Ординатура / Офтальмология / Английские материалы / Dry Eye and Ocular Surface Disorders_Pflugfelder, Beuerman, Elliot Stern_2004

Third, recently discovered antibodies against muscarinic receptors may interfere with the muscarinic M3 receptor or humoral-mediated toxicity [42–45].

Fourth, acinar/ductal cells must be spatially oriented correctly relative to their matrix for optimal function. Release of metalloproteinases from inflammatory cells and from residual ductal/acinar/stromal cells in response to cytokines can lead to destruction of the matrix, compromising correct orientation and optimal function of acinar/ductal cells.

Interactions with the extracellular matrix are also important for normal homeostasis, regeneration, and function of epithelial cells in salivary and lacrimal glands. Differentiation of salivary gland duct cells into acinar cells (including the morphological appearance of acinar structures and induction of acinar proteins such as amylase) depends on interaction of acinar cell membrane integrins with their ligands in the cell matrix [46]. Signals resulting from interactions with laminin, collagen IV, vitronectin, and fibronectin contribute to the proliferation and differentiation of salivary gland ductal epithelial cells [47]. Further, their responses to hormonal signals, cytokines, and growth factors depend on cell–matrix interactions. For example, stimulation of glandular ductal cells by interferon-γ in the presence of extracellular matrix leads to differentiation and induction of HLA-DR; however, in the absence of matrix, similar stimulation leads to apoptosis [48]. In lacrimal gland cells grown in vitro, cell–matrix interactions are necessary for secretory responses to muscarinic M3 agonists and are further augmented by novel nonmatrix proteins such as BM180 [49]. The requirement for cell–matrix interactions by salivary and lacrimal gland epithelial cells appears analogous to the requirement of mammary gland cells in lactating rats for integrin–matrix interactions in order to respond to hormones, growth factors, and neural signals. If the cell–matrix signals are not intact, rat mammary epithelial cells are triggered into apoptosis pathways [50]. The extracellular matrix in SSaffected glands may be modified by collagenases [51] and by other metalloproteinases [52].

VII. PATHOGENESIS OF SS: LOSS OF TOLERANCE TO SELF ANTIGENS

The correlation of SS with antibodies against nuclear antigens SS-A and SS-B has always been puzzling, since these antigens are found in all nucleated cells. SS patients provide an opportunity to study the factors necessary for the failure of tolerance to a cellular antigen in an organ-specific disease. The autoantigens SS-A and SS-B may be presented to CD4+ T cells by inflamed epithelial cells (but not by normal epithelial cells) as a result of upregulation of HLA-DR, HLADM, and invariant-chain molecules [53]. Antigen presentation by epithelial cells requires co-stimulation that can be provided by cell adhesion molecules such as

ICAM [54]. Each of the factors necessary for antigen presentation by epithelial cells has been detected in SS-affected glands [55].

It has been proposed that SS-A and SS-B antigens may escape the normal tolerance processes by acting as cryptic antigens, i.e., binding with relatively low affinity to self MHC molecules in the thymus and thus avoiding negative selection [56]. SS-A and SS-B antigens are found in the blebs of apoptotic cells and are not proteolyzed during apoptosis [57,58], in contrast to other autoantigens including fodrin (discussed below), poly-ADP-ribose polymerase (PARP), or topoisomerase. It is possible that increased cell death (either apoptotic or necrotic), or aberrant clearance and processing of antigens from dying cells, may lead to accumulation of potentially immunogenic forms of autoantigens [59]. These could, under the appropriate genetic background, amplify and maintain T-cell- dependent responses by autoimmunization processes. Alternative mechanisms that might expose immunocryptic epitopes in autoantigens include structural alterations caused by mutations or abnormal protein–protein interactions during aberrant cell death, and interactions with toxins and chemical or foreign antigens derived from viruses.

The SS-A 52-kDa antigen has an alternatively spliced form that is expressed in the fetal heart from 14 to 18 weeks of development [60]. It has been proposed as target for maternal anti-52-kDa antibodies that cross the placenta [61]. However, mothers who give birth to babies with heart block exhibit a pattern of antibody reactivity to antigenic epitopes on SS-A similar to that of SS mothers having normal infants [62,63]. An altered form of SS-B has also been reported [64] and antibodies against SS-B (but not SS-A) cross-react with laminin [65], leading to a proposal that anti-SS B antibody may be a cause for congenital heart block [66]. Complete heart block was reported to develop in an adult SS patient and was attributed to anti-SS A antibodies [67]. The initial pathogenetic epitope(s) for these antigens may be difficult to elucidate due to antigenic spreading from the original T-cell epitope to additional sites [68].

