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Autoantibody profile in autoimmune hepatitis and HLA class II
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PI53 AUTOANTIBODY PROFILE IN AUTOIMMUNE HEPATITIS AND HLACLASSII Goldberg. A. C.; Bitlencourt, P.L.; Porta, G.; cancado, E. R.• taudanna, A..A. l>. Kalil,J. Lab.Transplant Immunology-INCOR & Depl.Gastroenterology, Facully of Medicine, University of sao Paulo. sao Paulo- Brazil Autoimmune hepatitis (AH) is a progressive liver disease of unknown pathogenesis diagnosed by the presence of characteristic necrotic lesions, hyperglobulinemia and typical autoantibody profile. Type I and type II AH are defined respectively by the predominance of antibodies againstsmoothmuscle, or againstliver and kidneymicrosomal fraction.Association of HLA with susceptibility to AH has beendemonstrated in differentethnicgroups.For example. association with HLA-DR3 and 4 in anglo-saxon adults, HLA-DR4 in Japan and HLADRB1'1301 in Argentinian pediatricAH has beenshown to occur.We have typed 68 AH patients with clearcut antibody profile, using Workshop protocols and have compared HLA-DR typing of type I and type II patients. The majority of the patients (52) had type I AH and carriedpredominantly HLA-DR17 (29%) or DR13 (65%). 92% of the patients were positive for DR52, eventhough other DR52related antigens were low (DR11,12,14,18). Type II patients (n=16) had a completely differentHLA profile.69% were positivefor DRB1'0701, in contrast to 19% in type I patients and 21% in local controls.Furthermore, 88% were DR53 positive, ailhough DR4 antigens were present in normal frequency. Chi-square analysis showed associations oflype I with DR13andtype II with DR7to be highly significant. indicating that even if the same disease is diagnosed, genetic factors such as the HLA antigen profile must have an essential role in defining the ethiopathogenesis of AH.
PI55 ASSOCIATION OF AUTOIMMUNE HEPATITIS WITH THE 13TH AMINO ACID OF DRB1 CHAINS. Tetsuya Ichijou, Masao Ota", Hidetoshi Inokos, Kaname Yoshizawa, Akihiko Imai, Kendo Kiyosawa, Second Department of Internal Medicine and *Department of Legal Medicine, Shinshu University. Matsumoto. Japan, # Department of Genetic Information. Tokai University. Isehara, Japan. So far we have investigated the association between autoimmune hepatitis and HLA alleles in total 72 Japanese patients (last time we presented 53 patients I) by using serological typing and DNA typing(PCR-RFLP). This additional study showed that HLA-DR4 was significantly associated with autoimmune hepatitis than in control and DR4-negative patients had DR2 antigens without exception as we reported previously I). DNA typing showed a significant high frequency of DRB1*0405 in autoimmune hepatitis. These further findings convince that the basic amino acid at position 13 contributes to the susceptibility to autoimmune hepatitis among the Japanese. 1): Seki, T .• Ota, M. et al .• Gastroenterology. 1992. 103: 1041-1047.
Abstracts
PI54
HLA DRB*1301-Q2 PREVENTS FROM NON-RESPONSIVENESS AGAINST HBs-Ag IMMUNIZATION AND FROM CHRONIC HEPATITIS B; HLA DRB1*0301 and C4A*QO ARE FACTORS AT RISK Rittner Christian. Gerken Guido. NOlghi Arman, Stradmann-Bellinghausen Beate, Everke Petra, Taheri Horna, Hohler Thomas. Meyer zum BOschenfelde Kari-Hermann, Starke Roland, Schneider Peter M. Institute of Legal Medicine, I. Medical Clinic. Johannes Gutenberg University, Mainz; SmithKline Beecham Pharrna, Munich. Germany. The Major Histocompatibility Complex plays an important role in susceptibility for liver disease as shown for chronic Hepatitis C (Hohler et aI., subm.), and for autoimmune hepatitis and PBC (Manns et al.• 1991). The MHC. especially the extended haplotypes B8,SeOl.DRS and B44.FC31. DR7. were found to be risk haplotypes for non-response to HBs-Ag immunization (Craven et at, 1986). We demonstrate in 66 non-responders against Engerix BR compared to 101 normal controls that individuals carrying DRB1'0301 (RR 5.14. P < 0.001) and C4A'OO (RR 2.6. p:0.003) are at risk for non-response. In 53 pati-ents with chronic hepatitis B infection DRB1'0301 is elevated (though not significant after correction). and C4A*OO carriers have a RR of 2.64 (p=O.003). In contrast. in both groups. DRB1'1301-02 is protective (RR for non-response 0.13. p < 0.001; for chronic Hepatitis B 0.174. p=O.OOI). We conclude that both, defective T cell-antigen-presenting cell interaction and impaired neutralization of HBV may lead to chronic hepatitis B. [Supported by Deutsche Forschungsgemeinschaft. SFB 311. and Smith-Kline Beecham Pharrna.]
