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Reflections on an Interface
Medical Hypotheses Medical Hypotheses (1995) 45, 45~t7 © Pearson Professional Ltd 1995
Reflections on an Interface J. R. KENNEDY 1414 59th Street West, Bradenton, FL 34209, USA
Abstract - - This discusses an immune recognition model of autoimmunity and tolerance which is based on an idiotypic and an anti-idiotypic immune network response at a virus receptor interface. of the interfaces whose interactions will be considered. Immune recognition is a two-way street for these immune effectors - not only do they manifest specificity in immune recognition, but the spatial electro-chemical configuration responsible for that specificity allows them to be recognized. Because of this, when Id T cells and antibodies recognize the viral RTA they also recognize the anti-idiotypic (anti-Id) V-regions. Since immune responses are antigenicaUy driven, this dual Id stimulation should cause it to be dominant with the anti-Id response relegated to Id modulation. While this may be true in general, in the immune response under consideration, another possibility presents itself. Since the antiID V-regions may be able to recognize the viral receptor, the anti-Id response could be augmented and the immunologic equilibrium may be shifted.
Introduction
Complementarily is ubiquitous in biologic structures because of the close proximity required for the weak non-covalent electro-chemical forces that are necessary for many dynamic biological reactions. Such complementary interfaces are the necessary framework for specificity in the immune recognition process. This discussion concerns itself with a special interface - that between a virus and its receptor - and the immunologic consequences resulting from an immune response to the receptor tropic area (RTA) of that virus. Because of the complementary nature of this interface, an immune response to the RTA of the virus will be unique in that its idiotypic (Id) immune recognition surfaces will have the immunologic appearance of the viral receptor. This being so, an anti-idiotypic (anti-Id) response should be able to recognize the viral receptor. Only the physical aspects of recognition and recognition prevention (cloaking) are considered in the discussion of this immune recognition model.
The i m m u n e response
The standard immunological constraints of MHC restriction and V-region specificity apply to the cellular and humoral components of this virus-receptor network but special circumstances exist here. Though there are four separate physical interfaces (>receptor< >idiotypic< >receptor<), each interface has the same immunologic appearance, so that differential recognition is entirely based on context.
I m m u n e recognition and ID vs anti-ID dominance
The variable (V)-regions of T cell receptors (TCR) and antibodies determine the physical characteristics Date received15 September1994 Date accepted24 October1994 45
46 The immune response is driven by the viral RTA and the recognition process begins with its appearance. It recognizes its receptor and is in turn recognized by surface immunoglobulins (Ig) on the B cell surface. Next, B cells class II present the RTA while the infected cells are class I presenting it. Recognition of these MHC presented RTAs leads to RTA specific antibodies and cytotoxic lymphocytes (CTL) which prevent further viral attachment and destroy virusinfected cells. The above immunological scenario is an approximation of a successful immune response but the next phase, immune modulation, is even more problematic.
The modulation response
The appearance of Id V-regions on T cells and antibodies initiates the modulation process and begins a feedback process between the Id and the anti-ID immune effectors that is incredibly complex even when considering only the recognition constraints. Immune recognition between B cells, T cells and antibodies is dependent on complementary V-regions complexing in the proper context. As such in this network, CD4 ÷ cells are restricted to recognition of processed interface antigens presented on class II MHC by antigen presenting cells. CD8 + cells recognize all viable cells in this network but only if their V-regions are class I-presented. The immunoglobulins on the surface of B cells will only be able to recognize soluble antigens (the virus via its RTA, and antibodies with complementary V-regions). Finally, antibodies recognize all of the above but are limited in their recognition of MHC presented peptides. All of the above recognition, taken in context of the immune process, ultimately results in either immunity, autoimmunity, or tolerance.
The autoimmune response
Anti-Id responses to the viral RTA must occur on some occasions and, if that response is humoral, the receptor will be recognized, but, if it is cellular, such recognition will only occur if the receptor is MHCpresented. Such recognition could be an autoimmune catastrophe but in most cases it obviously is not. Nevertheless, the possibility of an attack on the receptor by lyric antibodies or CTLs is real and either possibility suggests a mechanism of autoimmune attack in a viral immune response gone awry. The autoimmune potential of such an anti-Id response suggests that it must not ordinarily be just an Id
MEDICAL HYPOTHESES
equivalent counteracting force but must be a unique modulatory one with the potential to fall.
