Resection of Renal Cell and Prostate Carcinoma Sternum Metastases with Long-Term Follow-Up: A Report of 2 Cases.

Introduction: Rarely solitary sternum metastases are addressed by resection. Two additional cases are presented as they are interesting because of their long-term follow-up. Case Presentation: Case 1: A renal cell carcinoma was treated by transabdominal nephrectomy at age 64. Right iliac bone and sternum metastases were diagnosed 7 months later and treated by internal hemipelvectomy followed by sternum metastasectomy 6 weeks after the internal hemipelvectomy. At 12-year follow-up, the patient appears disease free. Case 2: Prostate cancer was treated by prostatectomy at age 67. A subsequent solitary sternum metastasis was resected 10 years later for persistent PSA-activity despite repeated radiotherapy. The patient remains asymptomatic for 3 years now. Conclusion: Resection of sternum metastases may have curative potential and should be considered in tumours known to be rather resistant to chemo- and/or radiotherapy.

PPARγ is essential for the development of bone marrow erythroblastic island macrophages and splenic red pulp macrophages.

Tissue-resident macrophages play a crucial role in maintaining homeostasis. Macrophage progenitors migrate to tissues perinatally, where environmental cues shape their identity and unique functions. Here, we show that the absence of PPARγ affects neonatal development and VCAM-1 expression of splenic iron-recycling red pulp macrophages (RPMs) and bone marrow erythroblastic island macrophages (EIMs). Transcriptome analysis of the few remaining Pparg-deficient RPM-like and EIM-like cells suggests that PPARγ is required for RPM and EIM identity, cell cycling, migration, and localization, but not function in mature RPMs. Notably, Spi-C, another transcription factor implicated in RPM development, was not essential for neonatal expansion of RPMs, even though the transcriptome of Spic-deficient RPMs was strongly affected and indicated a loss of identity. Similarities shared by Pparg- and Spic-deficient RPM-like cells allowed us to identify pathways that rely on both factors. PPARγ and Spi-C collaborate in inducing transcriptional changes, including VCAM-1 and integrin αD expression, which could be required for progenitor retention in the tissue, allowing access to niche-related signals that finalize differentiation.

Efficacy of a CDK4/6 Inhibitor in a Patient with Breast Cancer and Liposarcoma: A Case Report and Review of the Literature.

BACKGROUND: The cyclin D/cyclin-dependent kinase (CDK)4/6 inhibitor of the CDK4 (INK4)/retinoblastoma (Rb) pathway plays a crucial role in cell cycle progression. Selective CDK4/6 inhibitors specifically target a variety of tumors, with the main focus on hormone receptor(HR)-positive and human epidermal growth factor receptor 2(HER2)-negative breast cancer (BC). CASE REPORT: We report on the efficacy of neoadjuvant palbociclib and letrozole application in a patient suffering from invasive estrogen receptor (ER)+/HER2- BC and concurrent well-differentiated and dedifferentiated liposarcoma (WD-DDLPS) of the thigh. Clinical and histological workup upon surgery revealed significant regressive changes in both the liposarcoma and the BC. The 24-month follow-up shows no signs of disease. CONCLUSION: CDK4/6 inhibitors exhibit a high therapeutic potential, although reliable prognostic markers need to be identified.

IL-21 promotes allergic airway inflammation by driving apoptosis of FoxP3+ regulatory T cells.

BACKGROUND: IL-21 is a key player of adaptive immunity, with well-established roles in B-cell and cytotoxic T-cell responses. IL-21 has been implicated in promotion of effector CD4+ T cells and inhibition of forkhead box P3-positive regulatory T (Treg) cells, but the mechanism and functional relevance of these findings remain controversial. OBJECTIVE: We sought to understand the mechanisms by which IL-21 controls effector CD4+ cell responses and Treg cell homeostasis. METHODS: We used IL-21 receptor-deficient mice to study the effect of IL-21 on T-cell responses in models of asthma and colitis. We used mixed bone marrow chimeras and adoptive transfer of naive CD4+ T cells and Treg cells into lymphopenic mice to assess the cell-intrinsic effects of IL-21. Using various in vitro T-cell assays, we characterized the mechanism of IL-21-mediated inhibition of Treg cells. RESULTS: We show that IL-21 production by TH2 and follicular helper T/ex-follicular helper T cells promotes asthma by inhibiting Treg cells. Il21r-/- mice displayed reduced generation of TH2 cells and increased generation of Treg cells. In mixed chimeras we demonstrate that IL-21 promotes TH2 responses indirectly through inhibition of Treg cells. Depleting Treg cells in Il21r-/- mice restored TH2 generation and eosinophilia. Furthermore, IL-21 inhibited Treg cell generation in mice with colitis. Using competitive transfer of Il21r+/+ and Il21r-/- CD4+ cells, we show that IL-21 directly inhibited expansion of differentiated Treg cells but was dispensable for TH1/TH17 effectors. We show that IL-21 sensitizes Treg cells to apoptosis by interfering with the expression of Bcl-2 family genes. CONCLUSION: IL-21 directly promotes apoptosis of Treg cells and therefore indirectly sustains generation of inflammatory TH cells and related effector responses.

