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Relationship: 1922

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Impaired T cell activation leads to Impaired Ab production

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

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 KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  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

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Mixed High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
Old Age High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

‘Help’ to B cells is not a single product of TFH cells and not even a single process. T cell help to B cells can be divided into seven distinct functions, proliferation, survival, plasma cell differentiation, somatic hypermutation, class-switch recombination, adhesion and attraction. These seven different forms of help are all contributors to TFHcell–B cell interactions, and each process consists of multiple pathways. Furthermore, some molecules have a role in several different forms of help.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER.  For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The simplest B cell help function that is provided by TFHcells is the induction of B cell proliferation. CD40L is the most prominent protein expressed by TFHcells that contributes to pro-mitotic signalling in B cells64. Survival signals from TFH cells are also crucial, as germinal centre B cells are exquisitely pro-apoptotic. IL-4 produced by TFHcells triggers pro-survival signals to germinal centre B cells via the IL-4 receptor complex. Somatic hypermutation is central to germinal centre biology and the primary purpose of germinal centres is to facilitate affinity maturation of B cells via sequential rounds of immunoglobulin gene mutation and selection. The enzyme activation-induced cytidine deaminase (AID) induces the DNA damage in the immunoglobulin genes that is then converted into mutations by DNA repair enzymes. BCL-6 must be co-expressed with AID by the germinal centre B cell to repress the DNA damage response programme that would otherwise trigger self-destruction of the cell. The signals that induce AID and BCL-6 expression by B cells are not entirely defined, but CD40L, IL-4 and IL-21 contribute. Indeed, the combination of CD40L, IL-4 and IL-21 in different ratios seems to be the primary mix of T cell help signals that control B cell proliferation, somatic hypermutation and differentiation. Class-switch recombination can also be induced by instructive signals from TFHcells to B cells. AID is necessary for class-switch recombination, but the specific target of the heavy chain constant region gene recombination depends on additional factors that are selectively activated by different cytokines, which predominantly, but not exclusively, come from CD4+ T cells. Human IgM to IgG class-switch recombination is most efficiently induced by IL-21, whereas IgE recombination is induced by a high IL-4 to IL-21 ratio.

B cell help crucially depends on cell contact, probably because of a mixture of cell-surface co-stimulatory ligand interactions and directional cytokine production during cognate interactions. Therefore, adhesion molecules expressed by TFHcells and B cells are necessary components of T cell help to B cells, as they regulate the overall duration of the ‘pas de deux’. The most dramatic example of this requirement is SAP, which is described above. SLAM-associated protein (SAP; also known as SH2D1A)binds to the intracellular domains of SLAM family surface receptors, which are involved in cell–cell adhesion. In the absence of SAP, the duration of B cell–T cell adhesion is short and inadequate for the TFHcell to provide sufficient help signals to the B cell. This leads to a general defect in SAP-dependent T cell help to B cells and thus a loss of antigen-specific B cell proliferation and survival, as well as a complete loss of germinal centres and of most memory B cells and long-lived plasma cells.

Finally, chemoattraction is another component of T cell help to B cells. CXC-chemokine ligand 13 (CXCL13) is the ligand for CXCR5 and human germinal centre TFH cells constitutively secrete copious quantities of CXCL13, which probably recruits B cells to colocalize with the TFH cells and to facilitate confinement of the B cells to the germinal centre. Notably, CXCL13 signalling via CXCR5 also modifies B cell adhesion and lymphotoxin synthesis, which shows that CXCL13 also has cytokine-type functions. Thus, chemoattraction is another form of T cell help to B cells.

Therefore, it is conceivable that impaired T cell activation leads to impaired B cell activation and antibody production (reviewed by Crotty (Crotty, 2015)).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. 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 KER description. More help

Crotty, S., 2015. A brief history of T cell help to B cells. Nat Rev Immunol 15, 185-189.

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