J. Endocrino!. Invest. 14: 131-134, 1991

CASE REPORT

Immunogenetic study of thyroid hormone autoantibodies in afamily S. Nakamura*, M. Sugimoto*, J. Kosaka*, T. Komaki**, H. Kamura***, T. Miyazaki****, H. Matsumoto****, and S. Sakata***** *Department of Internal Medicine, Gifu Red Cross Hospital , Iwakura 3-36 , Gifu 502; ** Department of Internal Medicine, Hashima Municipal Hospital, Shin-Sei 3-246, Hashima, Gifu 501-62 ; *** Histocompatibility Laboratory , Nagoya Second Red Cross Hospital, Myouken 2-9 , Shouwa, Nagoya, Aichi 466 ; **** Department of Legal Medicine, Osaka Medical College , Daigaku 2-7, Takatsuki, Osaka 569; and ***** The Third Department of Internal Medicine , Gifu University School of Medicine , Gifu 500, Japan. ABSTRACT. Haplotypes of the human major histocompatibility complex (HLA) and immunoglobulin G heavy chain allotype (Gm) were determined in nine members of a family in which three sisters had thyroid hormone autoantibodies (THAA) in serum. Among three sisters with THAA, two of them were hypothyroid and treated with synthetic thyroid hormones (patients nos. 1 and 2). The other remaining sister (patient no. 3) was euthyroid. Light chain allotype (Km) in them was also examined. Three patients had the same two Gm haplotypes. Km (1) al-

lotype was negative in these three patients. HLA haplotypes of patient no.1 were the same as those of patient no.2. However, HLA haplotypes of patient nO.3 were completely different from those of patients nos . 1 and 2. The same combination of Gm haplotypes and the absence of Km (1) allotype were not observed in the remaining members without THAA. These results suggest that genes linked to Gm and Km allotypes are associated with the production of THAA at least in our patients.

INTRODUCTION In physiological condition , thyroid hormones bind to serum thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin. In 1956, thyroxine binding to serum "(-globulin was first reported in a patient with papillary thyroid carcinoma treated with 1311 (1) . Since then , the presence of thyroid hormone autoantibodies (THAA) has been reported in various thyroidal and nonthyroidal illness (2) . However, underlying immunological mechanism(s) of the production of THAA remain s obscure , although THAA are thought to be a part of antibodies directed against epitope(s) of thyroglobulin (Tg) molecule containing thyroid hormones (2, 3) . In previous reports , we demonstrated the presence of THAA in three sisters in a family (4) , and report-

ed the effect of long-term thyroid hormone replacement on the titers of THAA (5) . Furthermore , correlation between titers of THAA and anti-Tg antibodies (Ab) in them was investigated (5) . In order to further examine immunolog ical mechanism(s) for the production of THAA in them, we determined the HLA type , and Gm and Km allotypes of immunoglobulin and discussed the immunogenetic background in the production of THAA. CASE REPORT

Family In August 1989, blood samples were obtained from nine members (no. 2-no. 10) of the family , as shown in Figure 1 (5). Two sisters (no . 7 and no . 8) had been diagnosed as having hypothyroidism due to Hashimoto's thyroiditis and treated with thyroid hormones. The other members had been euthyroid up to August, 1989 without any treatment. Three (no. 7, no. 8, and no. 10) out of four sisters had both THAA and anti-Tg Ab in their serum (5) . Presence of anti-Tg Ab (6) was also found in their mother (no . 6) and grandmother (no. 4) .

Key-words: Thyroi d hormone au toan tibodies, HLA ant igens, immunoglobulin allotype. Correspondence: Shi genori Nakamura, M. D., Department of Internal Medicine, Gifu Red Cross Hospital, Iwakura 3-36, Gifu 502, Japan.

Received May 10, 1990; accepted November 16, 1990.

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S. Nakamura, M. Sugimoto, J. Kosaka, et al.

