The Opposite Functions of CD30 Ligand Isoforms.

TNFSF8/CD30 ligand is a TNF superfamily member expressed on several major immune cell types, including activated monocytes, B, and T cells. The signaling of CD30 ligand through its cognate CD30 receptor has been shown to have effects on cell differentiation, cell death/survival, and cytokine production. The signaling pair has been implicated in hematopoietic malignancies and inflammatory disease, and a chemotherapy-CD30 antibody combination for the treatment of Hodgkin and other lymphomas has been developed. There are two recorded isoforms of CD30 ligand. All hitherto studies of CD30 ligand are of the first, canonical isoform, while the second isoform has never been described. This study aims to elucidate the properties and signaling functions of the second CD30 ligand isoform. We have found mRNA expression of both isoforms in the PBMCs of all six healthy donors tested. Through methods in cell biology and biochemistry, we were able to discover that the second CD30 ligand isoform has no discernable pro-inflammatory function and, in fact, isoform 2 can restrict the capacity of the canonical isoform to signal through the CD30 receptor by preventing their interaction. This discovery has implications for the future development of therapeutics targeting the CD30/CD30 ligand signaling pair in cancer and inflammatory disease.

Inflammation plays a causal role in fatigue-like behavior induced by pelvic irradiation in mice.

Fatigue is a persistent and debilitating symptom following radiation therapy for prostate cancer. However, it is not well-understood how radiation targeted to a small region of the body can lead to broad changes in behavior. In this study, we used targeted pelvic irradiation of healthy male mice to test whether inflammatory signaling mediates changes in voluntary physical activity levels. First, we tested the relationship between radiation dose, blood cell counts, and fatigue-like behavior measured as voluntary wheel-running activity. Next, we used oral minocycline treatments to reduce inflammation and found that minocycline reduces, but does not eliminate, the fatigue-like behavioral changes induced by radiation. We also used a strain of mice lacking the MyD88 adaptor protein and found that these mice also showed less fatigue-like behavior than the wild-type controls. Finally, using serum and brain tissue samples, we determined changes in inflammatory signaling induced by irradiation in wild-type, minocycline treated, and MyD88 knockout mice. We found that irradiation increased serum levels of IL-6, a change that was partially reversed in mice treated with minocycline or lacking MyD88. Overall, our results suggest that inflammation plays a causal role in radiation-induced fatigue and that IL-6 may be an important mediator.

CD30L+ classical monocytes play a pro-inflammatory role in the development of ulcerative colitis in patients.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease that affects the large intestine and exhibits a relapsing and remitting course. It is a complex immune-mediated disease of the gastrointestinal tract that increases morbidity and negatively influences the quality of life. Although our previous studies have indicated that CD30L is involved in the adaptive immune response in UC, it remains unclear whether it participates in the innate immune response. Our results revealed that the CD30L level significantly increased in the circulating classical monocytes of patients with UC and showed a positive correlation with the severity of UC. CD30L may participate in monocyte-mediated inflammation in patients with UC through the activation of circulating classical monocytes. The present study provides insights into a marker of severity and a potential target for the development of immunological therapy of UC.

Linfoma anaplásico de células grandes associado a implante mamários: um desafio diagnóstico / Breast implant-associated anaplastic large cell lymphoma: a diagnostic challenge

O linfoma anaplásico de células grandes associado a implante mamário (BIA-ALCL ) é uma entidade provisória com características morfológicas e imunofenotípicas indistinguíveis do linfoma anaplásico de células grandes (ALCL) ALK negativo. Ao contrário do ALCL, o BIA-ALCL surge principalmente em associação ao implante mamário. A confirmação diagnóstica do BIA-ALCL pode ser difícil e a associação de características morfológicas e patológicas com citometria de fluxo e imuno-histoquímica pode auxiliar no diagnóstico. O objetivo deste relatório é descrever um caso de BIA-ALCL no qual a análise citológica e imunofenotipológica utilizando citometria de fluxo sugeriu a presença de grandes células positivas para CD30 no líquido de derrame.

