università degli studi di genova claudia calcagno - dario ghersi how the immune system works a...
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Università degli Studi di Genova
Claudia Calcagno - Dario Ghersi
HOW THE IMMUNE SYSTEM WORKSA 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 13:56- 62.
[2] Bandini S (1996). Hyper-cellular automata for the simulation of complex biological systems: a model for the Immune System. Vol3 ISSN:1076- 5131, 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 grid
More than on one entity can be in a single site.More than on one entity can be in a single site.
Only entities in the same site can interact with each otherOnly entities in the same site can interact with each other
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 II4) 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.
11001100 204
Base-2 Base-10
8 bits simulation
12 bits simulation110110101100 3500
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) ifevery 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 =(2N- 1) -s
s = 51N = 8p = ?
p = 204
51: 00110011204: 11001100
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
Epitope
Peptide
Università degli Studi di Genova
Claudia Calcagno - Dario Ghersi
THE IMMSIM MODEL
The interactions
SPECIFIC NON 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
Te
APC
pM
pM
Tm
pM
pM
Tm
Te
T
Tm
Te
pM
pM
APC=Antigen Presenting CellT=T virgin CellTe=T effector CellTm=T memory CellpM=probability to become memoryn= number of cell cyclesnmc=total number of memory cells derived a single T virgin activated
nmc=2n * pMn
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: 1 - 28)- 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
IMMSIMA 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