Cloaking as a means of immune modulation
The prevention of immune recognition by physical cloaking of immune recognition surfaces seems a logical and simple means of immune modulation and one that is made to order for controlling the anti-Id autoimmune potential. Cloaking of specific V-regions of this network with other complementary V-regions could block immune recognition in a reversible nonlyric manner that quiets rather than stimulates the immune process. Non-complement-fixing antibodies such as IgG4 and V-region peptides secreted by CD8 ÷ suppressor cells (1) seem likely candidates for such a cloaking function and would be particularly effective in protecting the viral receptor. An animal model which seems to illustrate both receptor cloaking and an autoimmune response is murine coxsackievirus (COX) myocarditis. In this model, a cloaking antibody forms which has the potential to prevent myocyte infection by blocking viral access to its myocyte receptor (2). A myocyte-specific CTL also occurs in this infection and the above antibody protects the myocyte from it. This antibody and this CTL would appear to be anti-Id effectors which recognize the COX receptor. Immune cloaking is also suggested by the successful use of intravenous antibodies to modulate some autoimmuue diseases. If we assume that tolerance for some self antigens is provided by cloaking V-regions supplied by a network of Id and anti-Id immune cells, then in the usual tolerant state these suppressor V-regions would be in the majority. An antigen which loses this protection will be vulnerable to autoimmune attack and an intravenous infusion of pooled antibodies with a normal complement of suppressor V-regions could neutralize the autoimmune CTLs and antibodies. Antibodies should be able to cloak TCRs, the viral receptor, the viral RTA and to neutralize the complementary antibodies. They apparently will have only limited success with MHC-presented peptides. Soluble CD8-produced V-region peptides should be able to cloak all complementary surfaces and the complexes formed should be more stable.
Clinical model of cloaking and autoimmunity?
Perhaps the most investigated virus of all time, HIV, is the ultimate model for this hypothesis. Anti-Id recognition of the CD4 tropic area of HIV has the
47
REFLECTIONS ON AN INTERFACE
potential to recognize the CD4 molecule but theoretically such CD4 recognition is forbidden. Certain evidence, however, suggests that CD4 recognition is a natural response. The demonstration of B cells (3) and CTLs (4) that recognize HIV in subjects who are HIV-negative suggests that the V-regions of these immune cells may be capable of recognizing HIV but that their normal ligand is the TCRs of a CD4 specific clone which recognizes the same CD4 locus as does HIV. The discovery of CD4-specific CTL in HIV-positive subjects (5) which attack nonHIV infected cells supports this hypothesis. This suggests an Id, anti-Id network which normally functions either to produce tolerance for the CD4 molecule or as an immune modulation mechanism (6). If this is so, then the appearance of an immune response to HIV, which uses the same V-regions, has the potential to upset the immunological balance. In conclusion, this immune recognition model uses the virus receptor interface to demonstrate a possible mechanism for both autoimmunity and tolerance. Autoimmunity is suggested by anti-Id recognitions of the viral receptor and immune modulation is accom-
plished by physical cloaking of V-regions and viral receptors with antibodies and peptides secreted from the TCRs of CD8 ÷ lymphocytes.
References 1. Bissonnette R, Zheng H, Kubo R T, Singh B, Green D R. A T helper cell hybridoma produces an antigen-specific regulatory activity: relationship to the T cell receptor by serology and antigenic fine specificity. J Immunol 1991; 146: 2898-2907. 2. Weller A, Simpson K, Herzum M, VanHouten N, Huber S. Coxsackevirus-B3-induced myocarditis: virus receptor antibodies modulate myocardifls. J Immuno11989; 143: 1843-1850. 3. Berberian L, Goodglick L, Kipps T J, Braun J. Immunoglobulin VH3 gene products: natural ligands for HIV gpl20. Science 1993; 261: 1588-1591. 4. Hoffenbach A, Langlade-Demoyen P, Dadaglio G e t al. Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. J Immunol 1990; 142: 452-462. 5. Zarling J, Ledbetter J, Sias J e t al. HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4÷ cells. J Immunol 1990; 144: 2992-2998. 6. Kennedy J R. Does HIV disrupt a naturally occurring immune modulation system? Med Hypotheses 1993; 41: 445-449.
