ReviewAutoantibodies to the mitochondrial RNA processing (MRP) complex also known as Th/To autoantigen
Introduction
Systemic autoimmune rheumatic diseases (SARD), including systemic sclerosis (SSc), are characterized by the presence of circulating autoantibodies to intracellular antigens [1], [2] often referred to as antinuclear antibodies (ANA). ANA detected by indirect immunofluorescence (IIF) represent valuable biomarkers in the diagnosis of SSc [1], [3] being present in the vast majority of the patients. However, the ANA HEp-2 IIF assay is by no means specific for a particular SARD [4], [5]. Except for anti-centromere (CENP) antibodies that can be determined by screening ANA in most cases, additional testing to identify specificities such as anti-topoisomerase I and anti-RNA polymerase III antibodies is mandatory to efficiently utilize positive ANA results and to more accurately characterize SSc patients [6]. Besides anti-topoisomerase I, anti-CENP and anti-RNA polymerase III, several other autoantibodies can be present in SSc patients including autoantibodies targeting the PM/Scl complex (also known as the exosome) [7], U3-RNP/fibrillarin [8], [9] and the Th/To autoantigens [10], [11], [12], [13]. Anti-Th/To antibodies are one of the specificities that reportedly show homogenous nucleolar staining in conventional IIF ANA tests [10], [14], [15]. (See Fig. 1.) (See Table 1.)
Section snippets
Molecular characteristics of the Th/To complex
The Th/To autoantigens are a macromolecular protein–RNA complex [human RNase mitochondrial RNA processing (MRP) complex] consisting of a catalytic RNA and at least 9 proteins including Rpp14, Rpp20, Rpp21, Rpp29 (hPop4), Rpp25, Rpp30, Rpp38/40, hPop1 and hPop5 [2], [11]. Historically, Rpp38 and Rpp40 were considered as two individual antigens, but later on, it became evident that both proteins share the same identity [11]. RNase MRP is a ubiquitously expressed eukaryotic endoribonuclease that
Methods for the detection of anti-Th/To antibodies
Historically, anti-Th/To antibodies have been detected by immunoprecipitation (IP) of metabolically labeled cell lysates [10]. Anti-Th/To antibodies are one of a few specificities that confirmation based on protein components has not been utilized; detection was based on identification of 7-2 and 8-2 RNA by analysis of RNA components in immunoprecipitates. While some studies focused on serological cohorts, other investigations analyzed serum samples initially identified on the basis of a
Autoreactivity of Th/To components and epitope distribution
Recent studies, using ELISA and CIA, confirmed that Rpp25 is a major autoantigen targeted by anti-Th/To antibodies [11], [17], being detected in an approximately 60–100% of anti-Th/To antibody positive sera. When the prevalence of anti-Th/To (hPop1) or anti-Rpp25 antibodies in SSc patients was compared, similar prevalences of autoantibodies to different components were found: 3.3% (hPop1) [19], 2.1% (hPop1) [20] and 2.9% (Rpp25) [17]. However, statistically significant differences in the
Clinical association of anti-Th/To antibodies
Although known for over 20 years, the clinical association of anti-Th/To antibodies is not fully established, probably due to very limited availability of reliable immunoassays and technical challenges of screening large number of samples by IP. Although anti-Th/To antibodies are uncommon in serum samples from SARD patients, the observation that anti-Th/To antibodies are mostly detectable in SSc makes this specificity an important serological adjunct in the diagnosis and stratification of SSc
Abbreviations
- ANA
anti-nuclear antibodies
- CENP
centromere proteins
- CIA
chemiluminescence assay
- ELISA
enzyme linked immunosorbent assay
- IIF
indirect immunofluorescence
- ILD
interstitial lung disease
- IP
immunoprecipitation
- LIA
line immunoassay
- MRP
mitochondrial RNA processing
- SARD
systemic autoimmune rheumatic disease
- SS
Sjögren's syndrome
- SLE
systemic lupus erythematosus
- SSc
systemic sclerosis
- Topo I
topoisomerase I (Scl-70)
Competing interest
M. Mahler is employed at Inova Diagnostics Inc., a company that manufactures and markets autoantibody assays. Marvin Fritzler is the Director of Mitogen Advanced Diagnostics Laboratory (Calgary, Alberta, Canada) is a consultant to Inova Diagnostics Inc., and has received gifts in kind from Euroimmun GmbH and ImmunoConcepts Inc. M. Satoh has no conflict of interest.
Take-home messages
- •
Anti-Th/To antibodies are mostly found in patients with limited form of SSc and show association with nailfold capillary microscopy abnormalities and interstitial lung disease.
