Antimicrosomal Antibodies, Gastric Parietal Cell Antibodies and Antinuclear Factors in Insulin Dependent Diabetes Mellitus

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1 Endocrinol. Japon. 1979, 26 (5), Antimicrosomal Antibodies, Gastric Parietal Cell Antibodies and Antinuclear Factors in Insulin Dependent Diabetes Mellitus KENGO NAGAOKA1, TAKEHIKO SAKURAMI1, NOBORU NABEYA1, HIROO IMURA1, AND SHOTARO KUNO2 nd Department of Internal Medicine, Faculty of Medicine, Kyoto University2Osaka Red Cross Hospital Synopsis Thyroid antimicrosomal antibodies, gastric parietal cell antibodies (PCA) and antinuclear factors were studied in208insulin dependent diabetic (IDD) according to the duration of diabetes and patient's age at the time of testing. Antimicrosomal antibodies were found in11out of47 (23.4%) IDD with the duration of less than one year, however this value declined to13.1% at1to3years, 15.3% at4to5 years, 10.8% at6to10years and5.8% at more than10years. Of the47idd,7 (14.8%) were positive for gastric parietal cell antibodies. The prevalence of PCA declined with the increasing duration of diabetes. However, this decrease in the prevalence of antimicrosomal antibodies and PCA was not so extreme as that of pancreatic islet cell antibodies. Antinuclear factors did not reveal a significant correlation with the duration of diabetes. In normal controls, the prevalence of antimicrosomal antibodies, PCA and the antinuclear factors increased progressively with age. In IDD, the prevalence of the antinuclear factors was also progressively greater with age. However, the prevalence of antimicrosomal antibodies in IDD decreased with age and those of PCA showed the lowest percent in the40-69year-age group. There is an increasing evidence that autoimmune mechanism may have a role in the pathogenesis in insulin dependent diabetics (IDD). The clinical association between IDD and autoimmune diseases and a high incidence of thyroid or gastric autoantibodies and an antipancreatic cellular hypersensitivity in IDD have already been reported (Hecht et al., 1968; Irvine et al., 1970; Nagaoka et al., 1979; Nerup et al., 1971, 1973). By mean of the indirect immunofluorescence test, Bottazzo et al.(1974) and MacCuish et al.(1974) found respectively pancreatic islets cell antibodies (I. C. Ab.) in IDD with autoimmune polyendocrine disease. Using an improved technique and group-0 fresh human pancreas, Irvine et al.(1977) determined the prevalence of I. C. Ab. in IDD with and without other organ-specific autoimmune disorders and they found that I. C. Ab. declined with the duration. In collaboration with W. J. Irvine, the inverse relationship between the prevalence of I. C. Ab. and the duration of diabetes was already observed by us in Japanese insulin dependent diabetics (Nagaoka et al., 1978). The purpose of the present study was to study the relationship between thyroid antibodies, gastric parietal cell antibodies (PCA) and the duration of diabetes. Received January26, 1979.

2 600 NAGAOKA et al. Endocrinol. October1979 Japon. Patients Materials and Methods The patients were120insulin dependent diabetics (IDD) who were joining Kinki region summer-camp of diabetic children in1975, 1976, 1977, 1978and 88patients attending the diabetic out-patient departments of Osaka Red Cross Hospital. All of them had to receive insulin therapy absolutely to get an adequate control and all had no goiter. The patients comprised208idd with111females aged3to 66years and97males aged8to68years. IDD were classified according to the duration of diabetes and age distribution The age and sex matched control group ( 20 years) consisted of healthy students, medical staffs, nurses and university workers. Out-patients (0-19 years) who visited Kyoto University Hospital with some complaints were chosen as the disease control group for diabetes mellitus in childhood. Serum was separated as soon as possible after drawing blood and stored at-20 Ž. Methods Circulating antibodies to microsome of thyroid epithelial cells were determined by the tanned red cell hemagglutination method, using the commercially prepared reagent (Fuji Zoki Co. Tokyo). Antimicrosomal antibody titres were regarded as positive if hemagglutination occurred in1: 160dilutions of sera. For titration, v-shaped wells of plastic agglutination trays (Cooke Instruments) were used, because the settling pattern of the cells in the cup could be observed in the bottom. Gastric parietal cell antibodies were detected by the indirect immunofluorescence test. Fresh snapfrozen stomach of rat and fluorescein-conjugated antibodies against human immunoglobulins IgG+ IgA+IgM (Hoechst) were used. Antinuclear factors (ANF) were also tested by the indirect immunofluorescence test using nuclei provided by normal human leucocytes. of antimicrosomal antibodies in normal controls increased with age. In normal controls and IDD, significant difference was noted in two age groups between0-20and 21-40years (p<0.005). But to significant difference was found in the41-69age group. PCA were positive in8.2%, 18.1 % and5.6% of IDD, respectively according to the three age groups (Table2). In normal controls, PCA were progressively greater with age. A significant difference was found only in the2younger age-groups (p<0.005). Among the47idd with the duration of less than one year, 11 (23.4%) gave a positive result for antimicrosomal antibodies, however this value declined to 13.1% at1to3years, 15.3% at4to 5years, 10.8% at 6to 0years and5.8% at more than10years (Fig.1). The prevalence of PCA in IDD based on the duration of diabetes is shown Fig. 2. This prevalence was14.8% at less than one year, but thereafter fell as the duration increased. Only2.9% of IDD with the duration of more than10years had the PCA. The duration of diabetes strongly Prevalence of antimicrosomal antibodies in insulin dependent diabetes mellitus Results Prevalence of gastric parietal cell antibodies in insulin dependent diabetes mellitus shows the prevalence of antimicrosomal antibodies according to the age group in normal controls and IDD. In the 122IDD at the age of less than20years, 21 (17.2%) were positive for thyroid antimicrosomal antibodies. This prevalence fell to12.1% in the21-40age group and7.5% at41-69years. In contrast, the prevalence

