High serum level of soluble CD30 in acute primary HIV-1 infection

CD30 has been suggested to play a role in HIV infection. In this study the serum concentration of soluble CD30 (sCD30) was determined by an ELISA essay on samples collected from patients with acute primary HIV-1 infection during the acute phase (n = 17) and after seroconversion (n = 13). sCD30 during acute infection was consistently elevated (137.58 ± 120.33 versus 6.4 ± 5.4 U/ml (mean ± s.d.) in normal controls; P < 0.0001) and decreased after seroconversion (49.1 ± 66.17 U/ml; P = 0.0018 compared with acute infection). This trend mirrored the disappearance of detectable levels of HIV antigen in the blood, resulting in a direct correlation between sCD30 and HIVAg values (P = 0.002). These data suggest that the high levels of sCD30 observed during the peak concentration of HIVAg in acute primary HIV infection might reflect the high rate of viral replication.     

Treatment options for post-transplant lymphoproliferative disorder and other Epstein-Barr virus-associated malignancies

Epstein-Barr virus (EBV) is associated with a range of malignancies that largely arise from a defect in EBV-specific cytotoxic T lymphocyte (CTL) immunity and function. Much work has focused on the reconstitution of CTL immunity to EBV in transplant patients, in whom immunosuppression modalities render them susceptible to post-transplant lymphoproliferative disease (PTLD). Adoptive transfer of autologous CTLs is effective at both preventing and curing PTLD in solid organ transplant recipients and can produce a long-term memory response and protection against recurring disease. In this review, the benefits and restrictions of administering EBV-specific CTLs for the treatment of PTLD are discussed and compared with emerging therapies including the generation of allogeneic human leukocyte antigen-matched CTL banks and the anti-CD20 monoclonal antibody therapy, MabThera. Furthermore, studies involving other EBV-associated disorders have described the potential benefit of adoptive transfer of EBV-specific CTLs for Hodgkin's disease, nasopharyngeal carcinoma, chronic active EBV infection, and Burkitt's lymphoma. The challenges of tailor-making therapies for individual diseases and EBV antigen expression latencies are highlighted, in addition to considering vaccination strategies for optimal treatment.     

Soluble CD30 in pediatric patients with atopic dermatitis

Atopic dermatitis (AD) is a chronic, inflammatory skin disease in which a pathogenetic role of Th2 cells has been supposed. This study investigated the presence of soluble CD30 (sCD30), an activation marker of T-cell clones able to produce Th2-type cytokines, in sera from pediatric patients affected by AD ( n =25) with no symptoms of asthma or rhinitis. The severity of the disease was graded by both the SCORAD and Costa et al. clinical scoring systems. Serum levels of sCD30 were significantly higher in patients with AD in respect to both normal donors ( n =20) and urticaria patients ( n = 10), and a positive correlation between serum sCD30 and clinical score was found ( r =0.508; P =0.01) when AD patients were evaluated by Costa et al.'s method. Furthermore, a significant association ( r -=0.443; P =0.027) between sCD30 and serum levels of the soluble interleukin (IL)-2 receptor (sIL-2R) was observed in AD. The presence of high amounts of sCD30 in atopic patients seems to confirm the role of this molecule as an activation marker useful for in vivo evaluation of a Th2 immune response, and the correlation observed with both clinical score and sIL-2R levels indicates the role of sCD30 as an additional marker of disease activity in pediatric patients with AD.     

Soluble CD30 is more relevant to disease activity of atopic dermatitis than soluble CD26

It is suggested that CD30 and CD26 are surface molecules expressed on activated Th2 and Th1 cells, respectively. We examined plasma levels of soluble CD26 (sCD26) and sCD30 in patients with atopic dermatitis (AD) when their eruptions were aggravated and in non-atopic healthy controls, and then analysed the possible correlation between these values and the levels of several clinical markers. The plasma levels of both sCD30 and sCD26 were significantly higher in AD patients than in controls, both in exacerbation status and after conventional treatment. Multiple regression analyses showed that plasma sCD30 was a much better predictor of the levels of serum IgE, serum LDH and plasma sCD25, and the area and the score of AD eruption than sCD26, although elevated levels of both sCD30 and sCD26 are associated with these clinical predictors of AD. Importantly, sCD30 plasma levels decreased significantly in AD patients after conventional treatment, while no significant transition was noted in the concentration of sCD26. Moreover, a significant reduction of sCD30 levels was observed in the group of patients whose eruption score was reduced > 50%, whereas it was not in those < 50%. These findings provide evidence that the successful treatment of AD is associated with down-activation of Th2.     

