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Tertiary lymphoid tissues (TLTs) facilitate local T and B cell interactions in chronically inflamed organs. However, the cells and molecular pathways that govern TLT formation are poorly defined. Here, we identified TNF superfamily CD153/CD30 signaling between 2 unique age-dependent lymphocyte subpopulations, CD153+PD-1+CD4+ senescence-associated T (SAT) cells and CD30+T-bet+ age-associated B cells (ABCs), as a driver for TLT expansion. SAT cells, which produced ABC-inducing factors IL-21 and IFN-γ, and ABCs progressively accumulated within TLTs in aged kidneys after injury. Notably, in kidney injury models, CD153 or CD30 deficiency impaired functional SAT cell induction, which resulted in reduced ABC numbers and attenuated TLT formation with improved inflammation, fibrosis, and renal function. Attenuated TLT formation after transplantation of CD153-deficient bone marrow further supported the importance of CD153 in immune cells. Clonal analysis revealed that SAT cells and ABCs in the kidneys arose from both local differentiation and recruitment from the spleen. In the synovium of aged rheumatoid arthritis patients, T peripheral helper/T follicular helper cells and ABCs also expressed CD153 and CD30, respectively. Together, our data reveal a previously unappreciated function of CD153/CD30 signaling in TLT formation and propose targeting the CD153/CD30 signaling pathway as a therapeutic target for slowing kidney disease progression.

Recent data from mice and non-human primate models of tuberculosis suggested that CD153, a TNF super family member, plays an important role in Mycobacterium tuberculosis (Mtb) control. However, this molecule has not been comprehensively evaluated in humans. Here, we show that the proportion of Mtb-specific CD4 T cells expressing CD153 was significantly reduced in active TB patients compared to latently infected persons. Importantly, the CD153+ Mtb-specific CD4 response inversely correlated with lung bacterial load, inferred by Xpert cycle threshold, irrespective of HIV status. Antitubercular treatment partially restored CD153 expression on Mtb-specific CD4 T cells. This is the first report of a subset of Mtb-specific CD4 T cells showing strong negative correlation with bacterial burden. Building on substantial evidence from animal models implicating CD153 as a mediator of host protection, our findings suggest it may play a similar role in humans and its measurement may be useful to evaluate TB vaccine efficacy.

Inflammatory bowel disease is one of the major causes of colitis-associated colon cancer (CAC). Therefore, it is necessary to explore new therapies to prevent colon cancer (CRC) in view of the relationship between chronic inflammation and tumor development. Previous studies on the correlation between CD30L/CD30 and cancer were mostly limited to lymphoid or homogenous tumors, while there have been only a few reports on the role of CD30L/CD30 signal transduction in the pathogenesis of CAC. In this study, we established an AOM/DSS-induced CAC model with CD30LKO mice to explore the effect of CD30L/CD30 signal transduction on the formation of the intestinal tumor immune microenvironment (TIME) during the development of intestinal tumors. Our results revealed that CD30L deficiency promoted the accumulation of myeloid derived suppressor cells (MDSCs), increased the expression of PD-L1 on MDSCs and tumor associated macrophages (TAMs), and enhanced the secretion of various inflammatory and immunosuppressive factors in the intestinal mucosa of CAC mice. Furthermore, CD30L gene deletion could selectively promote the upregulation of PD-1 expression on CD4 + and CD8 + T cells and inhibit their activation, differentiation and secretion of effector cytokines, which led to an attenuation of antitumor immune responses mediated by T EM (CD44 + CD62L - ) cells. Thus, our data suggest that CD30L/CD30 signaling might be a potential candidate target for immunological therapy in CAC., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Psoriasis is a common, autoimmune, chronic inflammatory skin disease. It has been demonstrated that cutaneous T17 cells play an important pro-inflammatory role in the pathogenesis of psoriasis, through the production of various Th17-related cytokines. Our previous studies have demonstrated that CD30L/CD30 signal plays a pivotal role in the differentiation of CD4 + Th17 cells and Vγ6 + γδ T17 cells in the gut-associated lymphoid tissues of mouse. However, its effect on the pathogenesis of psoriasis is unknown. Here, we fully prove that CD30L/CD30 signaling plays a novel protective role in the development of psoriasis in mice, through selective inhibition of CCR6 expression and Th17-related cytokine synthesis in the Vγ4 + γδ T17 cell subset. Meanwhile, treatment with agonistic anti-CD30 mAb had a significant therapeutic effect on our psoriasis mouse model. Therefore, the CD30L/CD30 signaling pathway is an ideal target for antibody therapy, which may become a new approach for the immunobiological treatment of psoriasis., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

