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Epithelial MHC class II sub-region expression in autoimmunity
Immunology Today, voL 7, No, 1, 1986
Epithelial MHC class II subregion expression in autoimmunity Sir, Inappropriate expression of MHC class II molecules may enable epithelial cells to present their own surface molecules as autoantigens and thus play a part in the propagation, and possibly in the initiation, of autoimmune pathogenesis (Ref. 1 and Immunol. Today 1984, 5, 230231). The question of HLA-D subregion expression in these circumstances, raised by Peter Johnson and Judith Bulmer (Immunol. Today 1985, 6, 71), is therefore both topical and interesting. We have recently investigated this point in thyroid glands from patients with autoimmune thyroid diseases by performing indirect immunofluorescence with monoclonal antibodies specific for monomorphic determinants of DR (DA6.164) 2, DP (B7/21) 3 and DQ (TU.22) 4. The results show that thyroid epithelium (which is normally class II negative) is induced to express the products of all three HLA-D subregions in these diseasess. There is, however, a hierarchy of expression which follows the pattern DR > DP > DQ. This is observed in the extent and intensity of expression in individual samples and is also represented by heterogeneity amongst patients. Thus, in both patients with Hashimoto's thyroiditis we have investigated, thyrocytes were positive for DR, DP and DQ but, of those Graves' disease patients with thyrocytes positive for DR (n = 11), thyrocyte expression of DP was clearly detected in ten cases, but DQ in only six. The differences are probably related to the local tissue levels of class II modulating factors, which will vary with the nature and severity of disease. This is suggested by in-vitro investigations into the requirements for class II induction in normal human thyrocytes: interferon (IFN) -y induces class II expression in thyrocytes 6, but the induction of DP and DQ to levels comparable with DR requires higher concentrations of IFN-~ or enhancing cofactors such as thyroid stimulating hormone (TSH)~'7. In autoimmune thyroid diseases, autoreactive T cells activated by class II+ thyrocytes may induce more class II expression by secreting IFN-~, and indirectly affecting other factors (e.g. the hypothyroidism associated with Hashi-
moto's thyroiditis leads to increased TJH secretion). Our results therefore suggest that the autoimmune attack is self-perpetuating, epithelial class II expression being both a cause and a consequence of the pathology. The initial epithelial class II expression postulated to trigger the autoimmune activation could be (1) induced by IFN-3, produced in response to local infection, as originally proposed 1 or (2) triggered by other agents as yet undefined. The latter is suggested in insulindependent diabetes where [3-cells of the pancreatic islets selectively express class II molecules 8, although this expression cannot be induced in cultured normal islet cells by IFN-~/9. Regarding the more general point of the functional roles of DR and DQ molecules, the retarded and more restricted tissue distribution of DQ and its relative resistance to induction by IFN--ys'11'12, suggest that its role is distinct from that of DR. On the other hand, these molecules seem to play similar roles in antigen presentation, and responses to some antigens are clearly DR or DQ restricted 13-1s. It would thus seem premature to generalize about distinct functions for different HLA-D subregion products. Rather it appears probable that different class II molecules are active in the presentation of different antigens. For example, in mice certain antigenic peptides are only presented in the context of I-A while others are presented only by I-E (Ref. 16). So what do epithelial class II antigens contribute to autoimmune pathogenesis? If distinct class II molecules are required for the presentation of different autoantigens, then differences in HLA-D subregion expression by epithelial cells of individual patients may contribute to the diversity of pathological features with which they present.
