ImmunologyToday,vol. 7, No. 9, 1986
-letters, Bacterial 'cross-reacting' determinants in ankylosing spondylitis Sir, A. Keat (Immunol. Today, 1986, 7, 144-149) should be complimented for his comprehensive and balanced review of an exciting and controversial area. I should, however, like to make a comment about the central role attributed to Klebsiella in the phenomenon of cross-reactivity between environmental antigens and HLA-B27 or an associated structure. It is fair to say that at the outset Ebringer and his associates 1, and later our group 2.3 emphasized the apparent importance of Klebsiella as
AIDSand the thymus Sir,
254
Shearer and Moser (Immunol. Today, 1986, 7, 34-36) discussed AIDS as a consequence of la antigen recognition. They considered post-thymic T cells since the CD4 (= T4) antigen is an essential and specific component of the cell-surface receptor of HTLVIII, and CD4 is normally found on the helper subset of T cells and on some monocytes. AIDS patients show a depletion primarily of helper T (Th) cells and secondarily of monocytes. In this context it is important to realize that during the ontogeny of thymocytes within the thymus CD4 is expressed on most cortical thymocytes (Reinherz's stage II i.e. T l l +, T6 +, T4 +, T8 +, T3-) and that these cells form 60-70% of the total thymocyte population 1,2. Zinkernagel 3"4 showed the ability of the thymus to restrict T cells to class II MHC components and localized I-A antigens to the epithelial cells of the cortex and the medulla s. He also blocked Th-Cell differentiation with anti-la antibodies. Damaging the thymus with dexamethazone 7'8 or sublethal irradiation 9 changes the pattern of MHC expression on thymic epithelial cells. Zinkernagel postulated that this could be involved in defective T-cell differentiation. It is not uncommon for viruses to penetrate into the thymus 1°'11 and cause damage there. I have injected Procion yellow into types 2 and 3 epithelial cells and demonstrated
a possible triggering agent in ankylosing spondylitis. However since 1983 we have broadened our base by identifying a wide array of bacteria bearing 'cross-reactive' determinants (e.g. certain isolates of Salmonella, Shigella and E. coh)4 which have in common a freely transmissible genetic element s encoding the 'cross-reactive" determinant or modifying factor 6. This is an important distinction between our hypothesis s and the direct serological crossreactivity between Klebsiella and HLA-B27 championed by Ebringer and his group 7 during the past 10 years.
A. F. Geczy AustralianRedCrossSociety,Blood TransfusionService,Sydney,NSW2000, Australia
that it reaches all epithelial cells of the mouse thymic cortex in less than 30 min., suggesting a functional syncytium in this part of the gland ~2. It is possible that HTLV-III could pass equally easily around the human thymus cortex. The presence of HTLV-III within thymic epithelial cells could affect CD4 + cells in several ways. For example, it could adversely affect MHC expression since an intact stroma is necessary for normal T-cell development 13, or it could infect CD4 + cells an an early stage in their life cycle. The presence of virus in the: thymus might explain the atrophy of the thymus that is known to occur in AIDS patients, and atrophy could be a factor in the subsequent susceptibility to opportunistic infections. There are numerous examples of disease conditions (both natural and experimentally induced) where there is thymic agenesis