Here I present the idea that the immune system uses a computational strategy to carry out its many functions in protecting and maintaining the body. Along the way, I define the concepts of computation, Turing machines and system states. I attempt to show that reframing our view of the immune system in computational terms is worth our while.
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Lecture Notes in Computer Science 4163. Artificial Immune Systems. 5 th International Conference, ICARIS 2006. (eds Bersini, H. & Carneiro) (Springer-Verlag, Berlin, 2006).
Stepney, S. et al. Conceptual frameworks for artificial immune systems. Int. J. Unconventional Computing. 1, 315–338 (2005).
Hofmeyr, S. A. & Forrest, S. Architecture for an artificial immune system. Evol. Comput. 8, 443–73 (2000).
Timmis, J., Neal, M. & Hunt, J. An artificial immune system for data analysis. Biosystems 55, 143–150 (2000).
Bersini, H. & Carneiro, J. in Lecture Notes in Computer Science 4163. Artificial Immune Systems. 5th International Conference, ICARIS 2006. (eds Bersini H and Carneiro J) Preface (Springer-Verlag, Berlin, 2006).
Perelson, A. S. Modelling viral and immune system dynamics. Nature Rev. Immunol. 2, 28–36 (2002).
Garrett, S. How do we evaluate artificial immune systems? Evol. Comput. 13, 145–178 (2005).
Harel, D. Computers Ltd.: What They Really Can't Do, Revised paperback edition (Oxford Univ. Press, USA, 2003).
Harel, D. & Feldman, Y . Algorithmics: The Spirit of Computing 3rd edn (Addison-Wesley, 2004).
Ivanov, I. I., Diehl, G. E. & Littman, D. R. Lymphoid tissue inducer cells in intestinal immunity. Curr. Top. Microbiol. Immunol. 308, 59–82 (2006).
Sepehri, S., Kotlowski, R. Bernstein, C. N. & Krause, D. O. Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease. Inflamm. Bowel Dis. 13, 675–683 (2007).
Rozenfeld, R. A., Liu, X., DePlaen, I. & Hsueh, W. Role of gut flora on intestinal group II phospholipase A2 activity and intestinal injury in shock. Am. J. Physiol. Gastrointest. Liver Physiol. 281, G957–G963 (2001).
Schaffer, M., Bongartz, M., Hoffmann, W. & Viebahn, R. MHC-class-II-deficiency impairs wound healing. J. Surg. Res. 138, 100–105 (2007).
Gillitzer, R. & Goebeler, M. Chemokines in cutaneous wound healing. J. Leukoc. Biol. 69, 513–521 (2001).
Ziv, Y., Avidan, H., Pluchino, S., Martino, G. & Schwartz, M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc. Natl Acad. Sci. USA 103, 13174–13179 (2006).
Zhang, Z. & Schluesener, H. J. Mammalian Toll-like receptors: from endogenous ligands to tissue regeneration. Cell. Mol. Life Sci. 63, 2901–2907 (2006).
Cursiefen, C. Immune privilege and angiogenic privilege of the cornea. Chem. Immunol. Allergy 92, 50–57 (2007).
Tettamanti, G. et al. Growth factors and chemokines: a comparative functional approach between invertebrates and vertebrates. Curr. Med. Chem. 13, 2737–2750 (2006).
Savill, J. Apoptosis in resolution of inflammation. J. Leukoc. Biol. 61, 375–380 (1997).
Krysko, D. V., D'Herde, K. & Vandenabeele, P. Clearance of apoptotic and necrotic cells and its immunological consequences. Apoptosis 11, 1709–1726 (2006).
Cohen, I. R. Discrimination and dialogue in the immune system. Semin. Immunol. 12, 215–9; 321–323 (2000).
Cohen, I. R. Tending Adam's Garden: Evolving the Cognitive Immune Self (Academic Press, London, UK 2000).
Cohen, I. R. in Lecture Notes in Computer Science 4199 MoDELS 2006, (eds O. Niestrasz et al.) 499–512 (Springer-Verlag, Berlin, 2006).
Mazmanian, S. K., Liu, C. H., Tzianabos, A. O. & Kasper, D. L. An immunomodulatory molecule of symbiotic bacteria directs maturation of the host immune system. Cell 122, 107–118 (2005).
Cohen, I. R. Regen und Auferstehung: Talmud und Naturwissenschaft im Dialog mit der Welt. (Vandenhoek & Ruprecht, Göttingen, Germany 2005).
Kuhn, T. The Structure of Scientific Revolutions, 2nd edn (Univ. Chicago Press, 1970).
Fleck, L. Genesis and Development of a Scientific Fact (Univ. Chicago Press, 1979).
