulation Figure 1 Schematic representation of the secretory immune system of the human lacrimal gland. Topographical features include acinar cells, which contain endoplasmic reticulum (ER) and lysozyme-and lactoferrin-positive zymogen granules (ZG), and synthesize and secrete SC (termed secretory piece); myoepithelial cells, which are adjacent to acinar cells and surrounded by a basement membrane (BM); interstitial plasma cells, which are the primary lymphoid cell and produce principally Ig A, but also some IgG, IgM, or IgD; T helper (Th) and suppressor (T s ) cells, which are distributed throughout the interstitium, the intercellular spaces between acinar or ductal cells, and the periductular lymphoid aggregates; B cells (B), OKT6 + Langerhans-type dendritic cells (DC), and OKMl + monocyte-macrophages, predominantly located in periductular lymphoid aggregates, which most often appear as primary follicles without germinal center formation and may be active in antigen processing; and unlabeled darkened cells, which refer to circulating T or B lymphocytes, which may originate in other mucosal tissues (e.g., intestinal Peyer's patch) and, if not retained locally, possibly exit the lacrimal gland through lymphatic channels to regional cervical ro preauricular lymph nodes. Immunoglobulin A is secreted by plasma cells (1), bound by SC on the acinar cell basolateral membrane (2,3), transported in distinct vesicles (4), and released at the apical surface as SIgA into tear-containing lumina (5). [This figure has been reproduced and published, courtesy of Ophthalmology (1988). 95: 100-109.] in, or adherence to, lacrimal tissue appears to require calcium as well as functional oxidative phosphorylation and contractile microfilament systems, and to depend on cell-surface protein and carbohydrate determinants (O' Sullivan and Montgomery, 1990) .

In addition to the lacrimal gland, the conjunctiva has been postulated to play an active role in both inductive and effector actions of the ocular secretory immune system (Chandler and Gillette, 1983; Franklin and Remus, 1984; Franklin, 1989; Tagawa et al., 1989; Allansmith and Ross, 1991) . In support of this hypothesis, the rabbit conjunctiva contains a substantial number of Ig A, and occasional IgG and IgM, plasma cells in the substantia propria and numerous T and B cells in specialized lymphoid follicles (Shimada and Silverstein, 1975; Franklin et aL, 1979; Franklin and Remus, 1984) . Moreover, rabbit conjunctival B cells may be induced to differentiate into IgA-positive cells by mitogen stimulation (Franklin and Remus, 1984) and the rabbit conjunctival epithelium produces SC (Franklin etaL, 1979; Liu et aL, 1981 (Srinivasan et aL, 1990) in human conjunctival tissue, these findings might indicate that the conjunctiva is involved in antigen processing, lymphocyte migration, and ocular secretory immune defense (Chandler and Gillette, 1983 ). However, this conclusion is somewhat controversial and perhaps not entirely correct.

1. The evidence for plasma cell existence in normal human conjunctiva appears tenuous: plasma cell identification by light microscopy could not be verified by immunofluorescent staining for cell-associated IgA, IgG, IgM, IgD, or IgE (Aliensmith et aL, 1976b) and plasma cell enumeration in another study was performed with an antibody that cross-reacted with T cells (Bhan et aL, 1982) . In contrast, more recent investigations have demonstrated a complete absence of plasma cells in conjunctival tissue of humans (Sacks et aL, 1986) and rats (Gudmundsson et aL, 1985a) . Instead, the majority of lymphocytes in human conjunctiva appears to be primarily suppressor/cytotoxic T cells, with a smaller population of helper T cells that are distributed in a subclass-dependent manner throughout the epithelium and substantia propria of the forniceal, tarsal, and epibulbar conjunctiva (Sacks et aL, 1986. (Owen, 1977) , or lung (Bienenstock, 1985) , and appears to limit severely the passage of most antigens because of structural size and molecular weight restrictions (Huang et aL, 1989; Kahn et aL, 1990) . Therefore, the normal human or rat conjunctiva seems unlikely to synthesize IgA, transport IgA antibodies to the ocular surface, or play a direct and significant role in Bcell maturation or migration. Other tissues, organisms, and factors involved in mucosal defense of the eye (Smolin, 1985) include:

1. the orbital skeletal structure, which minimizes potential trauma 2. the eyelid architecture, which is relatively impermeable to macromolecules 3. the eyelid blink reflex and ciliary movement, which rapidly clear foreign objects from the ocular surface 4. the resident conjunctival populations of nonpathogenic bacteria, consisting of aerobes and facultative and obligate anaerobes, which may curtail the ability of invasive bacteria to attach and colonize (McNatt et aL, 1978 5. the continuous tear flow and reflex tearing, which act to remove microorganisms and cellular debris through hydrokinetics and eventual drainage into the nasolacrimal duct

The preocular tear film plays a critical role in the defense of the eye against microbial and antigenic exposure, as well as in the maintenance of corneal clarity and visual ability (Holly, 1987) . These functions are extremely dependent on the stability, tonicity, and composition of the tear film structure, which includes an underlying mucin foundation, a considerable middle aqueous component, and an overlying lipid layer (Holly, 1987; Whitcher, 1987) . Alteration, deficiency, or loss of the tear film may increase significantly the susceptibility to ocular surface desiccation and infection, corneal ulceration and perforation, and marked visual impairment and blindness (Lamberts, 1983; Whitcher, 1987; Lubniewski and Nelson, 1990) .

With respect to immune protection, the tear film contains numerous components (Gachon et aL, 1979; van Haeringen, 1981; Bron and Seal, 1986; Smolin, 1987 ) that combine to provide both specific and nonspecific immunological activity (Tables II and III) . Specific immunity is mediated primarily through the action of IgA antibodies, which are the predominant immunoglobulin in tears of humans (Josephson and Weiner, 1968;  Table III ) and experimental animals (Butler et aL, 1972; Hazlett et aL, 1981b; Allansmith, 1985,1987; Gudmundsson et aL, 1985; Wells and Hazlett, 1985; Sullivan and Hann, 1989a; Sullivan et aL, 1992a) , occur almost entirely in polymeric form (Delacroix et aL, 1982; Delacroix and Vaerman, 1983; Gudmundsson et aL, 1985a; Allansmitheia/., 1985; Coyle era/., 1987 Coyle era/., ,1989 , and originate from local production in lacrimal gland plasma cells (Butler et aL, 1972; Chao et aL, 1980; Janssen and van Bijisterveld, 1983; Sullivan and Allansmith, 1984; Peppard and Montgomery, 1987) . In humans, tear IgA is distributed almost equally among IgAl and IgA2 subclasses (Delacroix et aL, 1982; Fullard and Snyder, 1990; Fullard and Tucker, 1991) . Most tear IgA appears to be transported by and bound to SC, which is synthesized and secreted by lacrimal epithelial cells (Franklin et aL, 1973; Allansmith and Gillette, 1980; Sullivan et aL, 1984b; Gudmundsson et aL, 1985a; Hann etaL, 1989 Hann etaL, ,1991 Sullivan et aL, 1990b; Kelleher et aL, 1991; Lambert et aL, 1993) and is present in the tear film as an SIgA conjugate or as free SC (Gachon et aL, 1979; Delacroix and Vaerman, 1983; Sullivan et aL, 1984a; Sullivan and Allansmith, 1984 Gudmundsson et aL, 1985a; Watson et aL, 1985; Sullivan and Hann, 1989a) . The high concentrations of SIgA coexist with low levels of IgG and very limited quantities of IgM and IgE (Table III; Sullivan and Hann, 1989a; Sullivan et aL, 1990c) . Tear IgG may be derived, in part, from lacrimal tissue synthesis (Butlern aL, 1972; Chao et aL, 1980; Bijsterveld, 1983) , after which it moves down a steep concentration gradient into tears Sullivan and Hann, 1989a; Sullivan et aL, 1990c) , as well as from serum, after deposition in and passage through the conjunctival or lacrimal gland interstitium (McGill et aL, 1984; Fullard and Snyder, 1990; Fullard and Tucker, 1991; D. A. Sullivan, unpublished data) . The source of tear IgM may be lacrimal tissue (Fullard and Snyder, 1990; Fullard and Tucker, 1991) , whereas the origin of IgE in normal tears has yet to be determined. No IgD has been detected in the tear film (McClellan et aL, 1973; Bluestone et aL, 1975; Sen et aL, 1976 Sen et aL, ,1978 . It is important to note that the concentration of tear immunoglobulins, as shown in Table III , may be influenced significantly by the method of tear collection, the extent of tear stimulation, and the procedures that involve processing of tear samples (van Haeringen, 1981; Stuchell et aL, 1984; Fullard, 1988; Tuft and Dart, 1989; Fullard and Snyder, 1990; Fullard and Tucker, 1991; Kuizenga et aL, 1991) . In addition, although tear Ig levels do not appear to display diurnal rhythms (Horwitz et aL, 1978) , IgA concentrations may be exceedingly high after prolonged closure of the eyelids (Sack et aL, 1991) .