or atrophy and an increased susceptibility to infection 14. While mechanisms in such conditions may differ completely from AIDS, the impairment of immune competence resulting from the loss of an active thymus in AIDS could be of fundamental importance to the patients' prognoses. It would be interesting to investigate the presence or absence of HTLV-III in the thymus of symptomless people infected with HTLV-III who do not suffer the disease, and to compare the r~sults with those from patients in whom the disease is manifest. Further effects of damage to the epithelium could be disturbances in,
References 1 Ebringer,A. (1983) Br. J. Rheumatol. 22 (Suppl. 2) 53-66 2 Seager, K., Bashir, H.V. Geczy,A.F. et al. (1979)Nature (London)277, 68-70 3 Geczy,A.F. and Yap, J. (1982) J. Rheumatol. 9, 97-100 4 Prendergast,J.K., Sullivan,J.S., Geczy, A.F. et al. (1983)Infect. Immun. 41,935 5 Upfold, L.I., Sullivan,J.S., Prendergast, J.K. et al. (1985) Prog. Allergy36, 177 6 Geczy,A.F., Alexander, K., Bashir,H.V. etal. (1983)Immunol. Rev. 70, 23 7 Ebringer,A., Baines,M., Childerstone, M. et al. (1985)inAdvancesin Inflammation Research Vol. 9, The Spondyloarthropathies (Ziff, M. and Cohen, S.B., eds) pp. 101-128, Raven Press,New York
the balance of the neuroendocrinethymic axis15. There is sympathetic and parasympathetic innervation to the thymus 16 and feedback from the thymus to the brain is probable via the hypothalamus 17 or the pituitary particularly as in mice thymus extracts affect the acidophils of the anterior pituitary ~8. Talal ~9quotes an interesting model for AIDS where a non-cytopathic lymphocytic choriomeningitis viral infection displays a tropism for cells of the murine anterior pituitary2° and he questions whether a similar tropism of the AIDS agent for CD4 + cells results in defective T-cell growth factor production. Such interactions now seem possible.
M.D. Kendall Departmentof Anatomy, St Thomas's HospitalMedicalSchool,LondonSEI 7EH,UK
References 1 Reinherz,E.L.,Meuer, S.C. and Schlossman, S.F.(1983)in T Lymphocytes Today(Inglis,J.R.ed.) Elsevier,Amsterdam 2 Reinherz,E.L.(1985) Immunol. Today 6, 75-79 3 Zinkernagel, R.M (1978) Immunol. Rev. 42,225-270 4 Zinkernagel, R.M., Callahan,G.N., Althage, A. et al. (1978)J. Exp. Med. 147,882-896 5 Rouse,R.V., Parham, P., Grumet, F.C. et al. (1982) Human Immunol. 5, 21-35 6 Kruisbeek,A.M, Fultz, M.J., Sharrow, S.O. et al. (1983)J. Exp. Med. 157, 1932-1946 7 van Vliet, E. (1985) Ph. D. Thesis.
Immunology Today, voL 7, No. 9, 1986
Offsetdrukkerij KantersB.V., Alblasserdam. 8 van Vliet, E., Melis, M. and van Ewijk, W. (in press) 9 Huiskamp, R. and van Ewijk, W. J. Immunol. (in press) 10 Inamura, M. Matsuyama,T., Toh, K. etal. (1971) J. NatlCancerlnst. 47, 289-300 11 Santisteran,G.A., Riley,V. and Fitzmaurice, M.A. (1972)Proc. Soc. Exp. BioL Med., 139, 202-206
Contrasuppressor cells in mucosal immunity Sir, In their stimulating review of murine contrasuppressor T (TJ cells Immunol. Today, 1986, 7, 81-86), Green and Ptak emphasized the role of contrasuppression in the mucosal immune system. In particular, they proposed that prevention of hypersensitivity to dietary antigens reflects the concomitant induction of systemic immune tolerance and the restriction of antigen uptake from the gut, and that this is regulated by a local population of Tcs within the gut associated lymphoid tissues (GALT). While we agree that it is important to prevent systemic food hypersensitivity, we believe that the authors' arguments