clinical immunology 10 Rajnav61gyi,I~., Hudecz, F., Mez6, G. et al. (1986) Mol Immunol. 23, 27-37 11 Mez6, G., Szekerke, M., Kurucz, 1. et al. (1989) in Peptides 1988, Proc. 20th Eur. Peptide Syrup. (Bayer, D. and Jung, G., eds), pp. 701-703, Walter de Gruyter, Berlin 12 Dietzschold, B., Heber-Katz, E., Hudecz, F. et al. (1985; in Vaccines 85 (Lerner, R.A., Cbanock, R.M. and Brown, F.,
eds), pp. 227-234, Cold Spring Harbor Laboratory Press 13 Heber-Katz, E., Holl6si, M., Dietzschold, B. et al. (1985) J. hnmunol. 135, 1385-1390 14 Ralnav6lgyi, I~., L~nyi, A., Hudecz, F. et al. (1989) Mol. lmmunol. 26, 949-958 15 Hudecz, F. and Price, M.R. (1992)J. lmmunol. Meth. 147, 20[-21()
Susceptibility to autoimmune disease: a multigenic viewpoint G. Gy. Petrfinyi In Hungary, analysis of genetic predisposition to disease has generally been studied from a multigenic point of view. Alongside markers of the HLA system, other blood groups and allotypes of immunoglobulins and complement components have been studied. These have been correlated with functional parameters in different autoimmune conditions. This article reviews the findings of multiparameter analysis of three common autoimmune conditions, namely Graves' disease, systemic lupus erythematosus (SLE) and multiple sclerosis.
Graves' disease Gene frequencies were studied in 534 patients with clinically verified Graves' disease. The positive association between the disease and HLA-B8 and DR3 was confirmed and a negative association with DR5 revealed, particularly in connection with Graves' ophthalmopathy. The recessive inheritance of HLA-related susceptibility to Graves' disease over a range of gene frequencies was found to be 0.2-0.4. A correlation between the disease and the immunoglobulin G (IgG) allotype Gm (fb) was also unearthed. It was gene dosage dependent but was independent of the DR3 association 1-3. The known genetic heterogeneity within Graves' disease was further demonstrated by cluster analysis. Patients were divided, on the basis of disease activity, into group I (mild disease: good response to treatment, less marked evidence of autoaggression), group IIa (thyrotoxicosis and autoimmune thyroiditis), and group lib (severe relapsing disease, large goitres, family history of autoimmune disease). HLA-B8 was found in 9% of patients in group I, 21% in group lid and 87% in group IIb; 18% of normal controls were B8 + (Refs 4 and 5). A basic, significant connection between Graves' hyperthyroidism, infiltrative ophthalmopathy and HLA type has been identified. With Graves' disease per se there is a closer association with DR3 than with B8; the opposite is true for patients with ophthalmopathy. DR7 enhanced the risk of ophthalmopathy in the presence of B8 and the B8-DR7 phenotype was found to be associated with antibodies against eye muscle antigens. In contrast, in the absence of B8, DR7 was negatively associated with ophthalmopathy. Gm allotypes, considered in isolation,
showed no association with eye disease but did modify the risk for ophthalmopathy associated with B8. These findings are in keeping with the suggestion that Graves' ophthalmopathy is a separate autoimmune disease that overlaps with Graves' hyperthyroidism 6,v. In an effort to tease out the connection between the genetic associations and the mechanism of pathogenesis, we have uncovered a complex relationship among numerous factors, including lymphocytotoxic antibodies, increased C4 levels, increased "¢ globulins, T-cell proliferation to thyroglobulin, DR3 positivity and resistance to conventional therapy 4,6. The presentation to T cells of thyroid-specific antigens by major histocompatibility complex (MHC) class-IF positive thyroid cells has been proposed to be a critical event in the development of Graves' disease. Expression of MHC class II can be induced by gamma-interferon (IFN-~/) or by autoantibody to thyroid-stimulating hormone (TSH). Interestingly, methimazole, a standard therapy for Graves' patients, inhibits in vitro autoantibody-induced, but not IFN-~/-induced, MHC class II expression. This correlates well with clinical findings: in patients successfully treated with methimazole, DR expression in the thyroid is reduced to background levels while thyroid DR expression is still marked in methimazole-resistant patients 4,8.