Additional specific and nonspecific agents in human tears that support ocular mucosal immunity follow.

1. Lysozyme and lactoferrin, which are secreted by the lacrimal gland Gillette et aL, ,1981 , represent major tear components (van Haeringen, 1981; Gachon, 1982/83 ) and possess antibacterial activity (Smolin, 1987) . Lactoferrin also may prevent activation of the classical complement pathway through inhibition of C3 convertase and may modulate ocular inflammatory reactions (Kijlstra, 1990 /91). 2. 0-Lysin may rupture bacterial cell membranes (Ford et aL, 1976) . The presence of this substance in human tears is controversial (Selsted and Rafael, 1982; Janssen et aL, 1984) . 3. Complement factors C3 and C3 activator, properdin and properdin factor B (Chandler et aL, 1974; Bluestone et aL, 1975; Yamamoto and Allansmith, 1979; Liotet et aL, 1982; Ballow et aL, 1985; Smolin, 1987) , as well as anti-complement (Kijlstra and Veerhuis, 1981) and convertase decay-accelerating (Medof et aL, 1987; Lass et aL, 1990) factors are present. In certain eye diseases, tear IgA appears to fix complement (Barnett, 1968 ). 4. Nonlysozyme antibacterial factor (NLAF), which inhibits growth of staphylococci (Thompson and Gallardo, 1941) actually may be ß-lysin (Ford et aL, 1976) ; its presence is controversial (van Haeringen, 1981; Selsted and Rafael, 1982; Janssen et aL, 1984) . 5. Anti-chlamydial factor is a heat-stable substance that reduces Chlamydia attachment (Elbagir et aL, 1989) . 6. Peroxidase (van Haeringen et aL, 1979; Fullard and Snyder, 1990; Fullard and Tucker, 1991) may exert bactericidal, viricidal, and fungicidal activity, as observed in other secretions, given appropriate levels of H 2 0 2 and oxidizable cofactors . Such peroxidase functions, however, may not operate 

In human tears, a diverse array of bacterial and viral organisms has been identified, including Staphylococcus epidermidis, Corynebacterium Allansmith, 1986,1987) 

Antigenic challenge to the surface of the eye may result in a marked accumulation of specific SIgA, IgG, and IgM antibodies in tears (Table IV) (Table IV) . The nature (e.g., antibody isotype), extent, and kinetics of these immune reactions appear to be very dependent on the form (e.g., live versus inactivated microorganisms; strain), concentration, route, duration, and frequency of antigen administration: potential immune responses may be augmented, intermittent, suppressed, or absent ( The mechanism by which antigenic exposure to the surface of the eye stimulates a local (e.g., IgA) immune response remains to be elucidated. Direct antigen transfer across the conjunctival epithelium (Huang et aL, 1989; Kahn et aL, 1990) or countercurrent passage through the lacrimal duct (Sullivan et aL, 1990c) appears to be restricted severely. Further, the immunological architecture of healthy lacrimal tissue appears to be limited in its capacity to process and present antigen effectively (Weiczorek et aL, 1988) . Conse- Lue et al., 1988) . IgG antibodies from serum, however, may play a significant role in certain inflammatory disorders of the eye (Chandler et al., 1974; Mackie and Seal, 1984; Seal, 1985; Wilhelmus et al., 1986; Gupta and Sarin, 1983) . Overall, ocular immune protection may be conferred by both local and distant antigenic exposure; lacrimal tissue acts at least as a recipient of committed IgA-containing cells that elaborate antigen-specific antibodies. However, the development of an optimal strategy to promote secretory immunity in the eye has yet to be established.

As demonstrated in Table VI , various ocular and systemic diseases, as well as contact lens wear, may influence secretory immune expression in the human eye significantly. Thus, bacterial, viral, and fungal infections of the ocular surface; exposure to allergens; endocrine abnormalities; or graftversus-host disorders may increase levels of specific antibodies, total immunoglobulins, complement proteins, and nonspecific immune factors significantly or may induce changes in the lymphocytic profile of the conjunctiva. Interestingly, if pathological alterations are evident in only one eye, immune responses may (Krichevskayaeia/., 1980;Shanieiß/., 1985) or may not (Centifanto et al, 1970; Hall and O'Connor, 1970) occur in the contralateral unaffected eye. With respect to contact lenses, these may bind (Gudmundsson et al., 1985b) and also cause modifications in the concentrations of (Table  VI) immune components in the tear film; the precise immunological effects may depend on the composition of lens material, the efficacy of cleaning regimens, and the length of wear (Manucci et al., 1984; Vinding et al., 1987; Temel et al., 1991) .

In contrast, such conditions as IgA deficiency, intrauterine infection, ocular surgery, keratoconjunctivitis sicca, malnutrition, and autoimmune disease often may suppress ocular mucosal immunity (Table VI) . For example, severe malnutrition may lead to a significant decrease in tear IgA and SC concentrations, a diminished number of IgA-containing cells in lacrimal tissue, and a blunted SIgA antibody response to infectious challenge (McMurray et al., 1977; Watson et al., 1977 Watson et al., ,1985 Sullivan et al., 1990d; . Similarly, autoimmune disorders such as multiple sclerosis or Sjögren's syndrome may alter or disrupt immune function in the eye significantly. Multiple sclerosis, an autoimmune disease of possible viral origin, is associated with heightened levels of monomeric IgA and lymphocytes, and reduced amounts of SC, in tears of afflicted individuals Coyle, 1989; Coyle and Bulbank, 1989) . Sjögren's syndrome, an autoimmune disease that occurs almost exclusively in females, is characterized by a progressive lymphocytic infiltration into the lacrimal gland, an immunemediated destruction of lacrimal acinar and ductal epithelial cells, decreased tear IgA content, and keratoconjunctivitis, sicca (Tabbara, 1983; Boukes et al., 1987; Moutsopoulos and Talal, 1987; Talal and Moutsopoulos, 1987; Kincaid, 1987) . Further, in experimental models of this complex disorder, generation of autoantibodies to (Ohashi et al., 1985) and deposition of IgG, IgA, and complement in ductal epithelial cells of (DeLuise et al., 1982) lacrimal tissue may accompany the striking glandular inflammation (Kessler, 1968; Hoffman et al., 1984; Jabs et al., 1985; Jabs and Prendergast, 1988; Ariga et al., 1989; Vendramini et al., 1991; Sato et al., 1992) . The etiology of Sjögren's syndrome may involve the endocrine system (Ahmed et al., 1985 (Ahmed et al., ,1989 Raveche and Steinberg, 1986; Nelson and Steinberg, 1987; Talal and Ahmed, 1987; Ahmed and Talal, 1990; Carlsten et al., 1990 ), (Burns, 1983; Fox, 1988; Garry et al., 1990; Krueger et al., 1990; Prepose et al., 1990; Pflugfelder et al., 1990a,b; Mariette et al., 1991) and may stimulate the inappropriate epithelial-cell HLA-DR expression, T helper/inducercell activation, B-cell hyperactivity, and autoantibody production evident in these affected tissues (Maini, 1987; Moutsopoulos and Talal, 1987; Fox, 1988; Venables, 1989) . In support of this possibility, certain viral infections in experimental animals exert a striking impact on the lacrimal gland and induce a periductular infiltration of plasma cells, lymphocytes, and macrophages; distinct nonsuppurative periductular inflammation; significant interstitial edema; widespread necrosis of the acinar and ductal epithelium; degenerative and atrophic alterations in epithelial cells; diminished tear flow; and keratoconjunctivitis sicca (Jacoby et al., 1975; Lai et al., 1976; Percy et al., 1984 Percy et al., ,1990 Green et al., 1989) . Moreover, research has demonstrated that herpes viruses (e.g., cytomegalovirus) and coronaviruses (e.g., sialodacryoadenitis virus) may invade and replicate in rat lacrimal gland acinar cells , Wickham et al., 1992 ; Ulirsch and Jaffe, 1987; deClerck et al., 1988; Lucca et al., 1990) . However, the precise role of viruses in the induction of autoimmune disease, as well as the mechanism by which viral infection may interfere with lacrimal gland function and immune expression, remains to be determined.

