Immune network theory
Encyclopedia
The immune network theory is a theory of how the adaptive immune system
works, that has been developed since 1974 mainly by Niels Jerne and Geoffrey W. Hoffmann
. 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.
It has been suggested that the phenomena that the theory describes in terms of networks are also explained by clonal selection theory. 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
, and confirmed by Geoffrey Shellam and Sir Gustav Nossal, the helper and suppressor roles of T cells, the role of non-specific accessory cells in immune responses, 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.
Immune network theory has also inspired a subfield of optimization
algorithms similar to artificial neural networks, and unrelated to biological immunology.
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. Hoffmann has proposed that for brevity specific T cell factors should be called tabs. Tabs are able to exert a powerful suppressive effect on the production of IgG antibodies in response to foreign substances (antigens), as has been demonstrated rigorously by Tomio Tada and his collaborators. 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.
The resolution of the I-J paradox involves a process of mutual selection (or “co-selection”) of suppressor T cells and helper T cells, meaning that (a) those suppressor 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 suppressor T cell V regions. The helper T cells and suppressor 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.
pathogenesis was published in 1994 postulating that HIV-specific T cells are preferentially infected. The publication of this paper was followed in 2002 with the publication of a paper entitled "HIV preferentially infects HIV specific CD4+ T cells."
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
works, that has been developed since 1974 mainly by Niels Jerne and Geoffrey W. Hoffmann
Geoffrey W. Hoffmann
Geoffrey W. Hoffmann, is an Australian-Canadian theoretical biologist. Hoffmann was a faculty member in the Department of Physics at the University of British Columbia and is currently chairman and chief scientist at Network Immunology Inc. in Vancouver, Canada...
. 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.
It has been suggested that the phenomena that the theory describes in terms of networks are also explained by clonal selection theory. 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
Avrion Mitchison
The Honourable Avrion "Av" Mitchison FRS is a British zoologist and immunologist.- Biography :Mitchison was born in 1928, the son of the Labour politician Dick Mitchison and his wife, the writer Naomi . His uncle was the biologist J.B.S...
, and confirmed by Geoffrey Shellam and Sir Gustav Nossal, the helper and suppressor roles of T cells, the role of non-specific accessory cells in immune responses, and the very important phenomenon called I-J. Jerne was awarded the Nobel Prize
Nobel Prize
The Nobel Prizes are annual international awards bestowed by Scandinavian committees in recognition of cultural and scientific advances. The will of the Swedish chemist Alfred Nobel, the inventor of dynamite, established the prizes in 1895...
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.
Immune network theory has also inspired a subfield of optimization
Optimization problem
In mathematics and computer science, an optimization problem is the problem of finding the best solution from all feasible solutions. Optimization problems can be divided into two categories depending on whether the variables are continuous or discrete. An optimization problem with discrete...
algorithms similar to artificial neural networks, and unrelated to biological immunology.
The symmetrical immune network theory
Hoffmann 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. Hoffmann has proposed that for brevity specific T cell factors should be called tabs. Tabs are able to exert a powerful suppressive effect on the production of IgG antibodies in response to foreign substances (antigens), as has been demonstrated rigorously by Tomio Tada and his collaborators. 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.
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 two groups independently reported a phenomenon in mice called I-J. 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”. This is because I-J seemed to map to within the Major Histocompatibility Complex, and no gene could be found at the site where I-J had been mapped in numerous experiments. This became known as the “I-J paradox”. This paradox resulted in suppressor 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.The resolution of the I-J paradox involves a process of mutual selection (or “co-selection”) of suppressor T cells and helper T cells, meaning that (a) those suppressor 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 suppressor T cell V regions. The helper T cells and suppressor 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.
Relevance for understanding HIV pathogenesis
An immune network model for HIVHIV
Human immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
pathogenesis was published in 1994 postulating that HIV-specific T cells are preferentially infected. The publication of this paper was followed in 2002 with the publication of a paper entitled "HIV preferentially infects HIV specific CD4+ T cells."