Increased Serum Levels of Soluble CD30 in Patients with Common Variable Immunodeficiency and Its Clinical Implications

Common variable immunodeficiency (CVID) is a heterogeneous group of disorders, characterized by hypogammaglobulinemia and increased susceptibility to recurrent pyogenic infections, autoimmunity, and malignancies. Twenty-five cases with CVID (18 male and 7 female) and 25 healthy volunteers were investigate in this study. Soluble CD30 (sCD30) serum levels of the subjects were measured and compared. Serum levels of sCD30 in the patients with CVID were significantly increased in comparison with controls (36.93 ± 32.38 vs 5.27 ± 1.32 U/ml, P < 0.001). The group of patients with splenomegaly and reversed ratio of CD3+CD4+ T cells/CD3+CD8+ T cells had the highest serum levels of sCD30 (66.01 ± 43.34 U/ml) in comparison with other patients (P = 0.010). High levels of sCD30 in the CVID patients with splenomegaly and the presence of lymphoma in a patient with the highest level of sCD30 may suggest a soluble form of this marker as a prognostic tool in such diseases.     

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.     

Elevated serum levels of soluble CD30 in patients with atopic dermatitis (AD)

The immunopathology of AD is still unclear, but evidence for an immune response polarized towards Th2 activity has been provided. The CD30 molecule belongs to the tumour necrosis factor (TNF) receptor family and is expressed on activated T cells with a sustained expression in Th2 cells. This molecule also exists in a soluble form (sCD30). Elevated serum levels of sCD30 have been found in patients with Hodgkin's disease, chronic hepatitis B infection and HIV infection. Studies were undertaken to compare the serum levels of sCD30 in patients with AD (n=49) and healthy non-atopic controls (n=94). The presence of sCD30 was analysed with ELISA. A significantly higher concentration of sCD30 was noted in AD patients, median sCD30 level 29 U/ml (range 1–708 U/ml), compared with healthy non-atopic controls (P< 0.001), where the median level was 11 U/ml with a range of 1–1042 U/ml. No correlation was found between sCD30 levels and total serum IgE, or between the AD patients' SCORAD values and concentration of sCD30. sCD30 levels were also analysed in 20 AD patients, which during ketoconazole treatment had improved their clinical scores and reduced their serum IgE and eosinophil cationic protein levels. However, no significant decrease in sCD30 levels was noted after treatment. The results show that patients with AD have elevated levels of sCD30, but without correlation to total serum IgE or disease activity.     

In vivo relevance of CD30 in atopic dermatitis

CD30 expression was evaluated by immunohistochemistry in lesional skin biopsies of eight patients with active atopic dermatitis (AD) and three patients with allergic contact (nickel-induced) dermatitis (ACD). CD30 expression was also assessed in a large panel of CD4 + and CDS + T-cell clones generated from the skin biopsies of four patients with AD. Finally, the levels of soluble CD30 (sCD30) were measured in the serum of 41 patients with AD, 19 patients with ACD, and 60 healthy controls. In all specimens of lesional AD skin, where the great majority of infiltrating cells were CD4+ T cells, remarkable numbers of cells were CD30+, whereas virtually no CD30 + cells were found in the skin of patients with ACD. In CD4+ T-cell clones generated from the lesional AD skin, most of which produced both interleukin (IL)-4 and interferon-gamma (IFN-γ) (Th0–like cells) or IL-4 and 1L-5, but not IFN-γ (Th2–like cells), CD30 expression directly correlated with the ability to produce IL-4 and IL-5, but was inversely related to IFN-γ production. High levels of sCD30 (correlated with disease activity: r = 0.618) were detected in the serum of most AD patients, whereas there was no increase of sCD30 levels in the serum of patients with ACD. These data support the view that Th0/Th2–type responses predominate in the skin of patients with AD and suggest that the presence of CD30 + T cells in tissues and/or increased levels of sCD30 in biologic fluids are indicative of Th2–dominated responses.     