During the past three decades, scientists have recognized increasingly that the endocrine and nervous systems regulate multiple aspects of cellular and humoral immunity. The exact nature of this hormonal and neural control-which influences significantly such parameters as lymphocyte maturation, antigen presentation, lymphokine production, and antibody synthesis-critically depends on the specific signal, target cell, and local microenvironment (Besedovsky and Sorkin, 1977; Comsa et al., 1982; Grossman, 1984; Munck et al., 1984; Pay an et al., 1984; Ahmed et al., 1985; Besedovsky et al., 1985; Berczi, 1986; Berczi and Kovacs, 1987; Feiten et al., 1987; Jancovik et al., 1987; Weigent and Blalock, 1987; Freier, 1989; Hadden et al., 1989; Talal and Ahmed, 1987; Ahmed and Talal, 1990; Ader et al., 1991) . Moreover, this neuroendocrine-immune interrelationship is bidirectional, that is, antigenic exposure also may induce the lymphocytic secretion of lymphokines, hormones, and neuropeptides that directly modulate endocrine and neural function (Besedovsky and Sorkin, 1977; Besdovsky et al., 1985; Cotman et al., 1987; Weigent and Blalock, 1987; Raine, 1988; Freier, 1989; Hadden et al, 1989; Ader et al, 1990 Ader et al, ,1991 DOrisio and Panerai, 1990) . In fact, researchers have proposed that the immune system serves as a sensory organ, providing input to the endocrine and nervous compartments in response to noncognitive stimuli such as infection (Blalock, 1984) . Consequently, an extensive triangular association appears to exist between the endocrine, nervous, and immune systems that acts to promote and maintain homeostasis.

In the secretory immune system, diverse hormones and neural agonists are known to exert a tissue-selective influence that may augment, antagonize, or curtail immunological processes (Stead et al., 1987 (Stead et al., ,1991 Sullivan, 1990; Lambert et al., 1993) . Thus, depending on the precise agent and the specific mucosal site, neuroendocrine interactions may significantly modify 1. the accumulation, proliferation, retention, or function of IgA-and IgG-positive cells, T cells, mast cells, eosinophils, basophils, natural killer cells, polymorphonuclear leukocytes, and/or macrophages 2. the synthesis or secretion of IgA and IgG antibodies and cytokines, the expression of major histocompatibility complex (MHC) Class II antigens, the elaboration and release of SC, and the uptake and transport of plgA into luminal secretions 3. the adherence and presentation of microorganisms to mucosal cells, the magnitude of neurogenic inflammation, and the extent of local immune protection against infectious agents

In addition, antigen-induced immune responses may alter mucosal neuroendocrine structure, sensitivity, or function significantly (Rowson et al, 1953; Baker and Plotkin, 1978; Botta, 1979; Forslin et al, 1979; Stead et al, 1987 Stead et al, ,1991 Weisz-Carrington, 1987; Sullivan, 1990; Ader et al, 1991; Kelleher et al, 1991; Bienenstock, 1992; Lambert et al, 1993; McKay et al, 1992; Wira and Prabhala, 1992; Wood, 1992) . With respect to the ocular secretory immune system, endocrine and neural factors appear to exert a dramatic effect on immunological expression and activity (Table VII) . However, although this neuroendocrine-immune interrelationship has been shown definitively in eyes of experimental animals, it has yet to be evaluated in humans. In rats, androgens elicit a marked increase in the production and secretion Kelleher et al. (1991) a Symbols: f : increase; i: decrease; -: no change; blank: not determined. b The stimulatory effects of dihydrotestosterone and cholera toxin were reduced significantly by the presence of carbachol. c Low concentrations of glucocorticoid are required for optimal acinar cell production of SC in vitro . d Insulin's influence has been observed in vitro or inferred from studies with diabetic rats (Sullivan and Hann, 1989a; Hann et al., 1991) .

of SC by lacrimal gland acinar cells (Sullivan et al., 1984b (Sullivan et al., ,1990b Kelleher et al, 1991; Hann et al, 1991) , enhance the concentration of IgA in lacrimal tissue (Sullivan and Hann, 1989a) , and stimulate the transfer and accumulation of SC and IgA, but not IgG, in tears (Sullivan et al., 1984a; Sullivan and Allansmith, 1985; Sullivan and Hann, 1989a) . These hormone actions, which may be induced by various andogenic compounds , are not duplicated by estrogen, progestin, glucocorticoid, or mineralocorticoid treatment (Sullivan et al., 1984a (Sullivan et al., ,1990b Sullivan and Allansmith, 1985) . Morevoer, the immunological effects of androgens appear to be unique to the eye, because androgen administration does not seem to influence IgA or SC levels in salivary, respiratory, intestinal, uterine, or bladder tissues and actually suppresses mucosal immunity in the mammary gland (Weisz-Carrington et al., 1978) . The mechanism by which androgens regulate ocular SC dynamics may involve hormone association with specific nuclear receptors in lacrimal gland acinar cells, binding of these androgen-receptor complexes to genomic acceptor sites, and promotion of SC mRNA transcription and translation. In support of this hypothesis:

1. saturable, high-affinity, and androgen-specific receptors, which adhere to DNA, have been identified in lacrimal tissue (Ota et al., 1985; Edwards et al, 1990; Rocha et al, 1993) 2. androgens increase mRNA levels in lacrimal glands and stimulate lacrimal glycoprotein synthesis (Quintarelli and Dellovo, 1965; Shaw et al, 1983; Gubits et al, 1984) 3. androgen-induced SC production by acinar cells may be inhibited by androgen receptor (cyproterone acetate), transcription (actinomycin D), or translation (cycloheximide) antagonists (Sullivan et al, 1984b; Lambert et al, 1993) . In contrast, the processes underlying androgen action on IgA in the rat eye, as well as hormone enhancement of tear IgA levels in the mouse (Sullivan et al, 1992a) remain to be determined.

