Inherited human c-Rel deficiency disrupts myeloid and lymphoid immunity to multiple infectious agents.

We studied a child with severe viral, bacterial, fungal, and parasitic diseases, who was homozygous for a loss-of-function mutation of REL, encoding c-Rel, which is selectively expressed in lymphoid and myeloid cells. The patient had low frequencies of NK, effector memory cells reexpressing CD45RA (Temra) CD8+ T cells, memory CD4+ T cells, including Th1 and Th1*, Tregs, and memory B cells, whereas the counts and proportions of other leukocyte subsets were normal. Functional deficits of myeloid cells included the abolition of IL-12 and IL-23 production by conventional DC1s (cDC1s) and monocytes, but not cDC2s. c-Rel was also required for induction of CD86 expression on, and thus antigen-presenting cell function of, cDCs. Functional deficits of lymphoid cells included reduced IL-2 production by naive T cells, correlating with low proliferation and survival rates and poor production of Th1, Th2, and Th17 cytokines by memory CD4+ T cells. In naive CD4+ T cells, c-Rel is dispensable for early IL2 induction but contributes to later phases of IL2 expression. The patient's naive B cells displayed impaired MYC and BCL2L1 induction, compromising B cell survival and proliferation and preventing their differentiation into Ig-secreting plasmablasts. Inherited c-Rel deficiency disrupts the development and function of multiple myeloid and lymphoid cells, compromising innate and adaptive immunity to multiple infectious agents.

Study on the effect of regulation of Cordyceps militaris polypeptide on the immune function of mice based on a transcription factor regulatory network.

BACKGROUND: The pathogenesis of the abnormality of the immune system is still not clear at present. Chemosynthetic drugs, human or animal immune products and microbiological drugs are used as the main drugs in clinics currently, but these drugs have different side effects. So researchers turned to safer natural products in order to find immunomodulatory active substances from natural products and their extracts. METHODS: Immunosuppressed mice were induced by cyclophosphamide and administered with Cordyceps militaris polypeptide (CMP) for the study on the effect of CMP on the immune function of mice and its mechanism. Based on the 1748 differential gene sets selected in our previous work, the transcription factors and their corresponding target genes were screened by integrating the TRED (Transcriptional Regulatory Element Database), a transcriptional factor-target gene regulatory network was constructed, then the role of transcription factors in the regulatory network was elucidated by statistically analyzing the key nodes, and finally, the correlation of network genes with diseases was analyzed by using the DAVID database. RESULTS: The results of animal experiments showed that CMP could increase the immune organ indexes, the number of white blood cells, the degree of delayed allergy and the content of hemolysin in the serum of mice. CMP was found to be involved in the regulation of immune function in mice through genes Kdr, Spp1, Ptgs2, Rel, and Smad3, and transcription factors Ets1, E2f2 and E2f1. E2F2 and E2F1 are members of the E2F family, so we speculated that the E2F family might play an important role, and its main regulatory pathways were the PI3K-Akt signaling pathway and TNF signaling pathway. CONCLUSION: CMP can improve the immunity of mice. CMP can regulate the immune function of mice through multiple genes and transcription factors, and may also play a role in immune-related diseases, such as cancer.

A nucleotide-switch mechanism mediates opposing catalytic activities of Rel enzymes.

Bifunctional Rel stringent factors, the most abundant class of RelA/SpoT homologs, are ribosome-associated enzymes that transfer a pyrophosphate from ATP onto the 3' of guanosine tri-/diphosphate (GTP/GDP) to synthesize the bacterial alarmone (p)ppGpp, and also catalyze the 3' pyrophosphate hydrolysis to degrade it. The regulation of the opposing activities of Rel enzymes is a complex allosteric mechanism that remains an active research topic despite decades of research. We show that a guanine-nucleotide-switch mechanism controls catalysis by Thermus thermophilus Rel (RelTt). The binding of GDP/ATP opens the N-terminal catalytic domains (NTD) of RelTt (RelTtNTD) by stretching apart the two catalytic domains. This activates the synthetase domain and allosterically blocks hydrolysis. Conversely, binding of ppGpp to the hydrolase domain closes the NTD, burying the synthetase active site and precluding the binding of synthesis precursors. This allosteric mechanism is an activity switch that safeguards against futile cycles of alarmone synthesis and degradation.

