GO Content Meeting November 15 and 16, 2005 Improving the Representation of Immunology in the Gene Ontology

Proposal List for GO Content Meeting A. Self and Non-Self Processes B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Proposal List for GO Content Meeting A. Self and Non-Self Processes – Amelia and Jane B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Proposal List for GO Content Meeting A. Self and Non-Self Processes – Amelia and Jane B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Proposal List for GO Content Meeting A. Self and Non-Self Processes – Amelia and Jane B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Proposal List for GO Content Meeting A. Self and Non-Self Processes – Amelia and Jane B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Proposal List for GO Content Meeting A. Self and Non-Self Processes – Amelia and Jane B. Reorganization of Cytokine Function Terms C. Adding CD antigen binding terms D. Improvements to T cell differentiation hierarchy E. Reorganization of immune response terms in several ways 1) Activation of the immune system vs. effector mechanisms 2) Improving representation of innate immunity 3) Improving representation of immune cell differentiation 4) Improving GO: inflammatory response F. The problem of regulation terms under immune response G. Tumor surveillance terms

Problems for Immunology in the GO Incomplete Representation of Immunological Processes Conceptual Problems in Term Organization Poorly Formulated and Poorly Defined Terms

Incomplete Representation of Immunological Processes Current GO lacks whole groups of terms for processes such as mucosal immunity tolerance induction B cell differentiation And individual terms for important processes such as granuloma formation germinal center formation affinity maturation

Conceptual Problems in Immunology Term Organization in the GO Terms describing the development of immune system components are incorrectly placed under GO: immune response, when in fact many of the differentiation steps occur prior to an immune response. T cell differentiation (T cell development) B cell differentiation (B cell development)

Conceptual Problems in Immunology Term Organization in the GO (2) The GO terms for cytokine metabolism and cytokine production are children of immune response, when in fact many cytokines are produced independently of immune responses and have non-immunological functions (EGF or TGF-ß, for example).

Conceptual Problems in Immunology Term Organization in the GO (3) Separate GO terms for antigen processing and antigen presentation exist, without recognition of the relationship of these two concepts. Furthermore, the children of these terms are not well defined and important subprocesses are missing from the GO. This has led to confusion by annotators in the use of these terms, and reflects poorly on the GO.

Conceptual Problems in Immunology Term Organization in the GO (4) GO: immune response is a child of defense response in the current GO, yet immune responses include tolerance induction and regulatory processes that are not defense responses. GO: inflammatory response is a child of immune response, yet inflammatory responses include non-immunological components.

Poorly Formulated and Poorly Defined Terms humoral immune response ; GO: % humoral defense mechanism (sensu Vertebrata) ; GO: % humoral defense mechanism (sensu Protostomia) ; GO:

Poorly Formulated and Poorly Defined Terms humoral immune response ; GO: % humoral defense mechanism (sensu Vertebrata) ; GO: % humoral defense mechanism (sensu Protostomia) ; GO: An immune response mediated through a body fluid.

Poorly Formulated and Poorly Defined Terms humoral immune response ; GO: % humoral defense mechanism (sensu Vertebrata) ; GO: % humoral defense mechanism (sensu Protostomia) ; GO: The specific immune response mediated by antibodies, as in, but not restricted to, the vertebrates (Vertebrata, ncbi_taxonomy_id:7742).

Poorly Formulated and Poorly Defined Terms humoral immune response ; GO: % humoral defense mechanism (sensu Vertebrata) ; GO: % humoral defense mechanism (sensu Protostomia) ; GO: The specific immune response mediated by antibodies. As in, but not restricted to, the taxon Protostomia (Protostomia, ncbi_taxonomy_id:33317).

The Big Picture

Assumptions Behind Changes to Immune Response DAG Current definition of GO: immune response: Any process involved in the immunological reaction of an organism to an immunogenic stimulus.

Assumptions Behind Changes to Immune Response DAG 1. Immunological reactions involve largely, but not solely, hematopoietically derived cell types, commonly referred to as immune cells or leukocytes in the GO, and may target any tissue or cell type in the body as well as infecting organisms.

Assumptions Behind Changes to Immune Response DAG 2. An immunological stimulus is any stimulus capable of activating an immune response activating cell surface receptor pathway. Such pathways include: BCR and TCR signaling pathways on mature B and T cells C-type lectin receptor signaling pathways with activation activities KIR signaling pathways with activation activities Fc receptor signaling pathways with cellular activation activities Toll-like receptor signaling pathways (and Toll in drosophila) complement receptor signaling pathways with activation activities certain other pathways (scavenger receptors etc.)

Assumptions Behind Changes to Immune Response DAG 3. An immune response is considered to be the set of physiological processes carried out by immune cell types and certain additional cell types following an immunological stimulus. Differentiation processes for immune cell types (for instance thymic T cell development) prior to an immunogenic stimulus are not considered part of the immune response.

Assumptions Behind Changes to Immune Response DAG 4. An immune response may be made against both self and non-self determinants. Although the GO is intended to cover "normal" processes, these processes include immune responses against microbes, pests and parasites of all types, whether pathogenic or not, tolerance induction mechanisms against peripheral antigens whether of self or non- self origin, anti-tumor immune responses, and even beneficial autoimmune responses.

Changes to the GO: immune response hierarchy Multiple Modes of Immune Response 1. Innate Immune Response 2. Adaptive Immune Response 3. Humoral Immune Response 4. Mucosal Immune Response

Changes to the GO: immune response hierarchy

Innate Immune Response

Adaptive Immune Response

Humoral Immune Response

Mucosal Immune Response

Activation of the Immune Response

Immune Effector Process

Immune Cell Mediated Immunity

Regulation of Immune Response

Problems with Regulation GO dogma: positive regulation of a child term is a type of positive regulation of a parent term. However, this inference is not strictly true for many processes in the immune system.

Problems with Regulation

Inflammatory Response

Tolerance Induction

Cell Activation The current paradigm in the biological_process ontology is that T cell and B cell differentiation and proliferation are types of T cell and B cell activation, respectively. This DAG structure has certain advantages in annotation of things like T cell proliferation assays. T cell and B cell activation are defined in the GO to include any type of activation of those cell types, not just activation through the TCR or BCR, and included implicitly in activation are activation steps required for differentiation. The big change now is that T and B cell differentiation processes prior to an immune response (what immunologists know as T cell development and B cell development) are no longer children of GO: immune response.

Somatic Diversification of Immune Receptors

Immunoglobulin Production

Outstanding Questions 1.What other pathways of activation constitute immunological stimuli? 2.How should inhibitory pathways (ITIMs) be handled? 3.Should plant innate immunity be included under innate immunity? 4.What other pathways of innate immunity, particularly for invertebrates should be included?

Outstanding Questions 5.What is the proper relationship of the inflammatory response to the immune response? 6.Is the cell activation/differentiation/proliferation structure the best way to show the relationships of these terms? 7.Is central tolerance to non-self antigens via upregulation of CD4 + CD25 + T regulatory cell differentiation an immune response or not?