| 2021 | Correlation of CD38 expression with the progression of hemorrhagic fever with renal syndrome. | Arch Virol | To assess the relationship between the expression of CD38 and the progression of hemorrhagic fever with renal syndrome (HFRS), we determined the levels of CD38 during different phases of HFRS and evaluated the relationship between changes in CD38 expression and the progression of HFRS. The expression of CD38 in 68 patients with HFRS was analyzed by flow cytometry, and this method was also used to determine the levels of CD4T, CD8T, and B lymphocytes and NK cells. Furthermore, creatinine (Cr), uric acid (UA), and urea in serum at each stage of HFRS were measured using commercial kits. The basic clinical reference values for leukocytes, platelets (PLT), and red blood cells were determined by conventional methods. The colloidal gold method was used to measure HFRS antibody levels in the patients. A significant change in CD38 expression was observed from the fever phase to the recovery phase in patients with HFRS. Moreover, the expression of CD38 was proportionally correlated with the levels of Cr, UA, and urea in serum. In contrast, there was an inverse correlation between CD38 and PLT. Interestingly, an increase in CD38 expression correlated with an increase in CD8T lymphocytes, B cells, and NK cells, but with a decrease in CD4T lymphocytes. The expression of CD38 is associated with the progression of HFRS, suggesting that it may be a potent indicator of the stages of this disorder. |
| 2021 | Dynamic Changes of Lymphocyte Subsets in the Course of COVID-19. | Int Arch Allergy Immunol | Although the pathophysiology of coronavirus disease 2019 (COVID-19) is not clearly defined, among the proposed mechanisms, immune system dysfunction is more likely than others. The aim of this study was to clarify the characteristics and clinical significance of dynamic changes of lymphocyte subsets in the course of COVID-19.In this prospective study, the levels of peripheral lymphocyte subsets including CD4+, CD8+, CD4+CD25+FOXP3+, CD38+, CD3+HLA-DR+, CD19+, CD20+, and CD16+CD56+ cells were measured by flow cytometry in 52 confirmed hospitalized patients with COVID-19 at the day of admission and after 7 days of care. Clinical response was defined as improvement in symptoms (fever, dyspnea, and cough as well as blood oxygen saturation), and patients who met these criteria after 1 week of admission were classified as early responders; others who survived and finally discharged from the hospital were classified as late responders and patients who died were categorized as nonresponders. Immunophenotyping of studied cell changes on the first day of admission and 7 days after treatment were compared. Besides, the correlation between cellular subset variation and clinical response and outcome were analyzed.Total counts of white blood cell, T cells, CD4+ T cells, CD8+ T cells, CD38+ lymphocytes, and CD3+HLA-DR+ lymphocytes were significantly increased in both early and late responders. No statistically significant difference was observed in CD4+/CD8+ ratio, B cells, FOXP3+Treg lymphocytes, and FOXP3 median fluorescence intensity among studied groups. According to the multivariate analysis, an increase in CD4+ T cells (p = 0.019), CD8+ T cells (p = 0.001), and administration of interferon (p < 0.001) were independent predictors of clinical response.We found an increasing trend in total T cells, T helpers, cytotoxic T cells, activated lymphocytes, and natural killer cells among responders. This trend was not statistically significant among nonresponders. The findings of this study may enhance our knowledge about the pathogenesis of COVID-19. |
| 2020 | [Post colonoscopic Listeria monocytogenes meningitis in a patient with multiple myeloma during daratumumab-based therapy]. | Rinsho Ketsueki | A 69-year-old man with an unremarkable medical history presented with asymptomatic pancytopenia and diagnosed with Bence Jones protein-λ multiple myeloma (MM). Despite treatment with various chemotherapeutic regimens, myelosuppressive neutropenia occurred after each successive course; therefore, the treatment was determined to be ineffective and was discontinued. Consequently, one year after the diagnosis, a daratumumab-based therapy was initiated, and the MM was stabilized without clinical or laboratory evidences of myelosuppression. However, 18 months after the daratumumab induction, the patient developed hematochezia. Following an unremarkable lower gastrointestinal endoscopy, he presented fever and disturbed consciousness. Serum laboratory results showed liver dysfunction, and Listeria monocytogenes meningitis was diagnosed by cerebrospinal fluid examination. Empiric antibacterial treatment was administered for 3 weeks, which resolved the symptoms with no permanent neurological deficit.Daratumumab, a CD38 monoclonal antibodies, binds to expressed CD38 on myeloma cells and has an anti-myeloma cytotoxic effect but also binds to CD38 on activated macrophages. Additionally, activated macrophages play an important role in the immune defense of Listeria monocytogenes. Furthermore, inactivation of macrophages may increase the susceptibility to Listeria infection. Therefore, the possibility of infections such as Listeria meningitis should be considered in patients with MM receiving daratumumab-based therapy. |
| 2021 | Virus-infected peripheral blood plasmablasts in a patient with severe fever with thrombocytopenia syndrome. | Int J Hematol | Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral hemorrhagic disease with a high fatality rate. It is caused by the SFTS virus and is endemic in East Asian countries such as China, South Korea, and Japan. Previous studies have shown that plasmablasts appear transiently in peripheral blood during the acute phase of SFTS, but do not specify the characteristics of these plasmablasts. In this report, we describe the features of peripheral blood plasmablasts in a patient with SFTS. Immunohistochemical and immunofluorescence staining detected a small number of atypical lymphocytes expressing the SFTS virus antigen among peripheral leukocytes in a blood sample. The phenotype of the virus-infected cells was CD27+, CD38+, MUM1+, and CD138+, which is consistent with that of plasmablasts. This novel study demonstrates that plasmablasts in the peripheral blood of patients with SFTS are targets of the SFTS virus. |
