**1. Introduction**

Epithelial tissue constitutes a barrier between organs and the environment. The epithelium lines external surfaces of internal organs and inner surfaces of the walls of blood vessels. It is also a tissue that exocrine and endocrine glands consist of.

As they separate the organism from the outer environment, the epithelial structures form the first line of defense against external factors but, at the same time, an entry gate for them influencing the development of the body's microbiome and autoimmune diseases, which are associated with the disorders of microbiome composition (dysbiosis) [1, 2]. The epithelium, also as a target for viruses, interacts with the invading pathogens and is actively involved in immune response, whose course depends on particular genetic and epigenetic conditions.

Epithelial cells are often subject to apoptosis, which makes them an important source of autoantigens. Moreover, in many autoimmune diseases, epithelial cells are damaged, which leads to further release and exposition of autoantigens, with the epithelium being subject to the immune response. For example, thyrocytes are responsible for providing the main immunogens (e.g., thyroglobulin, thyroid peroxidase, TSH receptor) in autoimmune thyroiditis [3], synoviocytes are a source of cyclic citrullinated peptides in rheumatoid arthritis, and oligodendrocytes in multiple sclerosis or pancreatic endocrine glandular epithelium (beta-cells) in type 1 diabetes are a source among others of proinsulin or glutamic acid decarboxylase [4]. Hence the suggestion puts forward that autoimmune diseases could be otherwise classified as the autoimmune inflammation of the epithelium [5]. However, there are autoimmune diseases which, due to their effect on the exocrine glands, are particularly associated with epithelial damage and an autoimmune process, the primary Sjögren's syndrome (pSS) among them. The primary Sjögren's syndrome is an autoimmune disease in which the exocrine glandular epithelium is a main source of autoantigens—such as Ro/SS-A and La/SS-B ribonucleoproteins [6]. Quite often pSS may coexist with another autoimmune disorder—a primary biliary cholangitis (PBC). In PBC the epithelium (biliary epithelial cells of small bile duct) is the starting point of the autoimmune process [7]. The pathogenesis of both diseases is similar, with the significant role of epithelial cell apoptosis. **Table 1** presents the immunological and main clinical features of pSS and PBC.

The Sjögren's syndrome is an example of the development of an autoimmune epithelitis and consequences of such a process. The impact of environmental factors on the genetically susceptible subject is vital for the development of pSS. There are multiple genes (e.g., HLA-B8, HLA-Dw3, HLA-DR3, and DRw52) responsible for the individual's susceptibility to the pSS development. Particular attention has been paid to the genes for interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4 (STAT4) in the type I interferon (IFN) system, and B lymphocyte kinase (BLK) involved in B-cell activation, which are considered as risk loci in pSS development [10]. Additionally it has been recently revealed that also epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs, may influence expression of the involved genes in autoimmune diseases, including pSS [11].

The pSS development is associated with the infection with viruses, which mainly target B cells or display tropism to lacrimal and salivary glands. Such a strong association has been confirmed in case of the Epstein–Barr virus, as well as other viruses: *Cytomegalovirus*, herpes simplex virus, and hepatitis C virus [12].


**5**

damage are presented.

*Introductory Chapter: Autoimmune Epithelitis - Discussion about Sjögren's Syndrome…*

The epithelitis in pSS starts with an influence of certain external factors, such as viruses, rare bacteria, or ultraviolet radiation on epithelial cells. This leads to cell apoptosis and expression of autoantigens (SS-A and SS-B ribonucleoproteins), which are presented to autoreactive T cells. As it is recently highlighted in the literature, endothelial cells have, therefore, antigen presentation properties, although this is not their main feature, as it is the case with antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. Also salivary gland epithelial cells (SGEC) express MHC class I and MHC class II (HLA-DR) molecules and functional co-stimulator B7.1 (CD80) and B7.2 (CD86) molecules and may transmit signals to T

Other processes responsible for the development at this stage include the activation of the innate immune system, with the activation of Toll-like receptors (especially TLR3, TLR7, TLR9) and the production of interferon alpha (IFN-α) by plasma dendritic cells (pDCs) stimulating epithelial cells, dendritic cells, and neutrophils for the production of the B-cell stimulating factor and APRIL [15]. There are infiltrates in the exocrine glands initially composed mainly of T cells, whereas the activation of B lymphocytes by growth factors, such as BAFF and APRIL, results in hypergammaglobulinemia and the production of anti–SS-A and anti–SS-B autoantibodies as a secondary immune response. B cells and macrophages also produce