Association study between vitiligo and autoimmune-related genes CYP27B1, REL, TNFAIP3, IL2 and IL21.

The aetiology of vitiligo has not been fully elucidated, and several hypotheses have been investigated; among them, the most explored assumes an autoimmune basis for the disease. Supporting this hypothesis is the frequent co-occurrence of autoimmune diseases with vitiligo. In addition, various genetic loci associated with vitiligo harbour key immune response genes. Our general hypothesis is that autoimmunity-associated genes participate in the control of vitiligo susceptibility. To investigate this hypothesis, we tested for association between vitiligo and genes CYP27B1, REL, TNFAIP3 and IL2/IL21, all previously related to autoimmune diseases associated with vitiligo. The study was performed using two independent population samples: a family-based discovery set (211 trios) and a replication set (131 cases/119 controls). Statistically significant association with vitiligo was detected between markers of the REL and IL2 gene in the family-based sample. Both association signals were concentrated among patients displaying autoimmune comorbidity and non-segmental vitiligo. Evidence for validation was detected for IL2 marker. Our findings suggest REL and IL2 as new vitiligo susceptibility genes and reinforce the hypothesis of a shared genetic mechanism controlling vitiligo and other autoimmune diseases.

New uracil analog U-332 is an inhibitor of NF-κB in 5-fluorouracil-resistant human leukemia HL-60 cell line.

BACKGROUND: 5-Fluorouracil (5-FU) is an antimetabolite that interferes with DNA synthesis and has been widely used as a chemotherapeutic drug in various types of cancers. However, the development of drug resistance greatly limits its application. Overexpression of ATP-binding cassette (ABC) transporters in many types of cancer is responsible for the reduction of the cellular uptake of various anticancer drugs causing multidrug resistance (MDR), the major obstacle in cancer chemotherapy. Recently, we have obtained a novel synthetic 5-FU analog, U-332 [(R)-3-(4-bromophenyl)-1-ethyl-5-methylidene-6-phenyldihydrouracil], combining a uracil skeleton with an exo-cyclic methylidene group. U-332 was highly cytotoxic for HL-60 cells and showed similar cytotoxicity in the 5-FU resistant subclone (HL-60/5FU), in which this analog almost completely abolished expression of the ATP-binding cassette (ABC) transporter, multidrug resistance associate protein 1 (ABCC1). The expression of ABC transporters is usually correlated with NF-κB activation. The aim of this study was to determine the level of NF-κB subunits in the resistant HL-60/5-FU cells and to evaluate the potential of U-332 to inhibit activation of NF-κB family members in this cell line. METHODS: Anti-proliferative activity of compound U-332 was assessed by the MTT assay. In order to disclose the mechanism of U-332 cytotoxicity, quantitative real-time PCR analysis of the NF-κB family genes, c-Rel, RelA, RelB, NF-κB1, and NF-κB2, was investigated. The ability of U-332 to reduce the activity of NF-κB members was studied by ELISA test. RESULTS: In this report it was demonstrated, using RT-PCR and ELISA assay, that members of the NF-κB family c-Rel, RelA, RelB, NF-κB1, and NF-κB2 were all overexpressed in the 5-FU-resistant HL-60/5FU cells and that U-332 potently reduced the activity of c-Rel, RelA and NF-κB1 subunits in this cell line. CONCLUSIONS: This finding indicates that c-Rel, RelA and NF-κB1 subunits are responsible for the resistance of HL-60/5FU cells to 5-FU and that U-332 is able to reverse this resistance. U-332 can be viewed as an important lead compound in the search for novel drug candidates that would not cause multidrug resistance in cancer cells.

Over-expression of nuclear factor-κB family genes and inflammatory molecules is related to chronic obstructive pulmonary disease.

