- Email: [email protected]
Immunology and immunity against infection: General rules
Journal of Computational and Applied Mathematics 184 (2005) 4 – 9 www.elsevier.com/locate/cam
Immunology and immunity against infection: General rules Rolf M. Zinkernagel∗ Department of Pathology, Institute of Experimental Immunology, University Hospital, Schmelzbergstr. 12, CH-8091 Zürich, Switzerland Received 20 August 2002
Abstract Simplified and generalizable rules of immune responses against infections or vaccines have been summarized into 20 statements previously (Scand. J. Immunol. 60 (2004) 9–13) and are restated in a slightly different form here. The key terms of immunology (e.g. specificity, tolerance and memory) are explained in terms of their co-evolutionary importance in the equilibrium between infectious agents and diseases with higher vertebrate hosts. Specificity is best defined by protective antibodies or protective activated T cells; e.g. serotype specific neutralizing antibodies against polio viruses represent the discriminatory power of an immune response very well indeed. Tolerance is reviewed in terms of reactivity rather than self-nonself discrimination. Immune respones are deleted against antigens expressed at sufficient levels within the lymphoheamopoetic system, but may well exist at both, the T and the B cell level against antigens strictly outside of secondary lymphatic organs. In this respect the immune system behaves identically against virus infections and against self antigens. Persistent virus infections delete responsive T cells, once eliminated immune T cell responses wane, if a virus keeps outside of secondary lymphatic tissues no immune response is induced. Immunological memory is usually defined as earlier and greater responses but this does not correlate with protective immunity stringently. It is summarized here that pre-existing titers of protective neutralizing antibodies or pre-existence of activated T cells are the correlates of protection acute cytopathic lethal infections and toxins or against intracellular parasites. It is concluded that many discrepancies and uncertainties in immunological research derive from model situations and experimental results that are correctly measured but cannot be related to co-evolutionary contexts, i.e. survival. © 2005 Blackwell Publishing. Published by Elsevier B.V. All rights reserved. Keywords: Infections diseases; Neutralizing antibodies; Activated effector T cells; Vaccines; Specificity; Tolerance; Immunological memory
∗ Tel.: +41 1 255 2989; fax: +41 1 255 4420.
E-mail address: [email protected]. 0377-0427/$ - see front matter © 2005 Blackwell Publishing. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cam.2005.02.005
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
5
The many immunological observations and results from in-vitro or in-vivo experiments vary and their interpretations differ enormously. A major problem is that within a normal distribution of biological phenomena that are measurable with many methods virtually anything can be shown or is possible. Within a co-evolutionary context the definition of biologically relevant thresholds is an important key to improve our understanding of weaknesses and strengths of the immune system. We have been attempting over the past several years to compare textbook rules and experiments using model antigens, with observations on immunity against infections or tumours to critically evaluate our perception and understanding of specificity, affinity maturation, antigen presentation, selection of the class of the immune response, immunological memory and protective immunity, positive selection of T cells and self–non-self discrimination. The essential parts of the content of this review have been previously used, first in a review for the Swiss National Funds Foundation in 2003 and then in a review published in Scandinavian Journal of Immunology (see Ref. [52]). The necessary permission from Blackwell Publishing has been obtained. From the point of view [33,50] of an infectious disease the following general rules seem to apply to immunology: 1. T cells react against any antigen that freshly enters secondary lymphatic organs including Peyer’s patches and perhaps micropatches for a limited time and in a localized fashion either via a peripheral lymph node or via blood in the spleen [22,15]. This view contrasts with other hypotheses that attribute great importance to the role of signal 2 and regulation [10,30,45]. 2. T cells ignore antigens (self or foreign) that stay strictly outside of secondary lymphatic organs or reach them only for too short a period of time, less than 3 days and below minimal threshold in too low quantities [39–41]. This clashes with other views proposing that encounter of antigen in absence of signal 2 anergizes–tolerises T and B cells [10,30,45]. 3. All (i.e. 100%) T cells get induced if antigen reaches all lymphatic organs and is in circulation for too long and at too high levels. This T cell deletion happens best and earliest in the thymus when there are few precursors, but may happen systemically in the lymphatic periphery [36]. The alternative and general view is that thymic negative selection is “special” and that deletion in the periphery reflects mainly cytokine-deprivation and lack of signal 2 (see above references). 4. T cell receptor avidity, peptide concentration and coreceptor dependence of T cell induction and effector functions are still largely unclear [21,25]. 5. B cells also get induced only in lymphatic organs, including Peyer’s patches, micropatches and perhaps in the bone marrow. They respond with an IgM that is completely T independent (T-independent type I response) if antigen is highly repetitive [11,14], rigidly ordered as on infectious agents or is linked to polyclonal B cell activators [35] (e.g. LPS). B cells get induced by repetitive antigens in a mobile lipid bilayer such as on cell surfaces in the presence of unlinked T help (bystander T help), the so-called T-independent type II responses [4]. 6. B cells get induced by monomeric or oligomeric antigens and all other antigens at limiting doses only in complete dependence of a linked T helper cell response: conventional T-dependent antibody responses [23,34]. 7. B cells are not generally negatively selected, but autoreactive B cells are kept under control by lack of T helper cells specific for self-antigens (via negative selection of CD4+ T cells). This view is challenged by classical and new studies [16,38] favouring negative selection of B cells. 8. Switch to IgG is T help dependent requiring linkage of the T cell and the B cell epitope [23,34]. 9. The biologically relevant affinity–avidity of the protective IgG is poorly understood. While
6
10.
