Immune network theory

Last updated August 07, 2024

The immune network theory is a theory of how the adaptive immune system works, that has been developed since 1974 mainly by Niels Jerne ^[1] and Geoffrey W. Hoffmann.^[2]^[3] The theory states that the immune system is an interacting network of lymphocytes and molecules that have variable (V) regions. These V regions bind not only to things that are foreign to the vertebrate, but also to other V regions within the system. The immune system is therefore seen as a network, with the components connected to each other by V-V interactions.

The scope of the symmetrical network theory developed by Hoffmann includes the phenomena of low dose and high dose tolerance, first reported for a single antigen by Avrion Mitchison,^[6] and confirmed by Geoffrey Shellam and Sir Gustav Nossal,^[7] the helper^[8] and suppressor roles ^[9] of T cells, the role of non-specific accessory cells in immune responses,^[10] and the very important phenomenon called I-J. Jerne was awarded the Nobel Prize for Medicine or Physiology in 1984 partly for his work towards the clonal selection theory, as well as his proposal of the immune network concept.^[11]

The immune network theory has also inspired a subfield of optimization algorithms similar to artificial neural networks.^[12]

The symmetrical immune network theory

Heinz Kohler was involved in early idiotypic network research and was the first to suggest that idiotypic network interactions are symmetrical.^[13]^[3] He developed a detailed immune network theory based on symmetrical stimulatory, inhibitory and killing interactions. It offers a framework for understanding a large number of immunological phenomena based on a small number of postulates. The theory involves roles for B cells that make antibodies, T cells that regulate the production of antibodies by B cells, and non-specific accessory cells (A cells).

Antibodies called IgG have two V regions and a molecular weight of 150,000. A central role in the theory is played by specific T cell factors, which have a molecular weight of approximately 50,000, and are postulated in the theory to have only one V region.^[14]^[10]^[15] Hoffmann has proposed that for brevity specific T cell factors should be called tabs.^[3] Tabs are able to exert a powerful suppressive effect on the production of IgG antibodies in response to foreign substances (antigens), as was demonstrated rigorously by Takemori and Tada.^[14] Hoffmann and Gorczynski have reproduced the Takemori and Tada experiment, confirming the existence of specific T cell factors.^[16] In the symmetrical network theory tabs are able to block V regions and also to have a stimulatory role when bound to a tab receptor on A cells. Symmetrical stimulatory interactions follow from the postulate that activation of B cells, T cells and A cells involves cross-linking of receptors.

The symmetrical network theory has been developed with the assistance of mathematical modeling. In order to exhibit immune memory to any combination of a large number of different pathogens, the system has a large number of stable steady states. The system is also able to switch between steady states as has been observed experimentally. For example, low or high doses of an antigen can cause the system to switch to a suppressed state for the antigen, while intermediate doses can cause the induction of immunity.

I-J, the I-J paradox, and a resolution of the I-J paradox

The theory accounts for the ability of T cells to have regulatory roles in both helping and suppressing immune responses. In 1976 Murphy et al. and Tada et al. independently reported a phenomenon in mice called I-J.^[17]^[18] From the perspective of the symmetrical network theory, I-J is one of the most important phenomena in immunology, while for many immunologists who are not familiar with the details of the theory, I-J "does not exist". In practice I-J is defined by anti-I-J antibodies, that are produced when mice of certain strains are immunized with tissue of certain other strains; see Murphy et al. and Tada et al., op cit. I-J was found by these authors to map to within the Major Histocompatibility Complex, but no gene could be found at the site where I-J had been mapped in numerous experiments.^[19] The absence of I-J gene(s) within the MHC at the place where I-J had been mapped became known as the "I-J paradox". This paradox resulted in regulatory T cells and tabs, which both express I-J determinants, falling out of favour, together with the symmetrical network theory, that is based on the existence of tabs. In the meantime however, it has been shown that the I-J paradox can be resolved in the context of the symmetrical network theory.^[20]

The resolution of the I-J paradox involves a process of mutual selection (or "co-selection") of regulatory T cells and helper T cells, meaning that (a) those regulatory T cells are selected that have V regions with complementarity to as many helper T cells as possible, and (b) helper T cells are selected not only on the basis of their V regions having some affinity for MHC class II, but also on the basis of the V regions having some affinity for the selected regulatory T cell V regions. The helper T cells and regulatory T cells that are co-selected are then a mutually stabilizing construct, and for a given mouse genome, more than one such mutually stabilizing set can exist. This resolution of the I-J paradox leads to some testable predictions.