Androgen activity also may explain the pronounced gender-related differences in the rat ocular secretory immune system. The number of IgA-containing cells Hann et al, 1988) and the IgA and SC output (Sullivan et al, 1984b; Allansmith, 1985,1988) are significantly greater in adult male lacrimal tissue than in that of adult females. This sexual dimorphism also extends to tears in which, from puberty to senescence, free SC and IgA but not IgG occur at considerably higher levels in male rats (Sullivan ei al, 1984a (Sullivan ei al, ,1990c Allansmith, 1985,1988) . Indeed, androgen influence may be involved in the distinct gender-associated differences in the structural appearance, histochemistry, biochemistry, immunology, and molecular biological expression of the lacrimal gland in a variety of species, including mice, hamsters, guinea pigs, rats, rabbits, and humans (e.g., Tier, 1944; Martinazzi and Baroni, 1963 Cavallero, 1967; Shaw et al, 1983; Cornell-Bell et al, 1985 Mhatre et al, 1988 Pangerl et al, 1989; Warren et al, 1990 Sullivan and Sato, 1992a) . With respect to humans, gender appears to influence (1) the degree of lymphocyte accumulation in the lacrimal gland (Waterhouse, 1963) ; (2) the IgA concentrations in tear of adults (Sen et al, 1978) , but not elderly (Sand et al, 1986) ; and (3) the frequency of Sjögren's syndrome-related lacrimal gland imjunopathology (Tabbara, 1983; Moutsopoulos and Talal, 1987; Kincaid, 1987) . Interestingly, androgen administration to animal models of Sjögren's syndrome (i.e., MRL/Mp-lpr/lpr and NZB/NZW Fl female mice) results in an almost complete suppression of autoimmune sequelae in lacrimal tissue (Ariga et al, 1989; Vendramini et al, 1991; Sato et al, 1991 Sato et al, ,1992 Sullivan and Sato, 1992a) ; and an increased output of IgA (Sullivan et al, 1992b) .

In addition to androgens, the hypothalamic-pituitary axis appears to play an important role in the expression of the rat ocular secretory immune system. Disruption of this axis by hypophysectomy or extirpation of the anterior pituitary significantly reduces the number of IgA plasma cells in lacrimal tissue, diminishes the acinar cell production of SC, causes a striking decrease in the levels of tear IgA and SC, and almost completely curtails androgen action on ocular mucosal immunity (Sullivan and Allansmith, 1987; Sullivan, 1988; Sullivan and Hann, 1989a) . Moreover, this endocrine disturbance has a marked effect on lacrimal gland structure and function, leading to both acinar cell atrophy (Martinazzi, 1962) and diminished tear output (Sullivan and Allansmith, 1986 ). The physiological mechanisms responsible for hypothalamic-pituitary involvement in the ocular secretory immune system remain to be elucidated, but may include numerous neuroendocrine and immunological pathways: the hypothalamus and pituitary regulate multiple endocrine circuits, directly influence neural innervation in the lacrimal gland, and clearly modulate immune activity (Hosoya et al., 1983; Wilson and Foster, 1985; Berczi, 1990; Berczi and Nagy, 1990) . Further, the hypothalamic-pituitary axis is known to control many hormones, neurotransmitters, and lymphokines that modify androgen and acinar cell function and control mucosal immunity (Mooradian et al., 1987; Sullivan, 1990) .

Other studies in experimental animals also have demonstrated that (1) sex steroids may alter the development of allergic conjunctivitis in rabbits significantly (Saruya, 1968) and (2) diabetes may diminish significantly the expression of the secretory immune system of the eye. Thus, in diabetic rats, the density of IgA-containing cells in lacrimal tissue and the concentrations of IgA and SC in tears are reduced significantly (Sullivan and Hann, 1989a) . These diabetic effects most likely relate to the absence of insulin, which is essential for optimal SC synthesis by acinar as well as intestinal (Buts et al., 1988 ) cells, and apparently is required for maximal androgen action on target tissues (Jackson and Hutson, 1984) . Similarly, both the thyroid and the adrenal glands are necessary to achieve the full magnitude of androgen-induced effects on the secretory immune system of the eye (Sullivan and Allansmith, 1987) .

From the perspective of neural regulation, the stromal, periductal, perivascular, and acinar areas of lacrimal tissue are innervated by many parasympathetic, sympathetic, and peptidergic fibers that harbor numerous immunoactive transmitters, including vasoactive intestinal peptide (VIP), substance P, methionine enkephalin, leucine enkephalin, calcitonin gene-related peptide, and adrenergic and cholinergic agents (Ruskell, 1971 (Ruskell, ,1975 Uddman et al., 1980; Nikkinen etal., 1984 Nikkinen etal., ,1985 Lehtosaloei al., 1987 ;Uusitaloef a/., 1990; Walcott, 1990 ). These neural agonists are known to control lymphocyte retention or function at other mucosal sites (Ottoway, 1984; Stanisz et al., 1986; Walcott et al., 1986; Freier et al., 1987; Scicchitano et al., 1988; Hart et al., 1990) and their release may influence the adherence, distribution, or activity of IgA plasma cells or T cells in the lacrimal gland Oeschger et al., 1989; Sullivan et al., 1990/91) . Consistent with this possibility, VIP appears to augment T-cell attachment to murine lacrimal tissue (Oeschger et al., 1989) and systemic administration of the ß-adrenergic blocker practolol suppresses human tear IgA levels (Wright, 1975; Garner and Rahi, 1976) . However, the nature of the sympathetic-immune interaction requires further clarification, because ocular application of the ß-blocker timolol to humans (Coakes et al., 1981) and sympathetic denervation in rats (Sullivan et al., 1990/91) have no apparent effect on tear IgA content.

VIP and the ß-adrenergic agent isoproterenol have been demonstrated to increase, whereas the cholinergic agonist carbamyl choline has been shown to decrease, basal and androgen-stimulated SC production by rat acinar cells (Kelleher et al., 1991) . This neural regulation of SC synthesis may be mediated through the modulation of intracellular adenylate cyclase and cAMP activity. In support of this hypothesis, VIP and adrenergic agents are known to enhance (Mauduit et al., 1984; Dartt, 1989) , and cholinergic agents possibly suppress (Jumblatt et al., 1990) , the generation of cellular cAMP. Further, exposure of lacrimal gland acinar cells to cAMP analogs, cAMP inducers (i.e., PGE 2 and cholera toxin), or phosphodiesterase inhibitors may elevate SC production . This cAMP influence on SC elaboration, although pronounced in the lacrimal gland, is not necessarily reproduced in other mucosal epithelial cells .

Additionally, neural pathways are extremely important in the spread of herpes virus infection in the eye (Shimeld et al., 1987) and ocular viral transmission and activity may be modulated by neuropeptides (Herbort et al., 1989) . Moreover, although the optic nerve does not appear to regulate the ocular secretory immune system (Sullivan et al., 1990/ 91) , light does seem to control anterior chamber-associated immune deviation (Ferguson et al., 1988) , herpes virusrelated retinitis (Hayashi et al., 1988) , and various parameters of systemic immunity (Maestroni et al., 1987) . The secretory immune system of the eye in experimental animals also may be regulated by lymphokines. For example, interleukins (IL) la and 1/3 and tumor necrosis factor a (TNFa), but not IL-6 or interferon y (IFNy), stimulate the acinar cell synthesis and secretion of SC . The regulatory effect of TNFa on acinar cell SC production is similar to that found in colonic cell lines, in which TNFa increases the production, surface expression, and release of SC (Kvale et al., 1988a,b) . However, the absence of IFNy effect on SC output by acinar cells is notable because this lymphokine regulates SC dynamics in both intestinal (Sollid et al, 1987; Kvale et al., 1988a) and uterine (Wira and Prabhala, 1992) epithelial cells. Although IL-6 appears to have no influence on lacrimal SC production , both IL-6 and IL-5 stimulate the synthesis of IgA in lacrimal tissue explants (Pockley and Montgomery, 1990/ 91b) and, in combination, augment the secondary tear IgA antibody response to pneumococcal antigen (Pockley and Montgomery, 1991) and suppress IgG and IgM synthesis in lacrimal tissue (Pockley and Montgomery, 1990/9la). As a further consideration, androgens, VIP, and IL-1 all share the capacity to increase IgA production in specific tissues (Drew and Shearman, 1985; Stanisz et al, 1986; Crowdery et al, 1988; Sullivan and Hann, 1989a) ; plgA, in turn, may heighten the monocytic output of TNFa (Deviere et al, 1991) . If analogous activity occurs in the lacrimal gland, then various neuroimmunoendocrine factors may control the synthesis of both IgA antibodies and the IgA receptor, leading to enhanced antibody transfer to tears and improved ocular surface defense.

