Background/Purpose: The 14-3-3 proteins are ubiquitously-expressed intracellular chaperonins. Expression of the η (eta) isoform is restricted to synovial and CNS tissues. Extracellular 14-3-3η induces proinflammatory MAPK and NFkB cascades in THP-1 cells in vitro. Extracellular 14-3-3η has been proposed as a novel biomarker for joint damage in rheumatoid arthritis (RA) and psoriatic arthritis, with serum elevation occurring in early RA. 14-3-3η positivity may add diagnostic sensitivity to laboratory RA markers such as rheumatoid factor (RF) and citrullinated cyclic peptide antibody (CCP). However, 14-3-3η expression in arthritogenic viral infection has not been studied. The aim of this study was to determine the frequency of elevated 14-3-3η in patients with RA and in those with HCV, acute EBV, or acute B19 infections.

Methods: We developed a quantitative 14-3-3η sandwich ELISA and verified the reference range using 134 serum specimens from healthy donors (67 males, 67 females; ages 18-65). 14-3-3η was measured in de-identified residual clinical specimens originally submitted for routine RA or infectious disease diagnostic testing.

Results:

The 14-3-3η 95th-percentile reference range was defined as <0.2 ng/mL and the reportable range was <0.2 to >20.0 ng/mL. Six healthy subjects (4%) had elevated 14-3-3η levels; 2 of them were weakly RF positive. RF+/CCP+ subjects had the highest frequency of elevated 14-3-3η (56%) and the highest 14-3-3η median level (Table). Frequency of elevated 14-3-3η was lower in the RF+/CCP- and virus-infected groups.. None of the RF-/CCP+ subjects had elevated 14-3-3η, but the number of subjects was small (n=10). The frequency of elevated 14-3-3η in the RF-/CCP- group was 5%. Of 23 subjects with elevated 14-3-3η in the HCV group, 1 was RF+/CCP+, 13 RF+/CCP-, and 9 RF-/CCP-. Of 6 subjects with elevated 14-3-3η in the EBV group, 1 was RF+/CCP+, 2 RF+/CCP-, and 3 RF-/CCP+. All 5 subjects with elevated 14-3-3η in the B19 group were RF-/CCP-.

Subject Group	n	Number with Elevated 14-3-3η (%)	Median Abnormal 14-3-3η Value (Interquartile Range) (ng/mL)
Healthy	134	6 (4%)	1.19 (0.66-4.61)
RF+/CCP+	43	24 (56%)	4.37 (0.66-8.24)
RF+/CCP-	131	20 (15%)	0.73 (0.39-1.15)
RF-/CCP+	10	0 (0%)	NA
RF-/CCP-	305	14 (5%)	0.54 (0.33-0.73)
HCV (RIBA)+	162	23 (14%)	0.46 (0.29-1.21)
EBV VCA IgM+	101	17 (17%)	0.44 (0.33-1.54)
B19 IgM+	34	5 (15%)	0.26 (0.20-0.72)

Conclusion: 14-3-3η elevation was most frequent among patients with RF+/CCP+ results (consistent with an RA diagnosis). The data suggest that RA and some HCV, EBV, and parvovirus B19 infections may share pathogenetic mechanisms characterized by synovial release of 14-3-3η. Of note, the median abnormal 14-3-3η level was higher in the RF+/CCP+ group than in the virus-infected groups. This suggest less synovitis in viral arthritis than in RA, consistent with clinical observations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/chaperonin-protein-14-3-3n-eta-in-rheumatoid-arthritis-and-arthritogenic-viral-infections/