**3. Pathophysiology of SS**

42 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

ocular and oral symptoms, while the objective criteria are ocular signs, histopathology, salivary gland involvement, and autoantibodies. Experts have recommended making the diagnosis of SS when 4 of the 6 criteria are present, as long as histopathology or serology is

It necessary to bear in mind that the most frequent symptoms of SS include the triad of fatigue, polyarthralgia and sicca symptoms, which are often commonly found in the general population and aging population. Many drugs have anti-cholinergic properties, which complicate the diagnostic process of SS. Exclusion criteria for the diagnosis of SS include the presence of hepatitis C and HIV viruses, sarcoidosis, prior cervical radiation, lymphoma,

Ocular symptoms are taken into consideration when patients complain about troublesome dry eyes, recurrent sensation of sand or gravel in the eye, or the use of tear substituent.

Oral symptoms are considered pertinent when patients experience daily feeling of dry mouth, recurrent or persistent swollen salivary glands, or frequent drinking to facilitate dry

Evidence of ocular involvement relies on positive Schirmer's test (<5mm/min) or positive ocular dye score (score > 4 according to the van Bijsterveld score; Van Bijsterveld, 1969).

A histological sign is considered positive when minor salivary gland biopsy show a focus

Objective evidence of salivary gland involvement relies on low unstimulated saliva flow (<

Serological signs are considered positive when the presence of antibodies to either Ro (SSA)

To prevent excessive prescriptions of exams for establishing diagnosis of SS, newer diagnostic tools have been validated. However, these tools have not yet been included in the American-European diagnosis criteria of SS. For example, ultrasonography of salivary glands might prove to be useful to detect anatomical changes in parotid and submandibular glands, with similar diagnostic ability to sialography. Detection of hypoechoic areas, echogenic streaks, cysts and irregular gland margins are highly suggestive of SS (Tagaki et al., 2010). Parotid MRI can also prove to be an adjunct diagnostic tool to detect heterogeneity

score >1 (more than 50 lymphocytes per 4 mm2 of tissue).

1.5ml/15 min), abnormal sialography, or altered salivary scintigraphy.

in salivary glands and specific cystic lesions (Roberts et al., 2008).

positive, or when 3 of any of the 4 objective criteria are present (Vitali et al., 2002).

graft versus host disease and the use of anti-cholinergic drugs (Vitali et al., 2002).

**2.1 Ocular symptoms** 

**2.2 Oral symptoms** 

food swallowing.

**2.3 Ocular signs** 

**2.4 Histopathology** 

**2.6 Autoantibodies** 

**2.7 New diagnostic tools** 

**2.5 Salivary gland involvement** 

or La (SSB) or both are detected in the serum.

The pathophysiology of SS is highly complex. Despite tremendous progress made to unearth the different mechanistic processes underlying the autoimmune abnormality, the etiology of the disease still remains to be discovered. It is actually held that in patients with predisposed genetic background, the combination of viral infections and/or environmental stress leads to epithelial cell activation and upregulation of toll-like receptors(TLR). Initiation of disease is favored by alterations of glandular architecture such as modification of extracellular matrix and cell-cell interactions (that may lead to gene expression reprogramming by epigenetic gene modifications triggered by mecanotransduction). Activation of innate immunity through TLR, leads to T cell activation and secretion of proinflammatory cytokines. Moreover, following epithelial cell activation, there is an upregulation of pro-apoptotic molecules and autoantigen processing resulting in the formation of exosomes, activation of dendritic cells (secretion of IFN) and further activation of T cells. In advanced stages of the disease, following BAFF activation, B-cell proliferation, and aberrant lymphocyte homing favoring diseased gland destruction and the formation of germinal centers and ensuing lymphoma (Figure 1).