- •
Among the 9 protein components of the complex, Rpp25 is a major target of anti-Th/To antibodies.
Acknowledgments
We thank Cristina Gascon for the help with the table.
References (36)
- et al.
Autoantibodies in systemic sclerosis
Autoimmun Rev
(2013) - et al.
Novel aspects of autoantibodies to the PM/Scl complex: clinical, genetic and diagnostic insights
Autoimmun Rev
(2007) Autoantibodies in systemic sclerosis
Semin Arthritis Rheum
(2005)- et al.
Antinuclear antibodies: a contemporary nomenclature using HEp-2 cells
J Autoimmun
(2010) - et al.
Diagnostic accuracy and predictive value of extended autoantibody profile in systemic sclerosis
Autoimmun Rev
(2012) - et al.
Optimization and diagnostic performance of a single multiparameter lineblot in the serological workup of systemic sclerosis
J Immunol Methods
(2012) - et al.
The role of nail-videocapillaroscopy in early diagnosis of scleroderma
Autoimmun Rev
(2013) - et al.
Epitope specificity and significance in systemic autoimmune diseases
Ann N Y Acad Sci
(2010) - et al.
Clinical interpretation of antinuclear antibody tests in systemic rheumatic diseases
Mod Rheumatol
(2009) - et al.
The clinical significance of the dense fine speckled immunofluorescence pattern on HEp-2 cells for the diagnosis of systemic autoimmune diseases
Clin Dev Immunol
(2012)
Prevalence and sociodemographic correlates of antinuclear antibodies in the United States
Arthritis Rheum
Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database
Ann Rheum Dis
Autoantibodies to fibrillarin in systemic sclerosis (scleroderma). An immunogenetic, serologic, and clinical analysis
Arthritis Rheum
Anti-Th/To are common antinucleolar autoantibodies in Italian patients with scleroderma
J Rheumatol
Identity of the RNase MRP- and RNase P-associated Th/To autoantigen
Arthritis Rheum
Autoantibodies against small nucleolar ribonucleoprotein complexes and their clinical associations
Clin Exp Immunol
Autoantibody to Th ribonucleoprotein (nucleolar 7-2 RNA protein particle) in patients with systemic sclerosis
Arthritis Rheum
Anti-Th/To-positivity in a cohort of patients with idiopathic pulmonary fibrosis
J Rheumatol
Cited by (26)
Autoantibodies to stratify systemic sclerosis patients into clinically actionable subsets
2020, Autoimmunity ReviewsCitation Excerpt :RNase MRP is a ubiquitously expressed eukaryotic endoribonuclease that cleaves various RNAs, including ribosomal, messenger, and mitochondrial RNAs [20,25]. Almost all protein components of the RNase MRP and the evolutionarily related RNase P complex, have been reported as autoantibody targets in patients with ANA-associated rheumatic diseases (AARD), although Rpp25, Rpp38 and hPop1 are regarded as the major target autoantigens [20]. While some studies tested unselected cohorts, other investigations analyzed serum samples initially enriched on the basis of their nucleolar indirect immunofluorescence (IIF) staining pattern.
Autoantibodies in connective tissue disease
2020, Best Practice and Research: Clinical RheumatologySerum antinuclear and extractable nuclear antigen antibody prevalence and associated morbidity and mortality in the general population over 15years
2016, Autoimmunity ReviewsCitation Excerpt :Our analysis of administrative databases is limited by the fact that 11% of the target population in 2013 had a copayment exemption due to low income or age over 65 years, and this overtakes the emission of clinical exemptions for specific diseases such as CTD, and moreover limits the statistical power in older disadvantaged subjects. Despite using modern laboratory tests, autoantibodies were tested using IIF and ELISA, while no further testing for other autoantibodies (such as rheumatoid factor in Sjögren syndrome or anti-Th/To or -RNAPIII in systemic sclerosis) was performed [25–28]. We also acknowledge that the rarity of positive anti-ENA sera and the absence or small number of incident events did not allow estimating the HR for these conditions, while including tests for anti-phospholipid antibodies and rheumatoid factor would have led to a more complete CTD panel.
Systemic sclerosis: New evidence re-enforces the role of B cells
2016, Autoimmunity ReviewsCitation Excerpt :Anti-fibroblast antibodies induce fibroblast production of chemokines CCL2 (monocyte chemoattractant protein-1) and CXCL8 (interleukin-8) [34]. Anti-RNA polymerase III antibodies are associated with dcSSc [35] and anti-Th/To antibodies are associated with lcSSc and scleroderma renal crisis in some studies [36]. Autoantibodies against platelet-derived growth factor receptor (PDGFR) stimulated activation and collagen production in normal human fibroblasts [37].