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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. General rules governing immune reactivity
  5. Conclusion
  6. References

Resistance of vertebrate hosts against infections comprises important natural or innate resistance combined with adaptive immune responses of T and B cells. Viruses, bacteria or classical parasites all probe the limit of immune responses and of immunity. They, therefore, offer an excellent opportunity to assess the biology, physiology and molecular aspects of immune responses and help in characterizing the three basic parameters of immunology – specificity, tolerance and memory. Various experiments are summarized that indicate that the rules of antiviral, antitumour, antiorgan graft and of autoimmune responses are basically the same. The practical specificity repertoire of T and B cells is probably in the order of 104−105 specificities expressed by T cells or by neutralizing antibodies. Tolerance is best defined by rules of reactivity to eliminate infections while avoiding destruction of normal cells by complete elimination of T cells that are specific for antigens persisting within the blood and lymphatic (lymphohaemopoietic) system. Induction of a T-cell response is the result of antigens newly entering lymph nodes or spleen, initially in a local fashion and exhibiting an optimal distribution kinetics within the lymphohaemopoietic system. Antigen staying outside lymphatic tissues are immunologically ignored (e.g. are non-events). Thus immune reactivity is regulated by antigen dose, time and relative distribution kinetics. Memory is the fact that a host is resistant against disease caused by reinfection with the same agent. Memory correlates best with antigen-dependent maintenance of elevated antibody titres in serum and mucosal secretions, or with an antigen-driven activation of T cells, such that they are protective immediately against peripheral reinfections in solid tissues. While antibodies transferred from mother to offspring are a prerequisite for the survival of otherwise unprotected immuno-incompetent offsprings, activated memory T cells cannot be transmitted. Thus, attenuation of infections in newborns and babies by maternal antibodies is the physiological correlate of man-made vaccines. T cells not only play an essential role in maintaining T-help-dependent memory antibody titres, but also in controlling the many infections that persist in a host at rather low levels (such as tuberculosis, measles and HIV).


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. General rules governing immune reactivity
  5. Conclusion
  6. References

The many immunological observations and results from in vitro or in vivo experiments vary and their interpretations differ enormously [1, 2]. 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 coevolutionary context the definition of biologically relevant thresholds observed and/or measured 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.

General rules governing immune reactivity

  1. Top of page
  2. Abstract
  3. Introduction
  4. General rules governing immune reactivity
  5. Conclusion
  6. References

This view (or credo = translated ‘I believe’) will only summarize parameters of adaptive specific immune response mechanisms, which are based on important innate resistant mechanisms. The latter includes much less variable and less specific interferons, Toll-like receptor ligands and many other factors. Twenty apparent rules of specific immune responses as they have emerged mostly from studies of immunity against infection are:

