14.

15.

brancher deficiency myopathy. Clin Neurol Upn) 22:1159, 1982 Pellisier JF, de Barsy Th, Faugere MC, Rebuffel P: Type I11 glycogenosis with multicore structures. Muscle Nerve 2: 124- 132, 1979 Rossignol AM, Meyer M, Rossignol B, et al: La myocar- diopathie de la glycogenose type 111. Arch Fr Pediatr 36:303- 309, 1979

Effect of Thvmectomv on Blood T-cell Subiets in Myasthenia Gravis Adele Cox, MD,X Robert P. Lisak, MD,’ Paul Skolnik, MD,*t and Burton Zweiman, MD*t

We studied peripheral blood mononuclear T-cell subsets in 23 patients with myasthenia gravis who had under- gone thymectomy at least one year before study. An increase in the T4+/T8+ (helper-inducerlsupptessor- cytotoxic cell) ratio was seen, similar to that previously reported in nonthymectomized patients with myas- thenia gravis. Six patients were studied before and after thymectomy and no consistent alteration in the pattern of T-cell subsets was detected. We were not able to dem- onstrate a quantitative effect of thymectomy on periph- eral blood mononuclear T-cell subsets in patients with myasthenia gravis.

Cox A, Lisak RP, Skolnik P, Zweiman B: Effect of thymectomy on blood T-cell subsets in myasthenia

gravis. Ann Neurol 19:297-298, 1986

Thymectomy is widely held to benefit patients with myasthenia gravis (MG), although the mechanism by which this occurs is unclear. It has been suggested that thymectomy may alter functional T-cell subsets and lead to changes in cell-mediated andor humoral im- munity to acetylcholine receptor (reviewed in [3, 61). Conflicting results have been reported regarding alter- ation of T-cell subsets defined by monoclonal anti- bodies 12, 4, 7). Differences between studies include numbers of patients tested, medications at time of study, thymic histological findings, age at onset of MG, and length of time after thymectomy. Because of dis-

From the *Department of Neurology and the ?Section of Allergy and Immunology, Department of Medicine, and the Henry M. Watts, Jr, Muscular Dystrophy Research Center, University of Pennsylvania School of Medicine, Philadelphia, PA. Received July 9, 1985, and in revised form Aug 9. Accepted for publication Aug 12, 1985. Address reprint requests to Dr Lisak, Department of Neurology, Hospital of the University of Pennsylvania, 3400 Spruce St, Phila- delphia, PA 19104.

crepant previous reports and our interest in the long- term effects of thymectomy in patients with MG, we studied T-cell subsets in 23 patients, in each of whom at least 1 year had elapsed since thymectomy.

Methods Blood samples were obtained from 23 patients with MG and 20 normal control subjects. The patient population consisted of 14 women and 9 men with a mean age of 37 years (range, 21 to 52 years). The mean age of the control group was 32 years (range, 23 to 53 years); it consisted of 11 women and 9 men. Time since thymectomy ranged from 1 to 10 years (mean, 3.8 years). Nineteen patients had an early onset of MG (before 35 years of age); 4 had a late onset (after 35 years of age) [3,7}. No patient who had a thymoma removed was included in the study. In 17 patients, histological exami- nation of the thymus showed only hyperplasia, whereas 6 had “normal” thymic tissue removed, defined by the absence of germinal center follicular hyperplasia or thymoma. Before thymectomy, 14 patients were clinically graded as having Class IIB disease and 9 had IIA disease according to the Osserman classification (reviewed in [6]). All but 1 patient’s condition improved after thymectomy. Four patients had been treated with corticosteroids in the past, but had re- ceived none for at least six months before testing. Seventeen patients were taking anticholinesterase medications; the other 6 were receiving no medications. None was receiving cytotoxic or immunosuppressive drugs. Six patients were studied before thymectomy and at 8 to 18 months (n = 5 ) and/or 19 to 40 months (n = 5 ) after thymectomy. Periph- eral blood mononuclear cells were obtained and percentages of T3-, T4-, and T8-positive cells were determined by indi- rect immunofluorescence using visual microscopy, as previ- ously described {5, 7).

Results We found that patients who had undergone thymec- tomy 12 months or more before study had normal numbers of T3- and T4-positive cells (Table 1). How- ever, there was a modest decrease in the number of circulating T8 + cells with a statistically significant in- crease in the T4/T8 ratio compared with the normal control population @ < 0.05). The ratio was abnormal in 11 patients. In 1, this reflected an increase in T4, in 4 a decrease in T8, and in 6 both an increase in T4 and a decrease in T8. These changes were seen both in patients with thymic hyperplasia and in those from whom normal thymic tissue had been removed (Table 2). We found no difference between patients with early-onset (mean age, 26.4 years) and late-onset (mean age, 41.8 years) disease (data not shown). Stud- ies carried out before and after thymectomy on 6 pa- tients demonstrated no consistent pattern of change in T-cell profiles with passage of time after thymectomy.