lan Todd Ricardo PujoI-Borrell Gian Franco Bottazzo Departmentof Immunology, TheMiddlesex HospitalMedicalSchool,LondonW1P9PG,UK
Marc Feldmann CharingCrossMedicalResearchCentre,London W6 8LW, UK
References 1 Bot;tazzo,G.F., PujoI-Borrell,R., Hanafusa,T. et al. (1983)Lancet ii, 11151119 2 Guy, K., Vanheyningen,V., Cohen, B.B. etal. (1981)Prot. Biol. Fluids29, 729-732
3 Watson, A.J., DeMars,R., Trowbridge, I.S.et aL (1983) Nature (London) 304, 358-361 4 Pawelec,G.P.,Shaw, S., Ziegler,A. etal. (1982) J. Immunol. 129, 1070-1075 5 Todd, I., Abdul-Karim, B.A.S.,PujolBorrell, R., et al. in Proceedingsof the 9th International Thyroid Congress, 5bo Paulo, September 1985 Plenum Press,New York
(in press) 6 Todd, I., PujoI-Borrell,R., Hammond, L. J., et al. (1985) Clin. Exp. Immunol. 61, 26-%273 7 Todd, I., McNally,J.M., Hammond, L.J.et aL in Proceedingsof the 9th International Thyroid Congress, Sbo Paulo, September 1985 PlenumPress,New York (in press)
8 Bottazzo,G.F., Dean, BM., McNally,J.M. et al. (1985) N. Engl. J. Med. 313, 353-360 9 PujoI-Borrell,R., Todd, I., Bottazzo,G.F. et al. in Proceedingsof the Xllth Congress of the International Diabetes Federation, Madrid, September, 1985 EIsevierScience
Publishers,Amsterdam(in press) 10 Natali,P.G.,Segatto, O., Ferrone,S. et al. (1985) lmmunogenetics 19, 109-116 11 Collins,T., Korman,A.J., Wake, C.T. et a/. (1984) Proc NatlAcad. Sci. USA 81, 49174921 12 Berrih,S., Arenzana-Seisdedos,F., Cohen, S. etal. (1985)J. ImmunoL 135, 1165-1171 13 Fischer,A., Sterkers,G., Charron, D. et aL (1985) Eur. J. Immunol. 15, 620-626 14 Sone,T., Tsukamoto, K., Hirayama,K. etaL (1985) J. Immunol. 135, 1288-1298 15 Gonwa, T.A., Picker,L.J.,Raft,H.V. et aL (1983)J. Immunol. 130, 706-711 16 Nepom,J.T., 8enacerraf,B. and Germain, R.N.(1981)./. Immunol. 127, 31 34
Immunology of reproduction in Israel Sir, Immunology Today has provided a most comprehensive review of research and clinical investigation in Israel (July 1985). I would like to mention several topics in reproductive immunology research which were not included in your review but were presented at the International Symposium on the Immunology of Reproduction held in Tel Aviv, Israel, 21-25 October, 1984. Y. Soffer (Assaf Harofeh Medical Center) is examining the effect of various antibodies against human sperm antigens on the in-vitro hamster egg penetration test and has observed that only antibodies to external sperm antigens interfere with
Epithelial MHC class II subregion expression in autoimmunity Sir, Inappropriate expression of MHC class II molecules may enable epithelial cells to present their own surface molecules as autoantigens and thus play a part in the propagation, and possibly in the initiation, of autoimmune pathogenesis (Ref. 1 and Immunol. Today 1984, 5, 230231). The question of HLA-D subregion expression in these circumstances, raised by Peter Johnson and Judith Bulmer (Immunol. Today 1985, 6, 71), is therefore both topical and interesting. We have recently investigated this point in thyroid glands from patients with autoimmune thyroid diseases by performing indirect immunofluorescence with monoclonal antibodies specific for monomorphic determinants of DR (DA6.164) 2, DP (B7/21) 3 and DQ (TU.22) 4. The results show that thyroid epithelium (which is normally class II negative) is induced to express the products of all three HLA-D subregions in these diseasess. There is, however, a hierarchy of expression which follows the pattern DR > DP > DQ. This is observed in the extent and intensity of expression in individual samples and is also represented by heterogeneity amongst patients. Thus, in both patients with Hashimoto's thyroiditis we have investigated, thyrocytes were positive for DR, DP and DQ but, of those Graves' disease patients with thyrocytes positive for DR (n = 11), thyrocyte expression of DP was clearly detected in ten cases, but DQ in only six. The differences are probably related to the local tissue levels of class II modulating factors, which will vary with the nature and severity of disease. This is suggested by in-vitro investigations into the requirements for class II induction in normal human thyrocytes: interferon (IFN) -y induces class II expression in thyrocytes 6, but the induction of DP and DQ to levels comparable with DR requires higher concentrations of IFN-~ or enhancing cofactors such as thyroid stimulating hormone (TSH)~'7. In autoimmune thyroid diseases, autoreactive T cells activated by class II+ thyrocytes may induce more class II expression by secreting IFN-~, and indirectly affecting other factors (e.g. the hypothyroidism associated with Hashi-
moto's thyroiditis leads to increased TJH secretion). Our results therefore suggest that the autoimmune attack is self-perpetuating, epithelial class II expression being both a cause and a consequence of the pathology. The initial epithelial class II expression postulated to trigger the autoimmune activation could be (1) induced by IFN-3, produced in response to local infection, as originally proposed 1 or (2) triggered by other agents as yet undefined. The latter is suggested in insulindependent diabetes where [3-cells of the pancreatic islets selectively express class II molecules 8, although this expression cannot be induced in cultured normal islet cells by IFN-~/9. Regarding the more general point of the functional roles of DR and DQ molecules, the retarded and more restricted tissue distribution of DQ and its relative resistance to induction by IFN--ys'11'12, suggest that its role is distinct from that of DR. On the other hand, these molecules seem to play similar roles in antigen presentation, and responses to some antigens are clearly DR or DQ restricted 13-1s. It would thus seem premature to generalize about distinct functions for different HLA-D subregion products. Rather it appears probable that different class II molecules are active in the presentation of different antigens. For example, in mice certain antigenic peptides are only presented in the context of I-A while others are presented only by I-E (Ref. 16). So what do epithelial class II antigens contribute to autoimmune pathogenesis? If distinct class II molecules are required for the presentation of different autoantigens, then differences in HLA-D subregion expression by epithelial cells of individual patients may contribute to the diversity of pathological features with which they present.