PI56
SLA POSITIVE AUTOIMMUNE HEPATITIS IS STRONGLY ASSOCIATED WITH HLA DR3 DF Chen', HL Tillrnann-', W Endres3, 8 Uittig2 • C Stra(l,burg2 , LT Pastucha", M Robin-Winn ', W Stangel', MP Manns 2 'Blood
Bank-Immunohematology-Transfusion
Medicine,
20 ept.
of
Gastroenterology & Hepatology. Medical University of Hannover, FRG. 3Dept. of TransfusionMedicine/Med III, University of Munich, FRG. Classical autoimmune hepatitis characterized by antinuclear and smooth muscle antibodies is associated with the HLA-DR3 or DR4. In 1987 we defined a new subtype of autoimmune hepatitis, which is characterized by autoantibodies against soluble liver antigen ISLAI (Manns et al., 1987). To investigate the relationship between SLA and HLA antigens, we analyzed the phenotype frequencies of HLA-A, ORB, DCA and DOB alleles in 27 patients suffering from autoimmune hepatitis with autoantibodies against SLA and in 163 blood donors (controlsl, DRB, DQA and DOB were typed using PCR-ssa technique (Chen et al, 1994). HLA-A locus was analyzed by serology and/or PCRSSP (Dynall. Increased frequencies of HLA-Al Ip=0.0021, DR3 (p = 0.00000. RR= 7 .3). DOA1 '0501 (p = 0.0004, RR= 5.81 and D081 '0201 (p=0.007) were found in SLA patients compared to controls. Further-more. decreased frequencies of DR2 (p=0.02), DR7 Ip=0.02). DCA1'0201 I F=0.047) and D081 '0602 (p=O.Ol) were detected. After correction by multiplying the p values with the number of HLA alleles tested, only the higher frequencies of DR3 and DQA 1 '0501 remain significant. We conclude that the presence of autoantibodies against SLA is strongly associated with HLA-DR3 antigen, while no association was found for HLA-DR4.
PI5S
THE RELATIONSHIP BETWEEN THE CLINICAL COURSE, PATHOLOGIC FINDINGS AND HLA ANTIGENS IN GRAVES' DISEASE. Bubnov A.N., Trunin E.M., Kuzmichev A.S., Zubareva T.S .• Lysova L.V.• Novoseltzev K. Medical Academy Postgraduate Education,St.Petersburg, Russia Graves' disease is HLA-linked organospecific autoimmune disease. In our region it is associated with HLA-B8 and HLA-DR3. 145 Caucacian Graves' disease patients. operated in our surgical clinic. were divided into two groups according to presence of HLA-B8+DR3 (87 pts) or absence both of these HLA antigens (58 pts). Comparison of the clinic and morphologic features of the patients revealed that the patients of the group with HLA-B8+DR3 were younger, than those without these antigens when the onset of Graves' disease had been diagnosed. Average difference between the groups was about 5 years. Ophtalmopathy was diagnosed in 21 (87) - 24,1% pts with HLA-B8+DR3 and in 5 (58) - 8,6% without them. The thyroid stimulating immunoglobUlins were found in 39 (87) - 43,6% pts with HLA-B8+DR3 against 5 (58) - 10.2% pts without these antigens. The relapse of Graves' disease after subtotal thyroidectomy was registred in 7 (8,1%) pts of the first group and 1 (58) -1.8% pts of the second group.