  • 1
    T cells react against any antigen that freshly enters secondary lymphatic organs (including Peyer's patches and perhaps micropatches) for a limited but sufficient (>3 days) time and in a localized fashion either via afferent lymphatics into peripheral lymph nodes or via blood in the spleen [3, 4]. This view contrasts with other hypotheses that attribute great importance to the role of signal 2 and regulation [5–7].
  • 2
    T cells ignore antigens (self or foreign) that stay strictly outside secondary lymphatic organs or reach them only for too short a period of time (<3 days) and below a minimal quantitative threshold. Other views propose that encounter of antigen in absence of signal 2 anergizes-tolerizes T and B cells [6–10].
  • 3
    All (e.g. 100%) T cells get induced and because of a limited (2–4 day) half-life, die off if the antigen reaches almost all lymphatic organs and is in circulation for too long and at sufficiently high levels [11]. This T-cell deletion happens best and earliest in the thymus where there are few precursors, but may happen systemically in the lymphatic periphery. 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 [5–7].
  • 4
    The roles of T-cell receptor avidity, peptide concentration and co-receptor dependence in defining T-cell specificity of their effector functions are still largely unclear [12, 13]. There is evidence that (as for antibodies when one compares ELISA versus protection for specificity definition) current methods of measuring specificity may often be inadequate. For example, in vitro cytolysis by cytotoxic T cells (CTL) at peptide concentrations of 10−6 M reveals cross-reactivities that do not correlate with protection. In contrast, lysis of 10−10 M peptide loaded targets (or natural infections of target cells) correlates with CTL-dependent antiviral protection in vivo[14].
  • 5
    MHC-class I versus MHC-class II restricted T-cell induction is via distinct, cell-internally synthesized, versus cell-external phago-lysosomally processed peptides, respectively. External antigens may, under exceptional conditions (including very high protein concentrations of special antigens such as ovalbumine and/or combination of high doses with Toll-like receptor ligand engagement), may overcome the physiological limits and enter intracellular pathways of MHC-class I presentation [4, 15–21]. A rough titration of efficiency differences of direct versus cross-presented MHC-class I presentation suggests a difference of at least 103−104-fold in favour of direct presentation [9, 22]. Thus while not impossible, cross-presentation and cross-priming seem physiologically irrelevant but may be achieved by special methodological tricks.
  • 6
    T cell maturation: the thymus is required for T-cell receptor rearrangement. The role of hormonal influences is documented but mechanistically unclear [23, 24]. Positive selection had been originally assumed to be largely dependent upon the MHC of thymic epithelial cells [25, 26], but anecdotal [27, 28] and more recent data attribute this probably to an artefactial experimental situation [29]. Positive selection reflects maintenance of intermediate avidities of TCR for self-MHC plus peptides on cells in the thymus (not thymic epithelial cells) including the extrathymic periphery [29, 30]. Positive selection of B cells is a postulate for which experimental evidence is circumstantial and unclear [31, 32].
  • 7
    The role of 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 the host influences immune responses [33, 34]. In most cases where the antigen persists within the lymphohaemopoietic system, immunopathological consequences (immunopathology, autoimmunities, immune complex disease, etc.) are avoided if the antigen persists systematically at high enough levels to delete T cells. Whenever the antigen is eliminated within a reasonably short period of time, the immunopathological consequences are minimal and the protective aspect of immunity usually dominates.
  • 8
    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 [21, 35–37].
  • 9
    B cells get induced by monomeric or oligomeric antigens and all other antigens at limiting doses only in complete dependence of a contact-dependent MHC-class II restricted linked T-helper cell response (conventional T-dependent antibody responses) [38, 39].
  • 10
    B cells also get induced only in lymphatic organs, including Peyer's patches or perhaps micropatches. They respond with an IgM that is completely T-independent (T-independent type I response) if the antigen is highly repetitive, rigidly ordered as on infectious agents or is linked to polyclonal B-cell activators [40–43] or to other Toll-like receptor ligands. 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), so-called T-independent type II responses.
  • 11
    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). Potentially induced T-independent IgM autoantibodies are short lived and have apparently no relevant disease consequences [42]. This view is challenged by classical and new studies favouring negative selection of B cells [39, 44, 45]. The possibility that self-antigen expression on cell membranes in lymphatic tissues (including bone marrow) negatively selects B cells is to be analysed and confirmed [31, 32]. In general, lack of T help controls IgG autoantibody responses [38, 39].
  • 12
    Antibody specificity is defined by affinity–avidity of protective IgG (as defined by serotype specificity). While ELISA are often used assays that measure 10−5−10−7 m binding qualities, virus-neutralizing protective antibodies require 10−8−10−10 m qualities The role of affinity maturation for the latter antibodies is questioned for acute protective antibodies against cytopathic viruses, but may play an important role in chronic persistent infections (viruses, bacteria and importantly parasitic infections including malaria, etc.).
  • 13
    Ig-class selection: switch to IgA in mucosal membranes particularly against comensal flora is T and secondary lymphatic organ-independent [46, 47]. 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 and effector function are much less clear than for IgG responses.
  • 14
    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. With acute cytopathic agents, immunopathology is minimal and unimportant in disease, with non-cytopathic infectious agents immunopathology is the major damaging disease-causing process. Therefore, immunity means elimination of cytopathic damaging agents, and avoidance of immunopathology by infections that are, in general, not causing direct damage.
  • 15
    Immunological memory defined as quicker and higher response (studied under laboratory conditions, using inert model antigens as sheep red blood cells or foreign protein) is maintained largely independent of antigen [48–50]. In contrast, immune protection against infectious, i.e. immunity (prevention of re-emergence of disease after reinfection) is largely antigen-dependent both for T cells and for maintaining elevated protective antibody levels [2, 50, 51].
  • 16
    Non-cytopathic persistent infections (e.g. HBV, HCV, HIV and LCMV) are transferred to the next generation during pregnancy or at birth when immunoincompetence of offspring permits infection without inducing immunopathology [52]. Variably persistent, poorly cytopathic infections are transmitted at birth or during the first weeks of life (for example, Herpes viruses [53, 54], and/or slowly progressing infections, such as TB [55–58]) without threatening the life of too many species members.
  • 17
    Adoptive transfer of maternal antibodies (but of course not of T cells) protect offspring during their early immuno-incompetence [59]. ‘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, natural or physiological vaccines’ This adoptive transfer of maternal antibody immunity is the evolutionary basis of our successful artificial vaccines [52].
  • 18
    Low or absent maternal antibody titres may cause more severe disease, particularly by gastrointestinal infections that are usually attenuated by transferred milk antibodies in infants less than 12–24 months of age. Late infection at >2–4 years of age (after maternally transmitted protection has faded) may cause more severe infections later [60] (e.g. polio and sometimes more severe immunopathology/autoimmunity).
  • 19
    Vaccines that are efficient protect via ‘protective antibodies’[52]: All vaccines that are less or not efficient 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 for long enough to maintain sufficient numbers of activated effector T cells (e.g. BCG persists for 2–3 years and offers protection during this period of time, whereas wild type TB persists life-long [57, 58]; similar for HIV vaccines that do not persist versus HIV wild type viruses that persist life-long). TB or HIV-2 are perhaps ideal ‘vaccines’ themselves because they provide efficient protection against reinfection from within or from the outside in most humans for many years [56]. Vaccines protect against cytopathic agents by reducing direct cytopathic effects, against non-cytopathic agents by reducing immunopathology. Thereby they may not only reduce direct or indirect cell damage but also autoimmunity and perhaps some chronic degenerative diseases with an infectious and immunopathological component.
  • 20
    We must not forget that as for all biological parameters theoretically nothing is impossible in immunology to the immune systems. Mechanisms and efficiencies are frequent or exceptional, efficient in promoting survival (a very reliable readout) of hosts or not, under wild type conditions (e.g. not in an specific pathogen-free (SPF) animal house).

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. General rules governing immune reactivity
  5. Conclusion
  6. References

The apparent discrepancies and uncertainties in immunological research and immunology versus the hard clinical experience of immunity reflect differing points of view. Here, survival of infection within a coevolutionary context was chosen to define immunological parameters. Of course understanding cellular physiology and molecular details usually summarized by the term ‘system biology’ or ‘systematically, completely measured biology’ are eventually necessary to understand the strengths and weaknesses of immune defences. While persuing these studies, we must however, not forget, that the immune system is primarily about host survival of infections and for this we also need to understand the ‘biology of the system’.

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  1. Top of page
  2. Abstract
  3. Introduction
  4. General rules governing immune reactivity
  5. Conclusion
  6. References
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