Apoptotic cleavage of certain cellular proteins might reveal cryptic epitopes that can potentially stimulate an immunogenic response [57]. For example, antibodies against a cleaved (120-kDa) form of fodrin have been detected in the sera of patients with Sjögren’s syndrome [69]. Fodrin (also known as brain spectrin) is a 250-kDa membrane skeletal protein found in many tissues that serves to anchor other proteins including tubulin, actin, ankyrin, and E-cadherins, as well as phospholipids [70,71]. Fodrin is cleaved into 150-kDa and 120-kDa forms through apoptotic cleavage by calpain and caspase proteases [72,73] and then is redistributed in the cytoplasm [74]. Although T-cell clones reactive against 120-kDa fodrin were detected in a mouse model of SS [69], it remains unclear whether the reactivity to the fodrin 120-kDa fragment is a primary event in SS pathogenesis or even if antibodies to the fodrin 120-kDa protein are specific to Sjögren’s syndrome (unpublished observations). Antibodies to fodrin

are found at low titer in normal (non-SS) subjects, apparently to promote opsonization and removal of cell debris [75], and are found in increased amounts after cellular injury such as occurs in stroke and in Alzheimer’s disease [76].

Rheumatologists often place great importance on the sensitivity and specificity of autoantibodies in progressive systemic sclerosis and SS. Although these markers have specificity, they lack precise sensitivity in that patients with detectable characteristic autoantibodies may not develop clinical features of either SS or progressive systemic sclerosis [77]. Arnett has pointed out that certain class II antigens of the major histocompatibility complex (MHC), including HLA-DR1, DR2, and DR5, are associated with specific autoantibodies including anticentromere, antitopoisomerase I, and a variety of antinucleolar antibodies [78]. These specificities show little overlap, and each is a marker for certain clinical features of systemic sclerosis. For example, anticentromere antibodies are strongly associated with HLA-DQB1*0501 (DQ5), DQB1*0301 (DQ7), and other DQB1 alleles possessing a glycine or tyrosine residue in position 26 of the outermost domain. Antitopoisomerase I antibodies occur in progressive systemic sclerosis patients with HLA-DQB1*0301 (DQ7), DQB1*0302 (DQ8), DQB1*0601 (DQ6 in Japanese), and other DQB1 alleles possessing a tyrosine residue in position 30. In comparison, SS patients with antibodies against Sjögren’s SS-A and SS-B are associated with HLA-DR3 and linked DQ alleles in Caucasians [79–82].

VIII. INFECTIOUS AGENTS AS COFACTORS IN SS

Evidence to suggest an infectious agent as a cofactor in SS remains intriguing but unproven. Elevated antibody titers in SS patients have been reported for a variety of Epstein-Barr virus antigens, including BHRF1 (the viral homolog of bcl-2) and BMRF1 (an Epstein-Barr virus DNA-binding protein) [83]. Epstein-Barr virus genomes in SS-affected salivary and lacrimal glands have been detected by in-situ hybridization [84–86], by polymerase chain reaction methods [87,88], and by culture of salivary gland tissue in SCID mice [89]. However, the frequency of Epstein-Barr virus-infected cells is low (approximately 1 infected cell per 106 uninfected cells, and some studies failed to detect Epstein-Barr virus genomes in SS salivary gland biopsies [90].

An endogenous retrovirus (retrovirus 3) expresses in fetal heart from 11 to 16 weeks and could be a possible target for immune reactions leading to congenital heart block [91]. A novel retrovirus (termed retrovirus 5) was originally isolated from a patient with rheumatoid arthritis plus SS [92], but subsequent studies have not detected this retrovirus in a significant proportion of SS patients. Past studies that detected antibodies in SS patients to retroviral gag proteins were probably detecting a cross-reacting cellular protein [93,94].

Salivary gland tissues from Caucasian SS patients were negative for HTLV-1 tax genes by DNA methods [95], negating earlier findings of reactivity with a monoclonal anti-HTLV-1 antibody [96]. However, genomic sequences homologous to HTLV-1 tax have been found in SS-affected tissues in a subset of Japanese SS patients [97]. Although hepatitis C patients are considered as distinct

from SS in the San Diego classification, these patients may provide clues to environmental agents responsible for SS, since their minor salivary gland biopsies may contain lymphoid infiltrates [98], and animals with a hepatitis C transgene develop sialidenitis [99].

IX. SYSTEMIC MANIFESTATIONS AND MEDICATIONS IN SJÖGREN’S PATIENTS

Since ophthalmologists participate in the overall health care of SS patients, it is worthwhile to review the systemic manifestations of SS and medications used for treatment by rheumatologists. The extraglandular manifestations of SS are summarized in Table 2. The overall approach to systemic therapy in the patient with Sjögren’s syndrome is similar to that in the systemic lupus erythematosus patient. (Fig. 4). Disease manifestations are subdivided into nonvisceral (arthralgias, myalgias, skin, fatigue) and visceral (lung, heart, kidney, brain, peripheral nervous system). Nonvisceral manifestations are generally treated with salicylates, nonsteroidal agents, and often hydroxychloroquine. Physicians should be aware that some SS patients may experience difficulty in swallowing pills because of decreased salivary production, leading to pills sticking in the mid-esophagus with resultant erosion of the mucosa. Little improvement of salivary or lacrimal flow rates have been observed with NSAID therapy, although some increase in tearing and salivation may occur with administration of systemic corticosteroids. Indomethacin is the only NSAID readily available as a suppository for patients with difficulty swallowing tablets. In a pilot study, flurbiprofen decreased periodontal inflammation and resultant gum disease [100].

