Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS A brief summary The immune system is a complex of organs--highly specialized cells and even a circulatory system separate from blood vessels --all of which work together to clear infection from the body. Cells that will grow into the many types of more specialized cells that circulate throughout the immune system are produced in the bone marrow which, together with thymus, is included into central lymphoid organs. Spleen, lymph nodes and mucosa-associated lymphoid tissue are called peripheral lymphoid organs, where cells interactions take place. The cells most relevant are the lymphocytes, numbering close to one trillion. The two major classes of lymphocites are: Human immune system B CELLS They produce antibodies that circulate in the blood and lymph streams and attach to foreign antigens to mark them for destruction by other immune cells. They are generated in the bone marrow Humoral Immunity T CELLS They attack and destroy diseased cells recognized as foreign and they also orchestrate, regulate and coordinate the overall immune response. They mature in the thymus, high in the chest behind the breastbone. Cellular Immunity

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS Clonal selection theory Each lymphocyte bears a single type of receptor of a unique specificity Lymphocites bearing receptors specific for self molecules are deleted at an early stage in cell development and are therefore absent from the repertoire Interaction between a foreign molecule and a lymphocyte receptor capable of binding that molecule with high affinity leads to lymphocyte activation The differentiated effector cells derived from an activated lymphocyte will bear receptors of identical specificity to those of the parental cell from which that lymphocyte was derived

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS Memory Edward Jenner Jenner's experiments of vaccination in 1796 showed that memory is not privilege of the nervous system, but is shared by the immune system too. From Molecular Biology of the Cell Alberts et al.

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS A brief summary B and T cells in action against pathogens

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS A brief summary 3 Antigen and its recognition - Immune System Cells don't recognize a whole pathogen but small parts of it, called antigens (usually proteins), through their specific receptors. B Cells receptors are antibodies exposed on their membrane; they process the antigen themselves and present it on MHC II molecules. T Cells can recognize the antigen with their receptor (TCR) only if presented on a MHC molecule by other cells (B Cells and other Antigen Presenting Cells)

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS A brief summary 4 Antigen Presentation by APC Antigen Presentation to T cells: - Exogenous and Endogenous Bacteria, Virus: three different kind of pathogens. They are source of antigen (anything capable of eliciting an immune response). - MHC I and MHC II are two different kind of protein exposed on cell surface that display peptide antigen to T cells. - TH cells (T helper) and CTL (Cytotoxic Lymphocytes) : two specialized subsets of T cells. TH cells regulate interactions and cohoperation between various cellular types involved in immune response. CTLs are the effectors of the cellular branch of the immune system, killing infected or tumoral cells.

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi HOW THE IMMUNE SYSTEM WORKS A brief summary 5 Cellular Cooperation

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL A definition IMMSIM[1] has been defined as a hyper-cellular automaton[2]: it considers discrete events (e.g., in the immune response, the encounters between single cells and molecules). It works from these events to capture the consequences and delineate the whole phenomenon, that will be represented into a space divided into sites and evolving in discrete time steps. What happens at each step depends on the contents and conditions of each site, and is governed by rules imposed on them. [1] Celada F, Seiden P. (1992) A computer model of cellular interactions in the immune system. Immunol. Today 13: [2] Bandini S (1996). Hyper-cellular automata for the simulation of complex biological systems: a model for the Immune System. Vol3 ISSN: , Special issue on "Advance in mathematical modeling of Biological processes", D.Kirschner (ed.)