PPARγ in dendritic cells and T cells drives pathogenic type-2 effector responses in lung inflammation.

Type-2 immune responses are well-established drivers of chronic inflammatory diseases, such as asthma, and represent a large burden on public health systems. The transcription factor PPARγ is known to promote M2-macrophage and alveolar macrophage development. Here, we report that PPARγ plays a key role in both T cells and dendritic cells (DCs) for development of type-2 immune responses. It is predominantly expressed in mouse Th2 cells in vitro and in vivo as well as human Th2 cells from allergic patients. Using conditional knockouts, we show that PPARγ signaling in T cells, although largely dispensable for IL-4 induction, is critical for IL-33-driven Th2 effector function in type-2 allergic airway responses. Furthermore, we demonstrate that IL-4 and IL-33 promote up-regulation of PPARγ in lung-resident CD11b+ DCs, which enhances migration to draining lymph nodes and Th2 priming capacity. Thus, we uncover a surprising proinflammatory role for PPARγ and establish it as a novel, important mediator of DC-T cell interactions in type-2 immunity.

The tactics and technique of musculoskeletal biopsy.

The treatment of musculoskeletal neoplasms and infection is usually based on an initial diagnostic biopsy.Prior to biopsy, a hypothesis should be formed about the most likely diagnosis and a differential diagnosis. These deliberations should consider whether the lesion is a primary benign or malignant tumour, a metastasis, a haematological problem or an infection.A tactical plan should be developed which evaluates the necessity, the risk, the approach and finally defines the technique of biopsy most likely to achieve a representative result in the clinical case.In developing this technical approach, the pitfalls should be anticipated, i.e. inadequate sampling, difficulty of pathological interpretation and contamination.The tactical approach should be developed in conjunction with a multi-disciplinary team together with appropriate pre-biopsy imaging. Cite this article: EFORT Open Rev 2017;2:51-57. DOI: 10.1302/2058-5241.2.160065.

CD11c.DTR mice develop a fatal fulminant myocarditis after local or systemic treatment with diphtheria toxin.

To assess the role of alveolar macrophages (AMs) during a pulmonary Aspergillus fumigatus infection AMs were depleted by intratracheal application of diphtheria toxin (DTX) to transgenic CD11c.DTR mice prior to fungal infection. Unexpectedly, all CD11c.DTR mice treated with DTX died within 4-5 days, whether being infected with A. fumigatus or not. Despite measurable impact of DTX on lung functional parameters, these constrictions could not explain the high mortality rate. Instead, DTX-treated CD11c.DTR animals developed fulminant myocarditis (FM) characterized by massive leukocyte infiltration and myocardial cell destruction, including central parts of the heart's stimulus transmission system. In fact, standard limb lead ECG recordings of diseased but not healthy mice showed a "Brugada"-like pattern with an abnormally high ST segment pointing to enhanced susceptibility for potential lethal arrhythmias. While CD11c.DTR mice are extensively used for the characterization of CD11c(+) cells, including dendritic cells, several studies have already mentioned adverse side effects following DTX treatment. Our results demonstrate that this limitation is based on severe myocarditis but not on the expected lung constrictions, and has to be taken into consideration if this animal model is used. Based on these properties, however, the CD11c.DTR mouse might serve as useful animal model for FM.

Arthroscopic Synovectomy in Bilateral Lipoma Arborescens.

