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Intranuclear location of the myositis-specific Jo-1 antigenHopping histidyl-tRNA synthetase.

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After 48 hours, the pupils became dilated and unresponsive to light. Laboratory tests administered, including
complete blood count, urinalysis, radiographic series of the
skull, electroencephalogram, nerve conduction velocity,
Doppler test, and computed tomography, showed normal
results. Prostigmin test showed a negative result. The lumbar puncture showed 74 mg% of protein and 1 cell/mm3, with
a normal result op protein electrophoresis. After discontinuation of gold salts and initiation of treatment with prednisolone, <symptomsand signs disappeared within 3 months.
Neurologic complications due to treatment with gold
are infrequent; however, mixed sensorimotor polyneuritis
and, mrely, polyradiculitis do sometimes develop. The few
descriptions we found of this complication (3-9) revealed a
marked heterogeneity among patients regarding the period of
incubattion from the beginning of treatment to the development of the neurologic symptoms (from 1%-7 months) and
the total dosage of gold received (from 350-1,600 mg),
suggesting individual variations in susceptibility to the drug.
Agreement has not been reached on the pathogenetic
mechanism of the nerve lesion; while some researchers
believte it is caused by a direct toxic effect of the gold,
others (10) maintain that the drug causes an alteration of the
autoimmune systems of the individual, which produces an
allergic reaction in the nerve. We believe the latter theory is
a more likely explanation in polyradiculitis. It is interesting
to note that both Guillain-Barre syndrome and Miller-Fisher
syndrome frequently follow viral respiratory infections, influenza, cytomegalovirus infections, Hemophilus injhenzae, and antiflu and antitetanus vaccinations.
We believe our patient’s Miller-Fisher syndrome was
definitlely a result of the gold treatment. The presumed
cause-and-effect relationship seems more likely when we
consider that, to our knowledge, there are no cases of
associated rheumatoid arthritis and polyradiculitis unless a
slow-acting drug, such as sodium aurothiomalate, had been
adminrstered. In our opinion, the long period of incubation in
our patient (1 year) cannot be considered a valid argument
against the role played by the drug in the appearance of the
syndrome, since it has been established that both total
accumulated dose and period of incubation before development of Guillain-Barre syndrome vary greatly among patients.
The appearance of Miller-Fisher syndrome during
treatment with sodium aurothiomalate is a newly described
complication and, in spite of its benign character, should be
kept in mind by physicians who prescribe gold.
J. Roquer, MD
J. Herraiz, MD
J. Maymo, MD
A. OlivC, MD
J. Carbonell, MD
Hospital General Mare
de DPu de I’Esperanca
Barcelona, Spain
I . Mikol F, Simon F , Falcy M: Syndrome de Gougerot-Sjogren et
polyradiculoneurite au carbimazole. Rev Neurol (Paris) 138:
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2. Sahenk Z, Mendell JR, Rossio JL, Hurtubise P: Polyradiculooeuropathy accompanying procainamide-induced lupus erythematosus: evidence for drug-induced enhanced sensitization to
peripheral nerve myelin. Ann Neurol 1:378-384, 1979
3. Fledelius M: Neurite radiculaire aprts traitement par la Samolyne. Encephale 24:620-629, 1934
4. Enatz LJ: Complications nerveuses du traitement aurique:
apercu des sympthmes neurologiques et psychiatriques: resultats du traitement par le bal. Rev Neurol (Paris) 99:395-410,
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Nancy 12:249-257, 1973
6. Bontoux D, Lefevre JP, Mendejal A, Daban M: Complications
neurologiques de la crysotherapie: apropos de deux cas dont un
syndrome de Guillain-BarrC. Rev Rhum Ma1 Osteoartic 41:4851, 1974
7. Serre H, Morlock G, Sany J , Dubois A, Nalet B: Syndrome de
Guillain-Bad apres chrysotherapie. Rhumatologie 27:367-372,
8. Dick DJ, Ramap D: The Guillain-Barre syndrome following gold
therapy. Scand J Rheumatol 11:119-120, 1982
9. Schlumpf U, Meyer M, Ulrich J, Friede RL: Neurologic complications induced by gold treatment. Arthritis Rheum 26325-83 I ,
10. Gottlieb NL: Chrystotherapy. Bull Rheum Dis 27:912-917, 1977
Intranuclear location of the myositis-specific Jo-1
antigen: hopping histidyl-tRNA synthetase?
To the Editor:
The myositis-specific autoantibodies are now widely
recognized (1-6). Reichlin and Arnett showed in their instructive paper (7) that anti-Jo-1 positive sera stained cytoplasmic, nuclear, and nucleolar antigens, in contrast to
previous reports of only nuclear (1) or only cytoplasmic (3,4)
Using immunoaffinity chromatography with immobilized anti-.lo-I antibody, we purified histidyl-tRNA (histRNA) synthetase from rat liver and provided direct evidence that this enzyme is the Jo-l antigen (5). His-tRNA
synthetase belongs to the large family of aminoacyl-tRNA
synthetases, which are found almost exclusively in the
cytoplasm (8). His-tRNA synthetase is seldom found in the
multienzyme complexes of synthetases which occur on the
endoplasmic reticulum (8,9), but is found partially ribosomebound (10).
The predominance of nuclear staining by anti-Jo-1
positive sera observed by Reichlin and Arnett (7) suggests
that his-tRNA synthetase may “hop” into the nucleus or
that another antibody is responsible for nuclear fluoresence.