rely on certain assumptions about immune exclusion and oral tolerance to dietary antigens which have not yet been established beyond doubt. First, in mice fed ovalbumin (OVa,), Stokes et al. have shown that immune exclusion by the gut is a r,~.latively unusual occurrence and is highly strain dependent 1. Furthermore, the idea that a secretory antibody response and systemic tolerance are induced in parallel by oral immunization 2 has been challenged by recent studies which showed that local IgA production and systemic tolerance in mice fed keyhole limpet haemocyanin (KLH) did not occur simultaneously3. In contrast, the Ioc-
.letter$12 Kendall, M.D.J. Anat. (in press) 13 van Vliet, E., Jenkinson, E.J., Kingston, R. et al. Eur. J. Immunol. (in press) 14 Nezelof, Ch. (1986)in The Human Thymus. Histophysiology and Pathology (Muller-Hermelink, H.K. ed.) Curr. Top. PathoL 75, Springer-Verlag, Berlin 15 Hall, N.R., McGillis,J.P., Spanelo, B. et aL (1982) in Current Concepts in Human Immunology and Cancer Immunomodulation (Serrou, B. et al. eds.) Elsevier,Amsterdam
16 Kendall, M.D. in Surg~ry of the Thymus (Givel,J.-C. ed.) Springer-Verlag, Berlin 17 Rebar,R.W., Miyake, A., Low, T.L.K. et al. (1981 ) Science 214, 669-671 18 Pierpaoli,W. and Sorkin, E. (1967) Nature (London) 215, 834-837 19 Tatal, N. (1983)in TLymphocytes Today (Inglis,J.R. ed.) Elsevier, Amsterdam 20 Oldstone, M.B.A., Sinha,Y.N., Blount, P. et al. (1982) Science 218, 1125-1127
al and systemic immune responses behaved identically under these conditions, and the authors suggested that suppressor T cells were active in the GALT. The hypothesis that suppressor cells in the Peyer's patch (PP) can prevent a local IgA response has been confirmed using sheep red blood cells (SRBC) as an antigen 4. With respect to the presence of Tcs in the GALT, there are few reports of direct examination of mucosal contrasuppression. Thus, in their original study, Green and his co-workers used in-vitro techniques to show that the normal PP contained a population of cells which had some of the characteristics of Tcs inducers, and did not examine the effect of oral immunization on these cellss. The report by Domen and Mattingly cited in this review suggests that antigen-specific Tcs cells are present in the patch after feeding: however, more information is required on this, and we await publication of the results in full. Although a recent report has suggested that a population of Tcs is responsible for the absence of oral tolerance in SRBC fed C3H/HeJ mice6, it would be incautious to interpret these findings as support for the relevance of T~s to mucosal immunity in general. The T~s described by Suzuki et aL were isolated from the spleen rather than the GALT, they were induced after prolonged feeding of LPS-unresponsive C3H/ HeJ mice, and were not present in normal, congenic C3H mice. In addition, we believe that feeding SRBC to
mutant mice may not be an ideal system to study regulation of immunity to dietary antigens, as our own findings indicate that the protein antigen OVA and SRBC have very different effects after oral administration to both normal and LPS-unresponsive mice7. It is likely that immune responses to dietary protein antigens are more relevant to the clinical situation. Therefore, we suggest that detailed studies of mucosal Tcs activity in animals fed proteins are required to prove an essential role for this intriguing population of cells in preventing food hypersensitivity.