11.
12. 13.
14.
15.
16.
17.
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
immunologists often use ELISA assays that measure 105 –107 M−1 binding qualities, virus-neutralising protective antibodies require 108 –1010 M−1 qualities, the role of affinity maturation for the latter antibodies is unclear [3,13,32]. IgA responses in mucosae may be mounted independent of T help, particularly against commensal flora [7,29]. IgE responses seem to be induced in a so-called T-helper cell type-2 fashion (that is IL4 dependent), but rules of induction, requirements for T help, biological relevance, and effector function are much less clear than for other antibody responses. T cell maturation: the thymus is required for assembly of T cell receptors, the role of hormonal influences is unclear [2]. Positive selection had been originally assumed to be largely dependent upon the MHC of thymic epithelial cells [51], but anecdotal earlier [26,31] and more recent data attribute this probably to an artefactual experimental situation [26,49]. Positive selection therefore probably reflects maintenance of intermediate avidities of TCR for self MHC plus peptides on cells (not thymic epithelial cells) including the extrathymic periphery [42]. Positive selection of B cells: this is a postulate for which experimental evidence is circumstantial, if not unlikely [5,18]. Regulatory T cells: while there is no dispute about the fact that various influences may enhance or decrease various measurable parameters of immune responses, a special type of regulatory T cell that “knows” in foresight what is needed for an equilibrated immune response, has not been convincingly shown (and seems counterintuitive!?) [8,44,46,47]. Antigen: instead of regulation in the classical sense, it looks more likely that antigen dose, time period during which it is available and its “geographical” distribution within this host influences immune responses. In most cases where antigen persists, immunological problems (immunopathology, autoimmunities, immune complex disease, etc.) are only avoided if antigen persists at high enough levels to delete T cells [20,36]. Whenever antigen is eliminated within a reasonably short period of time, the immunopathological consequences are minimal and the protective aspect of immunity dominates. Overall, immunity is protection against infectious agents that cause cell and tissue damage that is not compatible with host survival. Nevertheless, immune protection always includes immunopathology [20]. With acute cytopathic agents, immunopathology is minimal and unimportant in disease, with non-cytopathic infectious agents immunopathology is the major damaging process. Therefore, immunity means elimination of cytopathic damaging agents, and avoidance of immunopathology by infections that are in general not causing direct damage. Immunological memory defined as a quicker and higher response is maintained largely independent of antigen [1,12]. In contrast, immune protection is largely antigen dependent both for T cells and for maintaining elevated protective antibody levels [17,50]. Non-cytopathic persistent infections (e.g. HBV, HCV, HIV) are transferred to the next generation during pregnancy or at birth when immunoincompetence of offspring permits infection without inducing immunopathology [48]. Variably persistent, poorly cytopathic infections are transmitted at birth or during the first weeks of life (for example herpes viruses [19,43], and/or slowly progressing infections, such as TB [27,28], etc.) without threatening the life of too many species members. Adoptive transfer of maternal antibodies (but of course not of T cells) protect the offspring during their early immunoincompetence [6]. “Attenuation” of infections by maternal antibodies (in serum and via milk in the gut) during the first few months of life acts to render them to become “attenuated live physiological vaccines” [48].
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
7
18. Low or absent maternal antibody titres may cause more severe disease, particularly by gastro-intestinal infections that are usually attenuated by passive milk antibodies in infants less than 12–24 months of age. Late infection at > 2–4 years of age (after maternally transmitted protection and attenuation of infection has waned) coupled with high hygiene standards and lack of childhood vaccinations may cause more severe infections (e.g. polio, and sometimes more severe immunopathology/autoimmunity) later [37]. 19. Vaccines against cytopathic or non-cytopathic agents reduce spread of infection, they protect against cytopathic effects of infections and against immunopathology, thereby they may not only reduce direct or indirect cell damage but also autoimmunity and perhaps some chronic degenerative diseases with an immunopathological component. Thus, vaccines protect against cytopathic agents by reducing direct cytopathic effects and against non-cytopathic agents by reducing immunopathology. 20. Vaccines that are efficient protect via “protective antibodies” [48]. All the vaccines that are less efficient or inefficient should in addition, or predominantly, maintain protective T cell responses. Although all the vaccines that are not protective increase T cell precursor frequencies, vaccines do not persist long enough to maintain sufficient numbers of activated effector T cells (e.g. BCG persists for 2–3 years and offers some protection during that period of time, TB persists life-long [24]; similarly for HIV vaccines that persist shorter vs. HIV wild-type viruses that persist life-long [9]). TB or HIV-2 are perhaps ideal “vaccines” themselves because they provide efficient protection against reinfection from within or from outside in most humans for many years [28]. Note: Essential parts of this review were first drafted for the Swiss National Funds Foundation in 2003 and slightly modified in a review in Ref. 52.
