**4.2. Antibodies against citrullinated proteins**

Citrullination is the post-translational process in proteins of deamination/conversion of the amino acids: arginine into citrulline. ACPA positive sera include antibodies to citrullinated proteins, such as fibrin and fibrinogen, vimentine (MCV—mutated citrullinated vimentine) and alpha-enolase (CEP-1).

**4.5. Anti-muscarinic antibodies**

to aquaporins [57].

further research.

**4.7. Autoantibodies binding to stathmin-4**

**4.6. Autoantibodies to aquaporins**

Muscarinic 3 receptor (M3R) is found in various places in the body, such as smooth muscles, the endocrine and the exocrine glands, lungs, pancreas and even the brain. This receptor is also expressed on pancreatic beta cells, modulating insulin secretion. Activation of the M3R

Primary Sjögren's Syndrome and Autoantibodies http://dx.doi.org/10.5772/intechopen.75011 127

It has been demonstrated that muscarinic acetylcholine type 3 receptor (M3R) antibodies are present in the serum of patients with pSS [54]. As it was presented by Kovacs et al., M3R antibodies are found in up to 90% of subjects with pSS [55]. In the group with M3R antibodies, leucopenia was more frequently observed [55]. Immune response to muscarinic receptor 3 plays a role in the pathogenesis of autoimmune sialoadenitis [56] and diabetes mellitus type 2. MR3 antibodies may be present in other autoimmune diseases and do not allow for differentiation between primary and secondary Sjögren's syndrome. The severity of symptoms of dryness or dysfunction of the exocrine system in pSS may be related not only to MR3 antibodies presence but also to other autoantibodies such as, for example, antibodies

Aquaporins (AQP; water channels) are integral membrane proteins that form pores in the membrane of biological cells, enabling transport of water between cells. Some genetic defects of aquaporin genes have been associated with diseases as neuromyelitis optica (Devic's syndrome) and nephrogenic diabetes insipidus. First, aquaporin—"aquaporin-1" was described in 1992 by Peter Agre, until today we know 13 aquaporins, of which four are best defined [58]. Because of their influence of water transport, aquaporins have an impact on saliva and tear production and changes in AQP expression may lead to dryness symptoms [59, 60]. Aquaporin-4 (AQP4) is found on perivascular and ependymal cells, but it has also been discovered in sera of patients with NMO and multiple sclerosis. Tzartos and his colleagues detected aquaporin antibodies (AQP-1, -3, -8, and -9) in pSS patients sera [61]. What is interesting in the pSS group, AQP-4 and AQP-5 antibodies were not present. The presence of AQP antibodies was associated with more severe xeropthalmia; the authors suggest potential role of AQ P-Ab in salivary gland secretions. Such hypothesis requires

Stathmins (STMN) are phosphoproteins which play a role in neuronal development and interact with tubulin. Presently, four stathmins have been identified. Stathmins are upregulated in a number of cancers and neuropathies [62]. Anti-stathmin-4 antibodies in IgG3 class were proposed as a biomarker of polyneuropathy and such observations were presented by Duda et al. in their study. The authors described anti-STMN4 antibodies in 33% of pSS patients with polyneuropathy (PNP)—vs. 7% of those without PNP—and in 45% of individuals with

vasculitis skin changes (as opposed to 13% in individuals without them) [63].

receptor induces smooth muscle constriction and increase glandular secretions [54].

It is known that arthritis may be one of the clinical symptoms of pSS. However, most of the pSS patients suffer from arthralgia, and only minority develop non-destructive arthritis. ACPA antibodies, a main marker of rheumatoid arthritis, are usually present in low concentrations in pSS according to various studies they are present in 3–22% of cases [46]. A higher incidence of arthritis was found in pSS patients with ACPA presence compared to patients without these antibodies [47]. It seems, however, that patients with pSS and ACPA positive require further observation toward the development of rheumatoid arthritis [48].

It should also be remembered that smoking and periodontal infection by *Porphyromonas gingivalis* are strong environmental factors stimulating protein citrullination and the emergence of ACPA antibodies [49].

#### **4.3. Citrullinated alpha-enolase**

Citrullinated alpha enolase (CEP-1) is an antigenic target for antibodies against citrullinated proteins (ACPA). In the Nezos et al. study [50], it was shown that CEP-1 antigen is a major antigen target in the ACPA positive subgroup of patients with pSS. The frequency of CEP-1 antibody in the RA ACPA positive group was not as high, while it was not found healthy group at all. The authors drew attention to the link of anti-CEP-1 antibodies presence to arthritis as well as to renal tubular dysfunction.

#### **4.4. Antibodies recognizing salivary gland and lacrimal gland tissue**

In recent years, researchers identified autoantibodies to carbonic anhydrase 6 (anti-CA6 antibodies), anti salivary gland protein 1 (SP-1) and anti-parotid secretory protein (PSP) [51]. These antibodies may emerge before pSS marker antibodies such as SS-A/Ro or SS-B/La and are associated with a minor focus score; these antibodies also occur more often in patients who did not have anti-SS-A/Ro antibodies [52]. Interestingly, in Langhe et al. work, anti CA6- IgA antibodies were detected primarily in patients with long pSS duration; other autoantibodies such as anti-CA6, PSP, and SP1 in IgG and IgM class were more frequently observed in SSc and MCTD with secondary SS. These autoantibodies do not allow distinguishing SLE from secondary SS. However, the described study was limited by a small group of SLE patients [52]. In the literature, some cases have been reported of patients with severe symptoms of eye or mouth dryness, in which there was no SS-A/Ro antibodies, but the presence of anti SP-1 antibody was confirmed [53]. It may suggest, that in case of a patients presenting unexplained dryness with no serology markers defined in current criteria for pSS, performing the test for novel, early antibodies to Sp1 and PSP may still be useful for diagnosing patient's condition [53].