3 Vol.26, No.5 HUMORAL IMMUNITY IN I. D. D. 601 Prevalence of antimicrosomal antibodies in insulin dependent diabetes mellitus. Prevalence of gastric parietal cell antibodies in insulin dependent diabetes mellitus. Prevalence of antinuclear factors in insulin dependent diabetes mellitus ANF did not reveal a signficant correlation with the duration of diabetes. Discussion affected PCA and antimicrosomal antibodies in IDD. shows the prevalence of ANF in IDD. The difference in prevalence of ANF in normal controls and IDD was statistically significant only in the0-20age group (p<0.005). In contrast to antimicrosomal antibodies and PCA in IDD, an evident correlation was observed between the prevalence of ANF and age. However, Using an immunofluorescence test, serum pancreatic islet cell antibodies (I. C. Ab.) were demonstrated in the sera of IDD with polyendocrine disease by Bottazzo et al., and MacCuish et al., respectively in1974. I. C. Ab. were of IgG class and complement-fixing and crossreacted with islets of the rat and reacted with all the cells of the pancreatic islets. Using snap-frozen human (blood group0) pancreas Lendrum et al.(1975) detected I. C. Ab. in nearly half of the105children with diabetes mellitus of recent onset, compared with only 1positive result among the72controls.

4 602 NAGAOKA et al. Endocrinol. October1979 Japon. However, they found no evident correlation between the duration of symptoms, agegroup and prevalence of I. C. Ab. Irvine et al.(1977) clarified that the prevalence of I. C. Ab. was strongly dependent on the duration of diabetes, being60% for less than1year in IDD and falling to20% at to5years and5% at10-20years. Moreover, Irvine et al. demonstrated that the persistence of I. C. Ab. had a correlation with the presence of HLA B8 and8% of the diabetics treated with oral agents had I. C. Ab. and these I. C. Ab.-positive patients with oral agents had a strong tendency to require insulin therapy later. Prete et al. (1977) have also shown the inverse relationship between the prevalence of I. C. Ab. and the duration of diabetes, and they found I. C. Ab. in18.9% of the chemical diabetes mellitus at the age of less than 35years and12.9% of those aged more than35years. Lendrum et al.(1976), afterwards, corrected there finding that the prevalence of I. C. Ab. declined with the increasing duration. In collaboration with Dr. W. J. Irvine of the Royal Infirmary (Edinburgh), we detected I. C. Ab. in Japanese IDD (1978). I. C. Ab. were present in 16% of Japanese IDD during the first year and in 8.3% between1and3years after the disease onset. This value fell to0% at more than4 years. A significant high incidence of organspecific autoantibodies such as thyroid antimicrosomal antibodies in IDD was already reported by many investigators. It is a very interesting problem whether the prevalence of antibodies such as antimicrosomal antibodies, PCA and ANF will decline or not as the duration diabetes increases. So, as to the correlation between the prevalence of these antibodies and the duration of diabetes, age was determind in this paper. Our diabetic patients were divided into 5 groups according to the duration of symptoms. In IDD with the duration of less than1year, the prevalence of antimicrosomal antibodies and PCA was23.4%, 14.8% respectively. Then the decrease of the prevalence of these antibodies was observed as soon as the duration became longer than1year, however, this derease was not so extreme as that of I. C. Ab. In1970, Irvine et al. reported that there was no significant difference in the prevalence of antibodies to thyroid cytoplasma or to gastric parietal cell cytoplasma in patients who had had insulin treatment for 5years or longer, compared to the prevalence in those who had had insulin for a shorter period. They suggested that the duration of diabetes might not be an important factor in the production of these antibodies. And Lendrum et al. suggested that thyrogastric antibodies increased in prevalence as the duration of diabetes increased. The reason for this discrepancy is not clear in the results of the three studies. In SLE, it is well known that the titres of anti-dna antibodies in untreated active SLE are very high, however, these decline with the treatment (Seligmann et al., 1965). Also in Hashimoto's thyroiditis, the titres of thyroid antibodies decline with the administration of desiccated thyroid, however, it is unusual for thyroid antibodies to become negative (Saito et al., 1975). But in previous data and our data, the prevalence of I.C.Ab. are strongly dependent on the duration and falls to0% at more than10years. The reason for this behavior in IDD is currently unkown. Irvine et al. suggested that the transitory presence of I. C. Ab. in IDD might be due to some exogeneous agent, such as a virus infection of the pancreatic islets. And the fact that human islet tissue is only about 1g compared to thyroid tissue may support the explanation. It is uncertain that a viral infection plays the role of a trigger in the pathogenesis of IDD. It seems, perhaps more, likely that I. C. Ab. may disappear from the circulation after the de-