Background: Nuclear factor-κB (NF-κB) signaling plays essential roles in inflammatory responses. However, whether the expression levels of NF-κB family genes affect inflammatory responses is unclear. Moreover, little is known regarding the association between NF-κB family genes expression and the pathogenesis of chronic obstructive pulmonary disease (COPD). The present study was undertaken to assess the relationship between the expression levels of NF-κB family genes mRNA and of inflammatory markers relevant to COPD pathogenesis. Methods: A total of 186 unrelated patients with acute exacerbations of COPD and 180 healthy controls were recruited. Total RNA was extracted from the peripheral fasting blood of each subject using trizol reagent. The mRNA levels of NF-κB family genes (NF-κB1, NF-κB2 and c-REL) were measured by real-time quantitative polymerase chain reaction. The serum levels of cyclooxygenase-2 (COX-2), C-reactive protein, interleukin (IL)-1ß, IL-6, IL-8, IL-12 and tumor necrosis factor-α were measured with enzyme-linked immunosorbent assay kits. Results: The relative mRNA levels of the NF-κB family genes and the levels of inflammatory molecules were significantly higher in the COPD group than in the control group after adjustment for smoking. The IL-1ß, IL-8 and COX-2 levels were significantly lower in the NF-κB2 under-expression subgroup as compared to the NF-κB2 over-expression subgroup. The COX-2 level was significantly lower (P < 0.05) in the c-REL under-expression subgroup as compared to the c-REL over-expression subgroup. Conclusion: NF-κB2 over-expression was associated with IL-1ß, IL-8 and COX-2 levels, whereas c-REL overexpression was associated with COX-2 level. Over-expression of both NF-κB2 and c-REL was found to be related to COPD.

Association of REL Polymorphism with Cow's Milk Proteins Allergy in Pediatric Algerian Population.

INTRODUCTION: Cow's milk proteins allergy (CMPA) pathogenesis involves complex immunological mechanisms with the participation of several cells and molecules involved in food allergy. The association of polymorphisms in the interleukin 4, Forkhead box P3 and the avian reticuloendotheliosis genes was investigated in an infant population with CMPA of Western Algeria. MATERIALS AND METHODS: We obtained DNA and clinical data from milk allergic subjects during active phase and from a group of non-atopic control subjects. RESULTS: Our findings showed that the allele G of the cRel gene intronic polymorphism at +7883 positions was significantly higher among cow's milk proteins allergic patients compared to control subjects. CONCLUSION: The results of this study suggest a possible association of CMPA with cRel G+7883T polymorphism.

The relationship of REL proto-oncogene to pathobiology and chemoresistance in follicular and transformed follicular lymphoma.

Follicular lymphoma (FL) is a common type of indolent lymphoma that occasionally transforms to more aggressive B-cell lymphomas. These transformed follicular lymphomas (tFL) are often associated with chemoresistance whose mechanisms are currently unknown. REL, a proto-oncogene located on frequently amplified 2p16.1-p15 locus, promotes tumorigenesis in many cancer types through deregulation of the NF-κB pathway; however, its role in FL pathobiology or chemoresistance has not been addressed. Here, we evaluated REL gene copy number by q-PCR on FFPE FL tumor samples, and observed REL amplification in 30.4% of FL cases that was associated with weak elevation of transcript levels. PCR-Sanger analysis did not show any somatic mutation in FL tumors. In support of a marginal oncogenic role, a REL-transduced FL cell line was positively selected under limiting serum conditions. Interestingly, reanalysis of previously reported gene expression profiles revealed significant enrichment of DNA damage-induced repair and cell cycle arrest pathways in tFL tumors with high REL expression compared to those with low REL expression consistent with the critical role of c-REL in genotoxicity-induced NF-κB signaling, which was reported to lead to drug resistance. In addition to DNA damage repair genes such as ATM and BRCA1, anti-apoptotic BCL2 was significantly elevated in REL-high FL and tFL tumors. Altogether these data suggest that other genes located in amplified 2p16.1-p15 locus may have more oncogenic role in FL etiology; however, high REL expression may be useful as a predictive biomarker of response to immunochemotherapy, and inhibition of c-REL may potentially sensitize resistant FL or tFL cells to chemotherapy.