| 2020 | Acute myeloid leukemia associated with t(16:21)(p11;q22) in a pediatric patient. | Bol Med Hosp Infant Mex | Background">Rare subgroups of pediatric patients with acute myeloid leukemia (AML), such as t(16:21) (p11;q22), require international cooperation to establish a proper stratification system to assign clinical risk.Here, we report a 13-year-old female who was admitted for asthenia, fatigue, and intermittent fever. The hematological data showed thrombocytopenia and anemia, and the bone marrow test showed 82.5% blast cells, which were positive for CD13, CD33, CD38, and CD117. Blast cells showed negative myeloperoxidase staining and positive periodic acid-Schiff staining. A diagnosis of AML M6 was made. Cells were positive for the fusion transcript FUS-ERG t(16;21)(p11;q22). The patient achieved morphological remission. However, molecular remission was not achieved, and she died 11 months after diagnosis.It is essential to report this sporadic case of AML to provide clinicians with data for clinical decision-making, such as for risk-group stratification. To the best of our knowledge, this is the first association between this translocation and this morphological subtype. |
| 2021 | Immunological imprint of COVID-19 on human peripheral blood leukocyte populations. | Allergy | SARS-CoV-2 has triggered a pandemic that is now claiming many lives. Several studies have investigated cellular immune responses in COVID-19-infected patients during disease but little is known regarding a possible protracted impact of COVID-19 on the adaptive and innate immune system in COVID-19 convalescent patients.We used multiparametric flow cytometry to analyze whole peripheral blood samples and determined SARS-CoV-2-specific antibody levels against the S-protein, its RBD-subunit, and viral nucleocapsid in a cohort of COVID-19 convalescent patients who had mild disease ~10 weeks after infection (n = 109) and healthy control subjects (n = 98). Furthermore, we correlated immunological changes with clinical and demographic parameters.Even ten weeks after disease COVID-19 convalescent patients had fewer neutrophils, while their cytotoxic CD8 T cells were activated, reflected as higher HLA-DR and CD38 expression. Multiparametric regression analyses showed that in COVID-19-infected patients both CD3 CD4 and CD3 CD8 effector memory cells were higher, while CD25 Foxp3 T regulatory cells were lower. In addition, both transitional B cell and plasmablast levels were significantly elevated in COVID-19-infected patients. Fever (duration, level) correlated with numbers of central memory CD4 T cells and anti-S and anti-RBD, but not anti-NC antibody levels. Moreover, a "young immunological age" as determined by numbers of CD3 CD45RA CD62L CD31 recent thymic emigrants was associated with a loss of sense of taste and/or smell.Acute SARS-CoV-2 infection leaves protracted beneficial (ie, activation of T cells) and potentially harmful (ie, reduction of neutrophils) imprints in the cellular immune system in addition to induction of specific antibody responses. |
| 2020 | Ontogeny of different subsets of yellow fever virus-specific circulatory CXCR5 CD4 T cells after yellow fever vaccination. | Sci Rep | Monitoring the frequency of circulatory CXCR5 (cCXCR5) CD4 T cells in periphery blood provides a potential biomarker to draw inferences about T follicular helper (T) activity within germinal center. However, cCXCR5 T cells are highly heterogeneous in their expression of ICOS, PD1 and CD38 and the relationship between different cCXCR5 subsets as delineated by these markers remains unclear. We applied class II tetramer reagents and mass cytometry to investigate the ontogeny of different subsets of cCXCR5 T cell following yellow fever immunization. Through unsupervised analyses of mass cytometry data, we show yellow fever virus-specific cCXCR5 T cells elicited by vaccination were initially CD38ICOSPD1, but then transitioned to become CD38ICOSPD1 and CD38ICOSPD1 before coming to rest as a CD38ICOSPD1 subset. These results imply that most antigen-specific cCXCR5 T cells, including the CD38ICOSPD1 CXCR5 T cells are derived from the CXCR5CD38ICOSPD1 subset, the subset that most resembles preT/T in the germinal center. |
| 2020 | Analysis of type I IFN response and T cell activation in severe COVID-19/HIV-1 coinfection: A case report. | Medicine (Baltimore) | Complex immune dysregulation in interferon (IFN) and T cell response has been observed in human immunodeficiency virus (HIV-1)-infected patients as well as in coronavirus disease-2019 (COVID-19) patients. However, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)/HIV-1 coinfection has been described in only few cases worldwide and no data are available on immunological outcomes in HIV-1-patients infected with SARS-CoV-2. Hence, this study aims to compare type I IFN response and T cell activation levels between a SARS-CoV-2/HIV-1-coinfected female patient and age-matched HIV-1-positive or uninfected women.A 52-year-old woman diagnosed with SARS-CoV-2/HIV-1 coinfection, ten HIV-1-positive women and five age-matched-healthy individuals were enrolled in this study.SARS-CoV-2 infection caused severe pneumonia in the second week of illness in HIV-1-positive patient under protease inhibitors. Chest high-resolution computed tomography images of the SARS-CoV-2/HIV-1-coinfected patient showed bilateral ground-glass opacities.SARS-CoV-2/HIV-1-coinfected female patient under darunavir/cobicistat regimen received a 7-days hydroxychloroquine therapy. Analysis of IFNα/β mRNA levels and CD4 and CD8 T cell (CD38, human leukocyte antigen-DR [HLA-DR], CD38 HLA-DR) frequencies were performed by RT/real-time PCR assays and flow cytometry, respectively. Median relative difference (MRD) was calculated for each immunological variable. For values greater than reference, MRD should be a positive number and for values that are smaller, MRD should be negative.The severe pneumonia observed in SARS-CoV-2/HIV-1-positive patient under protease inhibitors was reversed by a 7-days hydroxychloroquine therapy. At the end of treatment, on day 7, patient reported resolution of fever, normalization of respiratory rate (14 breaths/min), and improved oxygen arterial pressure with a FiO2 of 30%. MRD values for IFNα/β and CD4 and CD8 T cells expressing CD38 and/or HLA-DR found in SARS-CoV-2-/HIV-1-coinfected woman were approximatively equal to 0 when refereed respectively to HIV-1-positive female patients [MRDs IFNα/β: median -0.2545 (range: -0.5/0.1); T cells: median -0.11 (range: -0.8/1.3)] and ≥ 6 when referred to healthy individuals [MRDs IFNα/β: median 28.45 (range: 15/41.9); T cells: median 10 (range 6/22)].These results indicate that SARS-CoV-2 infection in HIV-1-positive female patient was associated with increased levels of IFNα/β-mRNAs and T cell activation compared to healthy individuals. |