References [1] R. Ahmed, D. Gray, Immunological memory and protective immunity: understanding their relation, Science 272 (1996) 54–60. [2] J.F. Bach, Thymic hormones, J. Immunopharmacol. 1 (1979) 277–310. [3] M.F. Bachmann, U. Kalinke, A. Althage, G. Freer, C. Burkhart, H. Roost, M. Aguet, H. Hengartner, R.M. Zinkernagel, The role of antibody concentration and avidity in antiviral protection, Science 276 (1997) 2024–2027. [4] M.F. Bachmann, T.M. Kündig, H. Hengartner, R.M. Zinkernagel, Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without “memory T cells”?, Proc. Natl. Acad. Sci. USA 94 (1997) 640–645. [5] G. Bannish, E.M. Fuentes-Panana, J.C. Cambier, W.S. Pear, J.G. Monroe, Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis, J. Exp. Med. 194 (2001) 1583–1596. [6] R.W.R. Brambell, The Transmission of Immunity from Mother to Young, North-Holland, Amsterdam, 1970. [7] P. Brandtzaeg, K. Bjerke, Human Peyer’s patches: lympho-epithelial relationships and characteristics of immunoglobulinproducing cells, Immunol. Invest. 18 (1989) 29–45. [8] L. Chatenoud, B. Salomon, J.A. Bluestone, Suppressor T cells—they’re back and critical for regulation of autoimmunity!, Immunol. Rev. 182 (2001) 149–163. [9] O.J. Cohen, A. Kinter, A.S. Fauci, Host factors in the pathogenesis of HIV disease, Immunol. Rev. 159 (1997) 31–48. [10] M. Cohn, R.E. Langman, The protection: the unit of humoral immunity selected by evolution, Immunol. Rev. 115 (1990) 11–147. [11] H.M. Dintzis, R.Z. Dintzis, Antigens as immunoregulators, Immunol. Rev. 115 (1990) 243–250. [12] R.W. Dutton, S.L. Swain, L.M. Bradley, The generation and maintenance of memory T and B cells, Immunol. Today 20 (1999) 291–293.
8
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[13] H.N. Eisen, G.W. Siskind, Variations in affinities of antibodies during the immune response, Biochemistry 3 (1964) 996–1008. [14] M. Feldmann, J.G. Howard, C. Desaymard, Role of antigen structure in the discrimination between tolerance and immunity by b cells, Transplant. Rev. 23 (1975) 78–97. [15] I.H. Frazer, R. Thomas, J. Zhou, G.R. Leggatt, L. Dunn, N. McMillan, R.W. Tindle, L. Filgueira, P. Manders, P. Barnard, M. Sharkey, Potential strategies utilised by papillomavirus to evade host immunity, Immunol. Rev. 168 (1999) 131–142. [16] C.C. Goodnow, B cell tolerance, Curr. Opin. Immunol. 4 (1992) 703–710. [17] D. Gray, Population kinetics of rat peripheral B cells, J. Exp. Med. 167 (1988) 805–816. [18] L.M. Heltemes, T. Manser, Level of B cell antigen receptor surface expression influences both positive and negative selection of B cells during primary development, J. Immunol. 169 (2002) 1283–1292. [19] A. Henrot, Mother-infant and indirect transmission of HSV infection: treatment and prevention, Ann. Dermatol. Venereol. 129 (2002) 533–549. [20] J. Hotchin, The biology of lymphocytic choriomeningitis infection: virus induced immune disease, Cold Spring Harbor Symp. Quant. Biol. 27 (1962) 479–499. [21] K. Karjalainen, High sensitivity, low affinity—paradox of T-cell receptor recognition, Curr. Opin. Immunol. 6 (1994) 9–12. [22] U. Karrer, A. Althage, B. Odermatt, C.W.M. Roberts, S.J. Korsmeyer, S. Miyawaki, H. Hengartner, R.M. Zinkernagel, On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/- ) mutant mice, J. Exp. Med. 185 (1997) 2157–2170. [23] D.H. Katz, B. Benacerraf, The regulatory influence of activated T cells on B cell responses to antigen, Adv. Immunol. 15 (1972) 1–94. [24] S.H. Kaufmann, How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1 (2001) 20–30. [25] M.F. Krummel, M.M. Davis, Dynamics of the immunological synapse: finding, establishing and solidifying a connection, Curr. Opin. Immunol. 