CD30 ligand (CD30L, CD153), belonging to the tumor necrosis factor superfamily, has been reported to act as an immune regulator mainly in several autoimmune diseases and Hodgkin's lymphoma. However, little is known about its regulation in the glioma microenvironment. In this study, using a GL261 mouse glioma model, we showed that CD30L deficiency in the host accelerated glioma growth and reduced mouse survival, which might be associated with the accumulation of tumor-infiltrating immune cells, especially tumor-associated macrophages, myeloid-derived suppressor cells and CD8 + PD-1 + T cells. Moreover, CD30L deficiency resulted in distinct subsets of tumor-associated macrophages compared with those of wild-type mice. Furthermore, compared with those of wild-type mice, tumor-associated macrophages and microglia in CD30L-deficient mice adopted a more pro-tumorigenic phenotype within tumors. CD8 + T cells in CD30L-deficient mice decreased the expression of ki-67. Therefore, these results suggest that CD30L deficiency promotes the exhaustion of CD8 + T cells and the infiltration of tumor-associated macrophages and microglia. Our findings provide evidence for a new potential immunotherapy for glioma targeting CD30/CD30L signaling., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study, we investigated the therapeutic potential of lentinan in mouse models of inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Lentinan decreased the disease activity index and macroscopic and microscopic colon tissue damage in dextran sulphate sodium (DSS)-induced or TNBS-induced models of colitis. High-dose lentinan was more effective than salicylazosulfapyridine in the mouse models of colitis. Lentinan decreased the number of tumours, inflammatory cell infiltration, atypical hyperplasia and nuclear atypia in azoxymethane/DSS-induced CAC model. It also decreased the expression of pro-inflammatory cytokines, such as IL-13 and CD30L, in IBD and CAC model mice possibly by inhibiting Toll-like receptor 4 (TLR4)/NF-κB signalling and the expression of colon cancer markers, such as carcinoembryonic antigen, cytokeratin 8, CK18 and p53, in CAC model mice. In addition, lentinan restored the intestinal bacterial microbiotal community structure in IBD model mice. Thus, it shows therapeutic potential in IBD and CAC model mice possibly by inhibiting TLR4/NF-κB signalling-mediated inflammatory responses and disruption of the intestinal microbiotal structure., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Leprosy is still a considerable health threat in pockets of several low and middle income countries worldwide where intense transmission is witnessed, and often results in irreversible disabilities and deformities due to delayed- or misdiagnosis. Early detection of leprosy represents a substantial hurdle in present-day leprosy health care. The dearth of timely diagnosis has, however, particularly severe consequences in the case of inflammatory episodes, designated leprosy reactions, which represent the major cause of leprosy-associated irreversible neuropathy. There is currently no accurate, routine diagnostic test to reliably detect leprosy reactions, or to predict which patients will develop these immunological exacerbations. Identification of host biomarkers for leprosy reactions, particularly if correlating with early onset prior to development of clinical symptoms, will allow timely interventions that contribute to decreased morbidity. Development of a point-of-care (POC) test based on such correlates would be a definite game changer in leprosy health care. In this review, proteomic-, transcriptomic and metabolomic research strategies aiming at identification of host biomarker-based correlates of leprosy reactions are discussed, next to external factors associated with occurrence of these episodes. The vast diversity in research strategies combined with the variability in patient- and control cohorts argues for harmonisation of biomarker discovery studies with geographically overarching study sites. This will improve identification of specific correlates associated with risk of these damaging inflammatory episodes in leprosy and subsequent application to rapid field tests., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder originating from hematopoietic stem cells and is a life-threating disease characterized by intravascular hemolysis, bone marrow (BM) failure, and venous thrombosis. The etiology of PNH is a somatic mutation in the phosphatidylinositol glycan class A gene ( PIG-A ) on the X chromosome, which blocks synthesis of the glycolipid moiety and causes deficiency in GPI-anchored proteins. PNH is closely related to aplastic anemia, in which T cells mediate destruction of BM. To identify aberrant molecular mechanisms involved in immune targeting of hematopoietic stem cells in BM, we applied RNA-seq to examine the transcriptome of T cell subsets (CD4 + naive, CD4 + memory, CD8 + naive, and CD8 + memory) from PNH patients and healthy control subjects. Differentially expressed gene analysis in four different T cell subsets from PNH and healthy control subjects showed distinct transcriptional profiles, depending on the T cell subsets. By pathway analysis, we identified novel signaling pathways in T cell subsets from PNH, including increased gene expression involved in TNFR, IGF1, NOTCH, AP-1, and ATF2 pathways. Dysregulation of several candidate genes ( JUN , TNFAIP3 , TOB1 , GIMAP4 , GIMAP6 , TRMT112 , NR4A2 , CD69 , and TNFSF8 ) was validated by quantitative real-time RT-PCR and flow cytometry. We have demonstrated molecular signatures associated with positive and negative regulators in T cells, suggesting novel pathophysiologic mechanisms in PNH. These pathways may be targets for new strategies to modulate T cell immune responses in BM failure., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Background: Mature T-cell and natural killer (NK)-cell lymphomas compose a heterogeneous group of non-Hodgkin lymphomas, and extranodal NK/T-cell lymphoma, nasal type (ENKTL) is an aggressive subtype with sporadic CD30 expression. However, the significance of CD30 expression in ENKTL is controversial. We aimed to classify a large cohort of patients with mature T-cell and NK-cell lymphomas according to the 2016 World Health Organization (WHO) classification guidelines and to study the association between CD30 expression and prognosis of patients with ENKTL., Methods: We selected consecutive patients with mature T-cell and NK-cell lymphomas who attended our institution between September 1, 2009 and August 31, 2013. We classified the lymphomas according to the 2016 revision of the WHO classification of lymphoid neoplasms, analyzed the associations between CD30 expression and clinicopathologic features of ENKTL patients, and evaluated the prognostic implications of CD30 expression., Results: We identified 622 consecutive patients with mature T-cell and NK-cell lymphomas, including 317 (51.0%) patients with ENKTL. In addition, CD30 expression was detected in 43 (47.3%) of a subset of 91 patients with ENKTL. No clinicopathologic features were associated with CD30 expression, and CD30 positivity showed no prognostic significance in patients with ENKTL., Conclusions: ENKTL is the most common type of mature T-cell and NK-cell lymphoma diagnosed at our institution. CD30 is frequently expressed in ENKTL and represents a therapeutic target; however, it may not be a prognostic marker.