Nobori, S. et al. Thymic rejuvenation and the induction of tolerance by adult thymic grafts. Proc. Natl Acad. Sci. USA 103, 19081–19086 (2006).
Li, Y., Louzoun, Y. & Weigert, M. Editing anti-DNA B cells by Vlambdax. J. Exp. Med. 199, 337–346 (2004).
Cabbage, S. E. et al. Regulatory T cells maintain long-term tolerance to myelin basic protein by inducing a novel, dynamic state of T cell tolerance. J. Immunol. 178, 887–896 (2007).
Cohen, I. R. The cognitive paradigm and the immunological homunculus. Immunol. Today 13, 490–494 (1992).
Nobrega, A. et al. Global analysis of antibody repertoires. II. Evidence for specificity, self-selection and the immunological 'homunculus' of antibodies in normal serum. Eur. J. Immunol. 23, 2851–2859 (1993).
Poletaev, A. B. The immunological homunculus (immunculus) in normal state and pathology. Biochemistry Mosc. 67, 600–608 (2002).
Avrameas, S. Natural autoantibodies: from 'horror autotoxicus' to 'gnothi seauton'. Immunol. Today 12, 154–159 (1991).
Merbl, Y., Zucker-Toledano, M., Quintana, F. J. & Cohen, I. R. Newborn humans manifest autoantibodies to defined self-molecules detected by antigen microarray informatics. J. Clin. Invest 117, 712–718 (2007).
Mouthon, L. et al. Invariance and restriction toward a limited set of self-antigens characterize neonatal IgM antibody repertoires and prevail in autoreactive repertoires of healthy adults. Proc. Natl Acad. Sci. USA 92, 3839–3843 (1995).
Mirilas, P., Fesel, C., Guilbert, B., Beratis, N. G. & Avrameas, S. Natural antibodies in childhood: development, individual stability, and injury effect indicate a contribution to immune memory. J. Clin. Immunol. 19, 109–115 (1999).
Srivastava, P. Roles of heat-shock proteins in innate and adaptive immunity. Nature Rev. Immunol. 2, 185–194 (2002).
Abulafia-Lapid, R. et al. T cell proliferative responses of type 1 diabetes patients and healthy individuals to human HSP60 and its peptides. J. Autoimmun. 12, 121–129 (1999).
Flohe, S. B. et al. Human heat shock protein 60 induces maturation of dendritic cells versus a Th1-promoting phenotype. J. Immunol. 170, 2340–2348 (2003).
Zanin-Zhorov, A. et al. Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling. J. Clin. Invest. 116, 2022–2032 (2006).
Cohen-Sfady, M. et al. Heat shock protein 60 activates B cells via the TLR4–MyD88 Pathway. J. Immunol. 175, 3594–3602 (2005).
Amir-Kroll, H. et al. A conjugate vaccine composed of a heat shock protein 60 T-cell epitope peptide (p458) and Neisseria meningitidis type B capsular polysaccharide. Vaccine 24, 6555–6563 (2006).
Quintana, F. J. & Cohen, I. R. Heat shock proteins as endogenous adjuvants in sterile and septic inflammation. J. Immunol. 175, 2777–2782 (2005).
Kirwan, S. E. & Burshtyn, D. N. Regulation of natural killer cell activity. Curr. Opin. Immunol. 19, 46–54 (2007).
Zwirner, N. W., Fuertes, M. B., Girart, M. V., Domaica, C. I. & Rossi, L. E. Cytokine-driven regulation of NK cell functions in tumor immunity: Role of the MICA–NKG2D system. Cytokine Growth Factor Rev. 18, 159–170 (2007).
Gasser, S., Orsulic, S., Brown, E. J. & Raulet, D. H. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature 436, 1186–1190 (2005).
Quintana, F. J., Carmi, P., Mor, F. & Cohen, I. R. DNA fragments of the human 60-kDa heat shock protein (HSP60) vaccinate against adjuvant arthritis: identification of a regulatory HSP60 peptide. J. Immunol. 171, 3533–3541 (2003).
Cohen, I. R. Peptide therapy for Type I diabetes: the immunological homunculus and the rationale for vaccination. Diabetologia 45, 1468–1474 (2002).
Quintana, F. J., Carmi, P., Mor, F. & Cohen, I. R. Inhibition of adjuvant-induced arthritis by DNA vaccination with the 70-kd or the 90-kd human heat-shock protein immune cross-regulation with the 60-kd heat-shock protein. Arthritis Rheum. 50, 3712–3720 (2004).
Oki, Y. et al. Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma. Cancer 109, 77–83 (2007).
van Eden. W., van der Zee, R. & Prakken, B. Heat-shock proteins induce T-cell regulation of chronic inflammation. Nature Rev. Immunol. 5, 318–330 (2005).