14 (2002) 66–74. [26] D.L. Longo, R.H. Schwartz, T-cell specificity for H-2 and Ir gene phenotype correlates with the phenotype of thymic antigen-presenting cells, Nature 287 (1980) 44–46. [27] G.B. Mackaness, The relationship of delayed hypersensitivity to acquired cellular resistance, Br. Med. Bull. 23 (1967) 52–54. [28] G.B. Mackaness, Resistance to intracellular infection, J. Infect. Dis. 123 (1971) 439–445. [29] A.J. Macpherson, D. Gatto, E. Sainsbury, G.R. Harriman, H. Hengartner, R.M. Zinkernagel, A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria [In Process Citation], Science 288 (2000) 2222–2226. [30] P. Matzinger, Tolerance, danger, and the extended family, Annu. Rev. Immunol. 12 (1994) 991–1045. [31] P. Matzinger, G. Mirkwood, In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type, J. Exp. Med. 148 (1978) 84–92. [32] C. Milstein, Affinity maturation of antibodies [letter; comment], Immunol. Today 12 (1991) 93–94. [33] C.A. Mims, Pathogenesis of Infectious Disease, Academic Press, London. [34] N.A. Mitchison, The carrier effect in the secondary response to hapten–protein conjugates. V. Use of antilymphocyte serum to deplete animals of helper cells, Eur. J. Immunol. 1 (1971) 68–75. [35] G. Möller, One non-specific signal triggers b lymphocytes, Transplant. Rev. 23 (1975) 126–137. [36] D. Moskophidis, F. Lechner, H.P. Pircher, R.M. Zinkernagel, Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells, Nature 362 (1993) 758–761. [37] N. Nathanson, Epidemiology, in: B.N. Fields, D.M. Knipe (Eds.), Virology, Raven Press, New York, 1990, pp. 267–291. [38] D. Nemazee, D. Russell, B. Arnold, G. Haemmerling, J. Allison, J.F. Miller, G. Morahan, K. Buerki, Clonal deletion of autospecific B lymphocytes, Immunol. Rev. 122 (1991) 117–132. [39] A.F. Ochsenbein, D.D. Pinschewer, B. Odermatt, A. Ciurea, H. Hengartner, R.M. Zinkernagel, Correlation of T cell independence of antibody responses with antigen dose reaching secondary lymphoid organs: implications for splenectomized patients and vaccine design, J. Immunol. 164 (2000) 6296–6302. [40] A.F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner, R.M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T cell induction, Nature 411 (2001) 1058–1064.
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[41] P.S. Ohashi, S. Oehen, K. Buerki, H.P. Pircher, C.T. Ohashi, B. Odermatt, B. Malissen, R.M. Zinkernagel, H. Hengartner, Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice, Cell 65 (1991) 305–317. [42] B. Rocha, H. von Boehmer, Peripheral selection of the T cell repertoire, Science 251 (1991) 1225–1228. [43] B. Roizman, R.J. Whitley, The nine ages of herpes simplex virus, Herpes. 8 (2001) 23–27. [44] S. Sakaguchi, N. Sakaguchi, J. Shimizu, S.Yamazaki, T. Sakihama, M. Itoh,Y. Kuniyasu, T. Nomura, M. Toda, T. Takahashi, Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumour immunity, and transplantation tolerance, Immunol. Rev. 182 (2001) 18–32. [45] R.H. Schwartz, T cell clonal anergy, Curr. Opin. Immunol. 9 (1997) 351–357. [46] E.M. Shevach, CD4+ CD25+ suppressor T cells: more questions than answers, Nat. Rev. Immunol. 2 (2002) 389–400. [47] R.M. Steinman, M.C. Nussenzweig, Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance, Proc. Natl. Acad. Sci. USA 99 (2002) 351–358. [48] R.M. Zinkernagel, Maternal antibodies, childhood infections and autoimmune diseases, N. Engl. J. Med. 345 (2001) 1331–1335. [49] R.M. Zinkernagel, A. Althage, On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells [In Process Citation], Proc. Natl. Acad. Sci. USA 96 (1999) 8092–8097. [50] R.M. Zinkernagel, M.F. Bachmann, T.M. Kündig, S. Oehen, H.P. Pircher, H. Hengartner, On immunological memory, Ann. Rev. Immunol. 14 (1996) 333–367. [51] R.M. Zinkernagel, G.N. Callahan, J. Klein, G. Dennert, Cytotoxic T cells learn specificity for self H-2 during differentiation in the thymus, Nature 271 (1978) 251–253. [52] R.M. Zinkernagel, On immunity against infections and vaccines: Credo 2004, Scand. J. Immunol. 60 (2004) 9–13.