Systemic lupus erythematosus Thirty-nine different laboratory and clinical parameters, including expression of HLA-A, B, C and DR, were analysed for 75 patients with SLE, using a cluster analysis technique. Three groups of patients were identified. Group I (46 patients) was characterized by lack of severity of disease, good response to therapy and infrequent multisystem involvement. Group II patients (24 patients) suffered a severe course of disease (although the tendency to remit after therapy was not unusual), and,
© 1992, ElsevierScience Publishers itd, UK
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clinical immunology frequently, renal involvement and pericarditis. Group III individuals (five patients) had a still more severe renal disease. Of the 75 patients studied, 39% were HLA-DR3+, compared to 17% of controls. Group I patients did not differ from the controls but 80% of group II patients and four out of five group III patients were DR3 ÷. Thus, the cluster analysis, based on differences in disease course and severity, revealed correlations between these features and possession of the HLA-B8-DR3 phenotype 9. One feature of SLE is mixed connective tissue disease. The correlation between the presence of various antibodies, the relationships between them, and the clinical symptoms of mixed connective tissue disease were studied. Anti-monocytic antibodies were associated with the presence of antibodies to endothelial cells, but not with antibodies to lymphocytes. The occurrence of the autoantibodies to monocytes and endothelial cells was linked to clinical symptoms, such as myocardial, pulmonary and neurophysiological symptoms, while there was no connection between these parameters and HLA alleles 1°.
Multiple sclerosis Some central european gypsy communities still live in social isolation and this has preserved immunogenetic peculiarities, such as the lack of HLA-B7 and the frequent occurrence of DR2. Despite the fact that DR2 is associated with multiple sclerosis, the incidence of multiple sclerosis appears to be tenfold less among gypsies than in Caucasians living in the same geographic area 11,12. A close connection between multiple sclerosis and DQwl has also been uncovered. DQwl can be subtyped to 5.2kb and 2.6kb DQI3 restriction fragment length polymorphism (RFLP) fragments. We have examined these DQI3 RFLPs in DR2 + Caucasian and gypsy mul-
tiple sclerosis patients and in healthy controls of both groups. The control healthy Caucasians carried the subtypes at an equal level (56%), while in the group of healthy gypsies, surprisingly, only the 2.6 kb fragment was detected. Of the Caucasian multiple sclerosis patients, 88 % were positive for the 5.2 kb fragment, and only 60% for the 2.6 kb type, while in the gypsy multiple sclerosis patients, the subtypes occurred with an even distribution. Two conclusions may be drawn from this study: first, the 5.2 kb DQI3 fragment is a better susceptibility marker for multiple sclerosis than any previously defined marker and, secondly, the rarity of this subtype in healthy gypsies may be associated with the low prevalence of multiple sclerosis in this ethnic group 13,14. Multiple sclerosis is associated with various immunopathological phenomena, probably based on defective immune reactivity to viral infection and myeloid basic protein. Certain immune parameters in multiple sclerosis, such as low natural killer (NK) cell activity and antibody-dependent cell cytotoxicity (ADCC) correlate with the presence of HLA-B7 or DR2, but others, such as decreased IFN-~ and IFN-~ and interleukin 6 (IL-6) production, do not. It is suggested that the various pathological immune functions in multiple sclerosis are based on both HLA and non-HLA associations 15-17. Gy6z6 Petrdnyi is at the National Institute of Haematology and Blood Transfusion, Dar6czi ~t 24, Budapest, H-1113 Hungary.