PI53 AUTOANTIBODY PROFILE IN AUTOIMMUNE HEPATITIS AND HLACLASSII Goldberg. A. C.; Bitlencourt, P.L.; Porta, G.; cancado, E. R.• taudanna, A..A. l>. Kalil,J. Lab.Transplant Immunology-INCOR & Depl.Gastroenterology, Facully of Medicine, University of sao Paulo. sao Paulo- Brazil Autoimmune hepatitis (AH) is a progressive liver disease of unknown pathogenesis diagnosed by the presence of characteristic necrotic lesions, hyperglobulinemia and typical autoantibody profile. Type I and type II AH are defined respectively by the predominance of antibodies againstsmoothmuscle, or againstliver and kidneymicrosomal fraction.Association of HLA with susceptibility to AH has beendemonstrated in differentethnicgroups.For example. association with HLA-DR3 and 4 in anglo-saxon adults, HLA-DR4 in Japan and HLADRB1'1301 in Argentinian pediatricAH has beenshown to occur.We have typed 68 AH patients with clearcut antibody profile, using Workshop protocols and have compared HLA-DR typing of type I and type II patients. The majority of the patients (52) had type I AH and carriedpredominantly HLA-DR17 (29%) or DR13 (65%). 92% of the patients were positive for DR52, eventhough other DR52related antigens were low (DR11,12,14,18). Type II patients (n=16) had a completely differentHLA profile.69% were positivefor DRB1'0701, in contrast to 19% in type I patients and 21% in local controls.Furthermore, 88% were DR53 positive, ailhough DR4 antigens were present in normal frequency. Chi-square analysis showed associations oflype I with DR13andtype II with DR7to be highly significant. indicating that even if the same disease is diagnosed, genetic factors such as the HLA antigen profile must have an essential role in defining the ethiopathogenesis of AH.
PI55 ASSOCIATION OF AUTOIMMUNE HEPATITIS WITH THE 13TH AMINO ACID OF DRB1 CHAINS. Tetsuya Ichijou, Masao Ota", Hidetoshi Inokos, Kaname Yoshizawa, Akihiko Imai, Kendo Kiyosawa, Second Department of Internal Medicine and *Department of Legal Medicine, Shinshu University. Matsumoto. Japan, # Department of Genetic Information. Tokai University. Isehara, Japan. So far we have investigated the association between autoimmune hepatitis and HLA alleles in total 72 Japanese patients (last time we presented 53 patients I) by using serological typing and DNA typing(PCR-RFLP). This additional study showed that HLA-DR4 was significantly associated with autoimmune hepatitis than in control and DR4-negative patients had DR2 antigens without exception as we reported previously I). DNA typing showed a significant high frequency of DRB1*0405 in autoimmune hepatitis. These further findings convince that the basic amino acid at position 13 contributes to the susceptibility to autoimmune hepatitis among the Japanese. 1): Seki, T .• Ota, M. et al .• Gastroenterology. 1992. 103: 1041-1047.
Abstracts
PI54
HLA DRB*1301-Q2 PREVENTS FROM NON-RESPONSIVENESS AGAINST HBs-Ag IMMUNIZATION AND FROM CHRONIC HEPATITIS B; HLA DRB1*0301 and C4A*QO ARE FACTORS AT RISK Rittner Christian. Gerken Guido. NOlghi Arman, Stradmann-Bellinghausen Beate, Everke Petra, Taheri Horna, Hohler Thomas. Meyer zum BOschenfelde Kari-Hermann, Starke Roland, Schneider Peter M. Institute of Legal Medicine, I. Medical Clinic. Johannes Gutenberg University, Mainz; SmithKline Beecham Pharrna, Munich. Germany. The Major Histocompatibility Complex plays an important role in susceptibility for liver disease as shown for chronic Hepatitis C (Hohler et aI., subm.), and for autoimmune hepatitis and PBC (Manns et al.• 1991). The MHC. especially the extended haplotypes B8,SeOl.DRS and B44.FC31. DR7. were found to be risk haplotypes for non-response to HBs-Ag immunization (Craven et at, 1986). We demonstrate in 66 non-responders against Engerix BR compared to 101 normal controls that individuals carrying DRB1'0301 (RR 5.14. P < 0.001) and C4A'OO (RR 2.6. p:0.003) are at risk for non-response. In 53 pati-ents with chronic hepatitis B infection DRB1'0301 is elevated (though not significant after correction). and C4A*OO carriers have a RR of 2.64 (p=O.003). In contrast. in both groups. DRB1'1301-02 is protective (RR for non-response 0.13. p < 0.001; for chronic Hepatitis B 0.174. p=O.OOI). We conclude that both, defective T cell-antigen-presenting cell interaction and impaired neutralization of HBV may lead to chronic hepatitis B. [Supported by Deutsche Forschungsgemeinschaft. SFB 311. and Smith-Kline Beecham Pharrna.]
