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

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



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




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.




A brief summary

B and T cells in action against pathogens




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)




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.




A brief summary

5

Cellular Cooperation



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.)



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



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



THE IMMSIM MODEL

The entities

CELLS

Antibody

Antigen

MOLECULES



THE IMMSIM MODEL

Internal variable of each cell type



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



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



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



THE IMMSIM MODEL

Antigen processing

Epitope

Peptide



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



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



THE IMMSIM MODEL

The interactions



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



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.



THE IMMSIM MODEL

A simulation

1

Antibodies during a primary and secondary response



THE IMMSIM MODEL

A simulation

2

Antigen during a primary and secondary response



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



THE IMMSIM MODEL

Experimental data and Immsim: vaccination

T killer cells during a first vaccine-challenge and then during an infection



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

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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