High serum sCD30 levels are associated with inflammatory disorders and poor outcome in renal transplantation. The contribution to these phenomena of transcripts and proteins related to CD30-activation and -cleavage is unknown. We assessed in peripheral blood of end-stage renal disease patients (ESRDP) transcripts of CD30-activation proteins CD30 and CD30L, CD30-cleavage proteins ADAM10 and ADAM17, and Th1- and Th2-type immunity-related factors t-bet and GATA3. Additionally, we evaluated the same transcripts and release of sCD30 and 32 cytokines after allogeneic and polyclonal T-cell activation. In peripheral blood, ESRDP showed increased levels of t-bet and GATA3 transcripts compared to healthy controls (HC) (both P<0.01) whereas levels of CD30, CD30L, ADAM10 and ADAM17 transcripts were similar. Polyclonal and allogeneic stimulation induced higher levels of CD30 transcripts in ESRDP than in HC (both P<0.001). Principal component analysis (PCA) in allogeneic cultures of ESRDP identified two correlation clusters, one consisting of sCD30, the Th-1 cytokine IFN-γ, MIP-1α, RANTES, sIL-2Rα, MIP-1β, TNF-β, MDC, GM-CSF and IL-5, and another one consisting of CD30 and t-bet transcripts, IL-13 and proinflammatory proteins IP-10, IL-8, IL-1Rα and MCP-1. Reflecting an activated immune state, ESRDP exhibited after allostimulation upregulation of CD30 transcripts in T cells, which was associated with Th1 and proinflammatory responses., (Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

Macrophages facilitate breast cancer progression. Macrophages were initially classified as M1 or M2 based on their distinct metabolic programs and then expanded to include antitumoral (M1) and protumoral (M2) activities. However, it is still uncertain what markers define the pro- and antitumoral phenotypes and what conditions lead to their formation. In this study, monocytic cell lines and primary monocytes were subjected to commonly reported protocols of M1/M2 polarization and conditions known to engage monocytes into protumoral functions. The results showed that only IDO enzyme and CD86 M1 markers were upregulated correlating with M1 polarization. TNF-α, CCR7, IL-10, arginase I, CD36, and CD163 were expressed indistinguishably from M1 or M2 polarization. Similarly, protumoral engaging resulted in upregulation of both M1 and M2 markers, with conditioned media from the most aggressive breast cancer cell line promoting the greatest changes. In spite of the mixed phenotype, M1-polarized macrophages exhibited the highest expression/secretion of inflammatory mediators, many of which have previously been associated with breast cancer aggressiveness. These data argue that although the existence of protumoral macrophages is unquestionable, their associated phenotypes and the precise conditions driving their formation are still unclear, and those conditions may need both M1 and M2 stimuli.

