HLA Antigens in Japanese Patients with Diabetes Mellitus Yoshinobu Nakao, M.D.,* Takanobu Fukunishi, M.D.,t Misako Koide, M.D.,% Kazuyoshi Akasawa, M.D.,t Masaki Ikeda, M.D.,§ Mikio Yahata, M.D.,*h and Hiroo Imura, M.D.,* Kobe, Nishinomiya, Kyoto, and Osaka, Japan
SUMMARY
Lymphocytes of 84 Japanese patients with diabetes mellitus and 150 normal controls were tested for HLA antigens by the microcytotoxicity test. HLA-B12 was found in 37.5 per cent of 32 patients with juvenile-onset diabetes mellitus, 13.5 per cent of 52 patients with late-onset diabetes, and 9.3 per cent of 150 normal controls. In the insulin-dependent juvenile form, HLA-B12 was associated with the disease more frequently and at a significant level (p 11.13t 0.0050.001 0.130.026 11 2 0.001> 14.68f 0.001-0.0005 0.0260.013
5 6.40 0.0250.01 0.650.026 4 4.72 0.050.025 1.30.65 8 7.53 0.010.005 0.260.13 5 7.00 0.010.005 0.260.13 3 3.90 0.050.025 1.30.65
7 0.07
7 0.002
17 0.71
13 2.24 0.500.01 13-
2.6 4 0.28
•"Corrected p value was calculated by multiplying p value by number of antigens tested. fStatistically significant. 738
DIABETES, VOL. 2 6 , NO. 8
YOSHINOBU NAKAO, M.D., AND ASSOCIATES
valid, 21 HLA-B12 can be associated with immuneresponse genes controlling the development of cellmediated immunity to infectious agents, which in turn may destroy pancreatic islet cells, thus causing insulin-dependent diabetes. Our present study suggests that there are genetically at least two different types of diabetes. The juvenile form of diabetes appears to be associated with histocompatibility antigens. Late-onset diabetes is shown by these data to be genetically different from juvenile diabetes, and therefore this is further evidence for heterogeneity of diabetes within the Japanese population, as has been demonstrated in the Caucasian population. ACKNOWLEDGMENTS The authors are grateful to Dr. R. T. Smith, Department of Pathology, University of Florida, and Dr. M. M. Yokoyama, Department of Pathology, University of Illinois, for their reviewing this manuscript. The skillful technical assistance of Miss Y. Itoo and Mr. S. Matsuda and the help of Mr. K. Nakane are also gratefully acknowledged. This work was supported in part by a Grant for Specific Disease from the Japanese Ministry of Health and Welfare. REFERENCES 'McDevitt, H. O., and Benacerraf, B.: Genetic control of specific immune responses. Adv. Immunol. 22:31-74, 1969. 2 McDevitt, H. O., and Bodmer, W. F.: HLA, immune response genes and disease. Lancet 2:1296-1375, 1974. 3 Svejgaard, A., Platz, P., Ryder, L. P., Nielsen, L. S., and Bacon, L. P.: HLA and disease associations. Transplant. Rev. 22:3-43, 1975. 4 Rose, N. R., Kite, J. H., Vladutiu, A. O., Tomazic, V., and Bacon, L. D.: Genetic aspects of autoimmune thyroiditis. Int. Arch. Allergy Appl. Immunol. 4.5:138-49, 19735 Gasser, D. L., Newbin, C. M., Palm, J., and Gonatas, N. K.: Genetic control of susceptibility to experimental allergic encephalomyelitis in rats. Science 282:872-73, 1975. 6 Maugh, T. H.: Diabetes, epidemiology suggests a viral connection. Science 288:347-51, 1975.