The disease starts with the epithelial inflammation and impaired function of the exocrine glands manifesting themselves, for example, in the enlargement of the glands and reduction of the secretion of saliva or tears. It evolves then into the phase of systemic disease with the organ involvement and general manifestations (fever, weight loss, fatigue). Although the Sjögren's syndrome is most often associated with the functional impairment of lacrimal and salivary glands (symptoms included in the current criteria of diagnosis [16]), it also affects glands of the digestive system, pancreas, liver, gall bladder, respiratory glands, and even sweat glands. Their function is impaired through the reduction of secretion of the aqueous phase and changes in density of the secretion, leading to the emergence of various clinical features: from the feeling of mouth or eye dryness, through recurrent cholelithiasis

The consequence of the involvement of epithelia in pSS and its damage is the emergence of the way of entry for pathogens in the alimentary tract (from the oral cavity to the rectum), as well as in the respiratory tract. In the case of imbalance of the microbiome and the occurrence of dysbiosis, also commensals, which become potential pathogens in such circumstances, may cross the damaged epithelial barrier. Proteins from the epithelial cells of the mouth, intestines, and skin, as well as bacterial (commensal) proteins, may initiate an immune response to Ro60 (theory of Ro60-reactive B cells) and activation of T cells, as consequence of molecular mimicry [17]. The role of fungal (*Candida*) infections in pSS development was also studied, revealing there was no significant relationship between *Candida albicans* and the rate and amount of salivary secretion, although such relationship was found

in pathogenic species, such as *C. tropicalis*, *C. glabrata*, and *C. krusei* [18].

In **Table 2** the main clinical manifestations of pSS resulting from the epithelial

What is particularly important, continuous stimulation of B lymphocytes by activating agents, primarily BAFF and APRIL, causes germinal center (GC) formation and the formation of secondary lymphoid tissue, which in turn leads to the increased risk of lymphoma development. The most common lymphoma emerging in the course of pSS is the marginal zone B-cell lymphoma (MZBCL), the mucosa-associated lymphoid tissue (MALT) type being predominant. The diffuse large B-cell lymphoma (DLBCL), rare T-cell lymphoma, or NK-cell lymphoma are

proinflammatory cytokines, chemokines, and adhesion molecules.

and nephrolithiasis, to stones in the salivary glands.

*DOI: http://dx.doi.org/10.5772/intechopen.86258*

lymphocytes as nonprofessional APCs [13, 14].

#### **Table 1.**

*The immunological and main clinical features of pSS and PBC [8, 9].*

*Introductory Chapter: Autoimmune Epithelitis - Discussion about Sjögren's Syndrome… DOI: http://dx.doi.org/10.5772/intechopen.86258*

The epithelitis in pSS starts with an influence of certain external factors, such as viruses, rare bacteria, or ultraviolet radiation on epithelial cells. This leads to cell apoptosis and expression of autoantigens (SS-A and SS-B ribonucleoproteins), which are presented to autoreactive T cells. As it is recently highlighted in the literature, endothelial cells have, therefore, antigen presentation properties, although this is not their main feature, as it is the case with antigen-presenting cells (APCs), such as dendritic cells, macrophages, and B cells. Also salivary gland epithelial cells (SGEC) express MHC class I and MHC class II (HLA-DR) molecules and functional co-stimulator B7.1 (CD80) and B7.2 (CD86) molecules and may transmit signals to T lymphocytes as nonprofessional APCs [13, 14].

Other processes responsible for the development at this stage include the activation of the innate immune system, with the activation of Toll-like receptors (especially TLR3, TLR7, TLR9) and the production of interferon alpha (IFN-α) by plasma dendritic cells (pDCs) stimulating epithelial cells, dendritic cells, and neutrophils for the production of the B-cell stimulating factor and APRIL [15]. There are infiltrates in the exocrine glands initially composed mainly of T cells, whereas the activation of B lymphocytes by growth factors, such as BAFF and APRIL, results in hypergammaglobulinemia and the production of anti–SS-A and anti–SS-B autoantibodies as a secondary immune response. B cells and macrophages also produce proinflammatory cytokines, chemokines, and adhesion molecules.

The disease starts with the epithelial inflammation and impaired function of the exocrine glands manifesting themselves, for example, in the enlargement of the glands and reduction of the secretion of saliva or tears. It evolves then into the phase of systemic disease with the organ involvement and general manifestations (fever, weight loss, fatigue). Although the Sjögren's syndrome is most often associated with the functional impairment of lacrimal and salivary glands (symptoms included in the current criteria of diagnosis [16]), it also affects glands of the digestive system, pancreas, liver, gall bladder, respiratory glands, and even sweat glands. Their function is impaired through the reduction of secretion of the aqueous phase and changes in density of the secretion, leading to the emergence of various clinical features: from the feeling of mouth or eye dryness, through recurrent cholelithiasis and nephrolithiasis, to stones in the salivary glands.