References 1 Stenszky, V., Kozma, L., Ballizs, Cs. et al. (1985)J. Clin. Endocrinol. Metabol. 61,735-740
2 Kozma, L., Stenszky, V., Kraszits, E. et al. (1985) Exp. Clin. lmmunogenet. 2, 154-157 3 Frecker, M., Stenszky, V., Balfizs, Cs. et al. (1986) Clin. Endocrinol. 25, 479-485 4 Stenszky, V., Kozma, L., Balfizs, Cs. et al. (1986) Mol. Biol. Med. 3, 53-62
5 Stenszky, V., Bal~izs, Cs., Kozma, L. et al. (1983) Clin. Endocrinol. 18,335-345
6 Balfizs, Cs., Bokk, A., Moln~ir, I. et al. (1989) Exp. Clin. lmmunogenet. 6, 190-192 7 Payami, H., Joe, Sh., Farid, N.R. et al. (1989) Am. J. Hum. Genet. 45,541-546
8 Bodolay, E., Sur~inyi,P., Juhfisz, F. et al. (1988) Immunol. Lett. 18, 167-172 9 Stenszky, V., Kozma, L., Szegedi, Gy. et al. (1986) J. Immunogenet. 13,327-340 10 Bodolay, E., Bojan, F., Szegedi, Gy. et al. (1989) Immunol. Lett. 20, 163-168 11 Gy6di, 1~.,Tauszik, T., Petrfinyi, G. Gy. et al. (1981) Tissue Antigens 18, 1-12 12 Petr~inyi,G. Gy. and Hollfin, S.R. (1980) Tissue Antigens 16, 1-22 13 Tak~ics,K., K~ilm~in,B., Gy6di, 1~. etal. (1990) Immunogenetics 31,383-385 14 K~ilmfin,B., Takfics, K., Gy6di, 1~.etal. (1991) Acta Neurol. Scand. 84, 181-185 15 Gy6di, I~., Benczfir,M., Pfilffy,Gy. et al. (1982) Hum. Immunol. 4, 209-217 16 Benczfir, M., Petrfinyi, G. Gy., Pfilffy,Gy. et al. (1980) Clin. Exp. Immunol. 39, 657-662 17 St6ger, I., Tfilas, M., Benczfir, M. et al. (1982) Arch. Virol. 71,259-265
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eds), pp. 227-234, Cold Spring Harbor Laboratory Press 13 Heber-Katz, E., Holl6si, M., Dietzschold, B. et al. (1985) J. hnmunol. 135, 1385-1390 14 Ralnav6lgyi, I~., L~nyi, A., Hudecz, F. et al. (1989) Mol. lmmunol. 26, 949-958 15 Hudecz, F. and Price, M.R. (1992)J. lmmunol. Meth. 147, 20[-21()
Susceptibility to autoimmune disease: a multigenic viewpoint G. Gy. Petrfinyi In Hungary, analysis of genetic predisposition to disease has generally been studied from a multigenic point of view. Alongside markers of the HLA system, other blood groups and allotypes of immunoglobulins and complement components have been studied. These have been correlated with functional parameters in different autoimmune conditions. This article reviews the findings of multiparameter analysis of three common autoimmune conditions, namely Graves' disease, systemic lupus erythematosus (SLE) and multiple sclerosis.