However, considering the importance of the (unfound) I-J determinant for the theory, the I-J paradox solution is still subject to strong criticism, e.g.Falsifiability.

Relevance for understanding HIV pathogenesis

An immune network model for HIV pathogenesis was published in 1994 postulating that HIV-specific T cells are preferentially infected (Hoffmann, 1994, op cit.). The publication of this paper was followed in 2002 with the publication of a paper entitled "HIV preferentially infects HIV specific CD4+ T cells."^[21]

Under the immune network theory, the main cause for progression to AIDS after HIV infection is not the direct killing of infected T helper cells by the virus. Following an infection with HIV that manages to establish itself, there is a complex interaction between the HIV virus, the T helper cells that it infects, and regulatory T cells.^[22] These three quasispecies apply selective pressure on one another and co-evolve in such a way that the viral epitopes eventually come to mimick the V regions of the main population of T regulatory cells. Once this happens, anti-HIV antibodies can bind to and kill most of the host's T regulatory cell population. This results in the dysregulation of the immune system, and eventually to other further anti-self reactions, including against the T helper cell population. At that point, the adaptive immune system is completely compromised and AIDS ensues. Hence in this model, the onset of AIDS is primarily an auto-immune reaction triggered by the cross-reaction of anti-HIV antibodies with T regulatory cells. Once this induced auto-immunity sets in, removing the HIV virus itself (for instance via HAART) would not be sufficient to restore proper immune function. The co-evolution of the quasispecies mentioned above will take a variable time depending on the initial conditions at the time of infection (i.e. the epitopes of the first infection and the steady state of the host's immune cell population), which would explain why there is a variable period, which differs greatly between individual patients, between HIV infection and the onset of AIDS. It also suggests that conventional vaccines are unlikely to be successful, since they would not prevent the auto-immune reaction. In fact such vaccines may do more harm in certain cases, since if the original infection comes from a source with a "mature" infection, those virions will have a high affinity for anti-HIV T helper cells (see above), and so increasing the anti-HIV population via vaccination only serves to provide the virus with more easy targets.

An HIV vaccine concept based on immune network theory

A hypothetical HIV vaccine concept based on immune network theory has been described.^[23] The vaccine concept was based on a network theory resolution of the Oudin-Cazenave paradox.^[24] This is a phenomenon that makes no sense in the context of clonal selection, without taking idiotypic network interactions into account. The vaccine concept comprised complexes of an anti-anti-HIV antibody and an HIV antigen, and was designed to induce the production of broadly neutralizing anti-HIV antibodies. A suitable anti-anti-HIV antibody envisaged for use in this vaccine is the monoclonal antibody 1F7, which was discovered by Sybille Muller and Heinz Kohler and their colleagues.^[25] This monoclonal antibody binds to all of six well characterized broadly neutralizing anti-HIV antibodies.^[26]

A more general vaccine based on immune network theory

A vaccine concept based on a more recent extension of immune network theory and also based on much more data has been described by Reginald Gorczynski and Geoffrey Hoffmann.^[27] The vaccine typically involves three immune systems, A, B and C that can be combined to make an exceptionally strong immune system in a treated vertebrate C. In mouse models the vaccine has been shown to be effective in the prevention of inflammatory bowel disease; the prevention of tumour growth and prevention of metastases in a transplantable breast cancer; and in the treatment of an allergy. The immune system of C is stimulated by a combination of A anti-B (antigen-specific) and B anti-anti-B (antiidiotypic) antibodies. The former stimulate anti-anti-B T cells and the latter stimulate anti-B T cells within C. Mutual selection ("co-selection") of the anti-B and anti-anti-B T cells takes the system to a new stable steady state in which there are elevated levels of these two populations of T cells. An untreated vertebrate C with self antigens denoted C is believed to have a one-dimensional axis of lymphocytes that is defined by co-selection of anti-C and anti-anti-C lymphocytes. The treated vertebrate C has a two dimensional system of lymphocytes defined by co-selection of both anti-C and anti-anti-C lymphocytes and co-selection of anti-B and anti-anti-B lymphocytes. Experiments indicate that the two-dimensional system is more stable than the one-dimensional system.