Because of the lack of purified Jo-1 antigen or his-tRNA
synthetase and the lack of appropriate antibody adsorption
control experiments, the nuclear immunofluorescence may
not be related to the Jo-1 antigen. The occurrence of histRNA synthetase in the nucleus appears to contradict the
results of cell fractionation studies which indicate that this
enzyme is predominantly cytoplasmic (1 1). Methionyl-tRNA
synthetase occurs on the endoplasmic reticulum, but it may
artifactually redistribute from the cytoplasm to the nucleus
due to certain cell extraction-fixation procedures (9).
Nuclear fluorescence by anti-Jo- 1 positive sera
should be interpreted with caution. The apparent intranuclear distribution of the Jo-1 antigen (7) is intriguing; however, this remains to be rigorously established in experiments
using freshly fixed, cultured cells and purified Jo-1 antigen
for appropriate controls. Determination of the exact intracellular location of the Jo-1 antigen will contribute to the
understanding of the basic nature of his-tRNA synthetase
and its possible role in the pathogenesis of myositis.
Chi V. Dang, MD, PhD
Johns Hopkins Hospital
Baltimore, MD
1 . Nishikai M, Reichlin M: Heterogeneity of precipitating antibodies in polymyositis and dermatomyositis: characterization of the
Jo-1 antibody system. Arthritis Rheum 23:881-888, 1980
2. Arnett FC, Hirsch TJ, Bias WB, Nishikai M, Reichlin M: The
Jo-1 antibody system in myositis: relationship to clinical features and HLA. J Rheumatol 8:925-930, 1981
3. Rosa MD, Hendrick JP Jr, Lerner MR, Steitz JA, Reichlin M: A
mammalian tRNAhIS containing antigen is recognized by the
polymyositis specific antibody anti-Jo-1. Nucleic Acids Res
11:853-870, 1983
4. Mathews MB, Bernstein RM: Myositis autoantibody inhibits
histidyl-tRNA synthetase: a model for autoimmunity. Nature
304:177-179, 1983
5 . Yang DCH, Dang CV, Arnett FC: Rat liver histidyl-tRNA
synthetase: purification and inhibition by the myositis-specific
anti-Jo-1 autoantibody. Biochem Biophys Res Commun 120:
15-21, 1984
6. Mathews MB, Reichlin M, Hughes GRV, Bernstein RM: Antithreonyl-tRNA synthetase: a second myositis-related autoantibody. J Exp Med 160:420-434, 1984
7. Reichlin M, Arnett FC Jr: Multiplicity of antibodies in myositis
sera. Arthritis Rheum 27:1150-1 156, 1984
8. Ilang CV, Johnson DL, Yang DCH: High molecular mass
aminoacyl-tRNA synthetase complexes in eukaryotes. FEBS
Lett 142:l-6, 1982
9. Dang CV, Yang DCH, Pollard TD: Association of methionyltRNA synthetase with detergent-insoluble components of the
rough endoplasmic reticulum. J Cell Biol 96:1138-1147, 1983
10. Ussery MA, Tanaka WK, Hardesty B: Subcellular distribution
of aminoacyl-tRNA synthetase in various eukaryotic cells. Eur
J Biochem 72:491-500, 1977
1 1 . Hampel AE, Enger MD: Subcellular distribution of aminoacyltransfer RNA synthetases in Chinese hamster ovary in culture. J
Mol Biol 79:285-293, 1973
To the Editor:
Dr. Dang notes that human sera with anti-Jo-l
activity have variable staining patterns in indirect immunofluorescence studies. That is of course correct, and of the
sera that we examined in our study, 8 had a nuclear pattern,
3 a cytoplasmic pattern, 1 a nucleolar pattern, and 7 were
negative on HEp-2 substrate at a 1:40 serum dilution.
Clearly, under the conditions of these experiments, no single
staining pattern correlates with the presence of the antibody,
and the absence of consistent cytoplasmic staining is curious
since it is thought the antigen histidyl-tRMA synthetase is a
cytoplasmic material.
Dr. Dang exhorts us to exercise caution in the
interpretation of such data. Indeed, there is no interpretation
of these data in our paper. He proceeds to make a speculative hypothesis about the fact that the Jo-1 antigen may
“hop” from the nucleus to the cytoplasm or vice versa. He
also points out that there may be artifactual redistribution of
antigens, that sera may contain more than 1 antibody, or that
there may be different forms of the enzyme.
We agree that there are numerous possibilities, and
indeed we are exploring many of them at the present time. It
is known that many of these connective tissue disease sera
have multiple antibodies, and it is possible that antigens
carrying the same specificity may have a variable distribution in tissue culture cells. The answer to this question lies in
specific purification of antibody and antigen with appropriate blocking experiments, with different cell lines, and
perhaps cells at different stages of the cell cycle. These
experiments are all in progress, and we have taken the
paradoxes presented by our own data as a starting point for
further experiments. To say any more about the data at this
time would be to proceed against Dr. Dang’s own good
advice to be cautious about the interpretation of such data.
Morris Reichlin, MD
Oklahoma Medical Research Foundation
University of Oklahoma Health Sciences Center
Oklahoma City, OK
Frank C. Arnett, Jr., MD
University of Texas Health Science Center
Houston, TX
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trna, intranuclear, antigenhopping, specific, myositis, histidyl, synthetase, location
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