Graves' disease Gene frequencies were studied in 534 patients with clinically verified Graves' disease. The positive association between the disease and HLA-B8 and DR3 was confirmed and a negative association with DR5 revealed, particularly in connection with Graves' ophthalmopathy. The recessive inheritance of HLA-related susceptibility to Graves' disease over a range of gene frequencies was found to be 0.2-0.4. A correlation between the disease and the immunoglobulin G (IgG) allotype Gm (fb) was also unearthed. It was gene dosage dependent but was independent of the DR3 association 1-3. The known genetic heterogeneity within Graves' disease was further demonstrated by cluster analysis. Patients were divided, on the basis of disease activity, into group I (mild disease: good response to treatment, less marked evidence of autoaggression), group IIa (thyrotoxicosis and autoimmune thyroiditis), and group lib (severe relapsing disease, large goitres, family history of autoimmune disease). HLA-B8 was found in 9% of patients in group I, 21% in group lid and 87% in group IIb; 18% of normal controls were B8 + (Refs 4 and 5). A basic, significant connection between Graves' hyperthyroidism, infiltrative ophthalmopathy and HLA type has been identified. With Graves' disease per se there is a closer association with DR3 than with B8; the opposite is true for patients with ophthalmopathy. DR7 enhanced the risk of ophthalmopathy in the presence of B8 and the B8-DR7 phenotype was found to be associated with antibodies against eye muscle antigens. In contrast, in the absence of B8, DR7 was negatively associated with ophthalmopathy. Gm allotypes, considered in isolation,
showed no association with eye disease but did modify the risk for ophthalmopathy associated with B8. These findings are in keeping with the suggestion that Graves' ophthalmopathy is a separate autoimmune disease that overlaps with Graves' hyperthyroidism 6,v. In an effort to tease out the connection between the genetic associations and the mechanism of pathogenesis, we have uncovered a complex relationship among numerous factors, including lymphocytotoxic antibodies, increased C4 levels, increased "¢ globulins, T-cell proliferation to thyroglobulin, DR3 positivity and resistance to conventional therapy 4,6. The presentation to T cells of thyroid-specific antigens by major histocompatibility complex (MHC) class-IF positive thyroid cells has been proposed to be a critical event in the development of Graves' disease. Expression of MHC class II can be induced by gamma-interferon (IFN-~/) or by autoantibody to thyroid-stimulating hormone (TSH). Interestingly, methimazole, a standard therapy for Graves' patients, inhibits in vitro autoantibody-induced, but not IFN-~/-induced, MHC class II expression. This correlates well with clinical findings: in patients successfully treated with methimazole, DR expression in the thyroid is reduced to background levels while thyroid DR expression is still marked in methimazole-resistant patients 4,8.
Systemic lupus erythematosus Thirty-nine different laboratory and clinical parameters, including expression of HLA-A, B, C and DR, were analysed for 75 patients with SLE, using a cluster analysis technique. Three groups of patients were identified. Group I (46 patients) was characterized by lack of severity of disease, good response to therapy and infrequent multisystem involvement. Group II patients (24 patients) suffered a severe course of disease (although the tendency to remit after therapy was not unusual), and,
© 1992, ElsevierScience Publishers itd, UK
Immunology Today
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N,,
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clinical immunology frequently, renal involvement and pericarditis. Group III individuals (five patients) had a still more severe renal disease. Of the 75 patients studied, 39% were HLA-DR3+, compared to 17% of controls. Group I patients did not differ from the controls but 80% of group II patients and four out of five group III patients were DR3 ÷. Thus, the cluster analysis, based on differences in disease course and severity, revealed correlations between these features and possession of the HLA-B8-DR3 phenotype 9. One feature of SLE is mixed connective tissue disease. The correlation between the presence of various antibodies, the relationships between them, and the clinical symptoms of mixed connective tissue disease were studied. Anti-monocytic antibodies were associated with the presence of antibodies to endothelial cells, but not with antibodies to lymphocytes. The occurrence of the autoantibodies to monocytes and endothelial cells was linked to clinical symptoms, such as myocardial, pulmonary and neurophysiological symptoms, while there was no connection between these parameters and HLA alleles 1°.
