Similarly, serum Ig levels were undetectable in mice reconstituted with c-Rel?/? / RelA?/? mice fetal liver cells, which could be attributed to defect in B cell terminal differentiation [35]. Emphasizing the role of NF-B proteins, it was shown that that different B cell activators such as T-cell dependent antigens and LPS differentially affects IgG1 class switching by differential induction of NF-B proteins [71]. both mouse models.98Germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL)DLBCL FR-190809 patientsc-Rel nuclear expressionCorrelated with decreased expression of AKT, Myc and p53.Lack of prognostic effect.90Activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL)DLBCL patientsc-Rel nuclear expression-Correlated with the poor survival in DLBCL patients with TP53 mutations.90Primary mediastinal B cell lymphoma (PMBL)PMBL patientsc-Rel nuclear accumulationMay associate with PMBL progression.91Large B cell lymphoma (LBCL)Human LBCL cell linesIncreased c-Rel activationDecreased CD 154 gene expression.Aggravate large B cell lymphoma.97Classical Hodgkin lymphoma (cHL)cHL patients2pl6.1 (rs 1432295, REL) identified as susceptibility locicHL progression.89Hodgkin and Reed-Stemberg (HRS) cells (Biopsies from cHL patients)c-Rel nuclear accumulation-cHL progression.85HRS cells from cHL patientsREL amplificationcHL progression.92Marginal zone lymphoma (MZL)B cell lymphoma patientIncrease in c-REL gene expressionMay associate with Marginal zone lymphoma.84infection.121Immunodeficiency in mice infected with pathogenc-Rel?/? mice (C57BL/6) infected with specific IgG in colon and serum.No protection against FR-190809 contamination.128 Open in a separate window Role of c-Rel in B cell development B cell development is a highly sophisticated and regulated process, which begins in primary lymphoid organs (fetal liver (before birth) and bone marrow (after birth)) with subsequent maturation in secondary lymphoid organs (lymph nodes and spleen) [26]. In antigen-independent phase of B cell development, progenitor B cells proliferate and undergo V-(D)-J recombination in bone marrow and further into immunocompetent na?ve mature B cells. Whereas, in the antigen-dependent phase, mature B cells differentiate into either memory B cells or antibody-secreting plasma B cells upon antigen binding and co-stimulation. Many B-cell-extrinsic and intrinsic factors [26] including c-Rel [27] coordinate B cell development FR-190809 and functions. Previous studies suggest that c-Rel is usually dispensable for the development of mature B cells from their progenitors but it is critical for the maintenance of mature B cell functions [20, 21]. It has been shown that c-Rel knockout mice (c-Rel?/?) develop normally with no defects in hematopoiesis and lymphocyte development, but display defects in mature B cell activation and proliferation [19]. Subsequent studies with c-Rel knockout mice also showed no developmental defects in B cell compartments but displayed significant decrease in memory and germinal center B FR-190809 cells (GC B) [20]. We generated c-Rel deficient non obese diabetic (NOD) mice and found no adverse effect on the development of major hematopoietic cells including B cells [28]. These studies suggest that c-Rel plays minimal role in developmental process of B cells and it is essential for mature B cell survival and functions (Table 1). In line with this, it has been shown that c-Rel expression remains low in B cell precursors and it increases during later stages of B cell development [29]. Role of c-Rel in B cell proliferation and survival The proliferation of B cells in response to cytokine stimuli and FR-190809 B cell receptor crosslinking is an essential event for the generation of antibody producing plasma cells and humoral immune response [30, 31]. c-Rel deficiency has been shown to reduce B cell proliferation and survival in response to lipopolysaccharide (LPS), anti-IgM or CD40 [20, 32, 33]. Studies using c-Rel?/? / NF-B1?/? double knockout mice also showed normal hematopoietic stem cell differentiation with defects in B cell activation, proliferation/survival and humoral immune response [34]. In cell culture, resting B cells from c-Rel?/? / NF-B1?/? double knockout mice failed to proliferate in response to various mitogens (LPS, anti-IgM F(ab)2, and anti-RP) due to G1 cell cycle arrest [34]. While B cells from NF-B1?/? knockout mice displayed proliferation defects in response to LPS [34], c-Rel?/? B cells p300 showed proliferation defects in response to multiple stimuli including LPS, anti-IgM and anti-RP [34, 19]. Interestingly, treatment with combined mitogen stimuli overcomes this proliferation defect in c-Rel?/? B cells, indicating a plausible compensatory role of other NF-B family members in the absence of c-Rel [34]. Similarly, mice engrafted with fetal liver hematopoietic stem cells from c-Rel?/? / RelA?/? mice displayed reduced number of mature B.