Table 6. Logical rules.
The set of Boolean rules defining the regulatory network of the terminal differentiation of B cells.
| Logic rule | Description | References |
|---|---|---|
| AID ← (STAT6 ∨ (NF-κB ∧ Pax5)) ∧¬ Blimp1 | AID node is positively regulated by the presence of Pax5 in response to CD40 and IL-4 signals, transduced by NF-κB and STAT6 respectively. AID is active only if its inhibitor Blimp1 is absent. | [91–93] |
| Bach2 ← Pax5 ∧¬ Blimp1 | Bach2 node is activated if its positive regulator Pax5 is active and the suppressor Blimp1 is absent. | [19, 31] |
| Bcl6 ← (STAT5 ∨ STAT6 ∨ (Pax5 ∧Bcl6)) ∧¬ (Blimp1 ∨ Irf4 ∨ ERK) | The node Bcl6 is induced in response to IL-2 and IL-4, transduced by STAT5 and STAT6 respectively. Its activation depends on the presence of Pax5 (proposed as a positive interaction), and on the mechanisms maintaining its own expression (proposed as a positive autoregulation). Bcl6 node is repressed if either the nodes Blimp1, Irf4 or ERK are active. | [35, 36, 46] |
| BCR ← Ag | BCR node is activated by the input node Ag, simulating the presence of extracellular antigen. | [100] |
| Blimp1 ← (ERK ∨ STAT3) ∨ (Irf4 ∧¬ (Pax5 ∨ Bcl6 ∨ Bach2)) | Blimp1 is activated by Irf4 if all its inhibitors, Pax5, Bcl6 and Bach2 are inactive. Blimp1 is induced by Ag and IL-21 which are transduced by ERK and STAT3, respectively. | [49, 50, 52–54] |
| CD40 ← CD40L | The CD40 node is activated by the input node CD40L simulating the direct contact of B with T cells mediated by the union of the CD40 receptor with its ligand. | [16] |
| ERK ← BCR | BCR cross-linking promotes ERK activation after Ag stimulation | [49, 51, 76] |
| IL-2R ← IL-2 | The IL-2R node is induced by the input node IL-2, simulating the activation of the IL-2R receptor by IL-2 stimulation, a signal involved in GC differentiation | [4] |
| IL-4R ← IL-4 | The IL-4 input node induces the IL-4R node simulating the activation of the IL-4R receptor activation by the cytokine IL-4 required for GC differentiation. | [4] |
| IL-21R ← IL-21 | The IL-21R receptor is induced by IL-21, a signal required for differentiation toward PCs | [101–103] |
| Irf4 ← (NF-κB ∨ Irf4) ∨ (Blimp1 ∧¬ Bcl6) | Irf4 is induced in response to CD40L signals, transduced by the node NF-κB. Irf4 regulates its own activation and is positively regulated by Blimp1 if its inhibitor Bcl6 is off. | [16, 18, 61, 89] |
| NF-κB ← CD40 | Activation of the CD40 receptor promotes the activation of the transcription factor NF-κB in response to CD40L stimulation | [16] |
| Pax5 ← (Pax5 ∨ ¬ Irf4) ∧¬(Blimp1 ∨ ERK) | Pax5 is maintained active by low levels of Irf4, proposed as a negative interaction, and possibly by a positive regulatory circuit with Ebf1 that plays a key role during early B cell differentiation, included as a positive autoregulatory interaction. Pax5 is inhibited if Blimp1 or ERK are present. | [11, 51, 78] |
| STAT3 ← IL-21R | IL-21 signals are transduced by STAT3, represented in the model as a positive interaction of the IL-21R receptor with STAT3. | [101–103] |
| STAT5 ← IL-2R | Activation of the IL-2R receptor by IL-2 induces STAT5 activation | [46] |
| STAT6 ← IL-4R | Activation of the IL-4R receptor induces STAT6 in response to IL-4 stimulation | [91] |
| XBP1 ← Blimp1 ∧¬ Pax5 | XBP1 is activated by Blimp1 if the suppressor Pax5 is absent | [65] |
The rules determining the state of activation of each node as a function of its regulatory inputs are expressed by the use of the logic operators ∧ (AND), ∨ (OR), and ¬ (NOT).