PI56
SLA POSITIVE AUTOIMMUNE HEPATITIS IS STRONGLY ASSOCIATED WITH HLA DR3 DF Chen', HL Tillrnann-', W Endres3, 8 Uittig2 • C Stra(l,burg2 , LT Pastucha", M Robin-Winn ', W Stangel', MP Manns 2 'Blood
Bank-Immunohematology-Transfusion
Medicine,
20 ept.
of
Gastroenterology & Hepatology. Medical University of Hannover, FRG. 3Dept. of TransfusionMedicine/Med III, University of Munich, FRG. Classical autoimmune hepatitis characterized by antinuclear and smooth muscle antibodies is associated with the HLA-DR3 or DR4. In 1987 we defined a new subtype of autoimmune hepatitis, which is characterized by autoantibodies against soluble liver antigen ISLAI (Manns et al., 1987). To investigate the relationship between SLA and HLA antigens, we analyzed the phenotype frequencies of HLA-A, ORB, DCA and DOB alleles in 27 patients suffering from autoimmune hepatitis with autoantibodies against SLA and in 163 blood donors (controlsl, DRB, DQA and DOB were typed using PCR-ssa technique (Chen et al, 1994). HLA-A locus was analyzed by serology and/or PCRSSP (Dynall. Increased frequencies of HLA-Al Ip=0.0021, DR3 (p = 0.00000. RR= 7 .3). DOA1 '0501 (p = 0.0004, RR= 5.81 and D081 '0201 (p=0.007) were found in SLA patients compared to controls. Further-more. decreased frequencies of DR2 (p=0.02), DR7 Ip=0.02). DCA1'0201 I F=0.047) and D081 '0602 (p=O.Ol) were detected. After correction by multiplying the p values with the number of HLA alleles tested, only the higher frequencies of DR3 and DQA 1 '0501 remain significant. We conclude that the presence of autoantibodies against SLA is strongly associated with HLA-DR3 antigen, while no association was found for HLA-DR4.
PI5S
THE RELATIONSHIP BETWEEN THE CLINICAL COURSE, PATHOLOGIC FINDINGS AND HLA ANTIGENS IN GRAVES' DISEASE. Bubnov A.N., Trunin E.M., Kuzmichev A.S., Zubareva T.S .• Lysova L.V.• Novoseltzev K. Medical Academy Postgraduate Education,St.Petersburg, Russia Graves' disease is HLA-linked organospecific autoimmune disease. In our region it is associated with HLA-B8 and HLA-DR3. 145 Caucacian Graves' disease patients. operated in our surgical clinic. were divided into two groups according to presence of HLA-B8+DR3 (87 pts) or absence both of these HLA antigens (58 pts). Comparison of the clinic and morphologic features of the patients revealed that the patients of the group with HLA-B8+DR3 were younger, than those without these antigens when the onset of Graves' disease had been diagnosed. Average difference between the groups was about 5 years. Ophtalmopathy was diagnosed in 21 (87) - 24,1% pts with HLA-B8+DR3 and in 5 (58) - 8,6% without them. The thyroid stimulating immunoglobUlins were found in 39 (87) - 43,6% pts with HLA-B8+DR3 against 5 (58) - 10.2% pts without these antigens. The relapse of Graves' disease after subtotal thyroidectomy was registred in 7 (8,1%) pts of the first group and 1 (58) -1.8% pts of the second group.