| 2020 | Human herpesvirus 8-positive multicentric Castleman disease with germinotropic plasmablastic aggregates: Overlapping spectrum of human herpesvirus 8-associated lymphoproliferative disorder. | Pathol Int | The diagnosis of human herpesvirus 8 (HHV8)-associated lymphoproliferative disorder (LPD) is challenging because of the rarity and extended spectrum of each entity. A 43-year-old, human immunodeficiency virus seropositive, Japanese man was referred to our department because of persistent fever, generalized lymphadenopathy, jaundice and anasarca. Biopsy of a left axially lymph node demonstrated relatively preserved nodal structure with multicentric Castleman disease (MCD) features. In the germinal center, there were aggregates of HHV8-infected plasmablasts that were diffusely positive for CD38, MUM1/IRF4, LCA, IgM and λ; partially positive for CD30, c-MYC, p53; and negative for CD138, CD20, PAX-5, κ, CD2, CD3 and CD5. A small number of Epstein-Barr virus encoded small RNA (EBER)-positive large cells infiltrated in the outer part of the germinal center and the mantle layer, but the cells copositive for EBER and HHV8 were not evident. We diagnosed the patient as HHV8-positive MCD with germinotropic plasmablastic aggregates, which demonstrated intermediate pathologic features between HHV8-positive MCD and germinotropic lymphoproliferative disorder. The pathogenesis of each HHV8-associated LPD differs in cellular origin, host immune status, cytoplasmic immunoglobulin expression, clonality pattern and EBV infection; however, these factors sometimes overlap and induce extended clinical and pathologic presentations. |
| 2020 | Immune Dysregulation in the Tonsillar Microenvironment of Periodic Fever, Aphthous Stomatitis, Pharyngitis, Adenitis (PFAPA) Syndrome. | J Clin Immunol | Periodic Fever, Aphthous stomatitis, Pharyngitis and Adenitis (PFAPA) syndrome is an inflammatory disorder of childhood classically characterized by recurrent fevers, pharyngitis, stomatitis, cervical adenitis, and leukocytosis. While the mechanism is unclear, previous studies have shown that tonsillectomy can be a therapeutic option with improvement in quality of life in many patients with PFAPA, but the mechanisms behind surgical success remain unknown. In addition, long-term clinical follow-up is lacking. In our tertiary care center cohort, 62 patients with PFAPA syndrome had complete resolution of symptoms after surgery (95.3%). Flow cytometric evaluation demonstrates an inflammatory cell population, distinct from patients with infectious pharyngitis, with increased numbers of CD8+ T cells (5.9% vs. 3.8%, p < 0.01), CD19+ B cells (51% vs. 35%, p < 0.05), and CD19+CD20+CD27+CD38-memory B cells (14% vs. 7.7%, p < 0.01). Cells are primed at baseline with increased percentage of IL-1β positive cells compared to control tonsil-derived cells, which require exogenous LPS stimulation. Gene expression analysis demonstrates a fivefold upregulation in IL1RN and TNF expression in whole tonsil compared to control tonsils, with persistent activation of the NF-κB signaling pathway, and differential microbial signatures, even in the afebrile period. Our data indicates that PFAPA patient tonsils have localized, persistent inflammation, in the absence of clinical symptoms, which may explain the success of tonsillectomy as an effective surgical treatment option. The differential expression of several genes and microbial signatures suggests the potential for a diagnostic biomarker for PFAPA syndrome. |
| 2019 | Impaired Antibody-Independent Immune Response of B Cells in Patients With Acute Dengue Infection. | Front Immunol | Dengue is a mosquito-borne viral disease caused by dengue virus (DENV). The disease is endemic to more than 100 countries with 390 million dengue infections per year. Humoral immune responses during primary and secondary DENV infections are well-investigated. However, the impact of DENV infection on B cell subsets and their antibody-independent functions are not well-documented. Through this study, we aimed to define the distribution of B cell subsets in the acute phase of DENV infection and characterize the effect of DENV infection on B cell functions such as differentiation into memory and plasma cells and cytokine production. In our cohort of Cambodian children, we observed decreased percentages of CD24CD38 B cells and CD27 naïve B cells within the CD19 population and increased percentages of CD27CD38CD138 plasma cells as early as 4 days post appearance of fever in patients with severe dengue compared to patients with mild disease. Lower percentages of CD19CD24CD38 B cells in DENV-infected patients were associated with decreased concentrations of soluble CD40L in patient plasma and decreased platelet counts in these patients. In addition, CD19CD24CD38 and CD19CD27 B cells from DENV-infected patients did not produce IL-10 or TNF-α upon stimulation , suggesting their contribution to an altered immune response during DENV infection. In addition, CD19CD27 naïve B cells isolated from dengue patients were refractory to TLR/anti-IgM stimulation , which correlated to the increased expression of inhibitory Fcγ receptors (FcγR) CD32 and LILRB1 on CD19CD27 naïve B cells from DENV-infected patients. Collectively, our results indicate that a defective B cell response in dengue patients may contribute to the pathogenesis of dengue during the early phase of infection. |
