The Catania Mouse Model (CMM) has been developed using Unified Modeling Language (UML) http://www.uml.org/. UML is a diagramming language or notation to specify, visualize and document different types of models and object oriented software systems. UML helps in visualizing design and in communication. We used Umbrello UML Modeller http://uml.sourceforge.net, an open source tool that allows to manage and create UML based models. UML was selected because it is a widely-used system for the representation of objects and their relationships. Moreover the Umbrello tool was used to export the CMM classes into Extensible Markup Language/Resource Description Format (XML/RDF), in order to create the concepts of CMM-Ontology. XML was developed by the W3C http://www.w3.org. The current standard for the XML Schema Language is controlled by the XML Schema Working Group of the W3C. XML is a good candidate to share ontologies because of the significance of the Web and Web-based applications [15–17]. It is clear that the Web is rapidly becoming the primary method for the exchange of information and data, and that XML is currently the leading candidate for a generic language for the exchange of semi-structured objects.
Distribution
CMM-Ontology main concepts, with controlled vocabularies and rules, are publicly available from the Computational Immunology and Immunomics Group homepage at http://www.immunomics.eu. Available formats are XML and XMI. The concepts of Identification for cellular components and the concepts of interaction have been added in IMGT-ONTOLOGY http://www.imgt.org.
From the model to the CMM-Ontology main concepts
CMM-Ontology concepts were generated from the model CMM. They provide a semantic standardization of the knowledge in the biological modeling field. They are used to identify the main biological entities used in the model as well as their interactions. We focus on two main types of concept: the concepts of identification and the concepts of interaction. These concepts bridge the gap between molecular component ontology and cellular component ontology. It is expected that they will allow scientists to easily identify the main biological entities they use, to model any given biological scenario.
Concepts of Identification
Concepts of identification for molecular components have been analyzed extensively in IMGT-ONTOLOGY [3–6]. We therefore focus, in CMM and CMM-Ontology, on the identification of the cellular entities involved in modeling the competition between cancer and the immune system with or without exogenous stimulation with a cancer vaccine. In CMM, and in accordance with UML, the classes have been developed as a "class diagram" (these classes correspond to concepts in CMM-Ontology). A class defines the attributes and the methods of a set of objects. All objects of a given class (instances of this class) share the same behavior, and have the same set of attributes (each object has its own set). In UML, classes are represented by rectangles, with the name of the class, and can also show the attributes and operations of the class in two other "compartments" inside the rectangle. Interfaces are abstract classes, which means that instances cannot be directly created inside them. They can contain operations but not attributes. An association represents a relationship between classes, and gives the common semantics and structure for many types of "connections" between objects. Associations are the mechanism that allows objects to communicate with each other. In UML, associations are represented as lines connecting the classes participating in the relationship. Aggregations are a special type of association in which the two participating classes do not have an equal status, but make a "whole-part" relationship. An aggregation describes how the class that takes the role of the whole, is composed of (has) other classes, which takes the role of the parts. In UML, aggregations are represented by an association line that ends in a diamond on the side of the whole. A generalization association between two classes puts them in a hierarchy representing the concept of inheritance of a derived class from a base class. In UML, generalizations are represented by a line connecting the two classes, with an ending arrow on the side of the base class. Containment associations represent an operation implementation. In UML, containments are represented by a line with a circle. In CMM-Ontology, the concepts of identification and their instances, generated from the model, are the following (Figure 2):
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MolecularComponent. This concept identifies the molecules. Instances of this concept are: immunoglobulin (IG), T cell receptor (TR), interleukin (IL), antigen (Ag), immunocomplex (IC), major histocompatibility complex (MHC), major histocompatibility complex class I (MHC-I), major histocompatibility complex class II (MHC-II), peptide/MHC-I (pMHC-I), peptide/MHC-II (pMHC-II), Fc receptor (FcR), interleukin receptor (IL-R), interferon (IFN), complement (Cpt).
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MoleculeActivity. This concept identifies activities mediated by molecules. Instances of this concept are binding, recognition, inhibition of proliferation, killing.
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CellularComponent. This concept identifies the cells. Instances of this concept are B lymphocyte (B), T lymphocyte (T), macrophage (M), natural killer (NK), dendritic cell (DC), cancer cell (CC), vaccine cell (VC), mast cell (MC).
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CellActivity. This concept identifies the activities that a cell can carry out. These activities can involve another cell and/or a molecule. Instances of this concept are detailed in Figure 2.
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CellActivationStatus. This concept identifies the activation status of a cell. Instances of this concept are: naive, primed, activated, resting, anergic.
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CellFunction. This concept identifies the functions that a cell can perform. Instances of this concept are: helper (helper 1, helper 2), regulatory, cytotoxic, antigen presenting cell (APC).
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CellDifferentiationStatus. This concept identifies the differentiation status of a cell. Instances of this concept are, for example, memory cell, plasma cell.
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CellLifeStatus. This concept identifies the life status of a cell and was specifically included for modeling purposes. Instances of this concept are: alive (i.e. a cell is performing its own job), dead (a cell to be removed from the system) or dying (a cell starting an apoptosis process and supposed to do some other actions before it dies, i.e. releasing of antigens or some other cell product).