Multiple sclerosis Some central european gypsy communities still live in social isolation and this has preserved immunogenetic peculiarities, such as the lack of HLA-B7 and the frequent occurrence of DR2. Despite the fact that DR2 is associated with multiple sclerosis, the incidence of multiple sclerosis appears to be tenfold less among gypsies than in Caucasians living in the same geographic area 11,12. A close connection between multiple sclerosis and DQwl has also been uncovered. DQwl can be subtyped to 5.2kb and 2.6kb DQI3 restriction fragment length polymorphism (RFLP) fragments. We have examined these DQI3 RFLPs in DR2 + Caucasian and gypsy mul-
tiple sclerosis patients and in healthy controls of both groups. The control healthy Caucasians carried the subtypes at an equal level (56%), while in the group of healthy gypsies, surprisingly, only the 2.6 kb fragment was detected. Of the Caucasian multiple sclerosis patients, 88 % were positive for the 5.2 kb fragment, and only 60% for the 2.6 kb type, while in the gypsy multiple sclerosis patients, the subtypes occurred with an even distribution. Two conclusions may be drawn from this study: first, the 5.2 kb DQI3 fragment is a better susceptibility marker for multiple sclerosis than any previously defined marker and, secondly, the rarity of this subtype in healthy gypsies may be associated with the low prevalence of multiple sclerosis in this ethnic group 13,14. Multiple sclerosis is associated with various immunopathological phenomena, probably based on defective immune reactivity to viral infection and myeloid basic protein. Certain immune parameters in multiple sclerosis, such as low natural killer (NK) cell activity and antibody-dependent cell cytotoxicity (ADCC) correlate with the presence of HLA-B7 or DR2, but others, such as decreased IFN-~ and IFN-~ and interleukin 6 (IL-6) production, do not. It is suggested that the various pathological immune functions in multiple sclerosis are based on both HLA and non-HLA associations 15-17. Gy6z6 Petrdnyi is at the National Institute of Haematology and Blood Transfusion, Dar6czi ~t 24, Budapest, H-1113 Hungary.
References 1 Stenszky, V., Kozma, L., Ballizs, Cs. et al. (1985)J. Clin. Endocrinol. Metabol. 61,735-740
2 Kozma, L., Stenszky, V., Kraszits, E. et al. (1985) Exp. Clin. lmmunogenet. 2, 154-157 3 Frecker, M., Stenszky, V., Balfizs, Cs. et al. (1986) Clin. Endocrinol. 25, 479-485 4 Stenszky, V., Kozma, L., Balfizs, Cs. et al. (1986) Mol. Biol. Med. 3, 53-62
5 Stenszky, V., Bal~izs, Cs., Kozma, L. et al. (1983) Clin. Endocrinol. 18,335-345
6 Balfizs, Cs., Bokk, A., Moln~ir, I. et al. (1989) Exp. Clin. lmmunogenet. 6, 190-192 7 Payami, H., Joe, Sh., Farid, N.R. et al. (1989) Am. J. Hum. Genet. 45,541-546
8 Bodolay, E., Sur~inyi,P., Juhfisz, F. et al. (1988) Immunol. Lett. 18, 167-172 9 Stenszky, V., Kozma, L., Szegedi, Gy. et al. (1986) J. Immunogenet. 13,327-340 10 Bodolay, E., Bojan, F., Szegedi, Gy. et al. (1989) Immunol. Lett. 20, 163-168 11 Gy6di, 1~.,Tauszik, T., Petrfinyi, G. Gy. et al. (1981) Tissue Antigens 18, 1-12 12 Petr~inyi,G. Gy. and Hollfin, S.R. (1980) Tissue Antigens 16, 1-22 13 Tak~ics,K., K~ilm~in,B., Gy6di, 1~. etal. (1990) Immunogenetics 31,383-385 14 K~ilmfin,B., Takfics, K., Gy6di, 1~.etal. (1991) Acta Neurol. Scand. 84, 181-185 15 Gy6di, I~., Benczfir,M., Pfilffy,Gy. et al. (1982) Hum. Immunol. 4, 209-217 16 Benczfir, M., Petrfinyi, G. Gy., Pfilffy,Gy. et al. (1980) Clin. Exp. Immunol. 39, 657-662 17 St6ger, I., Tfilas, M., Benczfir, M. et al. (1982) Arch. Virol. 71,259-265
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