lan Todd Ricardo PujoI-Borrell Gian Franco Bottazzo Departmentof Immunology, TheMiddlesex HospitalMedicalSchool,LondonW1P9PG,UK
Marc Feldmann CharingCrossMedicalResearchCentre,London W6 8LW, UK
References 1 Bot;tazzo,G.F., PujoI-Borrell,R., Hanafusa,T. et al. (1983)Lancet ii, 11151119 2 Guy, K., Vanheyningen,V., Cohen, B.B. etal. (1981)Prot. Biol. Fluids29, 729-732
3 Watson, A.J., DeMars,R., Trowbridge, I.S.et aL (1983) Nature (London) 304, 358-361 4 Pawelec,G.P.,Shaw, S., Ziegler,A. etal. (1982) J. Immunol. 129, 1070-1075 5 Todd, I., Abdul-Karim, B.A.S.,PujolBorrell, R., et al. in Proceedingsof the 9th International Thyroid Congress, 5bo Paulo, September 1985 Plenum Press,New York
(in press) 6 Todd, I., PujoI-Borrell,R., Hammond, L. J., et al. (1985) Clin. Exp. Immunol. 61, 26-%273 7 Todd, I., McNally,J.M., Hammond, L.J.et aL in Proceedingsof the 9th International Thyroid Congress, Sbo Paulo, September 1985 PlenumPress,New York (in press)
8 Bottazzo,G.F., Dean, BM., McNally,J.M. et al. (1985) N. Engl. J. Med. 313, 353-360 9 PujoI-Borrell,R., Todd, I., Bottazzo,G.F. et al. in Proceedingsof the Xllth Congress of the International Diabetes Federation, Madrid, September, 1985 EIsevierScience
Publishers,Amsterdam(in press) 10 Natali,P.G.,Segatto, O., Ferrone,S. et al. (1985) lmmunogenetics 19, 109-116 11 Collins,T., Korman,A.J., Wake, C.T. et a/. (1984) Proc NatlAcad. Sci. USA 81, 49174921 12 Berrih,S., Arenzana-Seisdedos,F., Cohen, S. etal. (1985)J. ImmunoL 135, 1165-1171 13 Fischer,A., Sterkers,G., Charron, D. et aL (1985) Eur. J. Immunol. 15, 620-626 14 Sone,T., Tsukamoto, K., Hirayama,K. etaL (1985) J. Immunol. 135, 1288-1298 15 Gonwa, T.A., Picker,L.J.,Raft,H.V. et aL (1983)J. Immunol. 130, 706-711 16 Nepom,J.T., 8enacerraf,B. and Germain, R.N.(1981)./. Immunol. 127, 31 34
Immunology of reproduction in Israel Sir, Immunology Today has provided a most comprehensive review of research and clinical investigation in Israel (July 1985). I would like to mention several topics in reproductive immunology research which were not included in your review but were presented at the International Symposium on the Immunology of Reproduction held in Tel Aviv, Israel, 21-25 October, 1984. Y. Soffer (Assaf Harofeh Medical Center) is examining the effect of various antibodies against human sperm antigens on the in-vitro hamster egg penetration test and has observed that only antibodies to external sperm antigens interfere with