CD30 cell expression and abnormal soluble CD30 serum accumulation in Omenn's syndrome: Evidence for a T helper 2-mediated condition

Omenn's syndrome (OS) is a severe immunodeficiency, characterized by clinical and laboratory features reminiscent of a T helper type-2 (Th2) response. CD30, a member of the tumor necrosis factor receptor superfamily, has been found to be preferentially expressed by human T cell clones exhibiting a Th2-like profile and function. We investigated whether there are derangement in CD30 expression in tissues, and/or abnormalities in soluble CD30 (sCD30) levels in the serum, or both, of three children with OS and one child with maternal engraftment and Omenn's-like syndrome (OLS). Large proportions of tissue-infiltrating T lymphocytes from all four patients expressed CD30, whereas in control tissues, including peripheral blood, CD30⁺ T lymphocytes were extremely few or absent. In addition, levels of sCD30 were abnormally increased in all patients' sera. T cell clones were generated from sorted CD30⁺ and CD30^? peripheral blood T cells of the patient with OLS who showed unusually high numbers of circulating CD30⁺ T lymphocytes. Most CD4⁺ T cell clones derived from CD30⁺ cells showed a Th2-like cytokine profile, whereas the majority of clones generated from CD30^? T cells were Th1. These findings support the hypothesis that Th2 cells are involved in the pathogenesis of OS. Moreover, they provide evidence that detection of CD30⁺ T cells in tissues, increased levels of sCD30 in biological fluids, or both, reflect the presence of immune responses characterized by prevalent activation of T cells producing Th2 cytokines.     

A new era for cutaneous CD30-positive T-cell lymphoproliferative disorders

Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ T-LPD) represent a spectrum encompassing lymphomatoid papulosis (LyP), primary cutaneous anaplastic large-cell lymphoma (pcALCL) and borderline lesions. They share the expression of CD30 as a common phenotypic marker. They differ however in their clinical presentation, the histological features and clinical course. Moreover, LyP and PcALCL show numerous clinical, histological and phenotypic variants. Overlapping features of LyP and pcALCL with themselves and with other cutaneous and systemic lymphomas emphasize the importance of careful clinicopathologic correlation and staging in the diagnosis of CD30+ T-LPD. Furthermore, an increasing number of inflammatory and infectious skin disorders harboring medium-sized to large CD30+ cells have to be considered in the differential diagnosis.Whereas the expression of CD30 in cutaneous CD30+ T-LPD stands for a favourable prognosis, its expression in other cutaneous and systemic lymphomas has a divergent impact. The assessment of CD30 expression does not only provide prognostic information, but is of potential therapeutic relevance as CD30 can serve as a therapeutic target.This review focuses on the clinicopathological and phenotypic spectrum of CD30+ T-LPD, its differential diagnoses and the role of CD30 as a diagnostic, prognostic and therapeutic marker.     

CD8 serum levels in acute graft-versus-host disease diagnosis

Attempts to identify an early and discriminating marker of acute graft-versus-host disease (aGvHD) have been unsuccessful. The levels of soluble CD4 and soluble CD8 in serum correlate with T cell subset activation and may be important in monitoring and characterizing immunological processes. We determined serum soluble CD4 (sCD4) and sCD8 levels with a two-site sandwich enzyme immunoassay on patients' serum samples collected prior to bone marrow transplantation and weekly after transplantation until day +28. No significant increment of sCD4 was documented in each determination. sCD8 rose significantly before diagnosis or development of maximal clinical symptoms in patients with grade II–III aGvHD than grade 0–I aGvHD [at day +21—median value 447 IU/ml; range 94–713; versus 1136 IU/ml, range 790–1416P=0.002); at day +28—median value 443 IU/ml, range 73–992, versus 1164 IU/ml, range 625–1960P=0.005)]. On the day of marrow infusion the sCD8 levels were significantly higher in patients who subsequently developed grade II–III than in patients with grade 0–I aGvHD (median value 155 IU/ml, range 10–332, versus 350 IU/ml, range 283–830;P=0.003). Careful monitoring of sCD8 is a useful tool for a prompt aGvHD diagnosis and may be used in a clinical bone marrow transplantation setting.     