INTRODUCTION: Lipoma arborescens (LA) is an uncommon condition that consists of a villous lipomatous proliferation of the synovial membrane. Open synovectomy has been previously selected as a curative treatment option. In recent years, some authors have published good results with arthroscopic interventions. We describe a well-documented case of bilateral LA of the knees treated with staged arthroscopic synovectomy. CASE REPORT: A 48-year-old North American woman without a history of trauma presented with recurrent effusions and mild pain in both knee joints for many years. Magnetic resonance imaging examinations confirmed the diagnosis of bilateral LA with multiple villous lipomatous synovial proliferations pattern. Degenerative changes of the medial meniscus were detected bilaterally. The patient underwent bilateral arthroscopic anterior synovectomy and partial medial meniscectomy of the knee with three portal techniques. Arthroscopic the knee joint contained a large number or finger-shaped synovial proliferations with yellowish good vascularized diffuse villous masses in the suprapatellar bursa and intercondylar fossa. The cartilage showed degenerative changes with Outerbridge Grade II to III, which was particularly severe in the femoropatellar compartment. Histopathological examination of the villous masses demonstrated papillary hypertrophy, slight hyperplasia, vascular hyperplasia with a slight degree of stromal fibrosis, and interstitial lymphoplasmacytic inflammation. The adipose cells were reduced in number in relation to a normal finding but had a normal aspect without any pathological changes. 25 months after the first operation, the patient reported pain relief with the preserved function. Magnetic resonance examination of both knee joints at the last follow-up showed no relapse of the disease. The Knee injury and Osteoarthritis Outcome Score improved on the right knee joint from 39.3 preoperatively to 85.1 at the last follow-up, and on the left knee joint from 54.2 preoperatively to 86.3 at the last follow-up. CONCLUSION: Arthroscopic anterior synovectomy is an efficient method of achieving good results in LA with multiple villous lipomatous synovial proliferations pattern.

The 2015 World Health Organization Classification of Tumors of the Thymus: Continuity and Changes.

This overview of the 4th edition of the World Health Organization (WHO) Classification of thymic tumors has two aims. First, to comprehensively list the established and new tumor entities and variants that are described in the new WHO Classification of thymic epithelial tumors, germ cell tumors, lymphomas, dendritic cell and myeloid neoplasms, and soft-tissue tumors of the thymus and mediastinum; second, to highlight major differences in the new WHO Classification that result from the progress that has been made since the 3rd edition in 2004 at immunohistochemical, genetic and conceptual levels. Refined diagnostic criteria for type A, AB, B1-B3 thymomas and thymic squamous cell carcinoma are given, and it is hoped that these criteria will improve the reproducibility of the classification and its clinical relevance. The clinical perspective of the classification has been strengthened by involving experts from radiology, thoracic surgery, and oncology; by incorporating state-of-the-art positron emission tomography/computed tomography images; and by depicting prototypic cytological specimens. This makes the thymus section of the new WHO Classification of Tumours of the Lung, Pleura, Thymus and Heart a valuable tool for pathologists, cytologists, and clinicians alike. The impact of the new WHO Classification on therapeutic decisions is exemplified in this overview for thymic epithelial tumors and mediastinal lymphomas, and future perspectives and challenges are discussed.

Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages.

Tissue-resident macrophages constitute heterogeneous populations with unique functions and distinct gene-expression signatures. While it has been established that they originate mostly from embryonic progenitor cells, the signals that induce a characteristic tissue-specific differentiation program remain unknown. We found that the nuclear receptor PPAR-γ determined the perinatal differentiation and identity of alveolar macrophages (AMs). In contrast, PPAR-γ was dispensable for the development of macrophages located in the peritoneum, liver, brain, heart, kidneys, intestine and fat. Transcriptome analysis of the precursors of AMs from newborn mice showed that PPAR-γ conferred a unique signature, including several transcription factors and genes associated with the differentiation and function of AMs. Expression of PPAR-γ in fetal lung monocytes was dependent on the cytokine GM-CSF. Therefore, GM-CSF has a lung-specific role in the perinatal development of AMs through the induction of PPAR-γ in fetal monocytes.

Alveolar macrophages are essential for protection from respiratory failure and associated morbidity following influenza virus infection.

