**3. Outline pathogenesis**

The pathogenesis of the disease is not entirely clear and factors responsible for its development are still being sought. It is recognized that environmental or endogenous antigens trigger an inflammatory response in susceptible individuals. Among the environmental factors, several viral infections are considered as primary pSS cause: Epstein-Barr virus (EBV), human T-cell lymphotrophic virus type-1 (HTLV-1), cytomegalovirus (CMV), and hepatitis C virus (HCV) [5–7]. These infections may result in the epithelial barrier damage and the release of autoan‐ tigens from the affected epithelial cells. In the case of individual genetic predisposition to pSS, the autoimmune process may develop, involving both mechanisms of innate and adaptive immunity. Genetic factors responsible for the predisposition to pSS development include the presence of HLA-B8, HLA-DW3, HLA-DR3, and DRw52 genes; polymorphism of interferon regulatory factor 5 (IRF 5) gene may also play similar role [1,8]. The release of autoantigens triggers innate immunity through the activation of epithelial (EC) and dendritic cells (DC). DC stimulation promotes interferon I and II pathways; DCs also produce IL-12, which activates natural killer cells (NKCs) and stimulates Th1 cells. Both NKC and Th1 cells secrete interferon gamma (INF-γ), responsible for the tissue damage and stimulating the secretion of B cell activation factor (BAFF). BAFF is produced by T and B cells—both activated by DC; BAFF production is also strongly stimulated by interferon (IFN)-α, released by pDC (plasmocytoid dendritic cells). Moreover, the activation of innate response by Toll-like receptors (TLR-9, TLR-7) additionally increases the secretion of BAFF. This overproduction of BAFF can cause constant stimulation of B cells through different pathways and causes the loss of self-tolerance by T and B cells, overproduction of immunoglobulins, of autoantibodies (predominantly SS-A, SS-B) in particular, and the formation of germinal centres (GC) in the target organs. The affected tissues (especially the salivary glands) display the overexpression of cytokines such as tumor necrosis factor (TNF), lymphotoxin, CXC, and chemokines (ligand 13, 9, 21). This process can lead to the development of lymphoma. The occurrence of primarily marginal zone B-cell lymphoma (MZBCL) has been observed in about 8% of pSS patients—40-fold frequency of the MZBCL in the healthy population [9,10]. The scheme of pathogenesis of pSS is shown on figure1.

<sup>\*</sup>Triggering factors as viral and bacterial infections, UVA (ultraviolet-A radiation), hormones, genetic predisposition DC-dendritic cell, pDC plasmocytoid DC cell, IFN-γ- interferon gamma, TLRs- Toll-like receptors, IL-12- interleukine 12, TH1-type1 helper cell, BAFF- B cell activating factor, NK-cell natural killer cell

**Figure 1.** Scheme of pathogenesis [1, 5]

a feeling of sand under the eyelids, eye irritation, and red eye caused by a decrease in tear secretion. In pSS, other exocrine glands could be affected—among them: salivary glands, pancreas, vaginal mucous membranes, and glands of gastrointestinal tract or situated in bronchial tree. The patient may complain of dry mouth, dry vagina, and inflammation of the gastric and esophageal reflux. Dry cough may also occur. In the course of pSS interstitial changes in the lungs may occur with a progressive reduction of lung function and a failure of cardiovascular system (in conjunction with the development of right ventricular failure and pulmonary hypertension). Autoimmune inflammatory process may also involve peripheral and central nervous system, including cranial nerves, with symptoms of mixed sensory and motor neuropathy or multiple sclerosis (MS)-like symptoms. In pSS, B lymphocytes (B-cells) play a key role, with their hyperreactivity, leading to the overproduction of autoantibodies. Through the interaction between the cells, stimulation reaches T lymphocytes (T-cells), which are the first to form infiltrates in exocrine glands. The gradual destruction of the exocrine glands by the inflammation and by the autoimmune process causes the above- described