Alan G. Lamont Allan Mcl. Mowat UniversityDepartment of Bacteriologyand Immunology, Western Infirmary, Glasgow G116NT, UK
References 1 Stokes,C.R. Swarbrick, E.T.and Soothill, J.F.(1983) C/in. Exp./mmuno/. 52,678-684 2 Challacombe,S.J.and Tomasi,T.B. (1980) J. Exp. Med. 152, 1459-1472 3 Elson,C.O. and Ealding, W. (1984) J. Immunol. 133, 2892-2897 4 MacDonald, T.T. (1983) Eur. J. Immunol. 13, 138-142 5 Green, D.R., Gold, J., St. Martin, S. et al. (1982) Proc. NatlAcad. Sci. USA 79, 889-892 6 Suzuki, I., Kiyono, H., Kitamura, K. et al. (1986) Nature (London) 320, 451454 7 Mowat, A.McI., Thomas, M.J.,. MacKenzie, S. et al. Immunology (in press)
255
-letters, Bacterial 'cross-reacting' determinants in ankylosing spondylitis Sir, A. Keat (Immunol. Today, 1986, 7, 144-149) should be complimented for his comprehensive and balanced review of an exciting and controversial area. I should, however, like to make a comment about the central role attributed to Klebsiella in the phenomenon of cross-reactivity between environmental antigens and HLA-B27 or an associated structure. It is fair to say that at the outset Ebringer and his associates 1, and later our group 2.3 emphasized the apparent importance of Klebsiella as
AIDSand the thymus Sir,
254
Shearer and Moser (Immunol. Today, 1986, 7, 34-36) discussed AIDS as a consequence of la antigen recognition. They considered post-thymic T cells since the CD4 (= T4) antigen is an essential and specific component of the cell-surface receptor of HTLVIII, and CD4 is normally found on the helper subset of T cells and on some monocytes. AIDS patients show a depletion primarily of helper T (Th) cells and secondarily of monocytes. In this context it is important to realize that during the ontogeny of thymocytes within the thymus CD4 is expressed on most cortical thymocytes (Reinherz's stage II i.e. T l l +, T6 +, T4 +, T8 +, T3-) and that these cells form 60-70% of the total thymocyte population 1,2. Zinkernagel 3"4 showed the ability of the thymus to restrict T cells to class II MHC components and localized I-A antigens to the epithelial cells of the cortex and the medulla s. He also blocked Th-Cell differentiation with anti-la antibodies. Damaging the thymus with dexamethazone 7'8 or sublethal irradiation 9 changes the pattern of MHC expression on thymic epithelial cells. Zinkernagel postulated that this could be involved in defective T-cell differentiation. It is not uncommon for viruses to penetrate into the thymus 1°'11 and cause damage there. I have injected Procion yellow into types 2 and 3 epithelial cells and demonstrated
a possible triggering agent in ankylosing spondylitis. However since 1983 we have broadened our base by identifying a wide array of bacteria bearing 'cross-reactive' determinants (e.g. certain isolates of Salmonella, Shigella and E. coh)4 which have in common a freely transmissible genetic element s encoding the 'cross-reactive" determinant or modifying factor 6. This is an important distinction between our hypothesis s and the direct serological crossreactivity between Klebsiella and HLA-B27 championed by Ebringer and his group 7 during the past 10 years.
A. F. Geczy AustralianRedCrossSociety,Blood TransfusionService,Sydney,NSW2000, Australia
that it reaches all epithelial cells of the mouse thymic cortex in less than 30 min., suggesting a functional syncytium in this part of the gland ~2. It is possible that HTLV-III could pass equally easily around the human thymus cortex. The presence of HTLV-III within thymic epithelial cells could affect CD4 + cells in several ways. For example, it could adversely affect MHC expression since an intact stroma is necessary for normal T-cell development 13, or it could infect CD4 + cells an an early stage in their life cycle. The presence of virus in the: thymus might explain the atrophy of the thymus that is known to occur in AIDS patients, and atrophy could be