Antinucleolar and AntiRNA Polymerase Antibodies

The term "anti-nucleolar antibodies" describes all autoantibodies that show a nucleolar pattern by IIF on Hep-2 cells. The autoantigenic targets that are relevant for SSc are fibrillarin, PM-Scl, RNA polymerase I, and To/Th antigen. High-titer anti-nucleolar antibodies are diagnostic markers for SSc, but may also be detected in patients with tumors (especially hepatocellular carcinoma) and other diseases, depending on the target specificity.

Anti-fibrillarin antibodies (AFAs) are directed against fibrillarin, the main protein component of the nucleolar U3-RNP complex, which is involved in pre-rRNA processing. Fibrillarin is also a component of other small nucleolar ribo-nucleoprotein (snoRNP) complexes. By IIF on Hep-2 cells, AFAs reveal a granular (clumpy) nucleolar immunofluorescence pattern. Chromosomal staining in metaphase may also be observed. Specific, highly sensitive methods for detection of fibrillarin antibodies are not yet available for routine use. AFAs are detectable in fewer than 10% of patients with SSc (associated with dcSSc) but have also been described in patients with SLE and localized scleroderma (reviewed in [42]). Fibrillarin antibody production was induced using mercury salts in a mouse model [43]. This suggests that exogenous factors may play a role in pathogenesis.

Anti-Th/To antibodies target components of the ribonuclease MRP and the ri-bonuclease P complexes. IIF using HEp-2 cells reveals a homogeneous nucleolar staining pattern. They are detectable in 2-5% of patients with SSc and are associated with milder skin and organ involvement, with one exception: pulmonary arterial hypertension (reviewed in [42]).

Anti-RNA polymerase antibodies target RNA polymerases (RNAPs) of the RNAP multiprotein complexes consisting of 8-14 proteins weighing 10-220 kDa. There are three classes of RNAPs (RNAPs I, II, III). Whereas only RNAP-I is localized in the nucleolus, RNAPs II and III are localized in the nucleoplasm. Since the different types of RNAP antibodies often occur in combination, it is hardly possible to make a differential assessment of the clinical relevance of the individual specificities. RNAP-I antibodies are observed in 4-11% of patients with systemic sclerosis (scleroderma) but are rarely detected in other autoimmune diseases. They are associated with severe, diffuse forms of scleroderma. These patients have a poor prognosis because they tend to have a higher frequency of cardiac, hepatic, and renal involvement. RNAP-III antibodies are detected in 12-23% of patients with systemic sclerosis and are frequently associated with RNAP-I and RNAP-II antibodies. RNAP-III antibodies seem to be specific for scleroderma since they have not yet been found in any other disease. They are associated with diffuse or extensive skin manifestations and with heart and kidney involvement [41]. RNAP-III antibodies have also been detected during a renal crisis in the absence of skin manifestations, i.e., sclerosis without scleroderma [44].

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