Treating psoriasis by targeting its susceptibility gene Rel.

Psoriasis is a chronic inflammatory disorder of the skin. Accumulating evidence indicates that the Rel gene, a member of the NF-κB family, is a risk factor for the disease. We sought to investigate whether psoriasis can be prevented by directly targeting the Rel gene transcript, i.e., the c-Rel mRNA. Using chemically-modified c-Rel specific siRNA (siRel) and poly(ethylene glycol)-b-poly(l-lysine)-b-poly(l-leucine) (PEG-PLL-PLLeu) micelles, we successfully knocked down the expression of c-Rel, and showed that the expression of cytokine IL-23, a direct target of c-Rel that can drive the development of IL-17-producing T cells, was markedly inhibited. More importantly, treating mice with siRel not only prevented but also ameliorated imiquimod (IMQ)-induced psoriasis. Mechanistic studies showed that siRel treatment down-regulated the expression of multiple inflammatory cytokines. Taken together, these results indicate that the susceptibility gene Rel can be targeted to treat and prevent psoriasis.

c-Rel and its many roles in cancer: an old story with new twists.

When the genes encoding NF-κB subunits were first isolated, their homology to the previously identified c-Rel proto-oncogene and its viral homologue v-Rel was clear. This provided the first indication that these transcription factors also had a role in cancer. Because of its homology to v-Rel, which transforms chicken B cells together with the important role c-Rel can have as a regulator of B- and T-cell proliferation, most attention has focussed on its role in B-cell lymphomas, where the REL gene is frequently amplified. However, a growing number of reports now indicate that c-Rel has important functions in many solid tumours, although studies in mice suggest it may not always function as an oncogene. Moreover, c-Rel is a critical regulator of fibrosis, which provides an environment for tumour development in many settings. Overall, c-Rel is emerging as a complex regulator of tumorigenesis, and there is still much to learn about its functions in human malignancies and the response to cancer therapies.

Deregulated Levels of the NF-κB1, NF-κB2, and Rel Genes in Ukrainian Patients with Leukemia and Lymphoma in the Post-Chernobyl Period.

OBJECTIVE: Nuclear factor kappa B (NF-κB) is an important transcription factor in cancer and NF-κB activation has been seen in angiogenesis, tumor progression, and metastasis. Relationships between specific NF-κB gene networks, leukemogenesis, and radiation exposure are still unknown. Our aim was to study the expression levels of the NF-κB1, NF-κB2, and Rel genes in hematological malignancies in the post-Chernobyl period. MATERIALS AND METHODS: We analyzed gene expression levels of NF-κB1, NF-κB2, and Rel in 49 B-cell chronic lymphocytic leukemia, 8 B-cell non-Hodgkin's lymphoma, 3 acute myeloid leukemia, 3 chronic myeloid leukemia, 2 hairy cell leukemia, 2 myelodysplastic syndrome, and 2 T-cell large granular lymphocytic leukemia patients using real-time polymerase chain reaction. RESULTS: Expression levels of NF-κB1, NF-κB2, and Rel genes were found to be deregulated. CONCLUSION: These results could be accepted as specific gene traces to radiation-induced leukemia or as potential candidates for new diagnostic biomarker studies. Larger experiments and non-exposed control malignant cell populations are needed to clarify these suggestions.

Evolution of akirin family in gene and genome levels and coexpressed patterns among family members and rel gene in croaker.

