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Celiac disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Most of the established loci harbor candidate genes with immune functions. These genes can be classified into different pathways. Many of the genes belong to pathways of T- and B-cell costimulation. Such genes include CTLA4, CD80, SH2B3, PTPN2, TAGAP, ICOSLG, and CD247. Also frequently represented are cytokine and cytokine receptor genes, including IL2/IL21, IL12A, and IL18RAP; genes involved in migration of immune cells such as the chemokine receptors CCR3/CCR5/CCR1 and CCR4; and the integrin gene ITGA4. Another interesting pathway involves molecules important for T-cell development in the thymus, such as THEMIS, which plays a role in both positive and negative T-cell selection during late thymocyte development, and RUNX3, which is involved in CD8+ T-cell differentiation. One network includes genes involved in nuclear factor (NF)-κB signaling, such as REL, which encodes a component of the NF-κB complex, and TNFAIP3, which encodes a molecule that inhibits NF-κB activity. Finally, a pathway involving molecules implicated in innate immune detection such as toll-like receptor 7 (TLR7), TLR8, and IRF4 has been identified. Both TLR7 and TLR8 recognize viral RNA, whereas IRF4 is a transcriptional activator that is part of the TLR7 pathway. This latter finding suggests involvement of viruses in the pathogenesis of celiac disease, likely initial events important for inducing the antigluten CD4+ T-cell response.
Classifications and Risk Factors
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The lymphoid neoplasms comprise of mature lymphoid, histiocytic and dendritic neoplasms, and are divided into 5 major subgroups and 14 provisional entities (Table 2.2): (i) mature B-cell neoplasms, (ii) mature T- and NK-neoplasms, (iii) Hodgkin lymphoma (HL), (iv) post-transplant lymphoproliferative disorders (PTLD) and (v) histiocytic and dendritic cell neoplasms. The provisional mature B-cell neoplasms entities are: (i) splenic diffuse red pulp small B-cell lymphoma; (ii) hairy-cell leukaemia variant; (iii) paediatric nodal marginal zone; (iv) large B-cell lymphoma with IRF4 rearrangement; (v) EBV positive mucocutaneous ulcer; (vi) human herpes virus (HHV8) positive diffuse large B-cell lymphoma, not otherwise specified and (vii) Burkitt lymphoma with 11q aberration. The provisional mature T- and NK-neoplasms are: (i) chronic lymphoproliferative disorder of NK cells, (ii) indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, (iii) primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma, (iv) primary cutaneous acral CD8 positive T-cell lymphoma, (v) primary cutaneous CD4 positive small/medium T-cell lymphoproliferative disorder, (vi) follicular T-cell lymphoma and (vii) breast implant-associated anaplastic large cell lymphoma. These revisions help clinicians to more accurately identify natural history, for example, patients who have a particularly indolent course, such as subtypes of follicular lymphomas; a better prognostication is needed to identify those for whom current standard clinical care is clearly suboptimal.
Genetics
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
Of the over 50 GWA loci identified to date (Table 4.1), a large number affect innate immunity. These include responses involving NF-κB signaling (TRAF3IP2,63TNFAIP3, TNIP1, NF-KBIA [IKBA], REL, COMMD1,64 CARD14); differentiation of T-helper 17 cells (IL23R, IL12B, IRF4, IL23A); and antigen processing, recognition, and response (HLA-C, ERAP1, ERAP2). There are also associations with genes playing important roles in the epidermis (LCE3, GJB2).65 Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) correlations also revealed significant findings with the genes encoding components of the JAK-STAT (signal transducer and sctivator) signaling pathway (IL28RA, IL23R, IL13, IL12B, IL23A, STAT2, SOCS1, STAT3, TYK2) and defense response to Gram-negative bacteria or viruses/RIG-1-like receptor signaling (IL-23R, IL-12B, IL-23A, NOS2, IFIH1, DDX58, NF-KBIA, IL-23R).