METHODS

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HLA-A, -B, -C, and -DR antigens were determined with the microcytotoxity technique (7). Twenty-three HLA-A antigens, 47 HLA-B antigens, 9 HLA-C antigens, and 10 HLA-DR antigens were tested. Immunoglobulin G heavy chain allotypes (Gm allotypes) and kappa-type light chain allotype (Km allotype) were determined by the passive hemagglutination method (8). Typing was carried out for the following antigens: Gm (1, 2, 3, 5, 10, 11, 13, 14, 15, 16,21, and 26) for Gm allotypes and Km (1) for Km allotype. Haplotypes of HLA and Gm allotypes were determined by complete analysis of HLA-A, -B, -C, and DR antigens and Gm phenotypes in the whole family. Statistical analysis was made with Fisher's exact test; p < 0.05 was considered significant.

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RESULTS

Figure 1 shows the HLA and Gm haplotypes, and the presence or absence of Km (1) allotype in members examined. Three siblings (no. 7, no. 8, and no. 10) with both THAA and anti-Tg Ab had the same Gm (p/q) haplotypes. In addition, Km (1) allotype was negative in these three sisters. However, HLA haplotypes (a/g) of no. 10 were completely different from those (c/e) of no. 7 and no. 8. On the other hand, the combination of Gm haplotype (p) and haplotype (q) was not obtained in any other members. The incidence of Km (1) negative and/or Gm haplotypes (p/q) was significantly higher in the three siblings with THAA than in the other family members without THAA (Table 1). Grandmother (no. 4) with anti-Tg Ab and Gm haplotype (p) was negative with THAA, although she showed the absence of Km (1) allotype. The mother (no. 6), who had anti-Tg Ab, Gm haplotype (q), and Km (1) allotype did not have THAA either.

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Fig. 1- A family with THAA. Haplotypes of no. 1 were speculated from those of no. 2 and no. 5. a. HLA-A24, B39, Cw7, ORw8. c: HLA-A2, Bw46, Cw11, ORw8, d HLA-A 11, Bw55, Cw3, OR9. e. HLA-A24, Bw61, -, OR9, f. HLA-A 11, Bw52, -, OR2 g. HLA-A2, Bw48, -, OR4, h HLA-A 11, Bw62, Cw4, OR9. p. Gm (1,21,26), q. Gm (1,2,21,26), r.' Gm (1, 10, 11, 13, 15, 16). (+). Km (1) positive, (-). Km (1) negative

major histocompatibility complex (MHC). However, the above authors reported that these responses were not linked to Igh-allotype. These results let us to determine the HLA and Gm and Km allotypes in the three siblings so that to know the immunogenetic role on the production of THAA in them. Three sisters with THAA showed the same Gm allotypes. In addition, none of them had Km (1) allotype. Two of them with hypothyroidism had the identical HLA haplotypes (HLA-A2, Bw46, Cw11, DRw8; HLA-A24, Bw61, DR9). However, the other euthyroid sister had different HLA haplotypes. These data indicate the gene linked to Gm and Km allotypes, but not HLA, may be associated with the production of THAA. The remaining sister without THAA (no. 9) showed the Gm haplotypes (1, 21, 26), suggesting the combination of the presence of Gm haplotype (1, 2, 21, 26) and the absence of Km (1) allotype could be an important genetic factor in the production THAA in this family. Interactive effects of genes associated with Gm and Km sys-

DISCUSSION

Autoimmune thyroid diseases such as Graves' disease and Hashimoto's thyroiditis are reported to be linked with HLA and Gm allotypes (9, 10). Recently, the association between the occurrence of these diseases and T cell receptor (TCR) betachain gene has been demonstrated (11,12). Demaine et al. (12) reported the possible association between the genes residing in the TCR betachain and HLA and immune response to Tg. Responses of anti-Tg (13) and anti-T4 Ab (3) by immunization with human Tg have been reported to be controlled by the genes coded within mouse

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Immunogenetics of THAA

Table 1 - Comparisons of the incidence of HLA and Gm haplotypes and Km (1) allotype between three siblings with THAA and the other six family members without THAA. THAA(+)

THAA(-)

p*

Gm (1, 2, 21, 26) (q)

3/3

2/6

Gm (1,10,11,13,15,16) (r)

0/3

4/6

NS NS NS NS NS NS NS NS NS NS

Km (1) negative

3/3

1/6

Immunogenetic study of thyroid hormone autoantibodies in a family.

Haplotypes of the human major histocompatibility complex (HLA) and immunoglobulin G heavy chain allotype (Gm) were determined in nine members of a fam...
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