Background/Purpose: Most targets of autoantibodies in systemic rheumatic diseases are multiprotein-nucleic acids complex. Small nuclear ribonucleoproteins (snRNPs, Sm and U1RNP), key functional components of the mRNA splicing, are one of the most common targets of autoantibodies in systemic lupus erythematosus (SLE) and other systemic autoimmune diseases. Survival of motor neuron (SMN) complex that plays a key role in snRNPs assembly and interacts with snRNPs has recently been identified as a novel target of autoantibodies in polymyositis/dermatomyositis (PM/DM). Autoantibodies to gemin5 that interacts with SMN complex were examined in unselected cohort of rheumatology clinic.

Methods: Sera from patients seen at the Center for Autoimmune Disease (n = 1966, including 453 SLE, 132 scleroderma, 125 PM/DM, 130 Rheumatoid Arthritis, 61 Sjögren’s syndrome) were screened for autoantibody specificities by immunoprecipitation (IP) using ³⁵S-labeled K562 cells extract. Anti-gemin5 antibodies were initially screened by IP of ~170kD protein and confirmed by IP-western blot (IP-WB) and antigen-capture ELISA using anti-gemin5 monoclonal antibodies. Sera of interest were also tested by WB using purified gemin5 and immunofluorescent antinuclear (ANA)/cytoplasmic antibodies

Results: Nineteen sera with anti-gemin5 antibodies were identified. All except one (18/19) also had anti-snRNPs (13 anti-U1RNP, 5 anti-U1RNP+Sm) and one had anti-SMN complex antibodies without anti-snRNPs. Among 18 with anti-snRNPs, 13 clearly had anti-SMN complex antibodies, 3 were inconclusive while 2 were negative. Anti-gemin5 sera were also positive for anti-snRNPs, thus showed nuclear speckled pattern and Cajal body ANA staining. In WB using affinity-purified gemin5, 10 sera were clearly positive, confirming their direct reactivity with gemin5. Anti-gemin5 was found in 6% of anti-snRNPs positive Caucasian or African American and 15% in Latin American. Diagnoses include 10 SLE, one each of SSc and PM and 7 undifferentiated connective tissue disease (UCTD). Clinical features of SLE in anti-gemin5+snRNPs (+) patients were similar to those of anti-snRNPs (+) patients except for absence of discoid lesions, seizures, and anti-phospholipid antibodies (0% vs 48%, P < 0.0001) in the former group. Among anti-gemin5 (+), 4 cases had symmetrical muscle weakness and elevated muscle enzymes and 32% (7/19) had at least one of these, suggesting muscle involvement may be common in this subset. Raynaud’s phenomenon was seen in 73%, interstitial lung disease (ILD) in 25%, and sclerodactyly in 14% of anti-gemin5 patients. A case of PM with anti-TIF1beta and U1RNP antibodies developed anti-gemin5 and SMN antibodies a few months later, consistent with the idea of epitope spreading within macromolecular complex.

Conclusion: Anti-gemin5 antibodies are produced in tight association with anti-snRNPs and anti-SMN complex antibodies in SLE and other systemic rheumatic diseases. Clinical features of anti-gemin5+snRNPs antibody positive patients are similar to those with anti-snRNPs although muscle involvement may be more common.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gemin5-is-a-new-target-of-autoantibodies-that-are-produced-in-tight-connection-with-antibodies-to-snrnps-and-survival-of-motor-neuron-smn-complex/