**1. Introduction**

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

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Sjogren's syndrome (SS) is a chronic autoimmune disease characterized by the lymphocytic infiltration of exocrine glands, mainly the salivary and lachrymal glands entailing the classical sicca syndrome of xerostomia (Sjögren, 1933) and xeropthalmia. Lymphocytic infiltration of other organs results in systemic manifestations. SS is classified as either primary (pSS), when occurring alone, or secondary (sSS), when occurring in addition to other autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus or myositis. As one of the most frequent autoimmune disease, affecting approximately 0.5% of the world population, SS is often associated with other diseases such as Hashimoto thyroiditis, coeliac disease, Biermer's disease or systemic sclerosis. SS evolves as a slow, insidious disease affecting predominantly middle-aged women (female to male ratio of 9:1), SS lies at the cross roads of autoimmune diseases characterized by both cellular and humoral abnormalities. The disease typically affects middle-aged women around their fourth and fifth decades with extremes ranging from to 2 to 83 years. The morbidity of patients suffering from SS is incapacitating ranging from severe fatigue to evolving arthralgia. Even if the patients suffering from SS have a mortality rate comparable to the general population, they present an increased risk of developing lymphoma. The diagnosis of SS is based upon defined criteria according to the American-European consensus encompassing subjective and objective clinical signs and symptoms as well as immunological alterations. The pathogenesis of SS is complex and involves many components taking part in the autoimmune destruction of exocrine glands: proinflammatory cytokines secretion, apoptosis, matrix metalloproteases upregulation, autoantibody formation, as well as T and B cell proliferation. In SS, the classical histological findings in exocrine glands comprise focal inflammatory infiltrates, cell destruction and fibrosis in later stages of the disease. So far, SS treatment has been mainly symptomatic, consisting in relieving the clinical signs. However, recent pathophysiological findings have led to the development of new treatments.

#### **2. Diagnostic criteria**

The diagnosis of SS is currently essentially based on the American-European criteria. These criteria, 6 in total, include 2 subjective and 4 objective criteria. The subjective criteria are

Primary Sjögren's Syndrome: Current Pathophysiological, Diagnostic and Therapeutic Advances 43

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

> Epithelial activation

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 .

T cell

IFN Chemokine IL-17

B cell

Aberrant lymphocyte homing Destruction of glandular tissue Apoptosis and production of autoantibodies T cell cytoxycity

BAFF

IFN, TNFα, IL-1β

formation of germinal centers and ensuing lymphoma (Figure 1).

type1 BAFF

**3. Pathophysiology of SS** 

Viral infection Hormones Genetic factors

DC IFN

Exosomes

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

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

#### **2.1 Ocular symptoms**

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.

#### **2.2 Oral symptoms**

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 food swallowing.

#### **2.3 Ocular signs**

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).

#### **2.4 Histopathology**

A histological sign is considered positive when minor salivary gland biopsy show a focus score >1 (more than 50 lymphocytes per 4 mm2 of tissue).

#### **2.5 Salivary gland involvement**

Objective evidence of salivary gland involvement relies on low unstimulated saliva flow (< 1.5ml/15 min), abnormal sialography, or altered salivary scintigraphy.

#### **2.6 Autoantibodies**

Serological signs are considered positive when the presence of antibodies to either Ro (SSA) or La (SSB) or both are detected in the serum.

#### **2.7 New diagnostic tools**

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