Figure 6. Model of possible network connecting stimulation conditions and induced proteins based on available findings.

The same stimulation conditions can result in either CD27^lo or CD27^hi phenotypes and progression from one to the other. CpG, through TLR9, can activate ΝΦ−κΒ, a marker of receptor editing in Bc. Gene targets of NF-κB include several genes shown to be upregulated in CD27^lo cells (in gold), including AICDA. BAFF (TNFSF13) also has been shown to increase AICDA production. In a separate pathway, Jak proteins, including Jak3 can be activated through action of the common gamma chain cytokines, IL2 or IL-15, resulting in the phosphorylation of STAT proteins such as STAT3, STAT5, and STAT6. IL-10 can also activate STAT3. STAT3, by itself or with STAT6 can increase production of IRF4, a key regulator of Bc differentiation. Induction of IRF4 at low levels can stimulate the production of AICDA, a product of NF-κB and at higher levels, IRF-4 induces production of PRDM-1, a key plasmablast regulator. Thus, as IRF-4 levels increase cells may progress from CD27^lo phenotype to a CD27^hi phenotype. NF-κB can also activate transcription of SPIB which negatively regulates PRDM1 (BLIMP1). PRDM1 then represses BCL6 and AICDA. PRDM1, STAT6, and IRF4 can also enhance production of XBP1 which is necessary for immunoglobulin production. HSPA5 (BiP), a mediator of immunoglobulin folding is also a target of XBP1 and is upregulated in CD27^hi cells.