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a provisional entity with morphological and immunophenotypic characteristics indistinguishable from ALKnegative anaplastic large cell lymphoma (ALCL). Unlike ALCL, BIA-ALCL arises mainly in association with breast implantation. Diagnostic confirmation of BIA-ALCL can be difficult and associating morphological and pathological hallmarks with flow cytometry and immunohistochemistry can assist in the diagnosis. The objective of this report is to describe a case of BIA-ALCL in which cytological and immunophenotypological analysis using flow cytometry suggested the presence of large CD30-positive cells in the effusion fluid.

CD30L/CD30 protects against psoriasiform skin inflammation by suppressing Th17-related cytokine production by Vγ4+ γδ T cells.

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.

Novel Immunotherapy Options for Extranodal NK/T-Cell Lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is a highly aggressive mature NK/T-cell neoplasm marked by NK-cell phenotypic expression of CD3ε and CD56. While the disease is reported worldwide, there is a significant geographic variation with its highest incidence in East Asian countries possibly related to the frequent early childhood exposure of Epstein-Barr virus (EBV) and specific ethnic-genetical background, which contributes to the tumorigenesis. Historically, anthracycline-based chemotherapy such as CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) was used, but resulted in poor outcomes. This is due in part to intrinsic ENKTCL resistance to anthracycline caused by high expression levels of P-glycoprotein. The recent application of combined modality therapy with concurrent or sequential radiation therapy for early stage disease, along with non-anthracycline-based chemotherapy regimens consisting of drugs independent of P-glycoprotein have significantly improved clinical outcomes. Particularly, this neoplasm shows high sensitivity to l-asparaginase as NK-cells lack asparagine synthase activity. Even still, outcomes of patients with advanced stage disease or those with relapsed/recurrent disease are dismal with overall survival of generally a few months. Thus, novel therapies are needed for this population. Clinical activity of targeted antibodies along with antibody-drug conjugates, such as daratumumab (naked anti-CD38 antibody) and brentuximab vedotin (anti-CD30 antibody conjugated with auristatin E), have been reported. Further promising data have been shown with checkpoint inhibitors as high levels of programmed death-ligand 1 expression are observed in ENKTCL due to EBV-driven overexpression of the latent membrane proteins [latent membrane protein 1 (LMP1) and LMP2] with activation of the NF-κB/MAPK pathways. Initial case series with programmed death 1 inhibitors showed an overall response rate of 100% in seven relapsed patients including five with a complete response (CR). Furthermore, cellular immunotherapy with engineered cytotoxic T lymphocytes targeted against LMP1 and LMP2 have shown encouraging results with durable CRs as either maintenance therapy after initial induction chemotherapy or in the relapsed/refractory setting. In this paper, we review this exciting field of novel immunotherapy options against ENKTCL that hopefully will change the treatment paradigm in this deadly disease.

Trogocytosis of ligand-receptor complex and its intracellular transport in CD30 signalling.

BACKGROUND INFORMATION: CD30, which is characteristically expressed in classical Hodgkin lymphoma (cHL), is thought to transduce signals by ligation of trimerised CD30 ligand (CD30L) on the surface of surrounding cells and recruitment of downstream molecules. In this report, we propose a new mechanism for CD30 signalling by its ligand. We prepared two stable transformants, CHO cells expressing CD30L fused to mCherry and HeLa cells expressing CD30 fused to GFP. RESULTS: Co-culture of these cells triggered clustering of CD30 and CD30L at the cellular interface, formation of multiple CD30L-CD30 complexes, internalisation of these complexes with a portion of the plasma membrane into the HeLa cells, and intracellular transport to the lysosomal compartment. The internalisation process was significantly inhibited by actin polymerisation inhibitors. The CD30L-CD30 interaction was found to trigger active signalling processes, as measured by Ca2+ influx, and similar mechanisms were observed using cHL cell lines. CONCLUSIONS: These results suggest that CD30 extracts CD30L from CD30L-expressing cells by actin-mediated trogocytosis, resulting in the generation of signalosomes, intracellular signalling, lysosomal degradation and a subsequent refractory phase. We postulate that similar processes may operate in tumours endogenously expressing CD30. These observations thus provide new insights into our understanding of the biological roles of CD30 in normal and malignant cells and, in particular, in cHL. SIGNIFICANCE: This study suggests a novel model of CD30 signalling that provides new insights into the biological roles of CD30 and other members of this family in normal and malignant cells.