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<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura, systemic lupus erythematosus, Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis, ankylosing spondylitis, polymyositis, dermatomyositis, and multiple sclerosis. Autoimmune diseases are very often treated with steroids.

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, including marsupials B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

The T helper cells (T_h cells), also known as CD4⁺ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4⁺ cells are mature T_h cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4⁺ cells determines susceptibility to a broad class of autoimmune diseases.

Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as activation immunotherapies, while immunotherapies that reduce or suppress are classified as suppression immunotherapies. Immunotherapy is under preliminary research for its potential to treat various forms of cancer.

In immunology, seroconversion is the development of specific antibodies in the blood serum as a result of infection or immunization, including vaccination. During infection or immunization, antigens enter the blood, and the immune system begins to produce antibodies in response. Before seroconversion, the antigen itself may or may not be detectable, but the antibody is absent. During seroconversion, the antibody is present but not yet detectable. After seroconversion, the antibody is detectable by standard techniques and remains detectable unless the individual seroreverts, in a phenomenon called seroreversion, or loss of antibody detectability, which can occur due to weakening of the immune system or decreasing antibody concentrations over time. Seroconversion refers the production of specific antibodies against specific antigens, meaning that a single infection could cause multiple waves of seroconversion against different antigens. Similarly, a single antigen could cause multiple waves of seroconversion with different classes of antibodies. For example, most antigens prompt seroconversion for the IgM class of antibodies first, and subsequently the IgG class.

In immunology, a memory B cell (MBC) is a type of B lymphocyte that forms part of the adaptive immune system. These cells develop within germinal centers of the secondary lymphoid organs. Memory B cells circulate in the blood stream in a quiescent state, sometimes for decades. Their function is to memorize the characteristics of the antigen that activated their parent B cell during initial infection such that if the memory B cell later encounters the same antigen, it triggers an accelerated and robust secondary immune response. Memory B cells have B cell receptors (BCRs) on their cell membrane, identical to the one on their parent cell, that allow them to recognize antigen and mount a specific antibody response.

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

In immunology, clonal selection theory explains the functions of cells of the immune system (lymphocytes) in response to specific antigens invading the body. The concept was introduced by Australian doctor Frank Macfarlane Burnet in 1957, in an attempt to explain the great diversity of antibodies formed during initiation of the immune response. The theory has become the widely accepted model for how the human immune system responds to infection and how certain types of B and T lymphocytes are selected for destruction of specific antigens.

The following are notable events in the Timeline of immunology:

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

T helper 3 cells (T_h3) are a subset of T lymphocytes with immunoregulary and immunosuppressive functions, that can be induced by administration of foreign oral antigen. T_h3 cells act mainly through the secretion of anti-inflammatory cytokine transforming growth factor beta (TGF-β). T_h3 have been described both in mice and human as CD4⁺FOXP3⁻ regulatory T cells. T_h3 cells were first described in research focusing on oral tolerance in the experimental autoimmune encephalitis (EAE) mouse model and later described as CD4⁺CD25⁻FOXP3⁻LAP⁺ cells, that can be induced in the gut by oral antigen through T cell receptor (TCR) signalling.

<span class="mw-page-title-main">Follicular B helper T cells</span>

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Immunodominance is the immunological phenomenon in which immune responses are mounted against only a few of the antigenic peptides out of the many produced. That is, despite multiple allelic variations of MHC molecules and multiple peptides presented on antigen presenting cells, the immune response is skewed to only specific combinations of the two. Immunodominance is evident for both antibody-mediated immunity and cell-mediated immunity. Epitopes that are not targeted or targeted to a lower degree during an immune response are known as subdominant epitopes. The impact of immunodominance is immunodomination, where immunodominant epitopes will curtail immune responses against non-dominant epitopes. Antigen-presenting cells such as dendritic cells, can have up to six different types of MHC molecules for antigen presentation. There is a potential for generation of hundreds to thousands of different peptides from the proteins of pathogens. Yet, the effector cell population that is reactive against the pathogen is dominated by cells that recognize only a certain class of MHC bound to only certain pathogen-derived peptides presented by that MHC class. Antigens from a particular pathogen can be of variable immunogenicity, with the antigen that stimulates the strongest response being the immunodominant one. The different levels of immunogenicity amongst antigens forms what is known as dominance hierarchy.

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