rournal of Autoimmunity (1990) 3,299-305

Immunoglobulin Allotypes in Myasthenia Gravis Patients with a Thymoma

Nils E. Gilhus,* Janardan l?. l?andey,l_ Per I. Gaarderj: and Johan A. Aarli* *Department

of Neurology,

University

of Bergen,

Bergen,

Norway;

TDepartment

of

Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA; $National Institute of Public Health, Oslo, Norway Gm and Km allotypes were examined in 29 myasthenia gravis patients with a thymoma and non-receptor skeletal muscle antibodies. The frequency of the phenotype Gm1,2,3;23;5,21 was significantly higher in the patients than in 292 healthy controls (P < 0.01). Km allotype frequencies did not differ in patients and controls.

Introduction The pathogenesis of myasthenia gravis involves hereditary, immunological and environmental factors. The hereditary influence has been demonstrated by family studies and by an HLA-antigen association in Caucasians with HLA-Al, -B8, -DR3 [I]. However, myasthenia gravis with a thymoma is a specific disease entity which has several important distinctions compared to myasthenia gravis in general. For this patient group, a genetic predisposition is less obvious, although a few reports also indicate an hereditary component in these patients [2,3,5]. Immunoglobulin allotype markers on IgG heavy chains (Gm) and on k light chains (Km) are useful genetic markers. Data regarding Gm typing in myasthenia gravis patients are conflicting, reflecting population differences but also heterogeneity within the myasthenia gravis patient population [4-lo]. There have been several reports of associations between IgG allotypes and autoimmune disorders in general [ 111, and also between IgG allotypes and humoral immune response [ 12,131. In the present study, we have examined Gm and Km allotypes and phenotypes in a selected group of myasthenia gravis patients: those with a thymoma. A thymoma in Correspondence to: Dr N. E. Gilhus, Department of Neurology, Haukeland University Hospital, 5021 Bergen, Norway. 299 0896-841 l/90/030299 +07 $03.00/O

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N. E. Gilhus et al.

myasthenia gravis is linked to the: presence of antibodies against skeletal muscle antigens apart from the acetylcholine receptor (anti-CA antibodies) [ 14, 151. We have examined the correlation between the anti-CA antibody response and the IgG allotype and phenotype in our myasthenia gravis patients. The associations between IgG allotypes and myasthenia gravis in general and between IgG allotypes and acetylcholine receptor antibody response have not been examined.

Patients and methods Patients Twenty-nine Norwegian and German Caucasians (13 men and 16 women) with myasthenia gravis and a thymic lymphoepithelioma (thymoma) were included. None of the patients were immigrants. The study included all the 16 patients with myasthenia gravis and a thymoma treated in Bergen during the last 10 years and 13 patients treated by Dr R. W. C. Janzen, Hamburg, FRG. The diagnosis ofmyasthenia gravis was based on conventional clinical criteria, a positive edrophonium test, an increased decrement after repetitive motor nerve stimulation, and an increased acetylcholine receptor antibody concentration [ 161. The thymoma was verified histologically and was malignant with local infiltration in five of the patients. Age at onset of myasthenia gravis was 20-75 years, mean age 5 1 years. Three other patients with a thymoma did not have any symptoms or signs of myasthenia gravis. However, they had acetylcholine receptor antibodies at low concentration. From our pool of myasthenia gravis patients without a thymoma, four were selected for IgG allotyping. The basis for this selection was that they all had circulating anti-CA antibodies. These four patients were older than 50 years at onset of myasthenia gravis and had thymic atrophy at thymectomy. Control sera were obtained from 292 healthy Norwegian blood donors. The results were compared to the previously reported Gm frequencies in 14,450 Germans, as well as to the frequencies in the population of the northern part of Germany [ 171.

Antibody

determination

and IgG allotyping

The serum anti-CA antibody concentration was determined in triplicate by indirect haemagglutination. Serum was mixed with a 0.75% suspension of tanned sheep erythrocytes coated with a muscle extract (CA extract) [ 181. The serum titer was defined as the reciprocal of the highest dilution of serum agglutinating CA-coated erythrocytes. The serum anti-CA antibody titer in a patient remains relatively stable for years (unpublished). Serum samples were allotyped at the Medical University of South Carolina (all patients and 42 controls) and at the National Institute of Public Health, Oslo (250 controls) by a standard haemagglutination-inhibition technique [ 19, 201. The notation follows the recommendation of the World Health Organization on human allotypic markers. Samples were typed for Glm(l/a, 2/x, 3/f, 17/z), G2m(23/n), G3m(5/bl, 6/c3, 13/b3, 21/g), and for Km( 1,3). The allotype frequencies for the controls typed in South Carolina and in Oslo were the same and the two groups of

Ig allotypes in myasthenia gravis with a thymoma

301

controls have therefore been pooled. All patients, but only 42 controls, were typed for Glm (17) and G3m(13). These allotypes occurred together with Glm(1) and G3m(5), respectively, and provided no additional information. Statistical analysis

Statistical comparisons were made using Chi-square tests with Yates’ correction for continuity. Analysis of variance was used to determine whether an association existed between antibody titres and IgG allotypes. Differences were considered statistically significant when P < 0.05. To correct for the number of comparisons undertaken, the P value obtained was multiplied with this number. Results Anti-CA

antibodies

All the myasthenia gravis patients with a thymoma had anti-CA antibodies in serum. The antibody titers were equally distributed between 256 and 256,000. The titers of the patients with a malignant thymoma were l,OOO-128,000. In two patients, antiCA antibody titers were 60 preoperatively but increased to 64,000 during the first 4 weeks after thymectomy with radical resection of the thymoma. The anti-CA antibody titers in the four patients without thymoma were 4,000, 8,000, 16,000 and 128,000. The antibody titers in the thymoma patients without myasthenia gravis were 4,000,8,000 and 64,000. IgG allotypes and phenotypes

The G2m(23) allotype occurred slightly more frequently in the myasthenia gravis patients with a thymoma than in the controls (P=O.O4) (Table 1). However, this difference is not significant when corrected for the total number of allotype comparisons. The frequency of the other Gm and the Km allotypes did not differ in patients and controls. The phenotype Gm1,2,3;23;5,21 occurred in nine of the 29 myasthenia gravis patients with a thymoma but only in 30 of the 292 controls (Table 2). This difference is highly significant (P3.,..,?J921 Other phenotypes

Controls

No.

“xl

No.

“/”

1 0 8 8 9 1 1 1 0

3 0 28 28 31* 3 3 3 0

9 20 94 63 30 20 29 20 7

3 7 32 22 10* 7 10 7 2

*p

Immunoglobulin allotypes in myasthenia gravis patients with a thymoma.

Gm and Km allotypes were examined in 29 myasthenia gravis patients with a thymoma and non-receptor skeletal muscle antibodies. The frequency of the ph...
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