Lohse, A. W., Mor, F., Karin, N. & Cohen, I. R. Control of experimental autoimmune encephalomyelitis by T cells responding to activated T cells. Science 244, 820–822 (1989).
Mimran, A. et al. DNA vaccination with CD25 protects rats from adjuvant arthritis and induces an antiergotypic response. J. Clin. Invest. 113, 924–932 (2004).
Cohen, I. R., Quintana, F. J. & Mimran, A. Tregs in T cell vaccination: exploring the regulation of regulation. J. Clin. Invest. 114, 1227–1232 (2004).
Zhang, X. Y., Liu, X. G., Wand, W., Wang, W. C. & Gao, X. M. Anti-T-cell humoral and cellular responses in healthy BALB/c mice following immunization with ovalbumin or ovalbumin-specific T cells. Immunol. 108, 465–473 (2003).
Quintana, F. J. & Cohen, I. R. Anti-ergotypic immunoregulation. Scand. J. Immunol. 64, 205–210 (2006).
Correale, J., Rojany, M. & Weiner, L. P. Human CD8+ TCR-αβ+ and TCR-γδ+ cells modulate autologous autoreactive neuroantigen-specific CD4+ T-cells by different mechanisms. J. Neuroimmunol. 80, 47–64 (1997).
Heinemann, M. & Panke, S. Synthetic biology—putting engineering into biology. Bioinformatics 22, 2790–2799 (2006).
Quintana, F. J. et al. Functional immunomics: microarray analysis of IgG autoantibody repertoires predicts the future response of mice to induced diabetes. Proc. Natl Acad. Sci. USA 101 (Suppl. 2), 14615–14621 (2004).
Quintana, J. F., Merbl, Y., Sahar, E., Domany, E. & Cohen, I. R. Antigen-chip technology for accessing global information about the state of the body. Lupus 15, 428–430 (2006).
Orimo, A. & Weinberg, R. A. Stromal fibroblasts in cancer: a novel tumor-promoting cell type. Cell Cycle 5, 1597–1601 (2006).
Witz, I. P. Tumor-microenvironment interactions: the selectin–selectin ligand axis in tumor-endothelium cross talk. Cancer Treat. Res. 130, 125–140 (2006).
Whiteside, T. L. The role of immune cells in the tumor microenvironment. Cancer Treat. Res. 130, 103–124 (2006).
Tan, T. T. & Coussens, L. M. Humoral immunity, inflammation and cancer. Curr. Opin. Immunol. 19, 209–216 (2007).
Elaraj, D. M. et al. The role of interleukin 1 in growth and metastasis of human cancer xenografts. Clin. Cancer Res. 12, 1088–1096 (2006).
Bergmann, C., van Hemmen. J. L. & Segel, L. A. How instruction and feedback can select the appropriate T helper response. Bull. Math. Biol. 64, 425–446 (2002).
Meier-Schellersheim M., Xu X., Angermann B., Kunkel E. J., Jin T., Germain R.N. Key role of local regulation in chemosensing revealed by a new molecular interaction-based modeling method. PLoS Comput. Biol. 2, e82 (2006).
Cohen, I. R. & Harel, D. Explaining a complex living system: dynamics, multi-scaling and emergence. J. R. Soc. Interface 4, 175–182 (2007).
Efroni, S., Harel, D. & Cohen, I. R. Emergent dynamics of thymocyte development and lineage determination. PLoS Comput. Biol. 3, e13 (2007).
I thank my students and colleagues for teaching me about computation and for their stimulating discussions: H. Amir-Kroll, H. Atlan, E. Ben Jacob, H. Bersini, A. Coutinho, E. Domany, S. Efroni, Z. Grossman, D. Harel, Y. Louzoun, M. Meier-Schellersheim, Y. Merbl, F. J. Quintana, A. Sadot, E. Sahar and S. Solomon. The late L. Segel made a unique contribution to my thinking. I thank S. Efroni for helping me prepare figure 4.
The author declares no competing financial interests.
A 'recipe' for carrying out a computation.
The process of obtaining a solution to a problem from given inputs by means of an algorithm.
- Immunogenic state of the body
The conditions and molecular signals of the body that affect or stimulate the immune system.
- Immunological homunculus concept
The concept that the adaptive and innate repertoires of the healthy immune system include receptors that recognize a defined set of body molecules. These self-recognizing receptors combine to encode a functional immune image of key body molecules. The immunological homunculus reads the immunogenic state of the body.
- Response state of the immune system
The responses of the immune system to the immunogenic states of the cells and tissues of the body.
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Cohen, I. Real and artificial immune systems: computing the state of the body. Nat Rev Immunol 7, 569–574 (2007). https://doi.org/10.1038/nri2102
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