Graded Expression of Interferon Regulatory Factor-4 Coordinates Isotype Switching with Plasma Cell Differentiation

Sciammas, Roger; Shaffer, Arthur L.; Schatz, Jonathan H.; Zhao, Hong; Staudt, Louis M.; Singh, Harinder

doi:10.1016/j.immuni.2006.07.009

Cited by 490 publications

(603 citation statements)

References 39 publications

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“…Also, the expression of MITF was dependent on Bcl6, but the exact mechanism remains unclear. Given that MITF is thought to suppress IRF4 expression [43], while IRF4 appears to induce Blimp-1 expression during plasma cell differentiation [44] it is likely that Bcl6 suppresses Blimp-1 expression also by sustaining MITF expression. Our previous findings also indicated a role for Pax5 in the maintenance of BCL6 expression [4].…”

Section: Discussionmentioning

confidence: 99%

“…We did not observe any binding of Bcl6 to the MITF gene, suggesting an indirect mechanism for Bcl6-mediated regulation of MITF expression. Interestingly, Bcl6 also bound to the IRF4 gene, an important regulator of PRDM1 and plasma cell differentiation [44,45]. Bcl6-specific enrichment peaks were observed in the region of the first $3000 bp from the TSS with the peak maxima occurring in the first, third and fourth introns (Fig.…”

Section: Relative Expressionmentioning

confidence: 90%

“…3), raising a possibility that the prominent mechanism by which Bcl6 regulates PRDM1 is not through direct DNA binding. Therefore, we searched for other Bcl6 regulated genes that have been reported to regulate PRDM1 or plasma cell differentiation, such as BACH2 [40][41][42], MITF [43], IRF4 [44,45].…”

Section: Bcl6 Binds Directly To Bach2 Ung and Irf4mentioning

confidence: 99%

“…However, together these data suggest that in addition to PRDM1, Bcl6 has a double-negative regulatory circuit with IRF4. Since IRF4 also promotes PRDM1 expression [44], this mechanism would further assure the irreversibility of the final differentiation step into plasma cells (Fig. 5).…”

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Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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The transcription factor Bcl6 regulates germinal center formation and differentiation of B cells into high-affinity antibody-producing plasma cells. The direct double-negative regulatory circuit between Bcl6 and Blimp-1 is well established. We now reveal alternative mechanisms for Bcl6-mediated regulation of B-cell differentiation to plasma cells and show with DT40 cells that Bcl6 directly promotes the expression of Bach2, a known suppressor of Blimp-1. Moreover, Bcl6 suppresses Blimp-1 expression through direct binding to the IRF4 gene, as well as by promoting the expression of MITF, a known suppressor of IRF4. We also provide evidence that Bcl6 is needed for the expression of AID and UNG, the indispensable proteins for somatic hypermutation and class-switch recombination, and UNG appears to be a direct Bcl6 target. Our findings reveal a complex regulatory network in which Bcl6 acts as a key element dictating the transition of DT40 B cells to plasma cells. Supporting Information available online See accompanying Commentary by Tarlinton IntroductionThe transition of activated B cells into high-affinity antibodyproducing plasmablasts, plasma cells and memory B cells in the germinal centers (GCs) is a biologically unique process involving rapid B-cell proliferation coupled with a high rate of mutation in the variable regions of immunoglobulin (Ig) genes. Considering that the majority of B-cell lymphomas originate from the GC B cells [1], a comprehensive understanding of the transcriptional regulation controlling the transition of B cells to plasma cells is essential. The transcription factors Blimp-1, Xbp-1 and IRF4 have been identified to be critical regulators promoting the Ig secretion and plasma cell phenotype, whereas Pax5, Bcl6, MITF and Bach2 are the known inhibitors of plasma cell development [2].Previous studies have shown that the downregulation of B-cell identity factor Pax5 occurs before the induction of the plasma cell transcription program [3,4], and that the loss of Pax5 expression [4] leads to the downregulation of BCL6. Furthermore, B-cell receptor (BCR) signaling of sufficient affinity leads to rapid phosphorylation and degradation of Bcl6 protein [5], while Bcl6 can also be functionally inactivated by acetylation [6]. These features of Bcl6 make it a prominent molecular trigger that controls the plasma cell differentiation.The transcription factor Bcl6 has been demonstrated to be essential for GC B-cell development, as Bcl6 knockout mice fail to develop GCs and do not produce high-affinity antibodies [7][8][9]. Recent work revealed that Bcl6 is also needed for follicular T helper cell development [10][11][12]. Analyses of Bcl6 target genes in B cells indicate that suppression of apoptosis and cell cycle arrest responses occur through p53, p21 and CHEK1 and Bcl6 also regulates DNA damage responses by controlling ATR [13][14][15][16]. Thus, Bcl6 appears to function as a factor permitting rapid B-cell 2404proliferation and tolerance for DNA damage in GCs. Bcl6 also represses genes that are involve...

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Section: Discussionmentioning

confidence: 99%

Section: Relative Expressionmentioning

confidence: 90%

Section: Bcl6 Binds Directly To Bach2 Ung and Irf4mentioning

confidence: 99%

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confidence: 99%

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Alternate pathways for Bcl6‐mediated regulation of B cell to plasma cell differentiation

et al. 2011

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“…*P-value o0.05 haplotypic differences compared to the controls. [27][28][29] Recent findings suggest that IRF4 is also involved in the development of Th17 cells 30 that are believed to be centrally involved in psoriasis. The polymorphisms rs1167846 in the IL20RA gene and rs747842 in the IL20RB gene appear as interesting candidates for further studies, however, these hypotheses are currently speculative and require functional support.…”

Section: Discussionmentioning

confidence: 99%

Association analysis of IL20RA and IL20RB genes in psoriasis

et al. 2008

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The interleukin-20-receptor I complex (IL-20-RI) is composed of two chains, IL20RA and IL20RB. Its ligands are the three members of the IL19 subfamily of cytokines, . These cytokines are important in the manifestation of psoriatic lesions and, recently, an association of polymorphisms of IL20 with psoriasis has been described. In the present study we tested the hypotheses that genetic variations of the IL-20-RI influence susceptibility to psoriasis and investigated single nucleotide polymorphisms (SNPs) in the IL20RA and IL20RB genes in psoriasis patients (n ¼ 254) and healthy controls (n ¼ 224). We found no association of any of the investigated SNPs with the disease. Analysis of pairwise linkage disequilibrium (LD) across studied markers revealed a strong level of LD between SNPs within the IL20RA gene and SNPs within the IL20RB gene, and, for both genes six common haplotypes were identified with an estimated frequency X1%. Haplotype analyses suggested that the IL20RA haplotype CCG (rs1184860, rs1167846, rs1167849) is significantly associated with psoriasis (OR 3.14, 95% CI 1.61-6.14), whereas the TTG haplotype had a protective effect (OR 0.20, 95% CI 0.07-0.55). The risk haplotype defining SNPs 1167846 and 1184860 were found to modify paired box 5 and homeobox A9 sites, respectively, two transcription factors related to the differentiation of immune cells. Further studies are needed to confirm the genetic association and to investigate the functional relevance of IL20RA haplotypes in psoriasis.

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