The epidemiology data of dry eye symptom (DES) reveal that it affects from 5 to 35% of the population. Such discrepancy in the assessment of the frequency of the DES occurrence might be the effect of using different dry eye definitions in each of the studies, as well as the research being performed on different ethnic populations. The data given by the Women's Health Study indicate that Hispanics and Asians display greater predisposition to more severe symptoms of dry eye than Caucasians [2]. The incidence of Sjögren's syndrome, in which DES is a dominant symptom, may also be underestimated. There are no accurate records on the prevalence of this disease, with its milder course prone to be undiagnosed [3,4]. It is estimated that pSS occurs in 0.1–3.0% of the general population. The disease is more common for women (female/male ratio 9:1), affecting mainly individuals between the age of 40 and 60, with the

The pathogenesis of the disease is not entirely clear and factors responsible for its development are still being sought. It is recognized that environmental or endogenous antigens trigger an inflammatory response in susceptible individuals. Among the environmental factors, several viral infections are considered as primary pSS cause: Epstein-Barr virus (EBV), human T-cell lymphotrophic virus type-1 (HTLV-1), cytomegalovirus (CMV), and hepatitis C virus (HCV) [5–7]. These infections may result in the epithelial barrier damage and the release of autoan‐ tigens from the affected epithelial cells. In the case of individual genetic predisposition to pSS, the autoimmune process may develop, involving both mechanisms of innate and adaptive immunity. Genetic factors responsible for the predisposition to pSS development include the

disease most frequently occurring around 50 years of age [5].

symptoms [1].

**2. Epidemiology**

150 Advances in Common Eye Infections

**3. Outline pathogenesis**

The symptoms of primary Sjögren's syndrome are not homogenous. The autoimmune process involving the epithelium affects many systems and organs, so its manifestations can be very diverse. Symptoms can be divided into two primary groups: common ones, such as dry eyes and mouth, and less frequent symptoms, such as peripheral neuropathy with legs numbness and weakness—with reduced or without reflexes, dysesthesia, feeling of temperature, and vibration. Neurological symptoms may also indicate the seizure of the autonomic nervous system with cardiac arrhythmias or gastrointestinal motility disorder. In the pSS, trigeminal neuralgia and seizure of various nerves ("multiple mononeuropathy") may also occur. The central nervous system can also be involved in pSS therefore myelitis with weakness of limbs and disturbances of urination may occur. Neurological symptoms can also suggest MS, which leads to misdiagnosis. The types of symptoms in pSS are presented in Table 1.


**Table 1.** Symptoms of pSS

Keratoconjunctivitis sicca (KCS) is the most frequent cause of complaints from the organ of sight of patients with Sjogren's syndrome, although it can be present in a number of other diseases [11]. KCS is caused by a decreased tear production or increased tear film evaporation. It manifests itself with a feeling of dryness— described as a sandy-gritty eye irritation burning, stinging, and feeling of tired eyes. In severe cases, the patients suffer from pain, redness, or even decreased vision. The decreased tear production affects the overall reduction of tear secretin as well as limits the aqueous phase of the tears. The causes of DES and complications associated with KCS are presented in Tables 2 and 3.

Primary Sjogren's syndrome may be associated with other autoimmune diseases. Their simultaneous presence can influence both the course and the prognosis of the disease. The most common coexisting diseases are presented in Table 4.

The initial symptoms of an infection in dry eye syndrome—the eye pain, burning, eye redness —can be associated with symptoms of dryness and aseptic KCS, as well as with an incipi‐ ent infection. However, when the pain and red eye are accompanied by a purulent excretion —a bacterial infection should be suspected. Viral infections primarily cause an eye pain and intense redness. These symptoms may also be associated with general symptoms of infec‐ tions such as muscle pain, fever, and fatigue. The diagnosis and treatment are determined by the result of the ophthalmological examination.


Refractive surgery : laser assisted keratomileusis (LASIK); photorefractive keratoplasty (PRK)

**Table 2.** Keratoconjunctivitis sicca —not only symptom of pSS

The symptoms of primary Sjögren's syndrome are not homogenous. The autoimmune process involving the epithelium affects many systems and organs, so its manifestations can be very diverse. Symptoms can be divided into two primary groups: common ones, such as dry eyes and mouth, and less frequent symptoms, such as peripheral neuropathy with legs numbness and weakness—with reduced or without reflexes, dysesthesia, feeling of temperature, and vibration. Neurological symptoms may also indicate the seizure of the autonomic nervous system with cardiac arrhythmias or gastrointestinal motility disorder. In the pSS, trigeminal neuralgia and seizure of various nerves ("multiple mononeuropathy") may also occur. The central nervous system can also be involved in pSS therefore myelitis with weakness of limbs and disturbances of urination may occur. Neurological symptoms can also suggest MS, which

leads to misdiagnosis. The types of symptoms in pSS are presented in Table 1.