Among the “slow-acting” drugs, antimalarials such as hydroxychloroquine have proven useful in decreasing arthralgias, myalgias, and lymphadenopathy in SS patients [101,102], similar to their benefits in some systemic lupus erythematosus patients [103]. We have used hydroxychloroquine (6–8 mg/kg/day) in SS patients exhibiting elevated erythrocyte sedimentation rate and polyclonal hyperglobulinemia, since these laboratory abnormalities suggest that symptoms of arthralgia and myalgia may have an “inflammatory” cause. In a European study [104], hydroxychloroquine improved the erythrocyte sedimentation rate but did not increase tear flow volumes. It should be noted that the drug benefit observed for SS patients in European and U.S. clinical studies is strongly influenced by the very different inclusion criteria employed for diagnosis of SS (described above). When taken at the proper dose (6–8 mg/kg/day), hydroxychloroquine has a very good safety record, although there remains a remote possibility (probably less than 1/1000) of macular toxicity in the eye [105]. For this reason, periodic eye checks (generally every 6–12 months) are recommended so that treatment can be discontinued at any

For life-threatening SS complications, cyclophosphamide is occasionally required. The increased frequency of lymphoma in SS patients [110] requires caution in the use of cyclophosphamide and suggests “pulse therapy” rather than daily administration.

X.OTHER AUTOIMMUNE DISEASES ASSOCIATED WITH LACRIMAL KERATOCONJUNCTIVITIS

The above sections have dealt in detail with primary SS. The pathology of glandular infiltrates and presumed mechanism of pathogenesis seem similar in lacrimal keratoconjunctivitis associated with systemic lupus and rheumatoid arthritis. However, salivary gland biopsies and presumably the pathogenesis of glandular dysfunction in progressive systemic scleritis appear different in terms of genetic predisposition (HLA-DR5 versus HLA-DR3) and autoantibody profiles. Of particular interest, recent studies have suggested similarity of glandular changes in progressive systemic sclerosis to those in graft-versus-host disease. Indeed, studies for microchimerism (i.e., detection of fetal DNA in a lip biopsy from a mother with sicca symptoms) have shown a much higher frequency of retained fetal DNA in progressive systemic sclerosis than in primary SS or in rheumatoid arthritisor systemic lupus erythematosus-associated SS.

In most progressive systemic sclerosis patients, the pattern of infiltrate in the salivary gland differs from that seen in SS. In one study [111], 33 patients with scleroderma, xerostomia, and xerophthalmia underwent biopsy of 3–5 labial salivary glands. Histological and ultrastructural studies were systematically performed on these specimens. In 27 patients, sclerosis was the main feature, with an active fibrosis, numerous secreting fibroblasts, and degranulating mast cells. This fibrosis was located around capillaries, excretory ducts, and the acini, progressively destroying them. Lymphocytes were not very numerous and were scattered in the fibrosis, but were not grouped around the ducts. Five biopsies showed similar fibrotic lesions, but they also had numerous lymphocytes grouped in foci around excretory ducts as in primary Sjögren’s syndrome. It was concluded that in scleroderma, xerostomia and xerophthalmia can be related either to a pure sclerotic process or to a “common” secondary Sjögren’s syndrome.

XI. INFECTIOUS CONDITIONS MIMICKING SJÖGREN’S SYNDROME

Although this chapter is directed to systemic autoimmune disease and the ocular surface, certain chronic infections may mimic autoimmune disease or manifest as autoimmune responses. The original description of keratoconjunctivitis sicca by

Mickulicz in 1892 may been a case of tuberculosis with glandular infiltrates due to scrofula-like manifestations [112–114]. Recently, the increased use of strong biological agents such as TNF inhibitors has been associated with reactivation of tuberculosis, often in extrapulmonary locations. Other infectious causes that may mimic primary SS (including a positive antinuclear antibody) include hepatitis C, syphilis, HIV (AIDS), and HTLV-1/2 infections [115]. Biopsies (as well as serologies for infectious agents or angiotensin-converting enzyme) can help in differential diagnosis.

XII. SUMMARY

1.Sjögren’s syndrome is a systemic autoimmune disease affecting lacrimal and salivary glands.

2.Pathological findings include infiltration of lymphocytes, a decrease in the rate of lymphocyte apoptosis, destruction of some glandular tissue, and reduced function of the remainder, and loss of immunological tolerance to self-antigens SS-A and SS-B.

3.Hydroxychloroquinolone, salicylates, and corticosteroids with sparing agents are used for systemic treatment of Sjögren’s syndrome. Ophthalmic cyclosporine emulsion shows promise for topical treatment of ocular signs and symptoms.

4.Similar pathologies are seen for lacrimal keratoconjunctivitis associated with systemic lupus or rheumatoid arthritis, although with different autoantibody profiles.

5.In progressive systemic sclerosis, the pathogenesis of glandular dysfunction differs slightly from that of Sjögren’s syndrome, with active fibrosis and fewer infiltrating lymphocytes.

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