Discussion The mechanism by which thymectomy is effective in patients with MG remains unclear. Our analysis of levels of peripheral blood T cells and T-cell subsets

297

Table I. Peripheral Blood T-cell Subsets in Patients with Myasthenia Grauis after Thymectomya Subjects T3 (%> T4 (%) T8 (%) T4/T8

Normals 65.6 % 1.9 39.9 2 2.6 26.1 2 1.1 1.6 5 0.1 (n = 20)

(n = 23)

(n = 131

(n = 8)

(n = 5 )

All patients 62.5 & 2.0 42.5 f 2.0 22.3 5 1.3b 2.2 2 0.2b

2-4 years PT 59.8 k 2.2 41.3 2 2.8 24.0 k 2.2 2.1 ? 0.4b

4-6 years PT ' 70.5 ? 2.7 44.0 5 2.9 22.8 2 2.5 2.1 f 0.3b

z 6 years PT 68.0 2 4.8 41.8 f 3.6 19.6 +- 2.7 2.3 5 0.4b

"Values are mean 2 SD. ' p < 0.05 versus normals (Student's t test).

PT = post thymectomy.

Table 2. Blood T-cell Subsets afer Tbymctomy for Myasthenia Grauis: Analysis by Thymic Histology"

Thymus PaLhology (v) T3 (%) T4 (%I T8 (%) T4IT8 Age at Onset

Thymic hyperplasia 29 64.4 2 11.5 40.3 5 9.3 23.1 +- 7.0 2.1 5 1.3 (n = 17)

(n = 6) Normalb 31.5 64.2 2 6.0 48.0 2 7.9 19.3 k 2.5 2.5 5 0.6

"Values are mean & SD. 'Normal = no germinal center follicular hyperplasia or thymoma.

employing mouse monoclonal antibodies fails to dem- onstrate any striking effect of thymectomy. An in- crease in the T4/T8 ratio was seen in postthymectomy patients as a group but has also been observed by us 171 and others 111 in patients with MG who have not undergone thymectomy.

Our findings differ from those in previous reports concerning the effect of thymectomy on T-cell subsets in patients with MG. Haynes and co-workers 147 found in later-onset MG decreased numbers of T3 (pancirculating) and T4 (helper-inducer) cells before thymectomy, which were restored to normal after op- eration. In contrast, we found no significant alterations in the quantity of T cells or T-cell subsets in patients with later-onset MG who had atrophic thymic tissue removed at operation. There were only small numbers of patients with later-onset MG in both series; never- theless, the mean age of the older patients at onset was different in the two studies (59 years in [4} versus 42 years in our study).

Our data also differ from those of Berrih and as- sociates 121, who reported reductions in T4/T8 ratios in patients 6 to 12 months after thymectomy, a change they found more striking in patients who were studied longer after thymectomy. Few of the latter patients were studied preoperatively. It is perhaps more impor-

tant that approximately one third of their patients were receiving corticosteroids at the time of study.

Our data suggest that changes in T-cell subsets as defined by currently employed phenotypic markers are not the primary mechanism by which thymectomy benefits patients with MG.

References 1. Berrih S, Gaud C, Bach MA, et al: Evaluation of T-cell subsets in

myasthenia gravis using anti-T-cell monoclonal antibodies. Clin Exp Immunol45:1-8, 1981

2. Berrih S, Lebrigand H, Levasseur P, et al: Depletion of helped inducer T-cells after thymectomy in myasthenic patients. Clin Immunol Immunopathol 28:272-281, 1983

3. Engel AG: Myasthenia gravis and myasthenic syndromes. Ann Neurol 16519-534, 1984

4. Haynes BF, Harde EA, Olanow CW, et ak Effect of thymectomy on peripheral lymphocyte subsets in myasthenia gravis: selective effect on T-cells in patients with thymic atrophy. J Immunol

5. Kung PC, Goldstein G, Reinhem EL, Schlossmann SF: Mono- clonal antibodies defining distinctive human T-cell surface anti- gens. Science 206:347-349, 1979

6. Lisak RP, Barchi RL: Myasthenia Gravis. Philadelphia, Saunders, 1982

7. Skolnik PR, Lisak RP, Zweiman B: Monoclonal antibody analysis of blood T-cell subsets in myasthenia gravis. Ann Neurol 11:170-176, 1982

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298 Annals of Neurology Vol 19 No 3 March 1986