Reflections on an Interface J. R. KENNEDY 1414 59th Street West, Bradenton, FL 34209, USA
Abstract - - This discusses an immune recognition model of autoimmunity and tolerance which is based on an idiotypic and an anti-idiotypic immune network response at a virus receptor interface. of the interfaces whose interactions will be considered. Immune recognition is a two-way street for these immune effectors - not only do they manifest specificity in immune recognition, but the spatial electro-chemical configuration responsible for that specificity allows them to be recognized. Because of this, when Id T cells and antibodies recognize the viral RTA they also recognize the anti-idiotypic (anti-Id) V-regions. Since immune responses are antigenicaUy driven, this dual Id stimulation should cause it to be dominant with the anti-Id response relegated to Id modulation. While this may be true in general, in the immune response under consideration, another possibility presents itself. Since the antiID V-regions may be able to recognize the viral receptor, the anti-Id response could be augmented and the immunologic equilibrium may be shifted.
Introduction
Complementarily is ubiquitous in biologic structures because of the close proximity required for the weak non-covalent electro-chemical forces that are necessary for many dynamic biological reactions. Such complementary interfaces are the necessary framework for specificity in the immune recognition process. This discussion concerns itself with a special interface - that between a virus and its receptor - and the immunologic consequences resulting from an immune response to the receptor tropic area (RTA) of that virus. Because of the complementary nature of this interface, an immune response to the RTA of the virus will be unique in that its idiotypic (Id) immune recognition surfaces will have the immunologic appearance of the viral receptor. This being so, an anti-idiotypic (anti-Id) response should be able to recognize the viral receptor. Only the physical aspects of recognition and recognition prevention (cloaking) are considered in the discussion of this immune recognition model.
The i m m u n e response
The standard immunological constraints of MHC restriction and V-region specificity apply to the cellular and humoral components of this virus-receptor network but special circumstances exist here. Though there are four separate physical interfaces (>receptor<
I m m u n e recognition and ID vs anti-ID dominance
The variable (V)-regions of T cell receptors (TCR) and antibodies determine the physical characteristics Date received15 September1994 Date accepted24 October1994 45
46 The immune response is driven by the viral RTA and the recognition process begins with its appearance. It recognizes its receptor and is in turn recognized by surface immunoglobulins (Ig) on the B cell surface. Next, B cells class II present the RTA while the infected cells are class I presenting it. Recognition of these MHC presented RTAs leads to RTA specific antibodies and cytotoxic lymphocytes (CTL) which prevent further viral attachment and destroy virusinfected cells. The above immunological scenario is an approximation of a successful immune response but the next phase, immune modulation, is even more problematic.
The modulation response
The appearance of Id V-regions on T cells and antibodies initiates the modulation process and begins a feedback process between the Id and the anti-ID immune effectors that is incredibly complex even when considering only the recognition constraints. Immune recognition between B cells, T cells and antibodies is dependent on complementary V-regions complexing in the proper context. As such in this network, CD4 ÷ cells are restricted to recognition of processed interface antigens presented on class II MHC by antigen presenting cells. CD8 + cells recognize all viable cells in this network but only if their V-regions are class I-presented. The immunoglobulins on the surface of B cells will only be able to recognize soluble antigens (the virus via its RTA, and antibodies with complementary V-regions). Finally, antibodies recognize all of the above but are limited in their recognition of MHC presented peptides. All of the above recognition, taken in context of the immune process, ultimately results in either immunity, autoimmunity, or tolerance.
The autoimmune response
Anti-Id responses to the viral RTA must occur on some occasions and, if that response is humoral, the receptor will be recognized, but, if it is cellular, such recognition will only occur if the receptor is MHCpresented. Such recognition could be an autoimmune catastrophe but in most cases it obviously is not. Nevertheless, the possibility of an attack on the receptor by lyric antibodies or CTLs is real and either possibility suggests a mechanism of autoimmune attack in a viral immune response gone awry. The autoimmune potential of such an anti-Id response suggests that it must not ordinarily be just an Id
MEDICAL HYPOTHESES
equivalent counteracting force but must be a unique modulatory one with the potential to fall.