Background: Type 1 reactions (T1R) affect a considerable proportion of patients with leprosy. In those with T1R, the host immune response pathologically overcompensates for the actual infectious threat, resulting in nerve damage and permanent disability. Based on the results of a genome-wide association study of leprosy per se, we investigated the TNFSF15 chromosomal region for a possible contribution to susceptibility to T1R., Methods: We performed a high-resolution association scan of the TNFSF15 locus to evaluate the association with T1R in 2 geographically and ethnically distinct populations: a family-based sample from Vietnam and a case-control sample from Brazil, comprising a total of 1768 subjects., Results: In the Vietnamese sample, 47 single-nucleotide polymorphisms (SNPs) overlapping TNFSF15 and the adjacent TNFSF8 gene were associated with T1R but not with leprosy. Of the 47 SNPs, 39 were cis-expression quantitative trait loci (cis-eQTL) for TNFSF8 including SNPs located within the TNFSF15 gene. In the Brazilian sample, 18 of these cis-eQTL SNPs overlapping the TNFSF8 gene were validated for association with T1R., Conclusions: Taken together, these results indicate TNFSF8 and not TNFSF15 as an important T1R susceptibility gene. Our data support the need for infection genetics to go beyond genes for pathogen control to explore genes involved in a commensurate host response., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The CD30 ligand (CD30L)/CD30 axis plays a critical role in Th1 and Th17 cell differentiation. However, the role in the pathogenesis of central nervous system autoimmunity remains unknown. Here we show the resistance for experimental autoimmune encephalomyelitis (EAE) with markedly reduced induction of antigen-specific Th1 and Th17 cells in CD30L knockout mice. Bone marrow chimera experiments indicated that CD30L on bone marrow-derived cells were critical for the development of EAE and that CD30L reverse signaling in CD4 T cells was dispensable for the pathogenic Th17 cell differentiation at the induction phase. Adoptive transfer experiment revealed an additional role for CD30L in the environment at the effector phase. In vivo neutralization of CD30L by soluble murine CD30-Immunoglobulin fusion protein before disease onset or even after disease onset significantly ameliorated the clinical symptoms. These results indicate that CD30L/CD30 signaling is critically involved in antigen-specific CD4 T cell responses at both the induction and effector phase, thus could be a new target molecule for the treatment of central nervous system autoimmunity., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In a broad attempt to improve the understanding of the genetic regulation of serum IgA levels, the heritability was estimated in over 12 000 Swedish twins, and a genome-wide association study was conducted in a subsample of 9617. Using the classical twin model the heritability was found to be significantly larger among females (61%) compared with males (21%), while contribution from shared environment (20%) was only seen for males. By modeling the genetic relationship matrix with IgA levels, we estimate that a substantial proportion (31%) of variance in IgA levels can ultimately be explained by the investigated SNPs. The genome-wide association study revealed significant association to two loci: (i) rs6928791 located on chromosome 6, 22 kb upstream of the gene SAM and SH3 domain containing 1 (SASH1) and (ii) rs13300483 on chromosome 9, situated 12 kb downstream the CD30 ligand (CD30L) encoding gene. The association to rs13300483 was replicated in two additional independent Swedish materials. The heritability of IgA levels is moderate and can partly be attributable to common variation in the CD30L locus., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

CD30 is a transmembrane receptor, normally not expressed by mast cells, which regulates proliferation/apoptosis and antibody responses. Aberrant expression of CD30 by mastocytosis mast cells and interaction with its ligand CD30L (CD153) appears to play an important role in the pathogenesis and clinical presentation of systemic mastocytosis. This article highlights the expression profile and role of CD30 and CD30L in physiologic and pathologic conditions, the applicability of CD30 as a marker for systemic mastocytosis, the consequences of mast cell-expressed CD30, and the possibility of future anti-CD30 based cytoreductive therapies., (Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.)