Measurement of total IgE antibody levels in lacrimal fluid of patients suffering from atopic and nonatopic eye disorders. Evidence for local IgE production in atopic eye disorders?

Duanes's Biomedical Foundations of Ophthalmology

Presence of HTLV-III in tears and cells from the eyes of AIDS patients

Protection against keratoconjunctivitis shigellosa induced by immunization with outer membrane proteins of Shigella spp

Interactions between the brain and immune system

Psychoneuroimmunology

Sex hormones and the immune system-Part 2. Animal data. Bailliere's Clin. Rheum

Sex hormones, immune responses, and autoimmune diseases

Estrogen induces the development of autoantibodies and promotes salivary gland lymphoid infiltrates in normal mice

Secretory component in human ocular tissues

Immunology of the anterior segment

Plasma cell content of main and accessory lacrimal glands and conjunctiva

Tissue, tear, and serum IgE concentrations in vernal conjunctivitis

Immunoglobulins in the cornea

Number of inflammatory cells in the normal conjunctiva

Ocular anaphylaxis induction by local injection of antigen

Sequence of mast-cell changes in ocular anaphylaxis

Molecular forms of tear Ig A and distribution of Ig A subclasses in human lacrimal glands

The immune response of the lacrimal gland to antigenic exposure

Androgen control of autoimmune expression in lacrimal glands of MRL/Mp-lpr/lpr mice

Enhancement of vaginal infection in mice by Herpes simplex virus type II with progesterone

The pathogenesis of murine cytomegalovirus ocular infection. Anterior chamber inoculation

IgG specific antibodies to rye grass and ragweed pollen antigens in the tear secretions of patients with vernal conjunctivitis

Complement proteins and C3 anaphylatoxin in the tears of patients with conjunctivitis

Tear lactoferrin levels in patients with external inflammatory ocular disease

A genetic influence on the appearance of specific antibodies in serum and secretions following challenge with antigen

Quantitation of immunoglobulins and L-chains by complement fixation tests

Further observations on immunoglobulins of external secretions

Pituitary Function and Immunity

Neurohormonal-immune interaction

Hormones and Immunity

Effects of hypophysectomy on immune function

Antibody in tears, saliva and nasal secretions following oral immunization of humans with inactivated influenza vaccine

Oral immunization against influenza in children with asthma and chronic bronchitis

Network of immuneneuroendocrine interactions

Immuneneuroendocrine interactions

T-Cell subsets and Langerhans cells in normal and diseased conjunctiva

Pathogenesis of corneal lesions in measles

Bronchus-associated lymphoid tissue

Neuroimmune interactions in the regulation of mucosal immunity

The immune system as a sensory organ

Lacrimal immunoglobulins and complement quantified by counter-immunoelectrophoresis

Hormonal and type-dependent adhesion of group B streptococci to human vaginal cells

Analysis of human tear protein profiles using high performance liquid chromatography

Le immunoglobuline nelle lacrime

Immunohistochemical characterization of intracellular J-chain and binding sites for secretory component (SC) in human immunoglobulin (Ig)-producing cells

Role of J chain and secretory component in receptor-mediated glandular and hepatic transport of immunoglobulins in man

Immunohistochemical characterization of intracellular J-chain and binding sites for secretory component (SC) in human immunoglobulin (Ig)-producing cells

The human secretory immune system shows striking heterogeneity with regard to involvement of J chainpositive IgD immunocytes

Subclass distribution of IgG-and IgA-producing cells in secretory tissues and alterations related to gut diseases

Immunoglobulin E in human tears

Eyelid secretions and the prevention and production of disease

The defences of the ocular surface

The liver and IgA: Immunological, cell biological, and clinical implications

Immunoglobulin A antibody levels in human tears, saliva, and serum

Persistent cytomegalovirus infection-The etiology of Sjögren's syndrome

Studies on the relative synthesis and distribution of IgA and IgGl in various tissues and body fluids of the cow

Intestinal development in the suckling rat: Effect of insulin on the maturation of villus and crypt cell functions

Oestrogen is a potent disease accelerator in SLE-prone MRL lpr/lpr mice

Relative effectiveness of various steroids in an androgen assay using the exorbital lacrimal gland of the castrated rat

The relationship between virus chemotherapy, secretory antibody formation and recurrent herpetic disease

Herpes simplex virusspecific antibodies present in tears during herpes keratitis

Immunologie defense mechanisms of the ocular surface

Quantitative determinations of complement components and immunoglobulins in tears and aqueous humor

Biosynthesis and partial characterization of tear film glycoproteins, incorporation of radioactive precursors by human lacrimal gland explants

Molecular mechanisms of immunoglobulin A defense

Gamma globulins: Quantitative relationships in human serum and nonvascular fluids

Effects of long-term treatment with timolol on lacrimal gland function

Hormonal coordination of the immune response

Gender-related differences in the morphology of the lacrimal gland

Characterization of a localized basophil hypersensitivity lesion in guinea pig conjunctiva

The Neuro-Immune-Endocrine Connection

Sicca complex and infection with human immunodeficiency virus

Interleukin 1 induces T cell-mediated differentiation of murine Peyer's patch B cells to IgA secretion

Cytomegalovirus in tears from patients with normal eyes and with acute cytomegalovirus chorioretinitis

Molecular analysis of IgA in multiple sclerosis

Immune-reactive cells in multiple sclerosis mucosal secretions

Tear immunoglobulins measured by ELISA

Viral specificity of multiple sclerosis tear immunoglobulins

Viral antibodies in normal tears

Increased monomeric immunoglobulin A levels in tears from multiple sclerosis patients

Oligoclonal IgG in tears

Electrophoresis combined with immunologic identification of human tear proteins

Distribution of IgAl-, IgA2-, and J chain-containing cells in human tissues

Oral immunization with bacterial antigen induces IgAsecreting cells in peripheral blood in humans

Senile atrophy of the human lacrimal gland: The contribution of chronic inflammatory disease

Signal transduction and control of lacrimal gland protein secretion: a review

Immunological characterization of soluble peroxidases from rat tissues including preputial gland

Acquired immunodeficiency syndrome mimicking Sjogren's syndrome and systemic lupus erythematosus

Function of the human liver in IgA homeostasis in plasma

IgA subclasses in various secretions and in serum

The effects of age, sex, and pregnancy on the histopathology and immunopathology of lacrimal glands of NZB/NZW Fl hybrid mice

IgA triggers tumor necrosis factor a secretion by monocytes: A study in normal subjects and patients with alcoholic cirrhosis

Tear immunoglobulins in giant papillary conjunctivitis induced by contact lenses

Neuropeptides and Immunopeptides: Messengers in a Neuroimmune Axis

Rhinovirus neutralizing antibody in tears, parotid saliva, nasal secretions and serum

Vasoactive intestinal peptide: a neurotransmitter which reduces human NK cell activity and increases Ig synthesis

Cellular and humoral IgA responses after single and multiple local injections of antigen

Identification of dihydrotestosterone binding sites in the rat lacrimal gland

Antichlamydial activity of tear fluid

Noradrenergic sympathetic neural interactions with the immune system: structure and function

Regulation of the systemic immune response by visible light and the eye

An enzyme-linked immunoassay (ELISA) for anti-chlamydial secretory immunoglobulin A in guinea pig tears

Identification of a nonlysozomal bacterial factor (0-lysin) in human tears and aqueous humour

Variations in attachment of Neisseria gonorrhoeae to vaginal epithelial cells during the menstrual cycle and early pregnancy