5 Vol.26, No.5 HUMORAL IMMUNITY IN I. D. D. 603 struction of islet tissue develops and antigen References Bottazzo, G. F., A. Florin-Christensen and D. Doniach (1974). Lancet2, Oohira, S.(1975). Jikeikai Medical Journal90, 883. (In Japanese) Hecht, A. and H. Gershberg (1968). Metabolism17, 108. Irvine, W. J., B. F. Clarke, L. Scarth, D. R. Cullen and L. J. P. Duncan (1970). Lancet2, 163. Irvine, W. J., C. J. McCallum, R. S. Gray, C. J. Campbell, L. J. P. Duncan, J. W. Farquhar, H. Vaughan and P. J. Morris (1977). Diabetes26, 138. Lendrum, R., G. Walker and D. R. Gamble (1975). Lancet1, 880. Lendrum, R., G. Walker, A. G. Cudworth, J. C. Woodrow and D. R. Gamble (1976). British Medical Journal1, MacCuish, A. C., J. Jordan, C. J. Campbell, L. J. P. Duncan and W. J. Irvine (1974). Lancet2, Nagaoka, K., T. Sakurami, N. Nabeya, H. Imura and S. Kuno (1978). J. Japan Dia. Soc. 21, (In Japanese) Nagaoka, K., T. Sakurami, N. Nabeya, H. Imura and S. Kuno (1979). Endocrinol. Japon. 26, 89. Nerup, J., O. O. Anderson, G. Bendixen, J. Egeberg and J. E.(1971). Diabetes20, 424. Nerup, J. and C. Binder (1973). Acta Endocrinol. 72, 279. Prete, G. F. D., C. Betterle, D. Padovan, G. Erle, A. Toffolo and G. Bersahi (1977). Diabetes26, 909. Saito, S. The intractable diseases-designated by Health and Welfare Ministry. Hashimoto's thyroiditis, p.237 (1975).(In Japanese) Seligmann, M., A. Cannat and M. Hamard (1965). Ann. N. Y. Acad. Sci. 124, 816. is exhausted. In this study, the prevalence of PCA, antimicrosomal antibodies in IDD showed the lowest percent in the40-69yearage group, however, those of auto-antibodies in normal controls were progressively greater with age. Irvine et al. found no significant difference in the prevalence of thyroid antibodies, PCA between0-39 years and more than40years of IDD. Oohira (1975) divided IDD into three age groups (29, 30-49, 50 ) and detected PCA at the highest prevalence in the30-40 year-age group and the lowest prevalence in more than50year-age group. In this study, a tendency of decrease in the prevalence of antimicrosomal antibodies and PCA with aging was also found. A possible explanation for this reason might be that most of our0-20year-age group of IDD suffered from the disease of short duration and that in the41-69year-age group it was of long duration. The high prevalence of these antibodies in the younger age group may be due to the influence of the duration of diabetics. On the other hand, ANF showed a progressive increase with age in IDD and normal controls. It is very interesting that organ-specific autoantibodies such as I. C. Ab., PCA, antimicrosomal antibodies and organ non-specific autoantibodies such as ANF showed opposite behavior in IDD. This evidence suggests the fact that organ specific antibodies including I. C. Ab. are more responsible for the pathogenesis in IDD than organ-specific autoantibodies.