xerophtalmia xerostomia

dental caries artralgia

myalgia fatigue

depression anxiety

troubles with swallowing

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arthritis (non-erosive)

general weakness weight loss fever

Reynaud's phenomenon

**Table 1.** Symptoms of pSS

**Common symptoms Less common symptoms/organ involvement**

intestinal like disease (ILD)

dysphagia, gastrointestinal reflux

distal renal tubular acidosis (RTA type 1)

symptoms of PBC (primary billary cirrhosis) and AIH

bronchitis

pericarditis

vasculitis

Keratoconjunctivitis sicca (KCS) is the most frequent cause of complaints from the organ of sight of patients with Sjogren's syndrome, although it can be present in a number of other diseases [11]. KCS is caused by a decreased tear production or increased tear film evaporation. It manifests itself with a feeling of dryness— described as a sandy-gritty eye irritation burning, stinging, and feeling of tired eyes. In severe cases, the patients suffer from pain, redness, or even decreased vision. The decreased tear production affects the overall reduction of tear secretin as well as limits the aqueous phase of the tears. The causes of DES and

complications associated with KCS are presented in Tables 2 and 3.

chronic gastritis

(autoimmune hepatitis)

pulmonary hypertension celiac-like diseas

nepritis/glomerulonephritis chronic renal insufficiency

peripheral polyneuropathy, cranial neuropathy, mononeuritis multiplex sensorineural hearing loss SM-like syndrome


**Table 3.** Eye complications associated with KCS

#### **The diseases coexisting with p SS**

Autoimmune Thyroid Disease (AITD) - Haschimoto disease Intestinal Lung Disease (ILD) Primary Billary Cirrhosis (PBC) Autoimmune hepatitis (AIH) Cryoglobulinemia Autoimmune pancreatitis (AIP) Distal renal tubular acidosis (RTA) Sclerosis-multiplex like syndrome

**Table 4.** The diseases coexisting with p SS

## **4. Risk of eye infections in KCS**

The conjunctivitis and changes in the cornea in the pSS are aseptic, yet coexisting infections that may play a part in the development and course of the pSS, KCS in particular. Due to the large differences in estimating the incidence and prevalence of dry eye syndrome (from 5 to 35%) and due to differences in the frequency of recognition of Sjögren's syndrome, it is difficult to accurately estimate the rate of incidence of sicca syndrome associated with eye infections. However, impaired humidification of the eye and related development of KCS undoubtedly significantly increase the risk of bacterial contamination, compared with the normal popula‐ tion.

Among viral infections, EBV plays an important role, which is not limited to the abovementioned impact on the immune system and lymphocytes. The EBV may be a separate, independent cause of the dry eye syndrome because the infection affects mucosal surfaces and lymphoid tissues. The EBV presence persists in ocular surface epithelia, following primary infection and may cause dacryoadenitis, which leads to abnormal tear secretion [12,13]. Although no direct link between the occurrence of KCS and EBV infection has been established, the influence of EBV on patient's immune status could cause the development of symptoms of dryness. Apart from EBV, other viral infections, which may contribute to the occurrence of KCS and clinical picture of Sjogren's disease, include in particular HCV, human T-cell lymphotropic virus (HTLV), Human (HSV-1), and HIV [7,14]. HCV infection may be respon‐ sible for the incidence of ocular symptoms in the course of pSS, such as KCS retinopathy, scleritis, and keratitis. In HSV-1 infection, besides KCS, keratitis, blepharitis, conjunctivitis, uveitis, and retinitis may develop [15]. Viral agents involved in pathogenesis of pSS, EBV in particular, can be simultaneously responsible for causing KCS, conjunctivitis, and reducing resistance of the corneal epithelium.