Tear and serum antibody levels in ocular herpetic infection: Diagnostic precision of secretory IgA

Epstein-Barr virus and human autoimmune disease: Possibilities and pitalls

Detection of Epstein-Barr virus-associated antigens and DNA in salivary gland biopsies from patients with Sjögren's syndrome

A mechanism for localization of IgA-producing cells in the lacrimal gland

The ocular secretory immune system: A review

Conjunctival-associated lymphoid tissue: Evidence for a role in the secretory immune system

/91). T-cell adherence to lacrimal gland: The event responsible for IgA plasma cell predominance in lacrimal gland

Immunohistologic studies of human lacrimal gland: Localization of immunoglobulins, secretory component and lactoferrin

Secretory immune system of rabbit ocular adnexa. Invest. Ophthalmol. Vis. Sei

Lacrimal gland directed B cell responses

Neuroregulation of lacrimal gland function

The role of substance P on neuro-immune mechanisms in the lacrimal gland

The Neuroendocrine-Immune Network

Effect of cholecystokinin and of its antagonist, of atropine, and of food on the release of immunoglobulin A and immunoglobulin G specific antibodies in the rat intestine

Antibodies in human tears during and after infection

Virus-specific IgA in serum, saliva, and tears of children with measles

Identification of proteins in small tear volumes with and without size exclusion HPLC fractionation

Protein levels in nonstimulated and stimulated tears of normal human subjects

Changes in human tear protein levels with progressively increasing stimulus. Invest. Ophthalmol

Immunofluorescent studies of ocular cicatricial pemphigoid

Human tears: Normal protein pattern and individual protein determinations in adults

Immunological and electrophoretic studies of human tear proteins

Practolol and ocular toxicity

Detection of a human intracisternal A-type retroviral particle antigenically related to HIV

Detection of HBs antigen, DNA polymerase activity, and hepatitis B virus DNA in tears; Relevance to hepatitis B transmission by tears

Enhancement of infectious bovine keratoconjunctivitis by modified-live infectious bovine rhinotracheitis virus vaccine

Retinal specific antigens and immunopathogenic processes they provoke

Lactoferrin in human ocular tissues

Histologie and immunohistologic comparison of main and accessory lacrimal tissue

Immunohistochemical localization of human tear lysozyme

Prostaglandin E 2 levels in tears during postoperative inflammation of the eye

Exocrinopathy resembling Sjögren's syndrome in HTLV-1 tax transgenic mice

Naturally occuring IgA antibodies to ocular and oral microorganisms in tears, saliva, and colostrum: Evidence for a common mucosal immune system and local immune response

Local immune responses in the ocular secretory immune system of humans

Protective secretory immunoglobulin A antibodies in humans following oral immunization with Streptococcus mutans

IgA antibodies to oral and ocular bacteria in human external secretions

The regulation of the immune system of sex steroids

Differential regulation of a2u globulin gene expression in liver, lachrymal gland, and salivary gland

Mononuclear and IgAcontaining cells in the lacrimal gland of germ-free and conventional rats

The ocular secretory immune system of the rat

Identification of protein in contact lens surface deposit by immunofluorescence microscopy

T cell populations in the lacrimal gland during aging

Serum and tear immunoglobulin levels in acute adenovirus conjunctivitis

Interactions among Central Nervous System, Neuroendocrine and Immune Systems

Antibiotic-producing bacteria of the ocular flora

Correlation between ocular inflammation and antibody production

IgG and IgA antibody in tears of rabbits immunized by topical application of ovalbumin

Conjunctival basophil hypersensitivity lesions in guinea pigs

Impact of aging and gender on the Ig-containing cell profile of the lacrimal gland

Morphology and function of lacrimal gland acinar cells in primary culture

Influence of culture conditions on the androgen control of secretory component production by acinar cells from the lacrimal gland

Effect of substance P on immunoglobulin and interferongamma secretion by cultured human duodenal mucosa

Contralateral HSV-1 retinitis is dependent upon visible light

Microscopic characterization of ocular damage produced by Pseudomonas aeruginosa toxin A

Immunocytochemical localization of IgA in the mouse cornea

Elevated tear IgG and conjunctival plasma cell infiltrate in a graft versus host disease patient

Role of peptidergic neurons in ocular herpes simplex infection in mice

Immune response in chlamydial conjunctivitis among neonates and adults with special reference to tear IgA

Clinical interest in the detection of IgE in tears

Sjögren's syndrome in MRL/1 and MRL/n mice

Tear film physiology

Diurnal profiles of tear lysozyme and gamma A globulin

A direct hypothalamic projection to the superior salivatory nucleus neurons in the rat. A study using anterograde autoradiographic and retrograde HRP methods

Paracellular permeability of corneal and conjunctival epithelia

Influence of the endocrine environment on herpes virus infection in rat lacrimal gland acinar cells

Lacrimal glands. In Duanes's Biomedical Foundations of Ophthalmology

Murine models of Sjögren's syndrome

Ocular inflammation in autoimmune MRL/Mp mice

Altered responses to androgen in diabetic male rats

Oral-parenteral immunization leads to the appearance of IgG auto-anti-idiotypic cells in mucosal tissues

Pathogenesis of sialodacryoadenitis in gnotobiotic rats

Neuroimmune Interactions. Ann. N. Y. Acad. Sei. 496

Origin and biosynthesis of human tear fluid proteins

Nonlysozyme antibacterial factor in human tears. Fact or fiction? Invest

The concentration of lactoferrin in tears during post-operative ocular inflammation

Studies of the proteins of lacrimal secretions

Muscarinic cholinergic inhibition of adenylate cyclase in the rabbit irisciliary body and ciliary epithelium

Penetrating the conjunctival barrier: the role of molecular weight

Allergic conjunctivitis, total and specific IgE in the tear fluid

Endocrine, neural and immune control of secretory component output by lacrimal gland acinar cells

A laboratory model for Sjögren's syndrome

Different subclass distribution of IgA-producing cells in human lymphoid organs and various secretory tissues

Secretory IgA and lysozyme in tears of patients with Graves' ophthalmopathy

/91). The role of lactoferrin in the nonspecific immune response on the ocular surface

The effect of an anticomplementary factor on normal human tears

Sjögren's Syndrome. Clinical and Immunological Aspects

Demonstration and characterization of antibody in tears following intranasal vaccination with inactivated type 13 rhinovirus: A preliminary report

The use of passive hemagglutination test (PHA) in the diagnosis of viral eye diseases. Investigation of lacrimal fluid for the presence of antibody to herpes simplex virus (HSV)

Latent herpesvirus-6 in salivary and bronchial glands

SDSminigel electrophoresis of human tears. Effect of sample treatment on protein patterns

Up-regulation of the expression of secretory component and HLA molecules in a human colonic cell line by tumour necrosis factor-á and gamma interferon

Tumor necrosis factor-á up-regulates expression of secretory component, the epithelial receptor for polymeric Ig

In vitro synthesis of immunoglobulins, secretory component and complement in normal and pathological skin and the adjacent mucous membranes

Keratoconjunctivitis associated with sialodacryoadenitis in rats

Serum and tear immunoglobulins in bacterial, fungal and viral corneal ulcers

Neural-endocrine control of secretory component synthesis by lacrimal gland acinar cells: specificity, temporal characteristics and molecular basis

Keratoconjunctivitis sicca

Human fibroblast interferon in tears of patients with picornavirus epidemic conjunctivitis

Virus-specific, early appearing neutralizing activity and interferon in tears of patients with acute hemorrhagic conjunctivitis

Expression of two molecular forms of the complement decay-accelerating factor in the eye and lacrimal gland

/91). HLA class II expression in normal and inflamed conjunctiva

Enkephalin-like immunoreactive nerve fibers in the lacrimal glands of the guinea pig

Parenteral immunization with Shigella ribosomal vaccine elicits local IgA response and primes for mucosal memory

