3.3.4. Local Production of Autoantibodies

The most common and studied antibodies in SS patients are those directed against the autoantigens Ro/SSA and La/SSB [148]. Anti-Ro, Anti-La, anti-SSA and anti-SSB were originally described as four antibodies directed against antigens expressed by salivary and lacrimal glands tissues from SS patients. Later, anti-Ro and anti-La were shown to be the same antibodies as anti-SSA and anti-SSB, respectively [149,150].

Ro antigen is constituted of two distinct Ro proteins of 52 and 60 kDa, with the latter binding to small cytoplasmic RNAs known as hY RNAs. The Ro52 protein, also known as TRIM21, is frequently targeted by SS antibodies, which makes it a useful diagnostic marker, but its function and why it becomes a target protein in a lot of rheumatic diseases is not completely understood. Ro52 is a member of the tripartite motif (TRIM) protein family, and it plays an important role in the ubiquitination of proteins. Several targets have been suggested as substrate of Ro52 activity, including various members of the IFN-regulatory factor (IRF) transcription factor family. The most speculated hypothesis attributes to Ro52 a role of IFN negative regulator. Indeed, in a Ro52-null mouse, the lack of ubiquitination mediated by Ro52 leads to an aberrant expression of type I IFNs and proinflammatory cytokines, such as IL-6, IL-12, IL-23, and TNF-α [151]. La/SSB antigen is a 48 kDa phosphorylated protein located in the nucleus and the cytoplasm. La/SSB binds to many RNA molecules newly synthesized by RNA polymerase III [152]. These two antibodies are detected in 50% to 70% of primary SS patients, but the anti-La/SSB alone is observed in only 2% of patients [153,154].

In most cases, anti-Ro/SSA and anti-La/SSB are correlated with severe dysfunction of the exocrine glands, associated with parotid gland enlargement and large number of lymphocytic infiltrates in the MSG [155,156].

Other antibodies believed to be pathogenic in SS are anti-centromere antibodies (ACA), anti-citrullinated protein antibodies (ACPA), anti-carbonic anhydrase II antibodies, anti-aquaporin-5, anti-muscarinic receptor 3 (anti-M3R) and anti-fodrin antibodies. ACA are directed against six antigens associated with the centromere (complex of kinetochore proteins). The incidence of ACA antibody ranges from 3.7% to 4% [157,158]. ACPA are directed against fibrin and fibrinogen, vimentine and alpha-enolase (CEP-1). In general, ACPA antibodies are the marker most observed in rheumatoid arthritis but are usually present in low concentrations in pSS as well, in about 3–22% of cases [159]. Anti-carbonic anhydrase II antibodies have been detected in 12.5–20.8% of SS patients and also play a pathogenic role in renal tubular acidosis (RTA) [160,161]. In fact, immunization of mice with human carbonic anhydrase II resulted in autoimmune sialadenitis, production of anti-carbonic-anhydrase-II antibodies and urinary acidification defect [162,163]. Anti-AQP5 antibodies were observed to be associated with serologic and histopathological features of SS [164]. Anti-M3R antibodies are present in serum of up to 90% of subjects with SS [165]. Antibodies against alpha-fodrin are detected in serum samples from patients with primary or secondary SS, especially in patients with sicca symptoms. However, anti-alpha-fodrin antibodies do not represent a sensitive nor a specific serological marker of SS [166]. Other novel tissue-specific autoantibodies are currently under investigation: autoantibodies against salivary protein 1 (SP-1), parotid secretory protein (PSP) and carbonic anhydrase 6 have been described in pSS and non-pSS patients with chronic pain, which may help to understand and diagnose early pSS and pSS-associated widespread pain syndrome in the future [167]. Anti-cofilin-1, anti-alpha-enolase and anti-RGI2 antibodies are associated with pSS MALT lymphoma [168]. Other autoantibodies have also been described to be more frequently found in pSS patients and variously associated with the clinical and biological characteristics of the disease [168]. Table 1 summarizes the novel autoantibodies that have been detected in pSS patients.


*J. Clin. Med.* **2020** , *9*, 2299

healthy controls; hyperγ =

Eular Sjögren Syndrome Disease Activity Index; RF+ =

positivity; -=

increase(d)/higher;

 -=

decrease(d)/lower;

 "−" =

negativity.

hypergammaglobulinemia;

 ANA =

rheumatoid factor positivity; NMOSD =

antinuclear antibodies; GC = germinal centre; SSA and SSB =

Neuromyelitis

 Optica Spectrum Disorder; ACPA+ =

anti-Ro/SSA (Ro52 and/or Ro60) and anti-La/SSB; ESSDAI =

anti-citrullinated

 protein antibodies