Serum levels of soluble CD30 in chronic hepatitis B virus infection

There is evidence that both cellular and humoral components of the immune response are required for viral clearance to occur in chronic hepatitis B. Recent studies demonstrated that CD30 molecule, a member of the tumour necrosis factor superfamily of membrane cytokine receptors, is expressed on, and released as a soluble molecule (sCD30) by activated T cells producing T helper 2 (Th2) cytokines, which modulate antibody responses. To better characterize the immunoregulatory mechanisms in chronic hepatitis B virus (HBV) infection, sCD30 values were evaluated by an ELISA in 90 hepatitis B surface (HBsAg)-positive patients with chronic hepatitis, selected on the basis of active viral replication and biochemical activity. At presentation abnormal levels (>20 U/ml) of sCD30 were detected in 57 (63%) out of 90 patients with chronic hepatitis B, and median value was significantly higher in this group of patients compared with that of healthy HBsAg carriers (26.7 versus 10.5 U/ml, P < 0.000 05) and with normal controls (26.7 versus 3 U/ml, P < 0.000 01). Sequential studies of chronic hepatitis B did confirm the association of raised sCD30 levels with the active phase of the illness. On the other hand, a significant decrease was noted when sCD30 levels at diagnosis and after termination of HBV replication and biochemical remission of hepatitis were compared in 10 untreated patients (median, 28 U/ml at entry versus 8 U/ml at remission, P < 0.01) and in six patients responding to interferon-alpha therapy (median, 29.5 U/ml at entry versus 6 U/ml at remission, P < 0.05). The high serum sCD30 levels reported during the active phase of HBsAg-positive chronic hepatitis suggest a certain degree of immune competence of these patients, at least with respect to a Th2-type response. These data are in agreement with recent serologic surveys showing that most chronic hepatitis B patients do demonstrate ongoing humoral immune response to HBV antigens, using novel immunoassays designed to detect antibody in the presence of excess serum viral antigen. Th2 functions that mainly promote humoral immunity to HBV antigens may be critical, in association with a competent virus-specific cytotoxicity, for efficient termination of HBV replication in chronic hepatitis B.     

Soluble CD26/CD30 levels in visceral leishmaniasis: markers of disease activity

Leishmania infantum is the causative agent of zoonotic visceral leishmaniasis (VL). If untreated the disease could be fatal; however, in some cases the infection can run a subclinical course. In subclinical infections a Th1-response predominates, while Th2-responses and/or probably Treg cells are related to unfavourable outcome of the disease in active VL. In the present study we determined the levels of soluble (s) CD26 and CD30 co-stimulatory molecules in sera from patients with active VL, asymptomatic individuals and healthy volunteers. Results showed a significant difference in both sCD26 and sCD30 between infected cases and normal individuals (P < or = 0.001). However, there was no significant difference in sCD26 levels between asymptomatic cases and patients, although the difference was not significant. sCD30 levels were significantly higher in VL patients than asymptomatic cases (P < or = 0.001). These findings suggest a possible association between sCD26 and sCD30 levels and the clinical manifestation of L. infantum infection.     

Concentrations of Soluble CD95 and CD8 Antigens in the Plasma and Levels of CD8+CD95+, CD8+CD38+, and CD4+CD95+ T Cells Are Markers for HIV-1 Infection and Clinical Status

Apoptosis mediated via the CD95 (FAS/APO-1) receptor is thought to play a role in the depletion of CD4+ T cells in HIV infection. In the present study expression of the CD95 antigen on lymphocyte subsets and the plasma level of soluble CD95 (sCD95) were determined in HIV-1-infected adults. The expression of CD95 was increased on CD8 cells in all groups of HIV+ individuals, while increased expression of CD95+ cells on CD4 cells was limited to individuals with CD4 counts of <200 mm³. The proportion of CD4+ that expressed CD95 was inversely correlated with the percentage of CD4+ PBL. The concentration of sCD95 was significantly higher in the plasma of HIV-infected individuals than in normal controls. The level of sCD95 in HIV-infected subjects showed no correlation with the percentage of PBL expressing CD95, indicating that the increased level of sCD95 did not reflect release from CD95+ PBL. The plasma sCD95 concentration was significantly correlated with the percentage of CD8+ cells and, particularly, with CD8+CD38– cells. A striking inverse correlation was found between the sCD95 plasma concentration and the proportion of CD4+CD95+ cells out of the total CD4+ population. There was no correlation between the serum level of sCD95 and that of soluble CD8 (sCD8), both of which were increased in the plasma of HIV+ individuals. Unlike the level of sCD95, the level of sCD8 in the plasma of HIV+ individuals. Unlike the level of sCD95, the level of sCD8 in the plasma of HIV+ individuals was correlated with the percentage of CD95+ and CD8+CD38+ cells. The present study indicates that plasma sCD95 may be one of the factors that regulate apoptotic death of lymphocytes in HIV infection.     