Concepts of interaction
An interaction between two entities is a complex action which eventually ends in a status change of one or both entities. In the immune system, interactions can be specific (adaptive immunity) or non specific (innate immunity). Specific interactions characterize the immune adaptive response and comprise a specific recognition phase between two entities, the antigen receptor and an antigen. These interactions involve the recognition of an antigen by:
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either an immunoglobulin (IG) specific for that antigen (in CMM, native p185 antigen). The antigen can be either soluble or adsorbed at the surface of a follicular dendritic cell in the lymph node;
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or a T cell receptor (TR) specific for a peptide/MHC. The peptide (p) resulting from antigen processing by a cell is presented at the surface of that cell in the groove of a MHC protein of class I or II (MHC-I or MHC-II) [18]. A TR is specific of a pMHC-I or pMHC-II (in CMM, peptides processed from p185 and presented by MHC-I or MHC-II). Immune recognition can be eventually enhanced by adjuvants.
In CMM, the interactions have been modeled using component diagrams. They show the components (either component technologies or sections of the system which are clearly distinguishable) and the artifacts they are made of, such as source code files, or relational database tables. Components can have interfaces (i.e. abstract classes with operations) that allow associations between components.
In CMM-Ontology, the concepts of interaction and their instances, generated from the model, are the following (Figure 3):
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1.
The "Molecule_Molecule_Interaction" concept. If the Molecule is a soluble immunoglobulin (IG) specific for an antigen, and if the other Molecule encountered is that antigen (Ag), IG binds to Ag and forms an immunocomplex (that can be captured by a macrophage). That instance of the "Molecule_Molecule_Interaction" concept is
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2.
The "Cell_Molecule_Interaction" concept. If the Cell is a B lymphocyte, a macrophage or a dendritic cell, and if the Molecule is an antigen, the cell can internalize the native antigen, process it and present it as peptide bound to MHC-II (pMHC-II) protein at the cell surface. The cell becomes a professional antigen presenting cell (or APC). Three instances can therefore be defined:
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B lymphocyte_Antigen (Figure 5). If, in a lymph node, a naive B lymphocyte expresses at the cell surface a membrane IG which is specific for the native antigen (in CMM, p185 antigen), B lymphocyte internalizes the membrane IG and the bound Ag and processes the IG-Ag complex into peptides which are then presented by MHC-II (pMHC-II) at the B lymphocyte surface. B lymphocyte becomes an APC.
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Macrophage_Antigen. If a macrophage encounters a native antigen (in CMM-Ontology, p185 antigen) or an immunocomplex, the macrophage internalizes the antigen or the immunocomplex and processes it into peptides which are then presented by MHC-II (pMHC-II) at the macrophage cell surface. Macrophage becomes an APC.
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Dendritic cell_Antigen. If a naive dendritic cell encounters a native antigen (in CMM, p185 antigen) or an immunocomplex, the dendritic cell internalizes the antigen or the immunocomplex and processes it into peptides which are then presented by MHC-II (pMHC-II) at the dendritic cell surface. Dendritic cell becomes an APC.
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3.
The "Cell_Cell_Interaction" concept.
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(a)
If, in a lymph node, one Cell is a T lymphocyte [helper] (Th) and the other Cell is a B lymphocyte [APC], the T cell (identified as CD4+) becomes an activated T helper lymphocyte that helps the B cell to differentiate into plasma cell or memory cell (Figure 6) At the molecular level, the T cell receptor (TR) at the surface of the T lymphocyte [helper] (Th) binds specifically pMHC-II at the surface of the B lymphocyte [APC], Th proliferates and secretes interleukin 2 (IL2). At the same time, B lymphocyte proliferates and differentiates into a plasma cell (that secretes IG) or into a memory cell (with IG at its surface). That instance of the "Cell_Cell_Interaction" concept is:
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(b)
If one Cell is a T lymphocyte [cytotoxic] (Tc) and the other Cell is a cancer cell (or a vaccine cell, a characteristic cell of the CMM-Ontology), the T cell (identified as CD8+) becomes, in presence of IL2, an activated T cytotoxic lymphocyte that kills the other cell (cancer cell or vaccine cell). At the molecular level, the T cell receptor (TR) at the surface of a naive T lymphocyte [cytotoxic] (Tc) binds specifically pMHC-I at the surface of the cell (cancer cell or vaccine cell), in the presence of IL2, T lymphocyte [cytotoxic] (Tc) is activated and kills the other cell (cancer cell or vaccine cell). The two corresponding instances of the Cell_Cell_Interaction concept are:
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4.
The "Molecule_Cell_Interaction" concept. If the Molecule is a specific soluble immunoglobulin (IG) and the Cell is a cancer cell (or a vaccine cell) that expresses the antigen at its cell surface (in CMM, p185), the soluble IG recognizes specifically the antigen (Figure 8). The opsonized cell (cell with bound IG on its surface) may be killed by complement dependent cytotoxicity (CDC) or by antibody dependent cell cytotoxicity (ADCC). At the molecular level, the first interaction is the recognition by the IG of the antigen expressed at the surface of the cancer cell or vaccine cell. The two corresponding instances of the "Molecule_Cell_Interaction" concept are:
The consequence of the "Molecule_Cell_Interaction" in these two instances, that results in the killing (by CDC or ADCC) of the opsonized cancer cell or vaccine cell involves new instances of concepts defined above:
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"Molecule_Cell_Interaction", for CDC (with the instance Complement_Opsonized cell), or
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"Cell_Cell_Interaction", for ADCC (with the instance Natural killer_Opsonized cell).
In CDC, complement (C1q) binds to the Fc of IG at the surface of the opsonized cell (cancer cell or vaccine cell), the complement cascade is activated, the membrane attack complex (MAC) is formed in the cell membrane and the cell is killed. In ADCC, Fc receptor gamma of natural killer cell (NK) binds to the Fc of IG at the surface of the opsonized cell (cancer cell or vaccine cell), NK kills the cell (cancer cell or vaccine cell).