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL 1. They consist of a discrete lattice of sites. 2. They evolve in discrete time steps. 3. Each site takes on a finite set of possible values. 4. The value of each site evolves according to the same deterministic rules. 5. The rules for the evolution of a site depend only on a local neighborhood of sites around it. IMMSIM basic rules Wolfram's classical rules 4. The value of each site evolves according to the same probabilistic rules. 5. The rules for the evolution of a site depend only by the site itself. Rules modified in IMMSIM 6. The entities move from site to site. Added rule

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL The lattice - IMMSIM lattice is hexagonal instead of the more familiar square lattice, because in this manner each site has six identical neighbors without edges and corners. - The left side is joined to the right and the top to the bottom making a toroidal surface so that entities moving off the grid in one direction appear at the opposite edge. The gri d

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL The entities CELLS Antibody Antigen MOLECULES

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Internal variable of each cell type

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL How specificity is implemented - Many immunological interactions involve some specificity (e.g. Ab - Ag, TCR - MHC/peptide) - In IMMSIM the most important SEs (Specificity Elements) are: 1) TCR (T Cell Receptor) 2) BCR (B Cell Receptor) 3) MHC I and MHC II 4) Ab (Antibodies) 5) Ag (Antigen) In IMMSIM SEs are implemented as bit strings, 0' and 1' sequences. Each different bit string defines a specificity. For the sake of conciseness we'll often use the base- 10 representation of the base- 2 number Base-2Base-10 8 bits simulation 12 bits simulation

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Affinity - Since each bit can take one of two values, we say that two bit strings complement each other (perfect match) if every 0 in one corresponds to a 1 in the other and conversely. A simple relation to calculate (in base-10) the perfect match(p) for a given bit string(s ) in a N bits simulation is the following: p =(2 N - 1) -s s = 51 N = 8 p = ? p = : :

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL How affinity is calculated - The affinity between two SEs corresponds directly to the probability that the SEs will bind each other. - The minimum number of matching bits allowed is set to MINMATCH (a modifiable parameter). We define Bit_Match() as a function that calculates the affinity of two SEs given the numbe r of matching bits. BIT_MATCH(MINMATCH)=Aff_Level

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Antigen processing Epitop e Peptide

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL The interactions SPECIFICNON SPECIFIC 1) Antibody - Antigen 2) B Cell (BCR) - Antigen 3) T Killer (TCR) - APC (MHC I) 4) T Helper (TCR) - APC (MHC II) 5) T Killer (TCR) - Infected Cell (MHC I) 6) B Cell (MHC II) - T Helper (TCR) 1) APC - Antigen 2) Epithelial Cell - Antigen

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL The core of the simulation 1) Load parameters Cells (randomly on the grid) Antigen Injection (randomly on the grid) 2) Populate the grid 3) Interactions between entities in a randomic order 4) Death 5) Birth Age T Killer Virus 6) Diffusion

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL The interactions

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL How memory is implemented in the model Te APC pM TmTm TmTm Te T TmTm pM APC=Antigen Presenting Cell T=T virgin Cell Te=T effector Cell Tm=T memory Cell pM=probability to become memory n= number of cell cycles nmc=total number of memory cells derived a single T virgin activated nmc=2 n * pM n

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Experimental data and Immsim: the secondary response - Two injections of virus A (days: ) - One injection of virus B (day: 28) Characteristics of secondary response: 1) Higher level of affinity 2) Stronger 3) Faster From:Molecular Biology of the Cell Alberts et al.

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL A simulation 1 Antibodies during a primary and secondary response

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL A simulation 2 Antigen during a primary and secondary response

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Experimental data and Immsim: vaccination Vaccine: any preparation (killed microbes of virulent strains or living microbes of attenuated strains) intended for active immunological prophylaxis ( Stedman's Medical Dictionary) Modified from Immunobiology - Janeway -Travers : Diphtheria and Polio virtually eliminated im the USA after the introduction of vaccination

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi THE IMMSIM MODEL Experimental data and Immsim: vaccination T killer cells during a first vaccine-challenge and then during an infection

Università degli Studi di Genova Claudia Calcagno - Dario Ghersi IMMSIM A model of the immune system Dr. Philip Seiden, the physicist father of the IMMSIM model Dr. Puzone, physicist, father of IMMSIM-C Prof. Franco Celada, the immunologist father of IMMSIM IMMSIM- C website: zzz.cba.unige.it/immsim