The consequence of the involvement of epithelia in pSS and its damage is the emergence of the way of entry for pathogens in the alimentary tract (from the oral cavity to the rectum), as well as in the respiratory tract. In the case of imbalance of the microbiome and the occurrence of dysbiosis, also commensals, which become potential pathogens in such circumstances, may cross the damaged epithelial barrier. Proteins from the epithelial cells of the mouth, intestines, and skin, as well as bacterial (commensal) proteins, may initiate an immune response to Ro60 (theory of Ro60-reactive B cells) and activation of T cells, as consequence of molecular mimicry [17]. The role of fungal (*Candida*) infections in pSS development was also studied, revealing there was no significant relationship between *Candida albicans* and the rate and amount of salivary secretion, although such relationship was found in pathogenic species, such as *C. tropicalis*, *C. glabrata*, and *C. krusei* [18].

In **Table 2** the main clinical manifestations of pSS resulting from the epithelial damage are presented.

What is particularly important, continuous stimulation of B lymphocytes by activating agents, primarily BAFF and APRIL, causes germinal center (GC) formation and the formation of secondary lymphoid tissue, which in turn leads to the increased risk of lymphoma development. The most common lymphoma emerging in the course of pSS is the marginal zone B-cell lymphoma (MZBCL), the mucosa-associated lymphoid tissue (MALT) type being predominant. The diffuse large B-cell lymphoma (DLBCL), rare T-cell lymphoma, or NK-cell lymphoma are

*Chronic Autoimmune Epithelitis - sjogren's Syndrome and Other Autoimmune Diseases...*

sion of the involved genes in autoimmune diseases, including pSS [11].

**Primary Sjögren's syndrome Primary biliary cholangitis**

Chronic autoimmune disease Chronic autoimmune disease

Exocrine glandular epithelium Biliary epithelial cells

Woman > men Woman > men Fifth decade of life Fifth decade of life

Exocrine glands Liver

Predominance of CD4+ infiltrate around the

Primary/secondary to other autoimmune

Infectious initiating factors: *Herpesviridae* particularly Epstein–Barr virus, CMV, herpes

**EULAR/ACR criteria for diagnosis (2016)** 1.Labial salivary gland biopsy (focal lymphocytic sialadenitis) FS ≥ 1 3 points 2.Anti–SS-A/Ro positivity 3 points 3.OSS ≥5 (or van Bijsterveld score ≥ 4 1

Schirmer's test ≤5 mm/5 min 1 point 4.Unstimulated salivary flow ≤0.1 mL/min

*The immunological and main clinical features of pSS and PBC [8, 9].*

Symptoms of eye and mouth dryness Extraglandular manifestations (organ impairment, vasculitis, neuropathy)

salivary duct

diseases

point

1 point Diagnosis ≥4 point Exclusions:

*ULN, upper limit of normal.*

The Sjögren's syndrome is an example of the development of an autoimmune epithelitis and consequences of such a process. The impact of environmental factors on the genetically susceptible subject is vital for the development of pSS. There are multiple genes (e.g., HLA-B8, HLA-Dw3, HLA-DR3, and DRw52) responsible for the individual's susceptibility to the pSS development. Particular attention has been paid to the genes for interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4 (STAT4) in the type I interferon (IFN) system, and B lymphocyte kinase (BLK) involved in B-cell activation, which are considered as risk loci in pSS development [10]. Additionally it has been recently revealed that also epigenetic mechanisms, such as DNA methylation, histone modifications, and noncoding RNAs, may influence expres-

The pSS development is associated with the infection with viruses, which mainly

the bile duct

*pylori* EBV

hepatosplenomegaly

**Diagnostic criteria for PBC**

2.Positivity for AMA antibodies

Granuloma and predominance of CD4+ infiltrate around

Primary/secondary to other autoimmune diseases

Fatigue, pruritus, skin hyperpigmentation,

encephalopathy, upper digestive bleeding)

Infectious initiating factors: *Escherichia coli*, *Helicobacter* 

Liver cirrhosis (late stage with ascites, jaundice, hepatic

1.Elevated alkaline level of >2× ULN or elevated gamma-glutamyltransferase level of >5× ULN

3.Chronic granulomatous cholangitis at liver biopsy Diagnosis presence of at least two of the three criteria

target B cells or display tropism to lacrimal and salivary glands. Such a strong association has been confirmed in case of the Epstein–Barr virus, as well as other

viruses: *Cytomegalovirus*, herpes simplex virus, and hepatitis C virus [12].

Anti–SS-A and anti–SS-B antibodies Anti-mitochondrial antibodies (AMA) ANA antibodies ANA antibodies may be present

Genetic factors—variability in genetic factors Genetic factors—predominant role

Lymphoma Hepatocellular carcinoma

**4**

**Table 1.**


#### **Table 2.**

*The main clinical manifestations of pSS due to the epithelial damage.*

less common. The occurrence of MZBCL has been observed in about 8% of pSS patients; it is 40 times higher than in the healthy population [21, 22].