Although viruses play a significant role in the pathogenesis of pSS, the importance of bacterial co-infections, e.g., *Chlamydia pneumonia* in the course of pSS should not be underestimated [16]. It is known that a tear film has antimicrobial properties, whereas the normal ocular surface contains bacterial flora, including *Staphylococcus epidermidis*, *S. aureus*, and diphteroides (e.g.,

*Corynebacterium diphtheriae* and *Propionibacterium acnes*). However, in patients with DESs and treated with immunosuppressants, such therapy, along with dryness and cornea damage, results in increased susceptibility to common bacterial infections. In the diagnosis of ocular symptoms, bacterial keratitis should come under consideration. This may more likely be caused by *S. aureus*, *Haemophilus influenzae*, *Streptococcus pneumoniae* and, in the case of use of contact lenses, more often *Pseudomonas aeruginosa*. Hori et al. [17] showed that infections with bacteria resistant to fluoroquinolones (*Staph.* sp. *Staph*. *aureus*) are more common in patients with dry eye syndrome, although among dry eye patients, regardless of use of punctual plugs or topical steroids, there were no differences in bacteria isolated from conjunctiva.

**The diseases coexisting with p SS**

Intestinal Lung Disease (ILD) Primary Billary Cirrhosis (PBC) Autoimmune hepatitis (AIH)

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Autoimmune pancreatitis (AIP) Distal renal tubular acidosis (RTA) Sclerosis-multiplex like syndrome

**Table 4.** The diseases coexisting with p SS

**4. Risk of eye infections in KCS**

resistance of the corneal epithelium.

The conjunctivitis and changes in the cornea in the pSS are aseptic, yet coexisting infections that may play a part in the development and course of the pSS, KCS in particular. Due to the large differences in estimating the incidence and prevalence of dry eye syndrome (from 5 to 35%) and due to differences in the frequency of recognition of Sjögren's syndrome, it is difficult to accurately estimate the rate of incidence of sicca syndrome associated with eye infections. However, impaired humidification of the eye and related development of KCS undoubtedly significantly increase the risk of bacterial contamination, compared with the normal popula‐

Among viral infections, EBV plays an important role, which is not limited to the abovementioned impact on the immune system and lymphocytes. The EBV may be a separate, independent cause of the dry eye syndrome because the infection affects mucosal surfaces and lymphoid tissues. The EBV presence persists in ocular surface epithelia, following primary infection and may cause dacryoadenitis, which leads to abnormal tear secretion [12,13]. Although no direct link between the occurrence of KCS and EBV infection has been established, the influence of EBV on patient's immune status could cause the development of symptoms of dryness. Apart from EBV, other viral infections, which may contribute to the occurrence of KCS and clinical picture of Sjogren's disease, include in particular HCV, human T-cell lymphotropic virus (HTLV), Human (HSV-1), and HIV [7,14]. HCV infection may be respon‐ sible for the incidence of ocular symptoms in the course of pSS, such as KCS retinopathy, scleritis, and keratitis. In HSV-1 infection, besides KCS, keratitis, blepharitis, conjunctivitis, uveitis, and retinitis may develop [15]. Viral agents involved in pathogenesis of pSS, EBV in particular, can be simultaneously responsible for causing KCS, conjunctivitis, and reducing

Although viruses play a significant role in the pathogenesis of pSS, the importance of bacterial co-infections, e.g., *Chlamydia pneumonia* in the course of pSS should not be underestimated [16]. It is known that a tear film has antimicrobial properties, whereas the normal ocular surface contains bacterial flora, including *Staphylococcus epidermidis*, *S. aureus*, and diphteroides (e.g.,

Cryoglobulinemia

tion.

Autoimmune Thyroid Disease (AITD) - Haschimoto disease

In the diagnosis of pSS, it must also be considered that some of the commonly known infections, such as HIV, tuberculosis, leprosy, spirochetes, hepatitis A, B, or C, parvovirus B19, Dengue fever, malaria, subacute bacterial endocarditis, and HIV can mimic Sjögren's syndrome with symptoms of eye dryness. Prognosis for the infection occurring in the course of a dry eye in Sjögren's syndrome is more serious compared to the infection cases with no additional risk factors present. This results from the, pre-existing in Sjögren's syndrome, surface damage and use of immunosuppressive therapy in this disease. Therefore, patients with Sjögren's syn‐ drome and a coexisting bacterial infection of the eye belong to a group in which immediate antibiotic therapy should be considered.