Immunology and immunity against infection: General rules Rolf M. Zinkernagel∗ Department of Pathology, Institute of Experimental Immunology, University Hospital, Schmelzbergstr. 12, CH-8091 Zürich, Switzerland Received 20 August 2002
Abstract Simplified and generalizable rules of immune responses against infections or vaccines have been summarized into 20 statements previously (Scand. J. Immunol. 60 (2004) 9–13) and are restated in a slightly different form here. The key terms of immunology (e.g. specificity, tolerance and memory) are explained in terms of their co-evolutionary importance in the equilibrium between infectious agents and diseases with higher vertebrate hosts. Specificity is best defined by protective antibodies or protective activated T cells; e.g. serotype specific neutralizing antibodies against polio viruses represent the discriminatory power of an immune response very well indeed. Tolerance is reviewed in terms of reactivity rather than self-nonself discrimination. Immune respones are deleted against antigens expressed at sufficient levels within the lymphoheamopoetic system, but may well exist at both, the T and the B cell level against antigens strictly outside of secondary lymphatic organs. In this respect the immune system behaves identically against virus infections and against self antigens. Persistent virus infections delete responsive T cells, once eliminated immune T cell responses wane, if a virus keeps outside of secondary lymphatic tissues no immune response is induced. Immunological memory is usually defined as earlier and greater responses but this does not correlate with protective immunity stringently. It is summarized here that pre-existing titers of protective neutralizing antibodies or pre-existence of activated T cells are the correlates of protection acute cytopathic lethal infections and toxins or against intracellular parasites. It is concluded that many discrepancies and uncertainties in immunological research derive from model situations and experimental results that are correctly measured but cannot be related to co-evolutionary contexts, i.e. survival. © 2005 Blackwell Publishing. Published by Elsevier B.V. All rights reserved. Keywords: Infections diseases; Neutralizing antibodies; Activated effector T cells; Vaccines; Specificity; Tolerance; Immunological memory
∗ Tel.: +41 1 255 2989; fax: +41 1 255 4420.
E-mail address: [email protected]. 0377-0427/$ - see front matter © 2005 Blackwell Publishing. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.cam.2005.02.005
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
5
The many immunological observations and results from in-vitro or in-vivo experiments vary and their interpretations differ enormously. A major problem is that within a normal distribution of biological phenomena that are measurable with many methods virtually anything can be shown or is possible. Within a co-evolutionary context the definition of biologically relevant thresholds is an important key to improve our understanding of weaknesses and strengths of the immune system. We have been attempting over the past several years to compare textbook rules and experiments using model antigens, with observations on immunity against infections or tumours to critically evaluate our perception and understanding of specificity, affinity maturation, antigen presentation, selection of the class of the immune response, immunological memory and protective immunity, positive selection of T cells and self–non-self discrimination. The essential parts of the content of this review have been previously used, first in a review for the Swiss National Funds Foundation in 2003 and then in a review published in Scandinavian Journal of Immunology (see Ref. [52]). The necessary permission from Blackwell Publishing has been obtained. From the point of view [33,50] of an infectious disease the following general rules seem to apply to immunology: 1. T cells react against any antigen that freshly enters secondary lymphatic organs including Peyer’s patches and perhaps micropatches for a limited time and in a localized fashion either via a peripheral lymph node or via blood in the spleen [22,15]. This view contrasts with other hypotheses that attribute great importance to the role of signal 2 and regulation [10,30,45]. 2. T cells ignore antigens (self or foreign) that stay strictly outside of secondary lymphatic organs or reach them only for too short a period of time, less than 3 days and below minimal threshold in too low quantities [39–41]. This clashes with other views proposing that encounter of antigen in absence of signal 2 anergizes–tolerises T and B cells [10,30,45]. 3. All (i.e. 100%) T cells get induced if antigen reaches all lymphatic organs and is in circulation for too long and at too high levels. This T cell deletion happens best and earliest in the thymus when there are few precursors, but may happen systemically in the lymphatic periphery [36]. The alternative and general view is that thymic negative selection is “special” and that deletion in the periphery reflects mainly cytokine-deprivation and lack of signal 2 (see above references). 4. T cell receptor avidity, peptide concentration and coreceptor dependence of T cell induction and effector functions are still largely unclear [21,25]. 5. B cells also get induced only in lymphatic organs, including Peyer’s patches, micropatches and perhaps in the bone marrow. They respond with an IgM that is completely T independent (T-independent type I response) if antigen is highly repetitive [11,14], rigidly ordered as on infectious agents or is linked to polyclonal B cell activators [35] (e.g. LPS). B cells get induced by repetitive antigens in a mobile lipid bilayer such as on cell surfaces in the presence of unlinked T help (bystander T help), the so-called T-independent type II responses [4]. 6. B cells get induced by monomeric or oligomeric antigens and all other antigens at limiting doses only in complete dependence of a linked T helper cell response: conventional T-dependent antibody responses [23,34]. 7. B cells are not generally negatively selected, but autoreactive B cells are kept under control by lack of T helper cells specific for self-antigens (via negative selection of CD4+ T cells). This view is challenged by classical and new studies [16,38] favouring negative selection of B cells. 8. Switch to IgG is T help dependent requiring linkage of the T cell and the B cell epitope [23,34]. 9. The biologically relevant affinity–avidity of the protective IgG is poorly understood. While
6
10.
11.
12. 13.
14.
15.
16.
17.