Primary mucosal CD30-positive T-cell lymphoproliferative disorders of the head and neck rarely involving epiglottis: clinicopathological,immunohistomchemical and genetic features of a case

A case of primary mucosal CD30-positive T-cell lymphoproliferative disorder of the head and neck rarely involving epiglottis in a 59-year-old male was reported. Histologically, the ulcerative mucosa was affected by sheets of mixed inflammatory infiltration, with scattered large atypical lymphoid cells arranging in an individual or small clusters with focal epidermotropism. Immunohistochemically, tumor cells were uniformly immunoreactive to antibodies against CD2, CD3, CD7, CD43, CD4, TIA-1, with a heterogeneous expression of CD30, but negative for CD20, CD79a, CD21, CD8, CD56, ALK, EMA, granzyme B. Epstein-Barr virus encoded RNA (EBER) were detected. Genetically, T-cell receptor (TCR) γ gene showed an oligoclonal rearrangement. This first case developing in epiglottis demonstrates mucosal CD30-positive T-cell lymphoproliferative disorders are characteristic of a broad clinicopathologic spectrum similar to the counterpart in the skin with a favorable prognosis.     

Epstein-Barr virus-associated gastric carcinoma in southern India: A comparison with a large-scale Japanese series

Epidemiological and clinicopathological features of Epstein-Barr virus (EBV) associated gastric carcinoma was compared in India and Japan, two countries differing markedly in gastric cancer incidence. Using in situ hybridization assay, the presence of EBV-encoded small RNA (EBER) was examined in 215, and 2,011 gastric cancer cases in Kerala, India, and Japan, respectively. Ten cases (5%), all males, in the Indian series were EBER-positive. This frequency was similar to that in the Japanese series (6.2%). As was the case with Japanese series, the EBV-associated gastric carcinoma in the Indian series was observed most frequently in the middle part of the stomach (1 in antrum, 4 in middle part, 2 in cardia, and 3 unknown), and, histologically, the diffuse type Lauren's classification (8 cases) was more common than the intestinal type (2 cases). Virus subtyping by PCR-RFLP revealed that all of the 10 EBV strains isolated from the EBER-positive Indian cases were subtype A, and wild-type F for Bam HI F region. In Bam HI I region, 8 cases were type C and the remaining 2 cases were type D. In either series, there was no significant difference in the frequency of tumors with p53 overexpression between EBER-positive and -negative cases. However, the proportion of cells with p53 overexpression in EBER-negative tumors was significantly higher than that in EBER-positive tumors regardless of histological type in both series. In conclusion, the frequency and major clinicopathological features of EBV-associated gastric carcinoma in south India were similar to those observed in Japanese series although gastric cancer incidence in these two countries differs markedly.     

Epstein-Barr virus-associated posttransplantation lymphoproliferative disorder after high-dose immunosuppressive therapy and autologous CD34-selected hematopoietic stem cell transplantation for severe autoimmune diseases.

High-dose immunosuppressive therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is currently being evaluated for the control of severe autoimmune diseases. The addition of antithymocyte globulin (ATG) to high-dose chemoradiotherapy in the high-dose immunosuppressive therapy regimen and CD34 selection of the autologous graft may induce a higher degree of immunosuppression compared with conventional autologous HSCT for malignant diseases. Patients may be at higher risk of transplant-related complications secondary to the immunosuppressed state, including Epstein-Barr virus (EBV)-associated posttransplantation lymphoproliferative disorder (PTLD), but this is an unusual complication after autologous HSCT. Fifty-six patients (median age, 42 years; range, 23-61 years) with either multiple sclerosis (n = 26) or systemic sclerosis (n = 30) have been treated. The median follow-up has been 24 months (range, 2-60 months). Two patients (multiple sclerosis, n = 1; systemic sclerosis, n = 1) had significant reactivations of herpesvirus infections early after HSCT and then developed aggressive EBV-PTLD and died on days +53 and +64. Multiorgan clonal B-cell infiltrates that were EBV positive by molecular studies or immunohistology were identified at both autopsies. Both patients had positive screening skin tests for equine ATG (Atgam) and had been converted to rabbit ATG (Thymoglobulin) from the first dose. Of the other 54 patients, 2 of whom had partial courses of rabbit ATG because of a reaction to the intravenous infusion of equine ATG, only 1 patient had a significant clinical reactivation of a herpesvirus infection (herpes simplex virus 2) early after HSCT, and none developed EBV-PTLD. The T-cell count in the peripheral blood on day 28 was 0/microL in all 4 patients who received rabbit ATG; this was significantly less than in patients who received equine ATG (median, 174/microL; P =.001; Mann-Whitney ranked sum test). Although the numbers are limited, the time course and similarity of the 2 cases of EBV-PTLD and the effect on day 28 T-cell counts support a relationship between the development of EBV-PTLD and the administration of rabbit ATG. The differences between equine and rabbit ATG are not yet clearly defined, and they should not be considered interchangeable in this regimen without further study.