AUGUST, 1977
7
MacCuish, A. C , Jordan, J., Campbell, C. J., Duncan, L. J. P., and Irvine, W. J.: Cell-mediated immunity to human pancreas in diabetes mellitus. Diabetes 23:693-97, 1974. 8 Lendrum, R., Waker, G., and Gamble, D. R.: Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Lancet 2: 880-87, 1975. 9 MacLaren, NxK., Huang, S. W., and Fogh, J.: Antibody to cultured human insulinoma cells in insulin-dependent diabetes. Lancet 2:997-1000, 1975. 10 Nerup, J., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Poulsen, J. E., Ryder, L. P., Nielsen, L. S., Thomsen, M., and Svejgaard, A.: HLA antigens and diabetes mellitus. Lancet 2:864-70, 1974. u Cudworth, A. G., and Woodrow, J. C : HLA system and diabetes mellitus. Diabetes 24:345-49, 1975. 12 Bodmer, J.: A serological report of the 6th Histocompatibility Testing Workshop. Histocompatibility Testing 1975. Kissmeyer-Nielsen, F., Ed. Copenhagen, Munksgaard. 13 Mittal, K. K., Mickey, M. R., Singal, D. P., and Terasaki, P. I.: Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:913-27, 1968. 14 Bottazzo, G. F., Florin-Christensen, A., and Doniach, D.: Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279-82, 1974. 15 Grumet, F. C , Payne, R. O., Konishi, J., and Krriss, J. P.: HLA antigens as marker for disease susceptibility and autoimmunity in Graves' disease. J. Clin. Endocrinol. Metab. 39:1115-19, 1974. 16 Thomsen, M., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Nerup, J., Rasmussen, K., Ryder, L. P., Nielsen, L. S., and Svejgaard, A.: MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant. Rev. 22:125-47, 1975. 17 Nakao, Y., Kishihara, M., Kuma, K., and Imura, H.: HLA antigens in autoimmune thyroid diseases in Japanese population. Clin. Immunol. 8:931-38, 1976. 18 Grumet, F. C , Payne, R. O., Konishi, J., Mori, T., and Krriss, J. P.: HLA antigens in Japanese patients with Graves' disease. Tissue Antigens 6:347, 1975. 19 Strober, W., Falchuk, Z. M., Rogentine, G. N., Nelson, D. L., and Klaeveman, H. L.: The pathogenesis of gluten-sensitive enteropathy. Ann. Intern. Med. 83:242-56, 1975. 20 Thomsen, M., Platz, J., Marks, J., Ryder, L. P., Shuster, S., Svejgaard, A., and Young, S. H.: Association of LD-8a and LD-12a with dermititis herpetiformis. Tissue Antigens 7:60-62, 1976. 2 'Gamble, D. R., Taylor, K. W., and Cumming, H.: Coxsackie viruses and diabetes mellitus. Br. Med. J. 4:260-62, 1973.
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SUMMARY
Lymphocytes of 84 Japanese patients with diabetes mellitus and 150 normal controls were tested for HLA antigens by the microcytotoxicity test. HLA-B12 was found in 37.5 per cent of 32 patients with juvenile-onset diabetes mellitus, 13.5 per cent of 52 patients with late-onset diabetes, and 9.3 per cent of 150 normal controls. In the insulin-dependent juvenile form, HLA-B12 was associated with the disease more frequently and at a significant level (p 11.13t 0.0050.001 0.130.026 11 2 0.001> 14.68f 0.001-0.0005 0.0260.013
5 6.40 0.0250.01 0.650.026 4 4.72 0.050.025 1.30.65 8 7.53 0.010.005 0.260.13 5 7.00 0.010.005 0.260.13 3 3.90 0.050.025 1.30.65
7 0.07
7 0.002
17 0.71
13 2.24 0.500.01 13-
2.6 4 0.28
•"Corrected p value was calculated by multiplying p value by number of antigens tested. fStatistically significant. 738
DIABETES, VOL. 2 6 , NO. 8
YOSHINOBU NAKAO, M.D., AND ASSOCIATES
valid, 21 HLA-B12 can be associated with immuneresponse genes controlling the development of cellmediated immunity to infectious agents, which in turn may destroy pancreatic islet cells, thus causing insulin-dependent diabetes. Our present study suggests that there are genetically at least two different types of diabetes. The juvenile form of diabetes appears to be associated with histocompatibility antigens. Late-onset diabetes is shown by these data to be genetically different from juvenile diabetes, and therefore this is further evidence for heterogeneity of diabetes within the Japanese population, as has been demonstrated in the Caucasian population. ACKNOWLEDGMENTS The authors are grateful to Dr. R. T. Smith, Department of Pathology, University of Florida, and Dr. M. M. Yokoyama, Department of Pathology, University of Illinois, for their reviewing this manuscript. The skillful technical assistance of Miss Y. Itoo and Mr. S. Matsuda and the help of Mr. K. Nakane are also gratefully acknowledged. This work was supported in part by a Grant for Specific Disease from the Japanese Ministry of Health and Welfare. REFERENCES 'McDevitt, H. O., and Benacerraf, B.: Genetic control of specific immune responses. Adv. Immunol. 22:31-74, 1969. 2 McDevitt, H. O., and Bodmer, W. F.: HLA, immune response genes and disease. Lancet 2:1296-1375, 1974. 3 Svejgaard, A., Platz, P., Ryder, L. P., Nielsen, L. S., and Bacon, L. P.: HLA and disease associations. Transplant. Rev. 22:3-43, 1975. 4 Rose, N. R., Kite, J. H., Vladutiu, A. O., Tomazic, V., and Bacon, L. D.: Genetic aspects of autoimmune thyroiditis. Int. Arch. Allergy Appl. Immunol. 4.5:138-49, 19735 Gasser, D. L., Newbin, C. M., Palm, J., and Gonatas, N. K.: Genetic control of susceptibility to experimental allergic encephalomyelitis in rats. Science 282:872-73, 1975. 6 Maugh, T. H.: Diabetes, epidemiology suggests a viral connection. Science 288:347-51, 1975.