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
immunologists often use ELISA assays that measure 105 –107 M−1 binding qualities, virus-neutralising protective antibodies require 108 –1010 M−1 qualities, the role of affinity maturation for the latter antibodies is unclear [3,13,32]. IgA responses in mucosae may be mounted independent of T help, particularly against commensal flora [7,29]. IgE responses seem to be induced in a so-called T-helper cell type-2 fashion (that is IL4 dependent), but rules of induction, requirements for T help, biological relevance, and effector function are much less clear than for other antibody responses. T cell maturation: the thymus is required for assembly of T cell receptors, the role of hormonal influences is unclear [2]. Positive selection had been originally assumed to be largely dependent upon the MHC of thymic epithelial cells [51], but anecdotal earlier [26,31] and more recent data attribute this probably to an artefactual experimental situation [26,49]. Positive selection therefore probably reflects maintenance of intermediate avidities of TCR for self MHC plus peptides on cells (not thymic epithelial cells) including the extrathymic periphery [42]. Positive selection of B cells: this is a postulate for which experimental evidence is circumstantial, if not unlikely [5,18]. Regulatory T cells: while there is no dispute about the fact that various influences may enhance or decrease various measurable parameters of immune responses, a special type of regulatory T cell that “knows” in foresight what is needed for an equilibrated immune response, has not been convincingly shown (and seems counterintuitive!?) [8,44,46,47]. Antigen: instead of regulation in the classical sense, it looks more likely that antigen dose, time period during which it is available and its “geographical” distribution within this host influences immune responses. In most cases where antigen persists, immunological problems (immunopathology, autoimmunities, immune complex disease, etc.) are only avoided if antigen persists at high enough levels to delete T cells [20,36]. Whenever antigen is eliminated within a reasonably short period of time, the immunopathological consequences are minimal and the protective aspect of immunity dominates. Overall, immunity is protection against infectious agents that cause cell and tissue damage that is not compatible with host survival. Nevertheless, immune protection always includes immunopathology [20]. With acute cytopathic agents, immunopathology is minimal and unimportant in disease, with non-cytopathic infectious agents immunopathology is the major damaging process. Therefore, immunity means elimination of cytopathic damaging agents, and avoidance of immunopathology by infections that are in general not causing direct damage. Immunological memory defined as a quicker and higher response is maintained largely independent of antigen [1,12]. In contrast, immune protection is largely antigen dependent both for T cells and for maintaining elevated protective antibody levels [17,50]. Non-cytopathic persistent infections (e.g. HBV, HCV, HIV) are transferred to the next generation during pregnancy or at birth when immunoincompetence of offspring permits infection without inducing immunopathology [48]. Variably persistent, poorly cytopathic infections are transmitted at birth or during the first weeks of life (for example herpes viruses [19,43], and/or slowly progressing infections, such as TB [27,28], etc.) without threatening the life of too many species members. Adoptive transfer of maternal antibodies (but of course not of T cells) protect the offspring during their early immunoincompetence [6]. “Attenuation” of infections by maternal antibodies (in serum and via milk in the gut) during the first few months of life acts to render them to become “attenuated live physiological vaccines” [48].
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
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18. Low or absent maternal antibody titres may cause more severe disease, particularly by gastro-intestinal infections that are usually attenuated by passive milk antibodies in infants less than 12–24 months of age. Late infection at > 2–4 years of age (after maternally transmitted protection and attenuation of infection has waned) coupled with high hygiene standards and lack of childhood vaccinations may cause more severe infections (e.g. polio, and sometimes more severe immunopathology/autoimmunity) later [37]. 19. Vaccines against cytopathic or non-cytopathic agents reduce spread of infection, they protect against cytopathic effects of infections and against immunopathology, thereby they may not only reduce direct or indirect cell damage but also autoimmunity and perhaps some chronic degenerative diseases with an immunopathological component. Thus, vaccines protect against cytopathic agents by reducing direct cytopathic effects and against non-cytopathic agents by reducing immunopathology. 20. Vaccines that are efficient protect via “protective antibodies” [48]. All the vaccines that are less efficient or inefficient should in addition, or predominantly, maintain protective T cell responses. Although all the vaccines that are not protective increase T cell precursor frequencies, vaccines do not persist long enough to maintain sufficient numbers of activated effector T cells (e.g. BCG persists for 2–3 years and offers some protection during that period of time, TB persists life-long [24]; similarly for HIV vaccines that persist shorter vs. HIV wild-type viruses that persist life-long [9]). TB or HIV-2 are perhaps ideal “vaccines” themselves because they provide efficient protection against reinfection from within or from outside in most humans for many years [28]. Note: Essential parts of this review were first drafted for the Swiss National Funds Foundation in 2003 and slightly modified in a review in Ref. 52.