Requirement of CD30 expression on CD4 T cells in the pathogenesis of experimental autoimmune encephalomyelitis.

CD30, a member of the tumor necrosis factor receptor superfamily, is expressed preferentially by effector or memory helper T cells. Here we show that experimental autoimmune encephalomyelitis (EAE) is ameliorated with markedly reduced induction of antigen-specific Th1 and Th17 cells in CD30 knockout mice. Passive EAE indicated that CD30 on non-hematopoietic parenchymal cell is not required and mixed bone marrow chimera experiments revealed that CD30 signaling on CD4 T cells amplified the development of antigen-specific and encephalitogenic CD4 T cells. Thus, CD30 expression on CD4 T cells is critically involved in the pathogenesis of central nervous system autoimmunity.

CD30 ligand is a new therapeutic target for central nervous system autoimmunity.

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.

CD30 in systemic mastocytosis.

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.

In rheumatoid arthritis soluble CD30 ligand is present at high levels and induces apoptosis of CD30(+)T cells.

CD30 and CD30 ligand (CD30L) are members of TNF-receptor and TNF superfamilies respectively. CD30(+)T cells are increased in several diseases and interaction between CD30(+) and CD30L(+)T cells leads either to cell proliferation or apoptosis. In patients with rheumatoid arthritis (RA), soluble CD30 (sCD30) levels seem to reflect the recruitment of CD30(+)T cells into the inflamed joints and are predictive of a positive response to classical and biological immunosuppressive therapy. We have evaluated the presence of soluble CD30L (sCD30L) in the sera and synovial fluid of patients with RA and defined whether it binds surface CD30 molecule and is functionally active. We found high levels of sCD30L in sera and synovial fluid of RA patients; the molecule is shedded upon direct contact of CD30(+)/CD30L(+)T cells. Moreover sCD30L binds surface CD30 constitutively expressed by Jurkat cell line. Finally recombinant sCD30L and sera from patients with high levels of sCD30L are able to inhibit CD30(+)T cell proliferation by inducing cell apoptosis. Our findings suggest that circulant sCD30L is functionally active and that it may favor persistence of active inflammation by inducing apoptosis of CD30(+)T cells, known to down-modulate inflammation in rheumatoid synovitis.

Determination and application of Cytokeratin fragment 21-1, cancer antigen153, neuron-specific enolase in patients with lung cancer / 中国基层医药

Objective To investigate the contents of cytokeratin fragment 21-1 (CYFRA21-1),cancer antigen-153(CA153) and neuron-specific enolase (NSE)in patients wuth lung cancer. Methods 60 cases with lung cancer using single and combined determination serum CYFRA21-1, CA153 and NSE levels by radioimmunoassay (RIA). Results The contents of CYFRA21-1 ,CA125 and NSE in lung cancer were significantly higher than the control group(t = 2.811,2.845,2.901,2.795,2.759,2.811,2. 852,2.799,2. 816, all P ＜ 0. 01); The content of CYFRA21-1 in squamous cell carcinoma were higher than that small cell undifferentiated carcinoma(t = 2. 214, P ＜0. 05) ;The content of NSE in squamous cell carcinoma group were lower than small cell undifferentiated carcinoma (t = 2.312,P ＜ 0.05) ;The content of CA125 in adeno-carcinoma were higher than the higher squamous cell carcinoma scales cancer(t = 2. 177, P ＜ 0. 05); The positive rate of combined detection of CYFRA21-1 + CA153 + NSE (86. 4%)was significantly higher than the single test(x2 =3.786,P ＜0.05) ;The combined detection of sensitivity and negative predictive value was significantly higher than single detection (x2 = 3. 846,3. 877, all P ＜ 0. 05).Conclusion The combined determination could make up for missed diagnosis, and had some clinical value.