API

Event: 1644

Key Event Title

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Impaired Ab production

Short name

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Impaired Ab production

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
B cell


Organ term

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Organ term
immune system


Key Event Components

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Process Object Action

Key Event Overview


AOPs Including This Key Event

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AOP Name Role of event in AOP
IL-1 inhibition KeyEvent

Stressors

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Taxonomic Applicability

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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

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Life stage Evidence
Not Otherwise Specified High

Sex Applicability

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Term Evidence
Mixed High

Key Event Description

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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

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Ab production can be measured by ELISA.


Domain of Applicability

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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



References

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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.