a factor in the subsequent susceptibility to opportunistic infections. There are numerous examples of disease conditions (both natural and experimentally induced) where there is thymic agenesis or atrophy and an increased susceptibility to infection 14. While mechanisms in such conditions may differ completely from AIDS, the impairment of immune competence resulting from the loss of an active thymus in AIDS could be of fundamental importance to the patients' prognoses. It would be interesting to investigate the presence or absence of HTLV-III in the thymus of symptomless people infected with HTLV-III who do not suffer the disease, and to compare the r~sults with those from patients in whom the disease is manifest. Further effects of damage to the epithelium could be disturbances in,
References 1 Ebringer,A. (1983) Br. J. Rheumatol. 22 (Suppl. 2) 53-66 2 Seager, K., Bashir, H.V. Geczy,A.F. et al. (1979)Nature (London)277, 68-70 3 Geczy,A.F. and Yap, J. (1982) J. Rheumatol. 9, 97-100 4 Prendergast,J.K., Sullivan,J.S., Geczy, A.F. et al. (1983)Infect. Immun. 41,935 5 Upfold, L.I., Sullivan,J.S., Prendergast, J.K. et al. (1985) Prog. Allergy36, 177 6 Geczy,A.F., Alexander, K., Bashir,H.V. etal. (1983)Immunol. Rev. 70, 23 7 Ebringer,A., Baines,M., Childerstone, M. et al. (1985)inAdvancesin Inflammation Research Vol. 9, The Spondyloarthropathies (Ziff, M. and Cohen, S.B., eds) pp. 101-128, Raven Press,New York
the balance of the neuroendocrinethymic axis15. There is sympathetic and parasympathetic innervation to the thymus 16 and feedback from the thymus to the brain is probable via the hypothalamus 17 or the pituitary particularly as in mice thymus extracts affect the acidophils of the anterior pituitary ~8. Talal ~9quotes an interesting model for AIDS where a non-cytopathic lymphocytic choriomeningitis viral infection displays a tropism for cells of the murine anterior pituitary2° and he questions whether a similar tropism of the AIDS agent for CD4 + cells results in defective T-cell growth factor production. Such interactions now seem possible.
M.D. Kendall Departmentof Anatomy, St Thomas's HospitalMedicalSchool,LondonSEI 7EH,UK
References 1 Reinherz,E.L.,Meuer, S.C. and Schlossman, S.F.(1983)in T Lymphocytes Today(Inglis,J.R.ed.) Elsevier,Amsterdam 2 Reinherz,E.L.(1985) Immunol. Today 6, 75-79 3 Zinkernagel, R.M (1978) Immunol. Rev. 42,225-270 4 Zinkernagel, R.M., Callahan,G.N., Althage, A. et al. (1978)J. Exp. Med. 147,882-896 5 Rouse,R.V., Parham, P., Grumet, F.C. et al. (1982) Human Immunol. 5, 21-35 6 Kruisbeek,A.M, Fultz, M.J., Sharrow, S.O. et al. (1983)J. Exp. Med. 157, 1932-1946 7 van Vliet, E. (1985) Ph. D. Thesis.
Immunology Today, voL 7, No. 9, 1986
Offsetdrukkerij KantersB.V., Alblasserdam. 8 van Vliet, E., Melis, M. and van Ewijk, W. (in press) 9 Huiskamp, R. and van Ewijk, W. J. Immunol. (in press) 10 Inamura, M. Matsuyama,T., Toh, K. etal. (1971) J. NatlCancerlnst. 47, 289-300 11 Santisteran,G.A., Riley,V. and Fitzmaurice, M.A. (1972)Proc. Soc. Exp. BioL Med., 139, 202-206
Contrasuppressor cells in mucosal immunity Sir, In their stimulating review of murine contrasuppressor T (TJ cells Immunol. Today, 1986, 7, 81-86), Green and Ptak emphasized the role of contrasuppression in the mucosal immune system. In particular, they proposed that prevention of hypersensitivity to dietary antigens reflects the concomitant induction of systemic immune tolerance and the restriction of antigen uptake from the gut, and that this is regulated by a local population of Tcs within the gut associated lymphoid tissues (GALT). While we agree that it is important to prevent systemic food hypersensitivity, we believe that the authors' arguments rely on certain assumptions about immune exclusion and oral tolerance to dietary antigens which have not yet been established beyond doubt. First, in mice fed ovalbumin (OVa,), Stokes et al. have shown that immune exclusion by the gut is a r,~.latively unusual occurrence and is highly strain dependent 1. Furthermore, the idea that a secretory antibody response and systemic tolerance are induced in parallel by oral immunization 2 has been challenged by recent studies which showed that local IgA production and systemic tolerance in mice fed keyhole limpet haemocyanin (KLH) did not occur simultaneously3. In contrast, the Ioc-
