Fig. 2

B-Cell Receptor (BCR), CD19 and CD40/BAFF receptors signaling, relationships and cross talk(s). The NF-κB is the most important pathway that activating by two: the classical (Canonical) and the alternative (noncanonical) pathways, with transcription factors including NF-κB1 (P50 and its precursor P105), NF-κB2(P52 and its precursor P100), RelA (P65) RelB, and c-Rel. The alternative pathway is the major pathway for B cell survival through BAFF-R, characterized by the presence of IKK1 and P100 phosphorylation cleaving to P52. The processed p52 heterodimerize with RelB, migrates to the nucleus, and induces transcription of anti-apoptotic genes. IKK1 is also phosphorylated by NIK. In unstimulated cells, TRAF3, TRAF2, and cIAPs1/2 factors are linked together, NIK is continuously destroyed by the proteasome, TRAF3, TRAF2, and cIAPs1/2 are factors for NIK ubiquitination and targeting it for degradation. After cell stimulation, TRAF3 is exposed to BAFF-R, which causes TRAF3 self-degradation by cIAPs 1/2 and TRAF2, this action leads to the stabilization of NIK and eventually causes cleavage of P100. The NF-κB alternative pathway is activated by the CD40 receptor too, a member of the TNF family. The BCR on mature naive recirculating B cells is achieved by the association of Igα/Igβ heterodimer. The classic pathway activated by the formation of P50 and P65 dimers after BAFF-R stimulation. Activation of canonical NF-κB signaling inducing through the Carma/Bcl10/ Malt1 (CBM) complex. In B cells, the PI3K signaling pathway activates PKCβ, so phosphorylated CARMA1 increases canonical activation of NF-κB through the CBM complex and phosphorylation of IKK2 by the TAB/TAK complex. IKK1 can contribute to the canonical IKK2/Nemo pathway, imparting important survival signals and it is also important in B cells for GC formation. recent studies show that the BCR induces p100 to facilitate BAFF-R signaling. The expression p100 acts as an inhibitor of p50 and p65. Therefore, canonical and non-canonical NF-κB pathways have special properties that ultimately determine the tempo and specificity of gene expression. Akt by disabling FOXO1, Prevents transcription of proapoptotic genes. It is observed that in the absence of FOXO1, peripheral B cells accumulate