Alveolar macrophages (AM) are critical for defense against bacterial and fungal infections. However, a definitive role of AM in viral infections remains unclear. We here report that AM play a key role in survival to influenza and vaccinia virus infection by maintaining lung function and thereby protecting from asphyxiation. Absence of AM in GM-CSF-deficient (Csf2-/-) mice or selective AM depletion in wild-type mice resulted in impaired gas exchange and fatal hypoxia associated with severe morbidity to influenza virus infection, while viral clearance was affected moderately. Virus-induced morbidity was far more severe in Csf2-/- mice lacking AM, as compared to Batf3-deficient mice lacking CD8α+ and CD103+ DCs. Csf2-/- mice showed intact anti-viral CD8+ T cell responses despite slightly impaired CD103+ DC development. Importantly, selective reconstitution of AM development in Csf2rb-/- mice by neonatal transfer of wild-type AM progenitors prevented severe morbidity and mortality, demonstrating that absence of AM alone is responsible for disease severity in mice lacking GM-CSF or its receptor. In addition, CD11c-Cre/Ppargfl/fl mice with a defect in AM but normal adaptive immunity showed increased morbidity and lung failure to influenza virus. Taken together, our results suggest a superior role of AM compared to CD103+ DCs in protection from acute influenza and vaccinia virus infection-induced morbidity and mortality.

ITMIG consensus statement on the use of the WHO histological classification of thymoma and thymic carcinoma: refined definitions, histological criteria, and reporting.

INTRODUCTION: The 2004 version of the World Health Organization classification subdivides thymic epithelial tumors into A, AB, B1, B2, and B3 (and rare other) thymomas and thymic carcinomas (TC). Due to a morphological continuum between some thymoma subtypes and some morphological overlap between thymomas and TC, a variable proportion of cases may pose problems in classification, contributing to the poor interobserver reproducibility in some studies. METHODS: To overcome this problem, hematoxylin-eosin-stained and immunohistochemically processed sections of prototypic, "borderland," and "combined" thymomas and TC (n = 72) were studied by 18 pathologists at an international consensus slide workshop supported by the International Thymic Malignancy Interest Group. RESULTS: Consensus was achieved on refined criteria for decision making at the A/AB borderland, the distinction between B1, B2, and B3 thymomas and the separation of B3 thymomas from TCs. "Atypical type A thymoma" is tentatively proposed as a new type A thymoma variant. New reporting strategies for tumors with more than one histological pattern are proposed. CONCLUSION: These guidelines can set the stage for reproducibility studies and the design of a clinically meaningful grading system for thymic epithelial tumors.

Endothelial overexpression of LOX-1 increases plaque formation and promotes atherosclerosis in vivo.

AIMS: Lectin-like oxLDL receptor-1 (LOX-1) mediates the uptake of oxidized low-density lipoprotein (oxLDL) in endothelial cells and macrophages. However, the different atherogenic potential of LOX-1-mediated endothelial and macrophage oxLDL uptake remains unclear. The present study was designed to investigate the in vivo role of endothelial LOX-1 in atherogenesis. METHODS AND RESULTS: Endothelial-specific LOX-1 transgenic mice were generated using the Tie2 promoter (LOX-1TG). Oxidized low-density lipoprotein uptake was enhanced in cultured endothelial cells, but not in macrophages of LOX-1TG mice. Six-week-old male LOX-1TG and wild-type (WT) mice were fed a high-cholesterol diet (HCD) for 30 weeks. Increased reactive oxygen species production, impaired endothelial nitric oxide synthase activity and endothelial dysfunction were observed in LOX-1TG mice as compared with WT littermates. LOX-1 overexpression led to p38 phosphorylation, increased nuclear factor κB activity and subsequent up-regulation of vascular cell adhesion molecule-1, thereby favouring macrophage accumulation and aortic fatty streaks. Consistently, HCD-fed double-mutant LOX-1TG/ApoE(-/-) displayed oxidative stress and vascular inflammation with higher aortic plaques than ApoE(-/-) controls. Finally, bone marrow transplantation experiments showed that endothelial LOX-1 was sufficient for atherosclerosis development in vivo. CONCLUSIONS: Endothelial-specific LOX-1 overexpression enhanced aortic oxLDL levels, thereby favouring endothelial dysfunction, vascular inflammation and plaque formation. Thus, LOX-1 may serve as a novel therapeutic target for atherosclerosis.

Differentiated dysplasia is a frequent precursor or associated lesion in invasive squamous cell carcinoma of the oral cavity and pharynx.