References [1] R. Ahmed, D. Gray, Immunological memory and protective immunity: understanding their relation, Science 272 (1996) 54–60. [2] J.F. Bach, Thymic hormones, J. Immunopharmacol. 1 (1979) 277–310. [3] M.F. Bachmann, U. Kalinke, A. Althage, G. Freer, C. Burkhart, H. Roost, M. Aguet, H. Hengartner, R.M. Zinkernagel, The role of antibody concentration and avidity in antiviral protection, Science 276 (1997) 2024–2027. [4] M.F. Bachmann, T.M. Kündig, H. Hengartner, R.M. Zinkernagel, Protection against immunopathological consequences of a viral infection by activated but not resting cytotoxic T cells: T cell memory without “memory T cells”?, Proc. Natl. Acad. Sci. USA 94 (1997) 640–645. [5] G. Bannish, E.M. Fuentes-Panana, J.C. Cambier, W.S. Pear, J.G. Monroe, Ligand-independent signaling functions for the B lymphocyte antigen receptor and their role in positive selection during B lymphopoiesis, J. Exp. Med. 194 (2001) 1583–1596. [6] R.W.R. Brambell, The Transmission of Immunity from Mother to Young, North-Holland, Amsterdam, 1970. [7] P. Brandtzaeg, K. Bjerke, Human Peyer’s patches: lympho-epithelial relationships and characteristics of immunoglobulinproducing cells, Immunol. Invest. 18 (1989) 29–45. [8] L. Chatenoud, B. Salomon, J.A. Bluestone, Suppressor T cells—they’re back and critical for regulation of autoimmunity!, Immunol. Rev. 182 (2001) 149–163. [9] O.J. Cohen, A. Kinter, A.S. Fauci, Host factors in the pathogenesis of HIV disease, Immunol. Rev. 159 (1997) 31–48. [10] M. Cohn, R.E. Langman, The protection: the unit of humoral immunity selected by evolution, Immunol. Rev. 115 (1990) 11–147. [11] H.M. Dintzis, R.Z. Dintzis, Antigens as immunoregulators, Immunol. Rev. 115 (1990) 243–250. [12] R.W. Dutton, S.L. Swain, L.M. Bradley, The generation and maintenance of memory T and B cells, Immunol. Today 20 (1999) 291–293.
8
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
[13] H.N. Eisen, G.W. Siskind, Variations in affinities of antibodies during the immune response, Biochemistry 3 (1964) 996–1008. [14] M. Feldmann, J.G. Howard, C. Desaymard, Role of antigen structure in the discrimination between tolerance and immunity by b cells, Transplant. Rev. 23 (1975) 78–97. [15] I.H. Frazer, R. Thomas, J. Zhou, G.R. Leggatt, L. Dunn, N. McMillan, R.W. Tindle, L. Filgueira, P. Manders, P. Barnard, M. Sharkey, Potential strategies utilised by papillomavirus to evade host immunity, Immunol. Rev. 168 (1999) 131–142. [16] C.C. Goodnow, B cell tolerance, Curr. Opin. Immunol. 4 (1992) 703–710. [17] D. Gray, Population kinetics of rat peripheral B cells, J. Exp. Med. 167 (1988) 805–816. [18] L.M. Heltemes, T. Manser, Level of B cell antigen receptor surface expression influences both positive and negative selection of B cells during primary development, J. Immunol. 169 (2002) 1283–1292. [19] A. Henrot, Mother-infant and indirect transmission of HSV infection: treatment and prevention, Ann. Dermatol. Venereol. 129 (2002) 533–549. [20] J. Hotchin, The biology of lymphocytic choriomeningitis infection: virus induced immune disease, Cold Spring Harbor Symp. Quant. Biol. 27 (1962) 479–499. [21] K. Karjalainen, High sensitivity, low affinity—paradox of T-cell receptor recognition, Curr. Opin. Immunol. 6 (1994) 9–12. [22] U. Karrer, A. Althage, B. Odermatt, C.W.M. Roberts, S.J. Korsmeyer, S. Miyawaki, H. Hengartner, R.M. Zinkernagel, On the key role of secondary lymphoid organs in antiviral immune responses studied in alymphoplastic (aly/aly) and spleenless (Hox11(-)/- ) mutant mice, J. Exp. Med. 185 (1997) 2157–2170. [23] D.H. Katz, B. Benacerraf, The regulatory influence of activated T cells on B cell responses to antigen, Adv. Immunol. 15 (1972) 1–94. [24] S.H. Kaufmann, How can immunology contribute to the control of tuberculosis? Nat. Rev. Immunol. 1 (2001) 20–30. [25] M.F. Krummel, M.M. Davis, Dynamics of the immunological synapse: finding, establishing and solidifying a connection, Curr. Opin. Immunol. 