C-ImmSim

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C-ImmSim started, in 1995, as the C-language "version" of IMMSIM, the IMMune system SIMulator, a program written back in 1991 in APL-2 (APL2 is a Registered Trademark of IBM Corp.) by the astrophysicist Phil E. Seiden together with the immunologist Franco Celada to implement the Celada-Seiden model. The porting was mainly conducted and further developed by Filippo Castiglione with the help of few other people.

Contents

The Celada-Seiden model

The Celada-Seiden model is a logical description of the mechanisms making up the adaptive immune humoral and cellular response to a genetic antigen at the mesoscopic level.

The computational counterpart of the Celada-Seiden model is the IMMSIM code.

The Celada-Seiden model, as well as C-ImmSim, is best viewed as a collection of models in a single program. In fact, there are various components realising a particular function which can be turned on or off. At its current stage, C-ImmSim incorporates the principal "core facts" of today's immunological knowledge, e.g.

Besides, an antigen can represent a bacterium, a virus or an allergen or a tumour cell.

The high degree of complexity of the Celada-Seiden model makes it suitable to simulate different immunological phenomena, e.g., the hypermutation of antibodies, the germinal centre reaction (GCR), immunization, Thymus selection, viral infections, hypersensitivity, etc.

Since the first release of C-ImmSim, the code has been modified many times. The actual version now includes features that were not in the original Celada-Seiden model.

C-ImmSim has been recently customised to simulate the HIV-1 infection. Moreover, it can simulate the immunotherapy to generic solid tumours. These features are all present in the code and people can choose to turn them on and off at compiling time. However, the present user guide deals with the description of the standard immune system response and gives no indication on the features of HIV-1 and cancer.

The latest version of C-ImmSim allows for the simulation of SARS-CoV-2 infection . [1]

Contributors

The porting was possible thank to the aid of Seiden, especially during the initial validation phase. Massimo Bernaschi contributed to the development of C-ImmSim starting as the "beta" release. Most of the optimization of the memory usage and I/O has been possible thanks to Bernaschi in particular for what concerns the development of the parallel version. Other few people contributed to the further development of the code in the coming years.

There are other computational models developed on the tracks of the Celada-Seiden model which come from (to a certain extent) the first porting in C-language of IMMSIM by F. Castiglione. They are IMMSIM++ developed by S. Kleinstein, IMMSIM-C developed by R. Puzone, Limmsim developed by J. Textor and SimTriplex developed by Pappalardo.

C-ImmSim has been partially described in a series of publications but never extensively, in part because of the availability of other references for the IMMSIM code which could serve as manuals for C-ImmSim as well, in part because it is impractical to compress a full description of C-ImmSim in a regular paper.

IMMSIM, in the authors' minds, was built around the idea of developing a computerized system to perform experiments similar to the real laboratory in vivo and in vivo experiments; a tool developed and maintained to help biologists to test theories and hypothesis about how the immune system works. They called it "in Machina" or "in silico" experiments. IMMSIM was in part developed keeping an eye on the educational potentialities of these kind of tools, in order to provide to students of biology/immunology courses, a way to play with the immune mechanisms to get a grasp on the fundamental concepts of the cellular and/or molecular interactions in the immune response.

For this purpose, IMMSIM++ was developed for Microsoft Windows® and offers the chance to explore various (but not all) features of the Celada-Seiden model. However, since only the executable is available that code is not open for testing/development.

LImmSim is available under the GNU GPL.

SimTriplex is a customized version of the same model and derives from version 6 of C-ImmSim. It has been developed to simulate cancer immunoprevention.

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the "Y" of an antibody contains a paratope that is specific for one particular epitope on an antigen, allowing these two structures to bind together with precision. Using this binding mechanism, an antibody can tag a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

<span class="mw-page-title-main">Immunology</span> Branch of medicine studying the immune system

Immunology is a branch of biology and medicine that covers the study of immune systems in all organisms.

<span class="mw-page-title-main">DNA vaccine</span> Vaccine containing DNA

A DNA vaccine is a type of vaccine that transfects a specific antigen-coding DNA sequence into the cells of an organism as a mechanism to induce an immune response.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system. They belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cell and other intracellular pathogens acting at around 3 days after infection, and respond to tumor formation. Most immune cells detect the antigen presented on major histocompatibility complex (MHC) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

In biology, immunity is the state of being insusceptible or resistant to a noxious agent or process, especially a pathogen or infectious disease. Immunity may occur naturally or be produced by prior exposure or immunization.