The source of precursor lesions of squamous cell carcinoma (SCC) of the oral cavity and pharynx, their classification, and grading are controversial. In contrast, vulvar and penile cancer precursor lesions are known to be related to human papillomavirus or chronic inflammation and can be described using the vulvar intraepithelial neoplasia (VIN) classification system (VIN 1-3) or as differentiated vulvar intraepithelial neoplasia (dVIN), respectively. Oral and pharyngeal SCC precursor lesions are more etiologically diverse, and the spectrum of lesions may thus be wider. No international consensus exists regarding the histological types of precursor lesions or the significance of individual types. We therefore reviewed resection specimens and preceding biopsies of 155 patients with SCC of the oral cavity and pharynx (excluding tonsils) and identified five basic patterns of SCC-associated or precursor lesions: (1) pleomorphic (22/155), (2) basaloid (5/155), (3) differentiated (63/155), (4) mixed (42/155), and (5) verrucous (12/155). Keratinization was a common but variable feature in differentiated, mixed, and verrucous dysplasia. In 11/155 patients, no precursor lesion could be identified. Progression of isolated differentiated dysplasia (ranging from months to years) was documented in 13/155 (8 %) of patients. Our data suggest that full-thickness epithelial dysplasia of pleomorphic or basaloid type is present in <20 % of oral and pharyngeal SCC, and differentiated dysplasia is a frequent precursor or associated in situ lesion. Failure to recognize differentiated dysplasia results in the underdiagnosis of many patients at risk for invasive carcinoma. These results indicate a need to refine criteria to distinguish differentiated dysplasia from morphologically related lichenoid lesions.

A VLP-based vaccine against interleukin-1α protects mice from atherosclerosis.

Interleukin (IL)-1α is a potent proinflammatory cytokine that has been implicated in the development of atherosclerosis. We investigated whether a vaccine inducing IL-1α neutralizing antibodies could interfere with disease progression in a murine model of atherosclerosis. We immunized Apolipoprothin E (ApoE)-deficient mice with a vaccine (IL-1α-C-Qß) consisting of full-length, native IL-1α chemically conjugated to virus-like particles derived from the bacteriophage Qß. ApoE(-/-) mice were administered six injections of IL-1α-C-Qß or nonconjugated Qß over a period of 160 days while being maintained on a western diet. Atherosclerosis was measured in the descending aorta and in cross-sections at the aortic root. Macrophage infiltration in the aorta was measured using CD68. Expression levels of VCAM-1, ICAM-1, and MCP-1 were quantified by RT-PCR. Immunization against IL-1α reduced plaque progression in the descending aorta by 50% and at the aortic root by 37%. Macrophage infiltration in the aorta was reduced by 22%. Inflammation was also reduced in the adventitia, with a decrease of 54% in peri-aortic infiltrate score and reduced expression levels of VCAM-1 and ICAM-1. Active immunization targeting IL-1α reduced both the inflammatory reaction in the plaque as well as plaque progression. In summary, vaccination against IL-1α protected ApoE(-/-) mice against disease, suggesting that this may be a potential treatment option for atherosclerosis.

Programmed death 1 protects from fatal circulatory failure during systemic virus infection of mice.

The inhibitory programmed death 1 (PD-1)-programmed death ligand 1 (PD-L1) pathway contributes to the functional down-regulation of T cell responses during persistent systemic and local virus infections. The blockade of PD-1-PD-L1-mediated inhibition is considered as a therapeutic approach to reinvigorate antiviral T cell responses. Yet previous studies reported that PD-L1-deficient mice develop fatal pathology during early systemic lymphocytic choriomeningitis virus (LCMV) infection, suggesting a host protective role of T cell down-regulation. As the exact mechanisms of pathology development remained unclear, we set out to delineate in detail the underlying pathogenesis. Mice deficient in PD-1-PD-L1 signaling or lacking PD-1 signaling in CD8 T cells succumbed to fatal CD8 T cell-mediated immunopathology early after systemic LCMV infection. In the absence of regulation via PD-1, CD8 T cells killed infected vascular endothelial cells via perforin-mediated cytolysis, thereby severely compromising vascular integrity. This resulted in systemic vascular leakage and a consequential collapse of the circulatory system. Our results indicate that the PD-1-PD-L1 pathway protects the vascular system from severe CD8 T cell-mediated damage during early systemic LCMV infection, highlighting a pivotal physiological role of T cell down-regulation and suggesting the potential development of immunopathological side effects when interfering with the PD-1-PD-L1 pathway during systemic virus infections.

Intra-tumoral budding in preoperative biopsy specimens predicts lymph node and distant metastasis in patients with colorectal cancer.

