The histidyl-tRNA synthetase (MM 57,4 kDa; chromosome 5q31.3), synonym of anti-Jo-1, belongs to the family of aminoacil tRNA synthetases, which catalyze the ester bound of aminoacids to their specific transport RNA (tRNA). The latter ones are engaged in the transport of aminoacids for their assembly into the nascent polypeptide chain within the ribosomes.
CHEMICAL STRUCTURE AND CELLULAR FUNCTIONS
The Jo-1 antigen (histidyl-tRNA synthetase) is part of the tRNA-synthetase, a family of enzymes capable of catalyze the formation of the complex aminoaciltRNA by the union of a specific amino acid with the corresponding tRNA.
The attack of an amino acid to its tRNA activates the carboxyl group making possible the formation of the peptide bond with an amino group of another amino acid. In the cytoplasm there are 20 aminoacyl-tRNA synthetases, one for each amino acid, very different from each other in size and structure. The basic structure of each enzyme molecule presents a substantial identity of amino acid sequence between species eukaryotes, and is therefore well-preserved from the evolutionary point of view, but there are also sequences additional to the carboxyl and amine which give to each of the characteristics synthetase uniqueness of their species.
The histidyl-tRNA synthetase is a homodimer consisting of two identical subunits of about 50 kDa, with the function to catalyze the binding of histidine residues the corresponding tRNA in the cytoplasm.
It is believed that the enzyme is localized exclusively in the cytoplasm, the place where protein synthesis happens, as shown by the distribution of the fluorescence and the positivity that observed in immunoblot only in cytoplasmic extracts and non-nuclear ones. The partial localization nuclear described in some studies would therefore due to the simultaneous presence of other specific antibody, although recently, by confocal microscopy techniques, it is seen that small amount of enzyme, perhaps with different functions, can in reality also found in the nucleus.
For more information about this enzyme:
|BRENDA - The Comprehensive Enzyme Information System||URL|
|Human Metabolome Database||URL|
The tissue-specific pattern of mRNA expression can indicate important clues about gene function.
Autoantibodies - The indirect immunofluorescence test (HEp-2-cells) of sera containing anti-tRNA synthetase antibodies reveals an exclusive cytoplasmic fluorescence pattern. Anti-Jo-1 autoantibodies re-act with multiple conformational and conformation independent epitopes of the antigen. Some antibodies also recognize the catalytic domain of the enzyme and inhibit the catalytic activity of the synthetase in vitro. The antibodies largely belong to the immunoglobulin isotype IgG. The serum-titer of anti-Jo-1 seems to correlate with the disease activity.
Prevalence - Antibodies against the histidyl-tRNA synthetase can be detected in about 35% of adult patients manifesting polymyositis/dermatomyositis and/or myositis associated interstitial lung disease. In adults the antibodies can be detected early in the beginning of the disease and sometimes also prior to the onset of the clinical manifestations.
Clinic - Patients exhibiting antibodies against histidyl-tRNA or other kinds of aminoalcyl-tRNA synthetases may develop the antisynthetase syndrome (in this special case also called anti-Jo-1 syndrome), presenting themselves with varying symptoms of myositis, interstitial lung disease, arthritis, so called “mechanic hands” (rough, cracked skin at the tips and lateral aspects of the fingers forming irregular dirty-appearing fissures because of hyperkeratosis), Raynaud’s phenomenon, sclerodactyly, calcinosis cutis and sicca-syndrome.
The clinical manifestations of the antisynthetase syndromes may vary according to the antigen specificity of the respective anti-synthetase antibodies.
Table: Clinical manifestations of anti-Jo-1 positive patients (Hamaguchi et al. 2013)
DM= dermatomyositis, CADM= clinically amyopathic dermatomyositis, DM/PM-OM= DM/PM-overlap , PM= polymyositis, SSC= systemic sclerosis, ILD= interstitial lung disease, SLE= systemic lupus erythematosus
Autoantibodies against tRNA synthetases are mutually exclusive. The simultaneous occurrence of two ant-tRNA-synthetase antibodies of different antigen specificities is extremely rare. But their association with antibodies not specific for myositis, so called myositis-associated anti-bodies (MAA), directed against topoisomerase, centromeres, U1snRNP, Th/To, U3snRNP, Sm, SS-A/Ro 52 or SS-A/La may be seen quite often.
Research Methods - The anti-Jo-1 in immunofluorescent ANA test indirect (IIF) on HEp-2 cells, produce a cytoplasmic pattern of granular type (granules arranged mainly around the nucleus and sparser toward the cell periphery). However, due to the small concentration of cellular synthetases, the presence of anti-Jo-1 is manifested mostly with blurred fluoroscopic pictures and low title, rarely greater than to 1:40, not always so easily detectable. It follows that in all cases where there is suspicion of myositis, with a test IIF ANA negative, you must still proceed with an examination of the second level for anti-ENA. Actually, the best method for sensitivity and specificity available is immunoprecipitation of tRNA after chromatrographic separation on protein A of extracts derived from human cells in culture which, however, is reserved for the search and is not available in clinical laboratories. The methods commonly used in the laboratory for research of the specific anti-Jo-1 are counterimmunoelectrophoresis (CIE), which typically uses extracts of rabbit or calf thymus, and the ELISA, immunoblot and the Immunodot instead employ purified antigens, extractive or recombinant. The ELISA methods are those with greater sensitivity, whether using natural or recombinant antigens, while the specificity is largely dependent on the purity of the antigenic preparations. Recent external audits of quality still revealed a substantial difficulties in identifying anti-Jo-1, with significant differences between the different methods and, within the same method, also between the different reagents. The experiences conducted by the European Consensus Workshop in 1991, and the group Studio for Autoimmune Diseases the SIMeL in 1997, found a sensitivity average of the different methods equal to 67-70 %. For the detection of anti- Jo -1 is therefore always advisable to the use of at least two different methods for anti-ENA.
For further information concerning the correlation between the Histidyl-tRNA Synthetase (Jo-1) and Polymyositis (Click here) / Myosytis (Click here)
Anyway NCBI Gene lists the following diseases or traits (phenotypes) known or believed to be associated with changes in the HARS gene:
• Usher syndrome, type 3B
Ambra Sedran, Andrea Previgliano
CdL in Odontoiatria e Protesi Dentaria