| 2019 | Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets. | BMC Infect Dis | Bendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described.We report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge.We hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen. |
| 2019 | Wuchereria bancrofti infection is linked to systemic activation of CD4 and CD8 T cells. | PLoS Negl Trop Dis | Susceptibility to HIV has been linked to systemic CD4+ T cell activation in cohorts of seronegative individuals with high HIV-exposure risk. We recently described an increased risk of HIV transmission in individuals infected with Wuchereria bancrofti, the causative agent for lymphatic filariasis, in a prospective cohort study. However, the reason for this phenomenon needs further investigation.Two-hundred and thirty-five HIV negative adults were tested using Trop Bio ELISA for detection of W. bancrofti infection and Kato Katz urine filtration and stool based RT-PCR for detection of soil transmitted helminths and schistosomiasis. FACS analysis of the fresh peripheral whole blood was used to measure T cell activation markers (HLA-DR, CD38), differentiation markers (CD45, CD27), markers for regulatory T cells (FoxP3, CD25) and the HIV entry receptor CCR5. Frequencies of activated HLA-DRpos CD4 T cells were significantly increased in subjects with W. bancrofti infection (n = 33 median: 10.71%) compared to subjects without any helminth infection (n = 42, median 6.97%, p = 0.011) or those with other helminths (Schistosoma haematobium, S. mansoni, Trichuris trichiura, Ascaris lumbricoides, hookworm) (n = 151, median 7.38%, p = 0.009). Similarly, a significant increase in HLA-DRposCD38pos CD4 T cells and effector memory cells CD4 T cells (CD45ROposCD27neg) was observed in filarial infected participants. Multivariable analyses further confirmed a link between W. bancrofti infection and systemic activation of CD4 T cells independent of age, fever, gender or other helminth infections.W. bancrofti infection is linked to systemic CD4 T cell activation, which may contribute to the increased susceptibility of W. bancrofti infected individuals to HIV infection. |
| 2019 | The potential role of follicular helper T cells in idiopathic multicentric Castleman disease with and without TAFRO syndrome. | Pathol Res Pract | Idiopathic multicentric Castleman disease (iMCD) is a systemic inflammatory disease of unknown etiology caused by hypercytokinemia. Recently, TAFRO (thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome has been reported, which shows similar histopathological findings to iMCD and factors associated with a poor prognosis. iMCD shows no plasma cell infiltration in the germinal center (GC), but CD38-positive (CD38)-plasma cells are observed in the interfollicular area. Our previous report revealed that atrophic change of GC, glomeruloid vascular proliferation, and abnormal proliferation of follicular dendritic cells are more prominent in iMCD with TAFRO (TAFRO) in comparison to iMCD without TAFRO (TAFRO). In addition, the numbers of CD38 and immunoglobulin G4-positive (IgG4) plasma cells were decreased in the interfollicular area. The roles of T follicular helper cells (Tfh) are well-known to assist B-cell proliferation, maturation, and differentiation．It maintains the formation of GC and is also related in the class switching of IgG isotypes, including IgG4. Thus, we immunohistochemically examined the number of Tfh in GCs in both TAFRO and TAFRO iMCD. The number of Tfh was significantly decreased in TAFRO iMCD (n = 9) and was further decreased in TAFRO iMCD (n = 18) in comparison to non-specific lymphadenopathy (n = 6) and IgG4-related disease (n = 4). These results suggest that decreased Tfh may be one etiology of iMCD. |
| 2019 | [Clinical and Laboratory Characteristics of Disseminated Non-tuberculous Mycobacterial Disease]. | Zhongguo Yi Xue Ke Xue Yuan Xue Bao | Objective To explore the clinical and laboratory characteristics and the prognosis of disseminated non-tuberculous mycobacteria(NTM)diseases in human immunodeficiency virus(HIV)negative patients. Methods Cases of disseminated NTM disease were retrospectively collected in Peking Union Medical College Hospital from January 2012 to October 2018.Clinical manifestations,laboratory findings,treatment,and prognosis of these cases were retrieved from the electronic medical record system. Results Among the 23 HIV negative patients with disseminated NTM disease,21 had underlying diseases,with rheumatoid immune disease(n=7)as the most common one.The main clinical manifestation was fever(n=23).Laboratory tests showed anemia [hemoglobin(85.78±25.47)g/L],hypoalbuminemia [albumin 29(27-32)g/L],elevated erythrocyte sedimentation rate [(85.73±43.78)mm/h] and hypersensitive C-reactive protein [(112.00±70.90)mg/L],and reduction of lymphocyte count [0.69(0.29-2.10)×10 /L].Lymphocyte subset analysis indicated reduction in CD4 T cells [213(113-775)/μl],CD8 T cells [267(99-457)/μl],B cells [39(4-165)/μl],and NK cells [88(32-279)/μl] and elevation of human leukocyte antigen-D related(HLA-DR),and CD38 expression in CD8 T cells [HLA-DR CD8 /CD8 ,60(40-68)%;CD38 CD8 /CD8 ,81(65-90)%].The most common species of NTM was Mycobacterium intracellular(n=6).Lymphocyte,CD8 T cell,B cell,and NK cell counts were significantly lower in dead patients than surviving patients(P =0.045,P=0.045,P=0.032,and P=0.010,respectively). Conclusions Disseminated NTM disease in HIV negative patients is mainly manifested as fever,anemia,hypoalbuminemia,and elevated inflammatory indicators.It is more likely to occur in immunocompromised patients.Patients with decreased lymphocytes,CD8 T cells,B cells and NK cells tend to have a poor prognosis. |
| 2019 | Transient Appearance of Plasmablasts in the Peripheral Blood of Japanese Patients With Severe Fever With Thrombocytopenia Syndrome. | J Infect Dis | Atypical lymphocytes in the peripheral blood in patients with severe fever with thrombocytopenia syndrome (SFTS) have not been well examined. In this study, we analyzed counts and characteristics of atypical lymphocytes in 7 patients with SFTS. Atypical lymphocytes resembled plasma cells morphologically and appeared in the peripheral blood of all patients 4-8 days after onset of disease. Among these lymphocytes flow cytometry showed a CD19+CD38+CD138-/+ phenotype, and immunohistochemical staining revealed a CD79a+CD38+CD138-/+CD27+ phenotype. From our observations, atypical lymphocytes transiently that appeared in the peripheral blood during the acute phase of SFTS were considered to be plasmablasts. |