14 (2002) 66–74. [26] D.L. Longo, R.H. Schwartz, T-cell specificity for H-2 and Ir gene phenotype correlates with the phenotype of thymic antigen-presenting cells, Nature 287 (1980) 44–46. [27] G.B. Mackaness, The relationship of delayed hypersensitivity to acquired cellular resistance, Br. Med. Bull. 23 (1967) 52–54. [28] G.B. Mackaness, Resistance to intracellular infection, J. Infect. Dis. 123 (1971) 439–445. [29] A.J. Macpherson, D. Gatto, E. Sainsbury, G.R. Harriman, H. Hengartner, R.M. Zinkernagel, A primitive T cell-independent mechanism of intestinal mucosal IgA responses to commensal bacteria [In Process Citation], Science 288 (2000) 2222–2226. [30] P. Matzinger, Tolerance, danger, and the extended family, Annu. Rev. Immunol. 12 (1994) 991–1045. [31] P. Matzinger, G. Mirkwood, In a fully H-2 incompatible chimera, T cells of donor origin can respond to minor histocompatibility antigens in association with either donor or host H-2 type, J. Exp. Med. 148 (1978) 84–92. [32] C. Milstein, Affinity maturation of antibodies [letter; comment], Immunol. Today 12 (1991) 93–94. [33] C.A. Mims, Pathogenesis of Infectious Disease, Academic Press, London. [34] N.A. Mitchison, The carrier effect in the secondary response to hapten–protein conjugates. V. Use of antilymphocyte serum to deplete animals of helper cells, Eur. J. Immunol. 1 (1971) 68–75. [35] G. Möller, One non-specific signal triggers b lymphocytes, Transplant. Rev. 23 (1975) 126–137. [36] D. Moskophidis, F. Lechner, H.P. Pircher, R.M. Zinkernagel, Virus persistence in acutely infected immunocompetent mice by exhaustion of antiviral cytotoxic effector T cells, Nature 362 (1993) 758–761. [37] N. Nathanson, Epidemiology, in: B.N. Fields, D.M. Knipe (Eds.), Virology, Raven Press, New York, 1990, pp. 267–291. [38] D. Nemazee, D. Russell, B. Arnold, G. Haemmerling, J. Allison, J.F. Miller, G. Morahan, K. Buerki, Clonal deletion of autospecific B lymphocytes, Immunol. Rev. 122 (1991) 117–132. [39] A.F. Ochsenbein, D.D. Pinschewer, B. Odermatt, A. Ciurea, H. Hengartner, R.M. Zinkernagel, Correlation of T cell independence of antibody responses with antigen dose reaching secondary lymphoid organs: implications for splenectomized patients and vaccine design, J. Immunol. 164 (2000) 6296–6302. [40] A.F. Ochsenbein, S. Sierro, B. Odermatt, M. Pericin, U. Karrer, J. Hermans, S. Hemmi, H. Hengartner, R.M. Zinkernagel, Roles of tumour localization, second signals and cross priming in cytotoxic T cell induction, Nature 411 (2001) 1058–1064.
R.M. Zinkernagel / Journal of Computational and Applied Mathematics 184 (2005) 4 – 9
9
[41] P.S. Ohashi, S. Oehen, K. Buerki, H.P. Pircher, C.T. Ohashi, B. Odermatt, B. Malissen, R.M. Zinkernagel, H. Hengartner, Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice, Cell 65 (1991) 305–317. [42] B. Rocha, H. von Boehmer, Peripheral selection of the T cell repertoire, Science 251 (1991) 1225–1228. [43] B. Roizman, R.J. Whitley, The nine ages of herpes simplex virus, Herpes. 8 (2001) 23–27. [44] S. Sakaguchi, N. Sakaguchi, J. Shimizu, S.Yamazaki, T. Sakihama, M. Itoh,Y. Kuniyasu, T. Nomura, M. Toda, T. Takahashi, Immunologic tolerance maintained by CD25+ CD4+ regulatory T cells: their common role in controlling autoimmunity, tumour immunity, and transplantation tolerance, Immunol. Rev. 182 (2001) 18–32. [45] R.H. Schwartz, T cell clonal anergy, Curr. Opin. Immunol. 9 (1997) 351–357. [46] E.M. Shevach, CD4+ CD25+ suppressor T cells: more questions than answers, Nat. Rev. Immunol. 2 (2002) 389–400. [47] R.M. Steinman, M.C. Nussenzweig, Avoiding horror autotoxicus: the importance of dendritic cells in peripheral T cell tolerance, Proc. Natl. Acad. Sci. USA 99 (2002) 351–358. [48] R.M. Zinkernagel, Maternal antibodies, childhood infections and autoimmune diseases, N. Engl. J. Med. 345 (2001) 1331–1335. [49] R.M. Zinkernagel, A. Althage, On the role of thymic epithelium vs. bone marrow-derived cells in repertoire selection of T cells [In Process Citation], Proc. Natl. Acad. Sci. USA 96 (1999) 8092–8097. [50] R.M. Zinkernagel, M.F. Bachmann, T.M. Kündig, S. Oehen, H.P. Pircher, H. Hengartner, On immunological memory, Ann. Rev. Immunol. 14 (1996) 333–367. [51] R.M. Zinkernagel, G.N. Callahan, J. Klein, G. Dennert, Cytotoxic T cells learn specificity for self H-2 during differentiation in the thymus, Nature 271 (1978) 251–253. [52] R.M. Zinkernagel, On immunity against infections and vaccines: Credo 2004, Scand. J. Immunol. 60 (2004) 9–13.