<span class="mw-page-title-main">Langerhans cell</span> Cell type

A Langerhans cell (LC) is a tissue-resident macrophage of the skin once thought to be a resident dendritic cell. These cells contain organelles called Birbeck granules. They are present in all layers of the epidermis and are most prominent in the stratum spinosum. They also occur in the papillary dermis, particularly around blood vessels, as well as in the mucosa of the mouth, foreskin, and vaginal epithelium. They can be found in other tissues, such as lymph nodes, particularly in association with the condition Langerhans cell histiocytosis (LCH).

<span class="mw-page-title-main">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

In academia, computational immunology is a field of science that encompasses high-throughput genomic and bioinformatics approaches to immunology. The field's main aim is to convert immunological data into computational problems, solve these problems using mathematical and computational approaches and then convert these results into immunologically meaningful interpretations.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

Systems immunology is a research field under systems biology that uses mathematical approaches and computational methods to examine the interactions within cellular and molecular networks of the immune system. The immune system has been thoroughly analyzed as regards to its components and function by using a "reductionist" approach, but its overall function can't be easily predicted by studying the characteristics of its isolated components because they strongly rely on the interactions among these numerous constituents. It focuses on in silico experiments rather than in vivo.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

A tetramer assay is a procedure that uses tetrameric proteins to detect and quantify T cells that are specific for a given antigen within a blood sample. The tetramers used in the assay are made up of four major histocompatibility complex (MHC) molecules, which are found on the surface of most cells in the body. MHC molecules present peptides to T-cells as a way to communicate the presence of viruses, bacteria, cancerous mutations, or other antigens in a cell. If a T-cell's receptor matches the peptide being presented by an MHC molecule, an immune response is triggered. Thus, MHC tetramers that are bioengineered to present a specific peptide can be used to find T-cells with receptors that match that peptide. The tetramers are labeled with a fluorophore, allowing tetramer-bound T-cells to be analyzed with flow cytometry. Quantification and sorting of T-cells by flow cytometry enables researchers to investigate immune response to viral infection and vaccine administration as well as functionality of antigen-specific T-cells. Generally, if a person's immune system has encountered a pathogen, the individual will possess T cells with specificity toward some peptide on that pathogen. Hence, if a tetramer stain specific for a pathogenic peptide results in a positive signal, this may indicate that the person's immune system has encountered and built a response to that pathogen.

In cell biology, the Celada–Seiden model is a logical description at the inter-cellular level of the mechanisms making up the adaptive immune humoral and cellular response to a genetic antigen.

A neutralizing antibody (NAb) is an antibody that defends a cell from a pathogen or infectious particle by neutralizing any effect it has biologically. Neutralization renders the particle no longer infectious or pathogenic. Neutralizing antibodies are part of the humoral response of the adaptive immune system against viruses, intracellular bacteria and microbial toxin. By binding specifically to surface structures (antigen) on an infectious particle, neutralizing antibodies prevent the particle from interacting with its host cells it might infect and destroy.

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.

Immunomics is the study of immune system regulation and response to pathogens using genome-wide approaches. With the rise of genomic and proteomic technologies, scientists have been able to visualize biological networks and infer interrelationships between genes and/or proteins; recently, these technologies have been used to help better understand how the immune system functions and how it is regulated. Two thirds of the genome is active in one or more immune cell types and less than 1% of genes are uniquely expressed in a given type of cell. Therefore, it is critical that the expression patterns of these immune cell types be deciphered in the context of a network, and not as an individual, so that their roles be correctly characterized and related to one another. Defects of the immune system such as autoimmune diseases, immunodeficiency, and malignancies can benefit from genomic insights on pathological processes. For example, analyzing the systematic variation of gene expression can relate these patterns with specific diseases and gene networks important for immune functions.

References

  1. Kar, T.; Narsaria, U.; Basak, S.; Deb, D.; Castiglione, F.; Mueller, D.; Srivastava, A (2020). "A candidate multi-epitope vaccine against SARS-CoV-2". Scientific Reports. Nature Research. 10 (10895): 10895. Bibcode:2020NatSR..1010895K. doi: 10.1038/s41598-020-67749-1 . PMC   7331818 . PMID   32616763.