| 2018 | B cell subset alteration and the expression of tissue homing molecules in dengue infected patients. | J Biomed Sci | B cells play an essential role during dengue viral infection. While a major expansion of antibody secreting cells (ASCs) was observed, the importance of these increased frequencies of ASCs remains unclear. The alteration of B cell subsets may result from the expression of tissue specific homing molecules leading to their mobilization and distribution to different target organs during acute dengue viral infection.In this study, whole blood samples were obtained from thirty pediatric dengue-infected patients and ten healthy children and then stained with fluorochrome-conjugated monoclonal antibodies against CD3, CD14, CD19, CD20, CD21, CD27, CD38, CD45, CD138 and homing molecules of interest before analyzed by polychromatic flow cytometry. B cell subsets were characterized throughout acute infection period.Data shows that there were no detectable differences in frequencies of resting, activated and tissue memory cells, whereas the frequency of ASCs was significantly increased and associated with the lower frequency of naïve cells. These results were found from patients with both dengue fever and dengue hemorrhagic fever, suggesting that such change or alteration of B cells was not associated with disease severity. Moreover, several homing molecules (e.g., CXCR3 and CCR2) were found in ASCs, indicating that ASCs may distribute to inflamed tissues and various organs.Findings from this study provide insight into B cell subset distribution. Furthermore, organ mobilization according to homing molecule expression on different B cell subsets during the course of dengue viral infection also suggests they are distributed to inflamed tissues and various organs. |
| 2018 | The clinicopathological comparison among nodal cases of idiopathic multicentric Castleman disease with and without TAFRO syndrome. | Hum Pathol | Multicentric Castleman disease (MCD) is a systemic inflammatory disease potentially caused by an increase in the serum interleukin-6 (IL-6) level. Idiopathic MCD (iMCD) is histopathologically classified into three types: plasmacytic (PC), mixed, and hypervascular (hyperV) types. Recently, a unique clinical phenotype with a poor prognosis overlap with iMCD, thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly (TAFRO syndrome), has been reported from Japan, but its detailed clinicopathological features remain unclear. In this study, we performed a clinicopathological analysis of 70 nodal cases of iMCD with and without TAFRO syndrome (n = 37 versus n = 33). Compared with iMCD without TAFRO, iMCD with TAFRO showed more atrophic lymphoid follicles (LF), greater distances between follicles, increased glomeruloid vascular proliferation within the germinal center, and increased follicular dendritic cells. In addition, the hyperV type in particular demonstrated severe atrophic LF and interfollicular vascular proliferation. Among the mixed-type cases, the serum IL-6 levels in iMCD with TAFRO were significantly higher than those in iMCD without TAFRO. Furthermore, compared to iMCD without TAFRO, the numbers of immunoglobulin G4 (IgG4)-positive and CD38-positive plasma cells were significantly decreased in iMCD with TAFRO. |
| 2018 | De Novo Unclassifiable CD20-Negative Diffuse Large B-Cell Lymphoma: A Diagnostic and Therapeutic Challenge. | Int J Surg Pathol | CD20-negative diffuse large B-cell lymphomas (DLBCLs) constitute a rare and heterogeneous group of aggressive lymphomas. Known well-documented variants include plasmablastic lymphomas, primary effusion lymphomas, anaplastic kinase-positive large B-cell lymphomas, and large B-cell lymphomas arising in human herpesvirus 8 (HHV8)-associated multicentric Castleman disease. They impose diagnostic challenges for pathologists and therapeutic confrontations for clinicians. CD20 loss in B-cell lymphomas is a well-known phenomenon after rituximab therapy. De novo loss of CD20 has been reported in human immunodeficiency virus (HIV)-positive patients. Rare cases of primary CD20-negative DLBCLs that did not meet the criteria of the well-established subtypes of CD20-negative DLBCLs have been reported. This might expand the spectrum of unclassifiable CD20-negative DLBCLs with aberrant genetic and immunophenotypes. This imposes further diagnostic and therapeutic challenges. We report a case of a primary CD20-negative DLBCL in an HIV-infected female patient with an Epstein Barr virus (EBV) coinfection, who presented with generalized lymphadenopathy and fever. The nodal neoplastic immunoblasts were positive for LCA, PAX5, CD30, OCT2, BOB1, MUM1, CD79a, and CD19. Ki67 proliferation index was 100%. They were negative for CD20, CD3, ALK, EMA, CD138, CD38, EBV, and HHV8. Our case did not meet the criteria of the known variants of CD20-negative DLBCLs. The aim of this study is to highlight the diagnostic challenges associated with CD20-negative DLBCLs. De novo unclassifiable CD20-negative DLBCLs might raise an insight into the complex genetic mechanisms of CD20 concealment with variable immunoprofiles and resistance to conventional chemotherapies. |