Fig. 1. Mechanisms underlying the pathogenesis of SS. Hormones, viral infections and environmental factors in appropriate genetic background are believed to trigger initial events in SS. Epithelial cells are activated resulting in T and B cell activation. T cells produce pro-inflammatory cytokines, which in turn perpetuates activation of epithelial cells, and stimulates B cell activation and proliferation resulting in aberrant lymphocyte homing, autoantibodies production, germinal ectopic centers and tissue destruction. Following epithelial cell activation, production of exosomes activates dendritic cells to produce type 1 IFN and thus BAFF secretion. BAFF stimulates aberrant B-cell maturation resulting in the production of self-reactive B cells synthesising autoantibodies. BAFF: B-cell activating factor; DC: dendritic cells; IFN: interferon; Il-1: interleukin-1 ; TNF-: tumor necrosis factor .

Primary Sjögren's Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances 45

Genetic predisposition is widely accepted as being an important etiological factor in many autoimmune diseases (Hewagama & Richardson, 2009). Several studies support the existence of predisposition to SS (Jonsson et al., 2007). Alleles within the major histocompatibility complex class II gene region, predominantly the HLA-DR and HLA-DQ (Loiseau et al., 2001), are implicated in the pathogenesis of SS. Susceptibility alleles in SS

An increasing body of evidence for the implication of other gene variants outside the HLA locus association is being put forth recently. Gene polymorphisms of IRF-5 and STAT-4 genes, two transcription factors of pivotal importance in interferon pathway, have been associated with various autoimmune diseases (Martinez et al., 2008), as well as with SS (Miceli-Richard et al., 2007; Korman et al., 2008; Miceli-Richard et al., 2009; Nordmark et al., 2009, Gestermann et al., 2010). The most significantly associated single nucleotide polymorphism (SNP) of the IRF5 gene was a 4 fold repetition, instead of three, of a sequence within the promoter region (Nordmark et al., 2009). An association between this polymorphism and high levels of IRF5 mRNA was demonstrated in PBMCs and in cultured salivary epithelial cells after viral infection (Miceli-Richard et al., 2009). STAT4 polymorphism was also associated with SS (Nordmark et al., 2009; Korman et al., 2008;

MECP2 and IL2-IL21 polymorphisms have also been associated with SS (Cobb et al., 2010; Maiti et al., 2010). Gene polymorphisms in IL-10, IL-6, IL-1 receptor antagonist, IL-4 receptor , TNF-, IFN- and TGF-1 have also been associated with pSS (Cobb et al., 2008). PTPN22 (protein tyrosine phosphatase nonreceptor 22), primarily expressed in lymphoid tissues, has been suggested to have prominent roles in T-cell signaling. The 1858 T allele of PTPN22 has been shown to be a risk factor for SS in one Columbian study whilst other studies did not find any significant association with SS (Gomez et al., 2005; Ittah et al., 2005). PTEN, a tumour suppressor gene, displayed a rare mutations shown to be associated concomitantly with SS and Cowden disease (Raizis et al., 1998) and may be associated, in

Very recently, a large Swedish-Norwegian study has associated potentially muscarinic receptor-3 gene variant with SS (Appel et al., 2011). In this study, focus scores, abnormal Schimer's test and autoantibody presence were associated with muscarinic receptor-3 SNPs. Recent data have suggested an increased association between immune system genes and the pathogenesis of primary SS. Indeed, an increase in the copy number of 2 genes linked to immune regulation-FCGR3B and CCL3L1-that can confer susceptibility to SS (Mamtani et al., 2010). A similar study revealed, besides confirming association of STAT4 and IRF5/TNPO3, three new loci as being associated as well with SS. However, the SNPs studied were not associated with the presence of anti-SSA/anti-SSB antibodies; though they

Finally, in contrast one polymorphic variant, 168His of the minor histocompatibilty antigen HA-1, has been described as protective, lowering the risk of pSS (Harangi et al., 2005).

Epigenetic mechanisms are currently and increasingly being associated in disease processes, including autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus,

are all involved in B-cell differentiation and activation (Nordmark et al., 2011).

patients may also vary according to ethnic origin (Bolstad and Jonsson, 2005).

Gestermann et al., 2010; Palomino-Morales et al., 2010).

diseases, with the latter occurrence of non-Hodgkin lymphoma.

**3.3.2 Epigenetic control** 

**3.3 Genetic factors 3.3.1 Genetic variation** 