Correlation of the transcription factors IRF4 and BACH2 with the abnormal NFATC1 expression in T cells from chronic myeloid leukemia patients
Published in Hematology, 2022
Yikai Zhang, Xiangbo Zeng, Xianfeng Zha, Jing Lai, Guangxiao Tan, Shaohua Chen, Xibao Yu, Yangqiu Li, Ling Xu
The IRF transcription factor family consists of nine members, IRF1 to IRF9. This family plays an important role in regulating innate and adaptive immune responses and tumorigenesis. IRF4 is closely related to IRF8 and was initially identified as a nuclear factor [50]. This protein plays an important role in the differentiation and functional regulation of CD4+ and CD8+ T cells [51]. In mice, Irf4 is necessary for the protective effects of CD8+ T cells during infection [35]. A recent study has further shown that IRF4 is an important regulatory factor in the formation of CD8+ memory T cells, and it is necessary for the effective reactivation of CD8+ T cells [36]. Moreover, the results predicted by hTFtarget database shown that IRF4 may regulate the expression of NFATC1, while our recent results have also demonstrated that NFATC1 is necessary for human CD8+ T cells to perform their normal immune function [30]. These results suggested that T cell dysfunction in CML patients may be associated with the reduced expression of IRF4 and NFATC1.
Mechanism of immunomodulatory drug resistance and novel therapeutic strategies in multiple myeloma
Published in Hematology, 2022
IRF4 is a member of the interferon regulatory family that is located downstream of CRBN and expressed in bone marrow plasma cells of MM patients, and IRF4 serves as a key B-cell fate determinant and survival factor of MM cells[33, 52–54]. Abnormal IRF4 activation plays an important role in the pathogenesis and progression of MM. IRF4 expression is regulated by IKZF1/3, CCAAT/enhancer binding protein β (C/EBPβ) and multiple myeloma SET region (MMSET)[43, 49, 55, 56]. IKZF1/3 are transcriptional targets of IRF4, and IKZF protein degradation leads to the downregulation of IRF4 expression[49, 57]. C/EBPβ is an IRF4 promoter binding protein, and its expression is regulated by the eIF4Eβ expression level[55]. Downregulation of C/EBPβ leads to inhibition of IRF4 transcription and expression[55]. MMSET, located upstream of IRF4, binds to the IRF4 promoter region, and loss of MMSET can downregulate IRF4 expression[56]. Additionally, IRF4 also induces the expression of chromatin protein positive coactivator 4 (PC4) through a super enhancer (Figure 1A). Knockdown of PC4 can downregulate IKZF1 expression, resulting in MM cell resistance to IMiDs[58]. Knockdown or downregulation of IRF4 promotes MM cell apoptosis and sensitivity to IMiDs. In contrast, IRF4 overexpression promotes the survival of MM cells and resistance to IMiDs. IRF4 expression is related not only to IMiD resistance but also to ISS stage[59]. Compared with ISS-I and ISS-II disease, ISS-III disease shows significantly upregulated IRF4 expression, indicating that IRF4 has a certain correlation with the prognosis of MM[59].
Altered expression of transcription factors IRF4 and IRF8 in peripheral blood B cells is associated with clinical severity and circulating plasma cells frequency in patients with myasthenia gravis
Published in Autoimmunity, 2018
Yong Zhang, Xiao Jia, Yan Xia, Hao Li, Fei Chen, Jie Zhu, Xiuying Zhang, Yanyan Zhang, YuZhong Wang, Yanan Xu, Meng Pan, Xiaoyu Huang, Tingyan Yu, Linlin Fu, Chenghua Xiao, Deqin Geng
The interferon regulatory factor family of transcription factor (IRF) consists of nine mammalian members that are important regulators of both immunity and other physiological processes [6]. Two members of this family, IRF4 (also known as Pip, LSIRF, LCSAT and MUM1) and IRF8 (also known as ICSBP) are unique in that they are highly homologous to each other rather than to other IRF family members and they are expressed exclusively in the immune system [7]. The roles of IRF4 and IRF8 in immune system development and function have been well-documented. For example, IRF4 play key roles in generation and functions of Th1/Th2/Th17/Tfh/Th9, macrophages and dendritic cells [8–14]. Similarly, IRF8 is important for Th1/Th17, macrophage and dendritic cell development and function [15–19]. In B cells specifically, IRF4 and IRF8 are expressed at multiple stages and have been shown to be critical for pre-B cell development, receptor editing, germinal center (GC) reaction and plasma cell differentiation [20–27]