| 2018 | Oxytocin release via activation of TRPM2 and CD38 in the hypothalamus during hyperthermia in mice: Implication for autism spectrum disorder. | Neurochem Int | Oxytocin (OT) is a critical molecule for social recognition that mediates social and emotional behaviors. OT is released during stress and acts as an anxiolytic factor. To know the precise molecular mechanisms underlying OT release into the brain during stress is important. It has been reported that intracellular concentrations of free calcium in the hypothalamic neurons are elevated by simultaneous stimulation of cyclic ADP-ribose (cADPR) and heat. We have reported in vitro and in vivo data that supports the idea that release of OT in the brain of male mice is regulated by cADPR and fever in relation to stress conditions. 1) Significantly higher levels of OT release were observed in hypothalamus cultures isolated from subordinate mice in group-housed males compared to dominant males after cage-switch stress; 2) OT concentrations in micro-perfusates at the paraventricular nucleus upon perfusion stimulation with cADPR were enhanced in subordinate mice compared to dominant mice; 3) The OT concentration in the cerebrospinal fluid (CSF) was higher in endotoxin-shock mice with fever compared to controls with no body temperature increase; and 4) In mice exposed to new environmental stress, the CSF OT level transiently increased 5 min after exposure, while the rectal temperature increased from 36.6 °C to 37.8 °C from 5 to 15 min after exposure. In this review, we examine whether or not cADPR and hyperthermia co-regulate hypothalamic OT secretion during social stress through the elevation of intracellular free Ca concentrations involved in CD38-dependent Ca mobilization and TRPM2-dependent Ca influx. Finally, we propose that the interaction between CD38 and TRPM2 seems to be a new mechanism for stress-induced release of OT, which may result in anxiolytic effects for temporal recovery from social impairments in children with autism spectrum disorder during hyperthermia. |
| 2017 | Challenge of Humans with Wild-type Serovar Typhi Elicits Changes in the Activation and Homing Characteristics of Mucosal-Associated Invariant T Cells. | Front Immunol | Gastrointestinal infections by serovar Typhi (. Typhi) are rare in industrialized countries. However, they remain a major public health problem in the developing world with an estimated 26.9 million new cases annually and significant mortality when untreated. Recently, we provided the first direct evidence that CD8 MAIT cells are activated and have the potential to kill cells exposed to . Typhi, and that these responses are dependent on bacterial load. However, MAIT cell kinetics and function during bacterial infections in humans remain largely unknown. In this study, we characterize the human CD8 MAIT cell immune response to . Typhi infection in subjects participating in a challenge clinical trial who received a low- or high dose of wild-type . Typhi. We define the kinetics of CD8 MAIT cells as well as their levels of activation, proliferation, exhaustion/apoptosis, and homing potential. Regardless of the dose, in volunteers resistant to infection (NoTD), the levels of CD8 MAIT cells after . Typhi challenge fluctuated around their baseline values (day 0). In contrast, volunteers susceptible to the development of typhoid disease (TD) exhibited a sharp decline in circulating MAIT cells during the development of typhoid fever. Interestingly, MAIT cells from low-dose TD volunteers had higher levels of CD38 coexpressing CCR9, CCR6, and Ki67 during the development of typhoid fever than high-dose TD volunteers. No substantial perturbations on the levels of these markers were observed in NoTD volunteers irrespective of the dose. In sum, we describe, for the first time, that exposure to an enteric bacterium, in this case . Typhi, results in changes in MAIT cell activation, proliferation, and homing characteristics, suggesting that MAIT cells are an important component of the human host response to bacterial infection. |
| 2016 | Cyclic ADP-Ribose and Heat Regulate Oxytocin Release via CD38 and TRPM2 in the Hypothalamus during Social or Psychological Stress in Mice. | Front Neurosci | Hypothalamic oxytocin (OT) is released into the brain by cyclic ADP-ribose (cADPR) with or without depolarizing stimulation. Previously, we showed that the intracellular free calcium concentration ([Ca(2+)]i) that seems to trigger OT release can be elevated by β-NAD(+), cADPR, and ADP in mouse oxytocinergic neurons. As these β-NAD(+) metabolites activate warm-sensitive TRPM2 cation channels, when the incubation temperature is increased, the [Ca(2+)]i in hypothalamic neurons is elevated. However, it has not been determined whether OT release is facilitated by heat in vitro or hyperthermia in vivo in combination with cADPR. Furthermore, it has not been examined whether CD38 and TRPM2 exert their functions on OT release during stress or stress-induced hyperthermia in relation to the anxiolytic roles and social behaviors of OT under stress conditions. Here, we report that OT release from the isolated hypothalami of male mice in culture was enhanced by extracellular application of cADPR or increasing the incubation temperature from 35°C to 38.5°C, and simultaneous stimulation showed a greater effect. This release was inhibited by a cADPR-dependent ryanodine receptor inhibitor and a nonspecific TRPM2 inhibitor. The facilitated release by heat and cADPR was suppressed in the hypothalamus isolated from CD38 knockout mice and CD38- or TRPM2-knockdown mice. In the course of these experiments, we noted that OT release differed markedly between individual mice under stress with group housing. That is, when male mice received cage-switch stress and eliminated due to their social subclass, significantly higher levels of OT release were found in subordinates compared with ordinates. In mice exposed to anxiety stress in an open field, the cerebrospinal fluid (CSF) OT level increased transiently at 5 min after exposure, and the rectal temperature also increased from 36.6°C to 37.8°C. OT levels in the CSF of mice with lipopolysaccharide-induced fever (+0.8°C) were higher than those of control mice. The TRPM2 mRNA levels and immunoreactivities increased in the subordinate group with cage-switch stress. These results showed that cADPR/CD38 and heat/TRPM2 are co-regulators of OT secretion and suggested that CD38 and TRPM2 are potential therapeutic targets for OT release in psychiatric diseases caused by social stress. |