AUGUST, 1977
7
MacCuish, A. C , Jordan, J., Campbell, C. J., Duncan, L. J. P., and Irvine, W. J.: Cell-mediated immunity to human pancreas in diabetes mellitus. Diabetes 23:693-97, 1974. 8 Lendrum, R., Waker, G., and Gamble, D. R.: Islet-cell antibodies in juvenile diabetes mellitus of recent onset. Lancet 2: 880-87, 1975. 9 MacLaren, NxK., Huang, S. W., and Fogh, J.: Antibody to cultured human insulinoma cells in insulin-dependent diabetes. Lancet 2:997-1000, 1975. 10 Nerup, J., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Poulsen, J. E., Ryder, L. P., Nielsen, L. S., Thomsen, M., and Svejgaard, A.: HLA antigens and diabetes mellitus. Lancet 2:864-70, 1974. u Cudworth, A. G., and Woodrow, J. C : HLA system and diabetes mellitus. Diabetes 24:345-49, 1975. 12 Bodmer, J.: A serological report of the 6th Histocompatibility Testing Workshop. Histocompatibility Testing 1975. Kissmeyer-Nielsen, F., Ed. Copenhagen, Munksgaard. 13 Mittal, K. K., Mickey, M. R., Singal, D. P., and Terasaki, P. I.: Serotyping for homotransplantation. XVIII. Refinement of microdroplet lymphocyte cytotoxicity test. Transplantation 6:913-27, 1968. 14 Bottazzo, G. F., Florin-Christensen, A., and Doniach, D.: Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279-82, 1974. 15 Grumet, F. C , Payne, R. O., Konishi, J., and Krriss, J. P.: HLA antigens as marker for disease susceptibility and autoimmunity in Graves' disease. J. Clin. Endocrinol. Metab. 39:1115-19, 1974. 16 Thomsen, M., Platz, P., Andersen, O. O., Christy, M., Lyngsoe, J., Nerup, J., Rasmussen, K., Ryder, L. P., Nielsen, L. S., and Svejgaard, A.: MLC typing in juvenile diabetes mellitus and idiopathic Addison's disease. Transplant. Rev. 22:125-47, 1975. 17 Nakao, Y., Kishihara, M., Kuma, K., and Imura, H.: HLA antigens in autoimmune thyroid diseases in Japanese population. Clin. Immunol. 8:931-38, 1976. 18 Grumet, F. C , Payne, R. O., Konishi, J., Mori, T., and Krriss, J. P.: HLA antigens in Japanese patients with Graves' disease. Tissue Antigens 6:347, 1975. 19 Strober, W., Falchuk, Z. M., Rogentine, G. N., Nelson, D. L., and Klaeveman, H. L.: The pathogenesis of gluten-sensitive enteropathy. Ann. Intern. Med. 83:242-56, 1975. 20 Thomsen, M., Platz, J., Marks, J., Ryder, L. P., Shuster, S., Svejgaard, A., and Young, S. H.: Association of LD-8a and LD-12a with dermititis herpetiformis. Tissue Antigens 7:60-62, 1976. 2 'Gamble, D. R., Taylor, K. W., and Cumming, H.: Coxsackie viruses and diabetes mellitus. Br. Med. J. 4:260-62, 1973.
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