The FDA recently approved an agonistic anti-CD30 drug conjugate, Brentuximab vedotin, for the treatment for CD30-positive lymphomas. The potent clinical activity of Brentuximab vedotin in Hodgkin's lymphoma and anaplastic large-cell lymphoma was greeted with great enthusiasm by oncologists as it provided a new treatment modality for these diseases. In this review, we will describe how we obtained the hybridoma by pursuing a basic research experiment unrelated to CD30. I will also review what we know about the normal biological functions of CD30 that were studied primarily in murine models of disease but also in patients. The picture emerging is that one of the primary functions of CD30 is the control of memory cells providing costimulation and trafficking information or inducing apoptosis in a microenvironment and cytokine milieu-dependent manner.

CD30 ligand (CD30L, CD153), a member of the tumor necrosis factor (TNF) superfamily, and its receptor CD30 are important for differentiation and activation of CD4(+) T helper type 17 (Th17) cells. In this report, we demonstrate that the interleukin 17A (IL-17A)-producing γδ T cells normally developed in the fetal thymus, whereas Vγ1(-)Vγ4(-) γδ T cells expressed Vγ6/Vδ1 gene transcript selectively decreased in mucosa-associated tissues in naive CD30KO or CD30LKO mice. Moreover, CD30 and CD30L were expressed preferentially by Vγ1(-)Vγ4(-) γδ T cells in naive mice. The bacteria clearance was attenuated by the impaired response of the IL-17A-producing γδ T cells and decreased infiltration of neutrophils in CD30KO or CD30LKO mice. In vivo administration of agonistic anti-CD30 monoclonal antibody restored the ability of protection against Listeria monocytogenes by enhancing Vγ1(-)Vγ4(-) γδ T cells producing IL-17A not only in wild-type but also CD30LKO mice. Taken together, it appears that CD30L/CD30 signaling plays an important role in the maintenance and activation of IL-17A-producing γδ T cells presumably bearing Vγ6 in the mucosa-associated tissues of mice.

Interleukin-17A (IL-17A)-producing γδ T cells are known to be activated following Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1(-) Vγ4(-) γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1(-) Vγ4(-) γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling by in vivo administration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells in WT mice, while stimulating CD30L/CD30 signaling by in vivo administration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1(-) Vγ4(-) γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1(-) Vγ4(-) γδ T cells bearing Vγ6 at an early stage of BCG infection.

Objective: To investigate the association between 347 single-nucleotide polymorphisms within candidate genes of the tumor necrosis factor, interleukin 1 and interleukin 6 families with neutrophil count., Patients and Methods: Four hundred cases with heart failure after myocardial infarction (MI) were matched by age, sex, and date of incident MI to 694 controls (MI without post-MI heart failure). Both genotypes and neutrophil count at admission for incident MI were available in 314 cases and 515 controls., Results: We found significant associations between the TNFSF8 poly morphisms rs927374 (P=5.1 x 10(-5)) and rs2295800 (P=1.3 x 10(-4)) and neutrophil count; these single-nucleotide polymorphisms are in high linkage disequilibrium (r(2)=0.97). Associations persisted after controlling for clinical characteristics and were unchanged after adjusting for case-control status. For rs927374, the neutrophil count of GG homozygotes (7.6±5.1) was 16% lower than that of CC homozygotes (9.0±5.2)., Conclusion: The TNFSF8 polymorphisms rs927374 and rs2295800 were associated with neutrophil count. This finding suggests that post-MI inflammatory response is genetically modulated.