Tumor budding, a histological hallmark of epithelial-mesenchymal transition in colorectal cancer, is a parameter of tumor progression and according to the International Union Against Cancer/American Joint Committee on Cancer an 'additional' prognostic factor. The current definition of tumor budding is reserved for the invasive tumor front of colorectal cancer (so called peri-tumoral budding), but tumor buds can also be observed in small preoperative biopsy specimens. Whereas the prognostic value of peri-tumoral budding assessed in resection specimens has found wide acceptance, the value of budding in preoperative biopsies, which normally do not encompass the invasive tumor margin and hence can be called intra-tumoral budding, has not been systematically investigated yet. Therefore, the aim of this study is to assess the predictive value of intra-tumoral budding for lymph node and distant metastasis in preoperative biopsies. Preoperative biopsy samples and consecutive resection specimens from 72 patients with pathological information on TNM stage, vascular, lymphatic and perineural invasion, and tumor border configuration were used to evaluate intra-tumoral budding and peri-tumoral budding. Both parameters were scored semiquantitatively as 'high' (detectable at low power magnification × 2.5) and 'low' (occasional budding at intermediate magnification × 10, difficult to find or absent). In biopsy samples high intra-tumoral budding was observed in 12/72 patients (17%) and associated with high peri-tumoral budding in the corresponding resection specimens (P=0.008). Additionally, there was a correlation between high intra-tumoral budding and lymph node metastasis (P=0.034), distant metastasis (P=0.007) and higher tumor grade (P=0.025). Peri-tumoral budding was associated with higher N stage (P=0.004), vascular (P=0.046) and lymphatic invasion (P=0.019) as well as with an infiltrating tumor border (P<0.001), reflecting the predictive power of peri-tumoral budding for tumor progression. High intra-tumoral budding in preoperative biopsy samples of colorectal cancer patients predicts high peri-tumoral budding at the invasive margin and lymph node metastasis in the corresponding resection specimens as well as distant metastasis.

Extranodal diffuse large B cell lymphoma of cutaneous follicle centre lymphoma type: a study of 24 patients with non-cutaneous primary limited stage extranodal diffuse large B cell lymphoma in support of a new concept.

AIMS: Follicle centre cell lymphoma of small cell type showing either a follicular or diffuse growth pattern similar to cutaneous follicle centre lymphoma (cFCL) has been recognized in extranodal non-cutaneous sites. Our aim was (i) to investigate whether diffuse large B cell lymphoma (DLBCL) of cFCL type could be identified in extranodal non-cutaneous sites and (ii) whether clinical characteristics similar to primary cFCL could be recognized. METHODS AND RESULTS: Of 24 extranodal non-cutaneous DLBCLs, nine (38%) had large centrocytoid morphology and 15 (62%) were either 'centrocytoid and centroblastic' or 'centroblastic and immunoblastic'. Six centrocytoid cases were Irf-4 negative, Bcl-6 positive and at most weakly CD10- or Bcl-2-positive by immunohistochemistry, consistent with DLBCL of cFCL type. All patients with cFCL type were stage IE and were significantly younger than other patients. Recurrences occurred in two patients and were exclusively extranodal. CONCLUSION: Our results suggest that DLBCL of cFCL type can be identified in extranodal non-cutaneous sites and shows clinical characteristics similar to genuine cFCL. We propose to expand the concept of cFCL to encompass large cell lymphomas in extranodal sites.

HVEM signalling promotes colitis.

BACKGROUND: Tumor necrosis factor super family (TNFSF) members regulate important processes involved in cell proliferation, survival and differentiation and are therefore crucial for the balance between homeostasis and inflammatory responses. Several members of the TNFSF are closely associated with inflammatory bowel disease (IBD). Thus, they represent interesting new targets for therapeutic treatment of IBD. METHODOLOGY/PRINCIPAL FINDINGS: We have used mice deficient in TNFSF member HVEM in experimental models of IBD to investigate its role in the disease process. Two models of IBD were employed: i) chemical-induced colitis primarily mediated by innate immune cells; and ii) colitis initiated by CD4(+)CD45RB(high) T cells following their transfer into immuno-deficient RAG1(-/-) hosts. In both models of disease the absence of HVEM resulted in a significant reduction in colitis and inflammatory cytokine production. CONCLUSIONS: These data show that HVEM stimulatory signals promote experimental colitis driven by innate or adaptive immune cells.