Akirins, which are highly conserved nuclear proteins, are present throughout the metazoan and regulate innate immunity, embryogenesis, myogenesis, and carcinogenesis. This study reports all akirin genes from miiuy croaker and analyzes comprehensively the akirin gene family combined with akirin genes from other species. A second nuclear localization signal (NLS) is observed in akirin2 homologues, which is not in akirin1 homologues in all teleosts and most other vertebrates. Thus, we deduced that the loss of second NLS in akirin1 homologues in teleosts likely occurred in an ancestor to all Osteichthyes after splitting with cartilaginous fish. Significantly, the akirin2(2) gene included six exons interrupted by five introns in the miiuy croaker, which may be caused by the intron insertion event as a novel evidence for the variation of akirin gene structure in some species. In addition, comparison of the genomic neighborhood genes of akirin1, akirin2(1), and akirin2(2) demonstrates a strong level of conserved synteny across the teleost classes, which further proved the deduction of Macqueen and Johnston 2009 that the produce of akirin paralogues can be attributed to whole-genome duplications and the loss of some akirin paralogues after genome duplications. Furthermore, akirin gene family members and relish gene are ubiquitously expressed across all tissues, and their expression levels are increased in three immune tissues after infection with Vibrio anguillarum. Combined with the expression patterns of LEAP-1 and LEAP-2 from miiuy croaker, an intricate network of co-regulation among family members is established. Thus, it is further proved that akirins acted in concert with the relish protein to induce the expression of a subset of downstream pathway elements in the NF-kB dependent signaling pathway.

The c-Rel subunit of NF-κB is a crucial regulator of phenotype and motility of HaCaT keratinocytes.

The transcription factor NF-κB exerts key functions in epidermal homeostasis and carcinogenesis. Its c-Rel subunit is expressed in squamous cell carcinoma, and c-Rel down-regulation results in increased apoptosis, G2/M cell cycle delay with reduced proliferation and aberrant mitotic spindle formation. To further study the impact of c-Rel on essential keratinocyte features such as migration and epithelial morphology, c-Rel was down-regulated in HaCaT keratinocytes by a siRNA approach. This inhibition of c-Rel impaired the keratinocyte-typical clustered growth leading to a more scattered appearance of the cultures. The cells were more spindle-shaped and elongated, albeit without expression changes of markers characteristic for epithelial mesenchymal transition. In addition, wound healing-related migration and adhesion to type I collagen, fibronectin, laminin and vitronectin were significantly impaired. On the sub-cellular level, these functional features were not associated with quantitatively altered adhesion receptor or Rho-GTPase expression, but rather with a significantly reduced length of cell-matrix adhesion complexes and altered appearance of filamentous actin. Thus, our studies support a role for c-Rel in processes crucial for keratinocyte integrity and malignant transformation such as adhesion and migration.

Characterizations and expression analyses of NF-κB and Rel genes in the Yesso scallop (Patinopecten yessoensis) suggest specific response patterns against Gram-negative infection in bivalves.

Rel/NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) genes are evolutionarily conserved and play a pivotal role in several physiological events. They have been extensively studied from various species, including both vertebrates and invertebrates. However, the Rel/NF-κB genes have not been systematically characterized in bivalves. In this study, we identified and characterized PyNF-κB and PyRel in the Yesso scallop (Patinopecten yessoensis). Phylogenetic and protein structural analyses were conducted to determine the identities and evolutionary relationships of Rel/NF-κB genes in Yesso scallop. Compared with the Rel/NF-κB genes from vertebrate species, the PyNF-κB and PyRel are relatively conserved in their structural features, but there were no paralogs found in P. yessoensis or other invertebrates. To gain insights into the roles of Rel/NF-κB genes during the innate immune response in scallop, quantitative real-time PCR was used to investigate the expression profiles of these genes at different developmental stages, in healthy adult tissues and in the hemolymph after bacterial infection with Micrococcus luteus and Vibrio anguillarum. The real-time PCR results indicated the abundance of PyNF-κB in the first four embryonic stages, including oocytes, fertilized eggs, morulae and blastulae. By contrast, PyRel was abundantly expressed in blastulae, trochophores and D-shaped larvae. In adult scallops, PyNF-κB and PyRel were ubiquitously expressed in most healthy tissues and highly expressed in most of the immune related tissues. Both genes were significantly up-regulated during the acute phase (3 h) after infection with Gram-positive (M. luteus) and negative (V. anguillarum) bacteria, while the much higher expression level of PyNF-κB suggested the involvement of the extra immune deficiency (IMD)-like pathway against the Gram-negative bacterial infection. The complex pattern of Rel/NF-κB induced expression suggested that PyNF-κB and PyRel both have specific and cooperative roles in the acute immune responses to bacterial infection.