CD30 ligand (CD30L) plays an important role in the amplification and/or activation of effector CD4(+) T cells, irrespective of Th cell subset. To examine the role of CD30L in allergic rhinitis, we evaluated an OVA model of allergic rhinitis in CD30L knock out (KO) mice on a BALB/c background sensitized with OVA. Symptoms of allergic rhinitis such as eosinophil infiltration into the nasal mucosa were drastically diminished in OVA-sensitized CD30L KO mice following intranasal challenge with OVA. The levels of OVA-specific IgE in the sera and the Th2 response in nasopharynx-associated lymphoid tissues and cervical LNs of CD30L KO mice were significantly lower than those of WT mice following intranasal challenge with OVA. Intranasal administration of CD30-Ig during the effector phase with OVA significantly prevented the development of allergic rhinitis in WT mice. These results suggest that CD30L plays an important role in allergic rhinitis and that the inhibition of CD30L/CD30 signaling might be useful as a novel biological therapy for allergic rhinitis., (Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Objective: Our group previously identified a new susceptibility region linked to spondylarthritis (SpA) on chromosome 9q31-34. Fine mapping of this SPA2 locus allowed us to refine the peak of linkage to a 1.3-Mb interval. The objective of this study was to resequence most positional candidate genes lying in that region, to identify polymorphisms, and to examine their association with SpA., Methods: Variants screening was performed in 30 independent patients with SpA from families with a high linkage score to the SPA2 locus and 30 control subjects. The coding regions, intron-exon boundaries, and 5'- and 3'-flanking regions of ZNF618, A1L4R1&#95;HUMAN (AF495724), AMBP, KIF12, ORM1, ORM2, C9ORF91, ENSESTG000000230601, and TNFSF8 were resequenced to identify polymorphisms. Selected variants were genotyped in an extended French cohort (442 patients and 268 control subjects overall). Replication was performed in a combined Belgian and Portuguese cohort (433 patients and 299 control subjects)., Results: Variants screening allowed us to identify 98 polymorphisms, 5 of which were selected for further studies, based on statistical significance. The rare intronic single-nucleotide polymorphism (SNP) rs3181357, located in TNFSF8, was significantly associated with SpA in the French and the replication cohorts (odds ratio [OR] 2.03, P = 0.009 and OR 2.26, P = 0.0014, respectively) and in the pooled analysis (OR 2.14, P = 0.0001)., Conclusion: Positional candidate gene screening in the SPA2 locus allowed us to identify and replicate an association between a rare SNP located in TNFSF8 and SpA. This new finding appears to be independent of an association with a haplotype near TNFSF15, which we recently reported., (Copyright © 2011 by the American College of Rheumatology.)

Published genome-wide association studies (GWASs) have identified few variants in the known biological pathways involved in lung cancer etiology. To mine the possibly hidden causal single nucleotide polymorphisms (SNPs), we explored all SNPs in the extrinsic apoptosis pathway from our published GWAS dataset for 1154 lung cancer cases and 1137 cancer-free controls. In an initial association analysis of 611 tagSNPs in 41 apoptosis-related genes, we identified only 10 tagSNPs associated with lung cancer risk with a P value<10(-2), including four tagSNPs in DAPK1 and three tagSNPs in TNFSF8. Unlike DAPK1 SNPs, TNFSF8 rs2181033 tagged other four predicted functional but untyped SNPs (rs776576, rs776577, rs31813148 and rs2075533) in the promoter region. Therefore, we further tested binding affinity of these four SNPs by performing the electrophoretic mobility shift assay. We found that only rs2075533T allele modified levels of nuclear proteins bound to DNA, leading to significantly decreased expression of luciferase reporter constructs by 5- to -10-fold in H1299, HeLa and HCT116 cell lines compared with the C allele. We also performed a replication study of the untyped rs2075533 in an independent Texas population but did not confirm the protective effect. We further performed a mini meta-analysis for SNPs of TNFSF8 obtained from other four published lung cancer GWASs with 12  214 cases and 47  721 controls, and we found that only rs3181366 (r2=0.69 with the untyped rs2075533) was associated to lung cancer risk (P=0.008). Our findings suggest a possible role of novel TNFSF8 variants in susceptibility to lung cancer.

Toll-like receptors (TLRs), which recognize structurally conserved components among pathogens, are mainly expressed by antigen-presenting cells such as dendritic cells (DCs), B cells, and macrophages. Recognition through TLRs triggers innate immune responses and influences antigen-specific adaptive immune responses. Although studies on the expression and functions of TLRs in antigen-presenting cells have been extensively reported, studies in lymphoid tissue inducer (LTi) cells have been limited. In this study, we observed that LTi cells expressed TLR2 and TLR4 mRNA as well as TLR2 protein and upregulated OX40L, CD30L, and TRANCE expression after stimulation with the TLR2 ligand zymosan or TLR4 ligand LPS. The expression of tumor necrosis factor superfamily (TNFSF) members was significantly upregulated when cells were cocultured with DCs, suggesting that upregulated TNFSF expression may contribute to antigen-specific adaptive immune responses.

