Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Autoantibodies to a Novel Cytoplasmic Rod/Ring Structure Target CTP/GTP Synthetic Pathway in HCV Infection after Interferon/Ribavirin Therapy.
Carcamo2, Wendy C., Ceribelli3, Angela, Chan3, Jason Y. F, Reeves2, Westley H., Covini, Giovanni, Von Muhlen1, Carlos A., Chen3, Liu
Autoantibodies (aab) can be important disease markers and basic research tools in molecular and cell biology. Cytoplasmic antigenic structures identified by ANA screening consisting of rods and rings (RR) are novel subcellular structures. The current aim is to identify clinical occurrences associated with RR aab, elucidate the antigenic targets and their biologic function.
Sera collected from multiple clinical centers were analyzed by HEp-2 slides as well as other mammalian cell lines for the presence of anti-RR. Positive samples were then analyzed by immunoprecipitation of 35S-labeled K562 cell extracts. Identity of candidate antigens associated with RR was validated by co-staining with established specific antibodies.
Anti-RR recognized cytoplasmic rods of 310mm in length and rings with ~25mm in diameter in HEp-2 cells, distinct from all known aab reported to date. A total of 80 anti-RR samples were identified, clinically linked to Hepatitis C virus (HCV), mostly after interferon-alpha/ribavirin (IFN/R) therapy. Clinical data were available from 23 Italian anti-RR+ patients: 15 HCV+, 6 HCV-, and 2 unknown. Prevalence of anti-RR did not correlate with specific HCV genotypes: Type 1 (6/15), 2a (3/15), 3 (1/15), and 4 (1/15). 14/15 HCV+ were treated with IFN/R therapy, indicating a strong link of RR aab to this therapy. 75% (9/12) of HCV with anti-RR had no response to IFN/R therapy, suggesting anti-RR may be associated with poor response. The 6 HCV(-)RR+ patients had no common diagnosis. However, prevalence of anti-RR in general hepatic disease population was low (3.5%, ~35/1000), indicating that HCV infection alone seldom induces anti-RR aab. In an autoimmune disease center setting, prevalence of anti-RR was also very low: only 2 SLE patients were identified among >2,000 in database. Analysis of the 2 SLE patients over 3-yr span was available. Interestingly, patient #1 had HCV(3a) and anti-RR was detected within 4 mo after IFN/R treatment. This patient was unresponsive and treated again with IFN/R after 6 mo. Liver function then normalized and anti-RR disappeared. Patient #2 had anti-Sm/RNP, anti-phospholipid aab with lupus nephritis, but was apparently HCV- and had stable anti-RR for at least 2 yrs. About a third of anti-RR+ sera immunoprecipitated 55kDa doublets. Candidate 55kDa antigens cytosine triphosphate synthase (CTPS1) and inosine monophosphate dehydrogenase 2 (IMPDH2) were identified to be highly enriched in RR. Multiple inhibitors of these enzymes were shown to be sensitive inducers of RR formation in all mammalian cell types analyzed.
CTPS1 and IMPDH2 are key enzymes in CTP and GTP synthesis respectively, inhibitors to which were demonstrated to induce RR formation. Development of anti-RR is most common in HCV+ patients with IFN/R treatment, but anti-RR may be found in HCV- patients. Ribavirin is a sensitive inhibitor of IMPDH2 enzymatic activity, may thus lead to aberrant RR formation, and trigger aab production during HCV treatment. Anti-RR production in other systemic diseases remains unclear.
To cite this abstract, please use the following information:
Carcamo, Wendy C., Ceribelli, Angela, Chan, Jason Y. F, Reeves, Westley H., Covini, Giovanni, Von Muhlen, Carlos A., et al; Autoantibodies to a Novel Cytoplasmic Rod/Ring Structure Target CTP/GTP Synthetic Pathway in HCV Infection after Interferon/Ribavirin Therapy. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1639