Cloaking as a means of immune modulation
The prevention of immune recognition by physical cloaking of immune recognition surfaces seems a logical and simple means of immune modulation and one that is made to order for controlling the anti-Id autoimmune potential. Cloaking of specific V-regions of this network with other complementary V-regions could block immune recognition in a reversible nonlyric manner that quiets rather than stimulates the immune process. Non-complement-fixing antibodies such as IgG4 and V-region peptides secreted by CD8 ÷ suppressor cells (1) seem likely candidates for such a cloaking function and would be particularly effective in protecting the viral receptor. An animal model which seems to illustrate both receptor cloaking and an autoimmune response is murine coxsackievirus (COX) myocarditis. In this model, a cloaking antibody forms which has the potential to prevent myocyte infection by blocking viral access to its myocyte receptor (2). A myocyte-specific CTL also occurs in this infection and the above antibody protects the myocyte from it. This antibody and this CTL would appear to be anti-Id effectors which recognize the COX receptor. Immune cloaking is also suggested by the successful use of intravenous antibodies to modulate some autoimmuue diseases. If we assume that tolerance for some self antigens is provided by cloaking V-regions supplied by a network of Id and anti-Id immune cells, then in the usual tolerant state these suppressor V-regions would be in the majority. An antigen which loses this protection will be vulnerable to autoimmune attack and an intravenous infusion of pooled antibodies with a normal complement of suppressor V-regions could neutralize the autoimmune CTLs and antibodies. Antibodies should be able to cloak TCRs, the viral receptor, the viral RTA and to neutralize the complementary antibodies. They apparently will have only limited success with MHC-presented peptides. Soluble CD8-produced V-region peptides should be able to cloak all complementary surfaces and the complexes formed should be more stable.
Clinical model of cloaking and autoimmunity?
Perhaps the most investigated virus of all time, HIV, is the ultimate model for this hypothesis. Anti-Id recognition of the CD4 tropic area of HIV has the
47
REFLECTIONS ON AN INTERFACE
potential to recognize the CD4 molecule but theoretically such CD4 recognition is forbidden. Certain evidence, however, suggests that CD4 recognition is a natural response. The demonstration of B cells (3) and CTLs (4) that recognize HIV in subjects who are HIV-negative suggests that the V-regions of these immune cells may be capable of recognizing HIV but that their normal ligand is the TCRs of a CD4 specific clone which recognizes the same CD4 locus as does HIV. The discovery of CD4-specific CTL in HIV-positive subjects (5) which attack nonHIV infected cells supports this hypothesis. This suggests an Id, anti-Id network which normally functions either to produce tolerance for the CD4 molecule or as an immune modulation mechanism (6). If this is so, then the appearance of an immune response to HIV, which uses the same V-regions, has the potential to upset the immunological balance. In conclusion, this immune recognition model uses the virus receptor interface to demonstrate a possible mechanism for both autoimmunity and tolerance. Autoimmunity is suggested by anti-Id recognitions of the viral receptor and immune modulation is accom-
plished by physical cloaking of V-regions and viral receptors with antibodies and peptides secreted from the TCRs of CD8 ÷ lymphocytes.
References 1. Bissonnette R, Zheng H, Kubo R T, Singh B, Green D R. A T helper cell hybridoma produces an antigen-specific regulatory activity: relationship to the T cell receptor by serology and antigenic fine specificity. J Immunol 1991; 146: 2898-2907. 2. Weller A, Simpson K, Herzum M, VanHouten N, Huber S. Coxsackevirus-B3-induced myocarditis: virus receptor antibodies modulate myocardifls. J Immuno11989; 143: 1843-1850. 3. Berberian L, Goodglick L, Kipps T J, Braun J. Immunoglobulin VH3 gene products: natural ligands for HIV gpl20. Science 1993; 261: 1588-1591. 4. Hoffenbach A, Langlade-Demoyen P, Dadaglio G e t al. Unusually high frequencies of HIV-specific cytotoxic T lymphocytes in humans. J Immunol 1990; 142: 452-462. 5. Zarling J, Ledbetter J, Sias J e t al. HIV-infected humans, but not chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected CD4÷ cells. J Immunol 1990; 144: 2992-2998. 6. Kennedy J R. Does HIV disrupt a naturally occurring immune modulation system? Med Hypotheses 1993; 41: 445-449.