Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|Pralnacasan (VX-740) and Belnacasan (VX-765)|
|IL-1 receptor antagonist（IL-1Ra）(Anakinra)|
|anti-IL-1b antibody (Canakinumab)|
|soluble IL-1R (Rilonacept)|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Rattus norvegicus||Rattus norvegicus||High||NCBI|
|Not Otherwise Specified||High|
Key Event Description
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.
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
Ab production can be measured by ELISA.
Domain of Applicability
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.
Evidence for Perturbation by Stressor
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.