We have previously found that CD30 ligand (CD30L; CD153)/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production. In this study, we investigated the role of CD30L in the development of colitis experimentally induced by dextran sulfate sodium (DSS), in which IL-17A is involved in the pathogenesis. CD30L(-/-) mice were resistant to both acute colitis induced by administration of 3 to ∼ 5% DSS and to chronic colitis induced by administration of 1.5% DSS on days 0-5, 10-15, and 20-25 as assessed by weight loss, survival rate, and histopathology. The levels of IFN-γ, IL-17A, and IL-10 were significantly lower but the IL-2 level higher in the lamina propria T lymphocytes of CD30L(-/-) mice than those in lamina propria T lymphocytes of wild-type mice after DSS administration. Soluble murine CD30-Ig fusion protein, which was capable of inhibiting Th17 cell differentiation in vitro, ameliorated both types of DSS-induced colitis in wild-type mice. Modulation of CD30L/CD30 signaling by soluble CD30 could be a novel biological therapy for inflammatory diseases associated with Th17 responses.

A CD30 ligand (CD30L; CD153) and its receptor, CD30, is a membrane-associated glycoprotein belonging to the TNF superfamily and TNFR superfamily. These were expressed preferentially by activated CD4(+)T cells. In this paper, we show that CD44(low)CD62(hi)CD4(+) T cells from CD30L(-/-) or CD30(-/-) mice exhibited impaired differentiation into Th17 cells but an increased ability to produce IL-2 after in vitro culture under Th17-polarizing conditions. Neutralization with IL-2 by anti-IL-2 mAb partly restored the ability of Th17 differentiation in CD30L(-/-) or CD30(-/-) T cells. Stimulation via CD30L by immobilized anti-CD30L mAb suppressed IL-2 production by CD30(-/-)CD4(+) T cells, indicating that the reverse signal to CD30L is responsible for downregulation of IL-2 production. In vivo Th17 differentiation of CD30L(-/-)CD4(+)CD45RB(high) T cells was also impaired after transfer into SCID mice, whereas CD30L(+/+)CD4(+)CD45RB(high) T cells normally differentiated into Th17 cells in CD30L(-/-) SCID mice. The results of these studies demonstrate that CD30L/CD30 signaling executed by the T-T cell interaction plays a critical role in Th17 cell differentiation, at least partly via downregulation of IL-2 production.

Bone disease in myeloma occurs as a result of complex interactions between myeloma cells and the bone marrow microenvironment. A custom-built DNA single nucleotide polymorphism (SNP) chip containing 3404 SNPs was used to test genomic DNA from myeloma patients classified by the extent of bone disease. Correlations identified with a Total Therapy 2 (TT2) (Arkansas) data set were validated with Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) data sets. Univariate correlates with bone disease included: EPHX1, IGF1R, IL-4 and Gsk3beta. SNP signatures were linked to the number of bone lesions, log(2) DKK-1 myeloma cell expression levels and patient survival. Using stepwise multivariate regression analysis, the following SNPs: EPHX1 (P=0.0026); log(2) DKK-1 expression (P=0.0046); serum lactic dehydrogenase (LDH) (P=0.0074); Gsk3beta (P=0.02) and TNFSF8 (P=0.04) were linked to bone disease. This assessment of genetic polymorphisms identifies SNPs with both potential biological relevance and utility in prognostic models of myeloma bone disease.

Death-associated protein kinase 2 (DAPK2) is a calcium/calmodulin-regulated proapoptotic serine/threonine kinase that acts as a tumor suppressor. Here we show that DAPK2 is down-regulated in Hodgkin lymphoma-derived tumor cell lines and that promoter-region hypermethylation is one mechanism for DAPK2 inactivation. To determine whether selective reconstitution of DAPK2 catalytic activity in these cells could induce apoptosis, we created a fusion protein comprising a human CD30 ligand conjugated to a human DAPK2 calmodulin-deletion mutant. Thus, recombinant immunokinase DAPK2'-CD30L has a constitutive kinase activity with enhanced proapoptotic function. We show that this immunokinase fusion protein inhibits cell proliferation and induces apoptotic cell death specifically in CD30/DAPK2-negative tumor cell lines. This proof-of-concept study provides the first demonstration of therapeutic strategies based on the restoration of a defective, tumor-suppressing kinase activity by a novel class of recombinant immunotherapeutics.