/91). Detection of the complement (CD21)/Epstein-Barr virus receptor in human lacrimal gland and ocular surface epithelia

Etude des prot6ines lacrymales au cours des syndromes sees

Etude de la barriere homato-lacrymale humaine normale

Anti-HIV antibodies in tears of patients with AIDS

Immunoglobulins in human tears

Experimental autoimmune dacryoadenitis: III. Induction by immunization with extracts of intraorbital lacrimal gland

Secretory component of IgA: A marker for differentiation of ocular epithelium

Experimental autoimmune dacryoadenitis. I. Lacrimal gland disease in the rat

Diagnosis and management of dry eye and ocular surface disorders

Keratoconjunctivitis sicca in male patients infected with human immunodeficiency virus type 1

Systemic immunization with pneumococcal polysaccharide vaccine induces a predominant IgA2 response of peripheral blood lymphocytes and increases of both serum and secretory antipneumococcal antibodies

Immunoglobulins in tears

Immune response of owl monkeys to topical vaccination with irradiated Chlamydia trachomatis

Advances in Mucosal Immunology

Lymphocyte migration into the lacrimal gland is random

Regulation of IgA synthesis and immune response by T cells and interleukins

Normal tear protein profiles and age-related changes

Neuroimmune amplification and inhibition of mucosal immune function

Diagnostic implications of tear protein profiles

Immunological sequelae of intrauterine infection

Effects of moderate malnutrition on concentrations of immunoglobulins and enzymes in tears and saliva of young Colombian children

Anaerobic flora of the normal human conjunctival sac

The pineal gland and the circadian, opiatergic, immunoregulatory role of melatonin

The relationship of Sjögren's syndrome to rheumatoid arthritis

Serum and tear antibodies to Chlamydia after reinfection with guinea pig inclusion conjunctivitis agent

HSVspecific IgA from tears blocks virus attachment to the cell membrane

The effect of extended wear contact lenses on tear immunoglobulins

Detection of Epstein-Barr virus DNA by in situ hybridization and polymerase chain reaction in salivary gland biopsy specimens from patients with Sjögren's syndrome

Effettidell'ipofisectomiasullaghiandolalacrimale extraorbitale del ratto

Controllo ormonale delle ghiandola lacrimale extraorbitale nel topo con nanismo ipofisario

Protein secretion induced by isoproterenol or pentoxifylline in lacrimal gland: Ca 2+ effects

The occurrence of oligoclonal IgG in tears from patients with MS and systemic immune disorders

Identification of the complement decayaccelerating factor (DAF) on epithelium and glandular cells and in body fluids

The common mucosal immune system and current strategies for induction of immune response in external secretions

Immunoglobulin A (IgA): Molecular and cellular interactions involved in IgA biosynthesis and immune response

Selective induction of an immune response in human external secretions by ingestion of bacterial antigen

Melatonin in the lacrimal gland: First demonstration and experimental manipulation

Class II antigen expression by lacrimal epithelial cells

Studies of autoimmune induction in the rat lacrimal gland

Corneal antibody levels to ribitol teichoic acid in rabbits immunized with staphylococcal antigens using various routes

Ocular immunity to Staphylococcus aureus

Antibody studies in a rabbit model of corneal phlyctenulosis and catarrhal infiltrates related to Staphylococcus aureus

Induction and expression of antibodies in secretions

Parameters influencing the expression of IgA antibodies in tears

The effect of immunization route and sequence of stimulation on the induction of IgA antibodies in tears

Evidence for migration of IgA bearing lymphocytes between peripheral mucosal sites

Isolation and characterization of mononuclear cell populations from lacrimal glands

A comparison of lymphocyte subset distribution in rat lacrimal 593

glands with cells from tissues of mucosal and non-mucosal origin

Biological actions of androgens

Immunologie abnormalities in Sjögren's syndrome

Physiological functions of glucocorticoids in stress and their relation to pharmacological actions

Immunity to chlamydial infections of the eye. I. The role of circulatory and secretory antibodies in resistance to reinfection with guinea pig inclusion conjunctivitis

Sex steroids, autoimmunity, and autoimmune diseases

Use of enteric vaccines in protection against chlamydial infection of the genital tract and the eye of guinea pigs

The lacrimal glands of the rat and the guinea pig are innervated by nerve fibers containing immunoreactivities for substance P and vasoactive intestinal polypeptide

Distribution of adrenergic nerves in the lacrimal glands of guineapig and rat

Detection of adenovirus-specific immunoglobulin A in tears from patients with keratoconjunctivitis

Herpes simplex virus specific secretory IgA in lacrimal fluid during herpes keratitis. Scand

Regulation of T-cell migration: Effect of neuropeptides and cell factors on the binding of T-cells to lacrimal gland epithelial cells

The presence of cytotoxic autoantibody to lacrimal gland cells in NZB/W mice

Selective interactions of lymphocytes with neonatal and adult lacrimal tissues

Demonstration and characterization of cytosol androgen receptor in rat exorbital lacrimal gland

In vitro alteration of receptors for vasoactive intestinal peptide changes the in vivo localization of mouse T cells

Sequential uptake of horseradish peroxidase by lymphoid follicle epithelium of Peyer's patches in the normal unobstructed mouse intestine: Anultrastructural study

/91). Chlamydia-specinc lymphocytes in conjunctiva during ocular infection: limiting dilution analysis

ß-Adrenoreceptors in the extraorbital lacrimal gland of the Syrian hamster. Characterization with [ 125 I]iodopindolol and evidence of sexual dimorphism

Phenotype and mononuclear leucocytes resident in rat major salivary and lacrimal glands

Tears and aqueous humor from horses inoculated with Leptospira contain antibodies which bind to cornea

Major ocular viral infections

Modulation of immunity and hypersensitivity by sensory neuropeptides

Secretory IgA specific for herpes simplex virus in lacrimal fluid from patients with herpes keratitis-A possible diagnostic parameter

Mononuclear cell phenotypes and immunoglobulin gene rearrangements in lacrimal gland biopsies from patients with Sjögren's syndrome

Studies on the origin and composition of IgA in rat tears

Optimising the expression of antibody in tears: Manipulation of the common mucosal immune respone?

Antibody production in rats following ocular-topical or gastrointestinal immunization: Kinetics of local and systemic antibody production

Comparison of strain susceptibility to experimental sialodacryoadenitis in rats

Duration of protection from reinfection following exposure to sialodacryoadenitis virus in Wistar rats

Amplification of Epstein-Barr virus genomic sequences in blood cells, lacrimal glands, and tears from primary Sjögren's syndrome patients

Epstein-Barr virus infection and immunological dysfunction in patients with aqueous tear deficiency

/91a). Identification of lacrimal gland associated immunomodulatory activities having differential effects on T and B cell proliferative responses

/91b). The effects of interleukins 5 and 6 on immunoglobulin production in rat lacrimal glands

In vivo adjuvant effect of interleukins 5 and 6 on rat tear IgA antibody responses

A superoxide-producing system in the conjunctival mucus thread

Conjunctival immunity: Compared effects of ocular or intestinal immunization in rats

Activation of glycoprotein biosynthesis by testosterone propionate on mouse exorbital glands

Glandular secretion of lactoferrin in a patient with neutrophil lactoferrin deficiency

Sex hormones in autoimmunity

Binding characteristics, immunocytochemical location and hormonal regulation of androgen receptors in lacrimal tissue

Influence of ovarian hormones on uterine infection

The distribution of autonomic post-ganglionic nerve fibers to the lacrimal gland in monkeys

Nerve terminals and epithelial cell variety in the human lacrimal gland

Detection of HSV nucleic acid sequences in the cornea during acute and latent ocular disease

Lymphocytic subpopulations in the normal human conjunctiva. A monoclonal antibody study

Vernal keratoconjunctivitis: The significance of immunoglobulin E levels in tears and serum