.letter$12 Kendall, M.D.J. Anat. (in press) 13 van Vliet, E., Jenkinson, E.J., Kingston, R. et al. Eur. J. Immunol. (in press) 14 Nezelof, Ch. (1986)in The Human Thymus. Histophysiology and Pathology (Muller-Hermelink, H.K. ed.) Curr. Top. PathoL 75, Springer-Verlag, Berlin 15 Hall, N.R., McGillis,J.P., Spanelo, B. et aL (1982) in Current Concepts in Human Immunology and Cancer Immunomodulation (Serrou, B. et al. eds.) Elsevier,Amsterdam
16 Kendall, M.D. in Surg~ry of the Thymus (Givel,J.-C. ed.) Springer-Verlag, Berlin 17 Rebar,R.W., Miyake, A., Low, T.L.K. et al. (1981 ) Science 214, 669-671 18 Pierpaoli,W. and Sorkin, E. (1967) Nature (London) 215, 834-837 19 Tatal, N. (1983)in TLymphocytes Today (Inglis,J.R. ed.) Elsevier, Amsterdam 20 Oldstone, M.B.A., Sinha,Y.N., Blount, P. et al. (1982) Science 218, 1125-1127
al and systemic immune responses behaved identically under these conditions, and the authors suggested that suppressor T cells were active in the GALT. The hypothesis that suppressor cells in the Peyer's patch (PP) can prevent a local IgA response has been confirmed using sheep red blood cells (SRBC) as an antigen 4. With respect to the presence of Tcs in the GALT, there are few reports of direct examination of mucosal contrasuppression. Thus, in their original study, Green and his co-workers used in-vitro techniques to show that the normal PP contained a population of cells which had some of the characteristics of Tcs inducers, and did not examine the effect of oral immunization on these cellss. The report by Domen and Mattingly cited in this review suggests that antigen-specific Tcs cells are present in the patch after feeding: however, more information is required on this, and we await publication of the results in full. Although a recent report has suggested that a population of Tcs is responsible for the absence of oral tolerance in SRBC fed C3H/HeJ mice6, it would be incautious to interpret these findings as support for the relevance of T~s to mucosal immunity in general. The T~s described by Suzuki et aL were isolated from the spleen rather than the GALT, they were induced after prolonged feeding of LPS-unresponsive C3H/ HeJ mice, and were not present in normal, congenic C3H mice. In addition, we believe that feeding SRBC to
mutant mice may not be an ideal system to study regulation of immunity to dietary antigens, as our own findings indicate that the protein antigen OVA and SRBC have very different effects after oral administration to both normal and LPS-unresponsive mice7. It is likely that immune responses to dietary protein antigens are more relevant to the clinical situation. Therefore, we suggest that detailed studies of mucosal Tcs activity in animals fed proteins are required to prove an essential role for this intriguing population of cells in preventing food hypersensitivity.
Alan G. Lamont Allan Mcl. Mowat UniversityDepartment of Bacteriologyand Immunology, Western Infirmary, Glasgow G116NT, UK
References 1 Stokes,C.R. Swarbrick, E.T.and Soothill, J.F.(1983) C/in. Exp./mmuno/. 52,678-684 2 Challacombe,S.J.and Tomasi,T.B. (1980) J. Exp. Med. 152, 1459-1472 3 Elson,C.O. and Ealding, W. (1984) J. Immunol. 133, 2892-2897 4 MacDonald, T.T. (1983) Eur. J. Immunol. 13, 138-142 5 Green, D.R., Gold, J., St. Martin, S. et al. (1982) Proc. NatlAcad. Sci. USA 79, 889-892 6 Suzuki, I., Kiyono, H., Kitamura, K. et al. (1986) Nature (London) 320, 451454 7 Mowat, A.McI., Thomas, M.J.,. MacKenzie, S. et al. Immunology (in press)
255
