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Event: 1644

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Impaired Ab production

Short name

The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help

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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help

Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place. For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable. For individual/population events, the organ context is not applicable. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Cell term
B cell

Organ term

Organ term
immune system

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE.Clicking on the name of the AOP will bring you to the individual page for that AOP. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Term	Scientific Term	Evidence	Link
Homo sapiens	Homo sapiens	High	NCBI
Mus musculus	Mus musculus	High	NCBI
Rattus norvegicus	Rattus norvegicus	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
Not Otherwise Specified	High

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Mixed	High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

ACTIVATION OF B CELLS

Initial encounter of antigen by B-cells occurs in peripheral lymphoid organ where free antigens gain access via lymphatics or are carried by homing dendritic cells, professional antigen-presenting cells from peripheral tissues. The B-cell receptor on B-lymphocytes efficiently captures antigen which is then internalized,processed and returned to the cell surface as peptides bound to Class II MHC molecules. Antigenactivated B-cells then migrate toward the T-cell zones of the lymphoid tissue. Humoral response to most protein antigens requires help from CD4+ T-cells. B-cell–T-cell interaction leads to activation, proliferation and further differentiation of B-cells into plasma cells. Some B-cells migrate from the T-cell zone into a nearby lymphoid follicle where they proliferate and differentiate and establish secondary germinal centers.The rapid proliferation of cells in the germinal centre greatly increases the number of B-cells specific for the pathogen that initiated the antibody response. Furthermore, in the germinal center, somatic hypermutation of immunoglobulin-variable domain genes and affinity maturation occur such that there is a switch from IgM to other isotypes of antibodies and increase in the affinity of antibodies for the inducing antigen. These antigen-activated B-cells then come into contact with specialized stromal cells called follicular dendritic cells that bear unprocessed antigens trapped within the lymphoid follicles. These cells provide survival signals for mature B-lymphocytes that bind cognate antigen on their surface with high affinity. Those B-cells that fail to bind die by apoptosis. Thus, those B-cells that have high-affinity binding to antigens survive the selection process, leave the germinal center to become either memory B-cells or antibody-secreting plasma cells. Plasma cells migrate to the bone marrow and produce the majority of circulating immunoglobins. B-cells that become memory B-cells reside in the lymphoid organ and can be rapidly activated upon subsequent challenge with the same antigen.

B-CELL–T-CELL INTERACTION

Helper T-cells which recognize antigen on the surface of B-cells become activated and synthesize both cell bound and secreted effector molecules that synergize in B-cell activation (Fig. 1). CD40 ligand (CD40L) is expressed on activated helper T-cells, that binds to CD40 on B-cell surface. Antigen binding and CD40–CD40L interaction provide signals that drive B-cell activation, proliferation and differentiation into plasma cells. Activated B-cells also express other co-stimulatory molecules such as surface B7.1 and B7.2 proteins that bind to CD28 on the surface of T-cells to enhance cognate interaction as well as driving T-cell activation. The B7 molecules are members of the immunoglobulin superfamily that bind to CD28 on naı¨ve T-cells and an additional receptor, CTLA-4 that is expressed on activated T-cells. CTLA-4 binds B7 molecules with higher avidity than CD28 and transduces a negative signal to the activated T-cells in order to limit excessive proliferative response of these activated

T-cells. Soluble factors like cytokines are also important inducers of B-cell activation. Interleukin (IL)-4 preferentially induce switching of immunoglobulin isotype to IgG1 and IgE, whereas tissue growth factor (TGF)-b induces switching to IgG2b and IgA. Interferon (IFN)-c induces IgG2a and IgG3 production by activated B-lymphocytes.(reviewed by Mok (Mok, 2010)).

Since full activation of B cells and antibody production and class switch depends on T cell help. The impaired activation of T cells leads to impaired B cell activation and antibody production.

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Ab production can be measured by ELISA.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided). More help

Although sex differences in immune responses are well known (Klein and Flanagan, 2016), there is no reports regarding the sex difference in IL-1 production, IL-1 function or susceptibility to infection as adverse effect of IL-1 blocking agent. Again, age-dependent difference in IL-1 signaling is not known.

The IL1B gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, and frog (https://www.ncbi.nlm.nih.gov/homologene/481), and the Myd88 gene is conserved in human, chimpanzee, Rhesus monkey, dog, cow, rat, chicken, zebrafish, mosquito, and frog (https://www.ncbi.nlm.nih.gov/homologene?Db=homologene&Cmd=Retrieve&list_uids=1849).

These data suggest that the proposed AOP regarding inhibition of IL-1 signaling is not dependent on life stage, sex, age or species.

References

List of the literature that was cited for this KE description. More help

Klein, S.L., Flanagan, K.L., 2016. Sex differences in immune responses. Nat Rev Immunol 16, 626-638.

Mok, M.Y., 2010. The immunological basis of B-cell therapy in systemic lupus erythematosus. Int J Rheum Dis 13, 3-11.