Changes in the concentration of secretory immunoglobulin A in tears during post-operative inflammation of the eye

Studies on allergic conjunctivitis. Effects of castration and sex hormone administration on experimental allergic conjunctivitis

Effect of steroids and immunosuppressive agents on lacrimal autoimmune disease in a mouse model of Sjögren's syndrome. Abstracts of the Seventeenth Cornea Research Conference

Impact of androgen therapy in Sjögren's syndrome: hormonal influence on lymphocyte populations and la expression in lacrimal glands of MRL/ Mp-lpr/lpr mice

Lysozyme concentration in tears of patients with sicca syndrome

In vivo immunomodulation by the neuropeptide substance P

The effect of ageing and disease on tear constituents

Isolation and purification of bactericides from human tears

Immunoglobulin concentrations in human tears in ocular diseases

Immunoassay of tear lysozyme in conjunctival diseases

Immunoglobulins in tears of normal Indian people

Biological variation of immunoglobulin concentrations in normal human tears related to age and sex

HLA-DR + / T6~ Langerhans cells of the human cornea

Unusual structure of rat conjunctival epithelium

Studies on HSV specific IgA antibodies in lacrimal fluid from patients with herpes keratitis by solid phase radioimmunoassay

The gene family for major urinary proteins: Expression in several secretory tissues of the mouse

Local antibody formation within the eye: A study of immunoglobulin class and antibody specificity

Spread of HSV-1 to the mouse eye after inoculation in the skin of the snout requires an intact nerve supply to the inoculation site

The defence mechanism of the outer eye

The role of tears in the prevention of infections

Duanes's Biomedical Foundations of Ophthalmology

Interferon-ã enhances expression of secretory component, the epithelial receptor for polymeric immunoglobulins

The IgA system. II. The clinical significance of IgA deficiency: Studies in patients with agammaglobulinemia and ataxia telangiectasia

Duanes's Biomedical Foundations of Ophthalmology

Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferation by lymphocytes from Peyer's patches, mesenteric lymph nodes, and spleen

Neuropeptide regulation of mucosal immunity

Interaction of the mucosal immune and peripheral nervous systems

Immune regulation and the eye: A dangerous compromise

The effect of collection technique on tear composition

Lacrimal proteins in Sjögren's syndrome. Ophthalmol

Influence of the hypothalamic-pituitary axis on the androgen regulation of the ocular secretory immune system

Hormonal influence on the secretory immune system of the eye

Source of IgA in tears of rats

Hormonal influence on the secretory immune system of the eye: Androgen modulation of IgA levels in tears of rats

Hormonal modulation of tear volume in the rat

Hormonal influence on the secretory immune system of the eye: Endocrine interactions in the control of IgA and secretory component levels in tears of rats

The effect of aging on the secretory immune system of teh eye

Mechanisms involved in the endocrine regulation of the ocular secretory immune system

Hormonal influence on the secretory immune system of the eye: Endocrine impact on the lacrimal gland accumulation and secretion of IgA and IgG

Principles and Practice of Ophthalmology

Potential therapeutic approach for the hormonal treatment of lacrimal gland dysfunction in Sjögren's syndrome

Influence of severe protein malnutrition on rat lacrimal, salivary and gastrointestinal immune expression during development, adulthood and aging

Hormonal influence on the secretory immune system of the eye: Androgen regulation of secretory component levels in rat tears

Hormonal influence on the secretory immune system of the eye: Androgen control of secretory component production by the rat exorbital gland

Production and utilization of a mouse monoclonal antibody to rat IgA: Identification of gender-related differences in the secretory immune system

Selectivity, specificity and kinetics of the androgen regulation of the ocular secretory immune system

Influence of ocular surface antigen on the postnatal accumulation of immunoglobulin-containing cells in the rat lacrimal gland

Androgen regulation of secretory component synthesis by lacrimal gland acinar cells in vitro

Age-and gender-related influence on the lacrimal gland and tears

Severe protein malnutrition: impact on tear IgA levels during development and aging

/91). Neural-immune interrelationship: Effect of optic, sympathetic, temporofacial or sensory denervation on the secretory immune system of the lacrimal gland

Influence of steroids and immunosuppressive compounds on tear IgA levels in a mouse model of Sjögren's syndrome

Sjögrens syndrome

Lymphocyte subsets of human conjunctival follicles

Sex hormones and autoimmune disease: A short review

Treatment of Sjögren's syndrome

Attempted oral immunization with chlamydial lipopolysaccharide subunit vaccine

Oral immunization against chlamydial eye infection

Oral immunization with chlamydial major outer membrane protein (MOMP)

The effect of contact lens wear on tear immunoglobulins

The antibacterial action of tears on staphylococci

Über Zeilteilung and Kernklassenbildung in der Glandula orbitalis externa der Ratte

Antichlamydial antibody in tears and sera, and serotypes of Chlamydia trachomatis isolated from schoolchildren in Southern Tunisia

Decrease of lactoferrin concentration in the tears of myotonic muscular dystrophy patients

The measurement of IgE in tear fluid: A comparison of collection by sponge or capillary

Vasoactive intestinal peptide nerves in ocular and orbital structures of the cat

Eosinophil granule major basic protein and Charcot-Leyden crystal protein in human tears

Sjögren's syndrome-like illness associated with acquired immunodeficiency syndromerelated complex

Immunoglobulin A: Strategic defense initiative at the mucosal surface

Neuropeptides in the autonomic and sensory nerves of the lacrimal gland

The peroxidase-thiocyanate-hydrogen peroxide system in tear fluid and saliva of different species

Persistence of Epstein-Barr virus in salivary gland biopsies from healthy individuals and patients with Sjögren's syndrome

Testosterone-induced suppression of autoimmune disease in lacrimal tissue of a mouse model (NZB/NZW Fl) of Sjögren's Syndrome

Diffusion of immunoglobulin G from the vascular compartment into the normal rabbit cornea

The concentration of lysozyme and secretory IgA in tears from healthy persons with and without contact lens use

Leu Enkephalin-like immunoreactivity and the innervation of the rat exorbital gland

Stimulation of secretory antibody following oral antigen administration

Prolactin binding and effects on peroxidase release in rat exorbital lacrimal gland

Focal adenitis in salivary and lacrimal glands

Suppression of secretory IgA antibodies in protein malnourished guinea pigs following a chlamydial eye and vaginal infection

Effect of age, malnutrition and renutrition on free secretory component and IgA in secretions

Interactions between the neuroendocrine and immune systems: Common hormones and receptors

Secretory immunology in the mammary gland

Hormonal induction of the secretory immune system in the mammary gland

Quantitation of immunoglobulins in mouse tears using enzyme-linked immunosorbent assay (ELISA)

Clinical diagnosis of the dry eye

Immunohistochemical study of the local inflammatory response to chlamydial ocular infection

Lacrimal Gland, Tear Film and Dry Eye Syndromes: Basic Science and Clininal Relevance

The immunoarchitecture of the normal human lacrimal gland. Relevancy for understanding pathologic conditions

Sequential antibody changes following ulcerative herpetic keratitis

Sequential analysis of antibody responses in serum, aqueous humor and tear film during latent and induced recurrent HSV infections

Sex hormone, glucocorticoid, and cytokine regulation of mucosal immunity: Hormonal influences on antibody levels and antigen presentation in the female genital tract

Enteric neuroimmune interactions

Untoward effects associated with practolol administration: Oculomucocutaneous syndrome

Improvement of tear lysosomal enzyme levels after treatment with bone marrow transplantation in a patient with Icell disease

Complement in tears from normal humans

Tear IgE in allergic conjunctival disorders

Proteins in tears from healthy and diseased eyes

Quantitative Bestimmung der Antiproteinasen in der menschlichen Tränenflüssigkeit

This research review was supported by NIH Grants EY05612 and EY02882.