A CD30 ligand (CD30L, CD153) is a type II membrane-associated glycoprotein belonging to the TNF family. To illustrate the potential role of CD30L in CD4(+) Th1 cell responses, we investigated the fate of Ag-specific CD4(+) T cells in CD30L-deficient (CD30L(-/-)) mice after Mycobacterium bovis bacillus Calmette-Guérin (BCG) infection. The number of bacteria was significantly higher in organs of CD30L(-/-) mice than in wild-type (WT) mice 4 wk postinfection. The numbers of purified protein derivative- or Ag85B-specific-IFN-gamma-producing-CD4(+) T cells in spleen, lung, or peritoneal exudate cells were significantly fewer in CD30L(-/-) mice than in WT mice. During the infection, CD30L was expressed mainly by CD44(+)CD3(+)CD4(+) T cells but not by CD3(+)CD8(+) T cells, B cells, dendritic cells, or macrophages. Costimulation with agonistic anti-CD30 mAb or coculturing with CD30L-transfected P815 cells restored IFN-gamma production by CD4(+) T cells from BCG-infected CD30L(-/-) mice. Coculturing with CD30L(+/+)CD4(+) T cells from BCG-infected WT mice also restored the number of IFN-gamma(+)CD30L(-/-)CD4(+) T cells. When transferred into the CD30L(+/+) mice, Ag-specific donor CD30L(-/-) CD4(+) T cells capable of producing IFN-gamma were restored to the compared level seen in CD30L(+/+) CD4(+) T cells on day 10 after BCG infection. When naive CD30L(+/+) T cells were transferred into CD30L(-/-) mice, IFN-gamma-producing-CD4(+) Th1 cells of donor origin were normally generated following BCG infection, and IFN-gamma-producing-CD30L(-/-)CD4(+) Th1 cells of host origin were partly restored. These results suggest that CD30L/CD30 signaling executed by CD30(+) T-CD30L(+) T cell interaction partly play a critical role in augmentation of Th1 response capable of producing IFN-gamma against BCG infection.

Background & Aims: A CD30-ligand (CD30L) is a 40-kilodalton, type II membrane-associated glycoprotein belonging to the tumor necrosis factor family. Serum levels of soluble CD30 increased in inflammatory bowel diseases (IBD), suggesting that CD30L/CD30 signaling is involved in the pathogenesis of IBD. In this study, we investigated the role of CD30L in oxazolone (OXA)- and trinitrobenzene sulfonic acid (TNBS)-induced colitis in CD30L knockout (KO) mice., Methods: Colitis was induced by OXA or TNBS in CD30LKO mice with BALB/c or C57BL/6 background, respectively, and diverse clinical signs of the disease were evaluated. Cytokine production from lamina propria T cells of the colon was assessed by enzyme-linked immunosorbent assay. Anti-interleukin (IL)-4 monoclonal antibody (mAb) or agonistic anti-CD30 mAb was inoculated in mice with colitis induced by OXA or TNBS., Results: CD30LKO mice were susceptible to OXA-induced colitis but resistant to TNBS-induced acute colitis. The levels of T helper cell 2 type cytokines such as IL-4 and IL-13 in the LP T cells were significantly higher, but the levels of interferon gamma were lower in OXA- or TNBS-treated CD30LKO mice than in wild-type mice. In vivo administration of agonistic anti-CD30 mAb ameliorated OXA-induced colitis but aggravated TNBS-induced colitis in CD30LKO mice., Conclusions: These results suggest that CD30L/CD30 signaling is involved in development of both OXA- and TNBS-induced colitis. Modulation of CD30L/CD30 signaling by mAb could be a novel biologic therapy for IBD.

In this report, we identify an important function for CD30 signals in the effective segregation of B and T lymphocytes in the murine spleen, additional to the recognized requirement for lymphotoxin signals. We show that CD30 signals are not required for transcription or protein expression of homeostatic chemokines, but CD30-deficient mice display impaired B/T segregation. This defect correlates with defective expression as detected by Abs of the transmembrane mucin-type protein podoplanin on T zone stroma, although expression at other sites is normal. Defective segregation is not intrinsic to CD30-deficient lymphocytes which segregate normally following transfer into RAG-deficient mice and significantly up-regulate the expression of both CCL21 and podoplanin on T zone stroma of RAG-deficient mice. During development, induction of expression of the CD30 ligand by lymphoid tissue inducer cells and podoplanin by T zone stroma are temporally linked, and the spatial association of these cells suggests that lymphoid tissue inducer cells are capable of providing the CD30 signals. Finally, we show that the appearance of podoplanin on T zone stroma in development is associated with B/T segregation of splenic white pulp areas. Our studies indicate that homeostatic chemokine expression by itself is not sufficient for B/T segregation and our data point to a significant role for podoplanin or molecules associated with podoplanin expressing stroma in the effective segregation of lymphocytes.