| T-Lymphocyte Subset Absolute Counts in the Peripheral Blood of Mediterranean Spotted Fever Patients: Relations to Disease Severity. | Folia Med (Plovdiv) | Mediterranean spotted fever (MSF) in Bulgaria is caused by Rickettsia conorii conorii.This study aims at investigating the absolute counts of T-lymphocyte subsets in the peripheral blood of patients with MSF in order to establish relationships with disease severity.The absolute counts of T-lymphocyte subsets were tested in the blood of 62 patients in the acute stage of MSF. They were assigned into three age and sex matched groups, based on the severity of disease - with mild, moderate or severe forms. Controls were 32 age and sex matched healthy individuals. The diagnosis was confirmed by an immunofluorescence assay. Immunophenotyping was performed using Epics XL-MCL Coulter, USA flow-cytometer.The absolute counts of immune competent (CD3+) cells, as well as the counts of helper/inducer (CD3+ CD4+) and suppressor/ cytotoxic (CD3+ CD8+) T-cell subsets decreased in parallel with disease severity. Naïve (CD4+ CD45RA+) and activated memory (CD4+ CD45RO+) T-cell subsets were reduced, particularly in severe MSF. Taken as a whole, the counts of activated (CD3+ HLA-DR+) and that of presenting accessory (CD28+) or stimulatory (CD38+) molecules Т-cell subsets was increased, but in the first two subsets the trend from mild to severe forms of the disease was descending.Reduced T-lymphocyte subset counts are likely related to trans-migration into perivascular inflammatory foci. The increased number of T-lymphocytes bearing activation molecules reflects a mobilization of the cell-mediated immune response. An important issue of this study is the possible prognostic value of T-cell subsets counting, predicting the evolution of a clinical condition to clinical forms, according to the disease severity. |
| 2015 | [The clinical characteristics of twenty-five cases of acute HIV-1 infection in China]. | Zhonghua Nei Ke Za Zhi | To summarize the clinical features, immunological and virological characteristics of HIV-1 infected patients in the acute phase for the sake of improving the understanding of acute HIV-1 infection and early diagnosis.To retrospectively analyze the clinical manifestation and laboratory data of 25 patients with acute HIV infection, who were admitted to the Department of Infectious Diseases, Peking Union Medical College Hospital from 2006 to 2013.Among the total 25 patients, 19 (76%) patients were sexually transmitted, including 17 (68%) of whom were homosexual. Twenty two (88%) patients presented significant symptoms. Common symptoms consisted of fever (15 patients, 60%), cervical lymphoadenopathy (8 patients, 32%), skin rashes (6 patients, 24%), diarrhea (5 patients, 20%), shortness of breath (3 patients, 12%), sore throat (3 patients, 12%), and cough (3 patients, 12%), while only one case represented as Guillain-Barr syndrome, upper arm cellulitis, headache and vomiting, and perianal abscess. Laboratory examination indicated elevated peripheral lymphocytes (13 patients, 52%), abnormal liver function (11 patients, 44%), thrombocytopenia (1 patients, 4%). Notably, 2 patients (8%) revealed negative results of HIV antibody, who were diagnosed with positive plasma viral load. The average viral load was (4.68 ± 0.83) lg copies/ml. CD(+)(4) T cell count was 473 (343,621) cells/µl. CD(+)(8) T cell count was 1 296 (997, 2 177) cells/µl with maximal value of 7 984 cells/µl. The CD₄/CD₈ ratio was 0.33 (0.22, 0.53) including 24 (96%) patients with obvious inverted ratio. The positive rates of immune activation markers HLA-DR and CD38 on the surface of CD(+)(8) T cells were (74.9 ± 16.1) % and (84.9 ± 12.5) % respectively. The viral load had a significant positive correlation with the expression of HLA-DR and CD₃₈.The most common symptoms of acute HIV-1 infection are fever, cervical lymphadenopathy, skin rashes and diarrhea. Significantly elevated CD(+)(8) T cell count, inverted CD₄/CD₈ ratio and abnormal immune activation markers contribute to the early diagnosis of acute HIV infection. |
| 2015 | Recurrent inflammatory myofibroblastic tumor of the inguinal region: A case report and review of the literature. | Oncol Lett | Inflammatory myofibroblastic tumors (IMTs) of the inguinal region are exceptionally rare. The current study reported the case of a 49 year-old male patient with IMT, who presented with a fever, night sweats, anorexia, loss of weight and frequent urination. Computed tomography (CT) revealed a lesion occupying the soft tissue of the right inguinal region and surgery was performed to resect the lesion. Histopathological analysis of the lesion revealed a composition of spindle and inflammatory cells, including plasma cells and lymphocytes. In addition, immunohistochemical analysis demonstrated that the tumor cells were positive for CD34, vimentin, actin, Ki-67, B cell lymphoma-2, CD99, epithelial membrane antigen and CD38; however, tumor cells were negative for CD117, desmin, anaplastic lymphoma kinase and creatine kinase. Thus, the patient was diagnosed with IMT and was advised to return for regular follow-up appointments. Subsequently, the patient developed a local recurrence 12 months following the initial surgery. Of note, the histopathological characteristics of the recurrent lesions were consistent with those of the initial specimen. Thus, a second surgery was performed, followed by fractionated radiotherapy (FRT). At 3 and 6 months following the FRT, magnetic resonance imaging scans did not indicate tumor recurrence or metastasis. In conclusion, surgical excision is the current recommended treatment for IMT; however, for cases similar to that of the current study, which are not successfully controlled by surgical excision, radiotherapy should be considered and long-term follow-up is essential. |