A role for BMP-induced homeobox gene MIXL1 in acute myelogenous leukemia and identification of type I BMP receptor as a potential target for therapy.

Mesoderm Inducer in Xenopus Like1 (MIXL1), a paired-type homeobox transcription factor induced by TGF-ß family of ligands is required for early embryonic specification of mesoderm and endoderm. Retrovirally transduced Mixl1 is reported to induce acute myelogenous leukemia (AML) with a high penetrance. But the mechanistic underpinnings of MIXL1 mediated leukemogenesis are unknown. Here, we establish the protooncogene c-REL to be a transcriptional target of MIXL1 by genome wide chromatin immune precipitation. Accordingly, expression of c-REL and its downstream targets BCL2L1 and BCL2A2 are elevated in MIXL1 expressing cells. Notably, MIXL1 regulates c-REL through a zinc finger binding motif, potentially by a MIXL1-Zinc finger protein transcriptional complex. Furthermore, MIXL1 expression is detected in the cancer genome atlas (TCGA) AML samples in a pattern mutually exclusive from that of HOXA9, CDX2 and HLX suggesting the existence of a core, yet distinct HOX transcriptional program. Finally, we demonstrate MIXL1 to be induced by BMP4 and not TGF-ß in primary human hematopoietic stem and progenitor cells. Consequently, MIXL1 expressing AML cells are preferentially sensitive to the BMPR1 kinase inhibitor LDN-193189. These findings support the existence of a novel MIXL1-c REL mediated survival axis in AML that can be targeted by BMPR1 inhibitors. (MIXL1- human gene, Mixl1- mouse ortholog, MIXL1- protein).

Cleavage of roquin and regnase-1 by the paracaspase MALT1 releases their cooperatively repressed targets to promote T(H)17 differentiation.

Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.

Identification and expression analysis of immune-related genes linked to Rel/NF-κB signaling pathway under stresses and bacterial challenge from the small abalone Haliotis diversicolor.

Inhibitor of NF-κB (IκB), nuclear factor-κB (NF-κB), and Akirin2 are all important members of Rel/NF-κB signaling pathway, which plays a pivotal role in regulating the innate immune response of vertebrates and invertebrates. In this study, the IκB (SaIκB) and Akirin2 (SaAkirin2) cDNAs of small abalone Haliotis diversicolor were cloned and characterized. The full length cDNA of SaIκB and SaAkirin2 were 1748 bp and 1452 bp respectively, encoding a protein of 401 aa and 187 aa respectively. A conserved degradation motif (DS56GIYS60) and six ankyrin repeats were identified in the SaIκB by SMART analysis. Meanwhile, a typical nuclear localization signal (NLS) was found at the N-terminal region of the SaAkirin2 protein. Also, the mRNA expression level of SaIκB, SaAkirin2, and AbNF-κB were detected by quantitative real-time PCR. The results revealed that all these three genes were ubiquitously expressed in 7 selected tissues. The expression level of SaIκB in gills was higher than that in other tissues (P < 0.05) while the expression level of AbNF-κB was significantly higher in hepatopancreas and haemocytes. The highest expression level of SaAkirin2 was detected in hepatopancreas, followed by mantle. The mRNA expression levels in either gills or haemocytes of SaIκB, SaAkirin2, and AbNF-κB were significantly up-regulated (P < 0.05) post thermal stress, hypoxia exposure, thermal plus hypoxia stress and the injection of Vibrio parahaemolyticus. These results indicated that these three NF-κB signaling pathway-related genes are involved in response to bacterial infection and play essential roles in response to thermal and hypoxia stress.

Association of rheumatoid arthritis susceptibility gene with lipid profiles in patients with rheumatoid arthritis.

OBJECTIVE: RA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects. METHODS: Patients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor-associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels. RESULTS: The REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI. CONCLUSION: The REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry.

A Mendelian predisposition to B-cell lymphoma caused by IL-10R deficiency.

Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.