| 2015 | Oral Wild-Type Salmonella Typhi Challenge Induces Activation of Circulating Monocytes and Dendritic Cells in Individuals Who Develop Typhoid Disease. | PLoS Negl Trop Dis | A new human oral challenge model with wild-type Salmonella Typhi (S. Typhi) was recently developed. In this model, ingestion of 104 CFU of Salmonella resulted in 65% of subjects developing typhoid fever (referred here as typhoid diagnosis -TD-) 5-10 days post-challenge. TD criteria included meeting clinical (oral temperature ≥38°C for ≥12 h) and/or microbiological (S. Typhi bacteremia) endpoints. One of the first lines of defense against pathogens are the cells of the innate immune system (e.g., monocytes, dendritic cells -DCs-). Various changes in circulating monocytes and DCs have been described in the murine S. Typhimurium model; however, whether similar changes are present in humans remains to be explored. To address these questions, a subset of volunteers (5 TD and 3 who did not develop typhoid despite oral challenge -NoTD-) were evaluated for changes in circulating monocytes and DCs. Expression of CD38 and CD40 were upregulated in monocytes and DCs in TD volunteers during the disease days (TD-0h to TD-96h). Moreover, integrin α4β7, a gut homing molecule, was upregulated on monocytes but not DCs. CD21 upregulation was only identified in DCs. These changes were not observed among NoTD volunteers despite the same oral challenge. Moreover, monocytes and DCs from NoTD volunteers showed increased binding to S. Typhi one day after challenge. These monocytes showed phosphorylation of p38MAPK, NFkB and Erk1/2 upon stimulation with S. Typhi-LPS-QDot micelles. In contrast, monocytes from TD volunteers showed only a moderate increase in S. Typhi binding 48 h and 96 h post-TD, and only Erk1/2 phosphorylation. This is the first study to describe different activation and migration profiles, as well as differential signaling patterns, in monocytes and DCs which relate directly to the clinical outcome following oral challenge with wild type S. Typhi. |
| 2015 | CD8+ T lymphocyte expansion, proliferation and activation in dengue fever. | PLoS Negl Trop Dis | Dengue fever induces a robust immune response, including massive T cell activation. The level of T cell activation may, however, be associated with more severe disease. In this study, we explored the level of CD8+ T lymphocyte activation in the first six days after onset of symptoms during a DENV2 outbreak in early 2010 on the coast of São Paulo State, Brazil. Using flow cytometry we detected a progressive increase in the percentage of CD8+ T cells in 74 dengue fever cases. Peripheral blood mononuclear cells from 30 cases were thawed and evaluated using expanded phenotyping. The expansion of the CD8+ T cells was coupled with increased Ki67 expression. Cell activation was observed later in the course of disease, as determined by the expression of the activation markers CD38 and HLA-DR. This increased CD8+ T lymphocyte activation was observed in all memory subsets, but was more pronounced in the effector memory subset, as defined by higher CD38 expression. Our results show that most CD8+ T cell subsets are expanded during DENV2 infection and that the effector memory subset is the predominantly affected sub population. |
| 2014 | Detection of acute lymphoblastic leukemia involvement in pleural fluid in an adult patient with ataxia telangiectasia by flow cytometry method. | Indian J Hematol Blood Transfus | Ataxia-telangiectasia (AT) is a rare multisystem, neurodegenerative genetic disorder. Patients should be closely monitored due to risk of malignancy development. Due to its wide clinical heterogeneity, it often leads physicians to an inaccurate or missed diagnosis, and insight into this rare disease is important. Pediatric patients may develop lymphomas and acute lymphoblastic leukemia (ALL). However, in adults, there are limited numbers of reports regarding association of AT and ALL. Rarely, ALL cases may present with pleural fluid involvement. In our study, we presented an adult case with AT, in which ALL involvement was detected in pleural fluid by flow cytometry (FC). A 20-years old male presented to emergency department with fever, shortness of breath and cough, as he had been followed with a diagnosis of AT. The following findings were detected in laboratory tests: Hb, 11.5 g/L; WBC, 36 × 10(9)/L; Plt: 140 × 10(9)/L. Blastic cells were observed in peripheral blood smear. On chest radiography, pleural fluid appearance was observed. On thorax CT, pleural fluid was detected in both hemithorax. Cytoplasmic CD3(+) and superficial CD3 (+), CD45 (+), CD5 (+), CD7 (+) and CD38 (+) was found in the flow cytometric evaluation of peripheral blood. Superficial CD3 (+), CD2 (+), CD5 (+) and CD7 (+) were found in flow cytometric evaluation of pleural fluid. These findings were considered as consistent with pleural involvement of T-ALL. FC is a potentially useful diagnostic tool for clinical practice and it is a convenience method which has an important role in detection of ALL in patients with pleural fluid. |
| 2013 | Precursor B-cell lymphoblastic leukemia with surface immunoglobulin light chain expression in 2 chinese patients. | Acta Haematol | Precursor B-cell acute lymphocytic leukemia (ALL) with surface immunoglobulin light chain expression is a rare disease entity. The differential diagnosis is difficult but critical for disease management.We report 2 cases (1 adult and 1 infant) of precursor B-cell ALL who presented at diagnosis with surface immunoglobulin light chain expression revealed by flow cytometric immunophenotyping and discuss its clinical significance.The 2 patients presented with nonspecific symptoms such as fever, pallor, fatigue or lymphadenopathy. Flow cytometric immunophenotyping showed that both patients expressed CD34/CD19/CD10/CD22/CD9/HLA-DR/CD38/CD123/CD13 (partial) and had unexpected single λ light chain expression. Cytogenetic analysis revealed t(9;22)(q34;q11) in the adult patient and normal karyotype in the infant. Both cases were diagnosed and managed as precursor B-ALL, and the patients showed good response to treatment regimens.We describe 2 cases of precursor B-ALL with unexpected surface light chain expression. The exceedingly rare immunophenotypes have diagnostic implication for immunophenotyping of this malignancy. Treatment regimens for precursor B-cell ALL are suitable for such cases. |
| 2012 | Epstein-Barr virus-negative aggressive natural killer-cell leukaemia with high P-glycoprotein activity and phosphorylated extracellular signal-regulated protein kinases 1 and 2. | Hematol Rep | Aggressive natural killer-cell leukaemia (ANKL) is a rare type of disease with fulminant course and poor outcome. The disease is more prevalent among Asians than in other ethnic groups and shows strong association with Epstein-Barr virus (EBV) and P-glycoprotein (P-gp) expression associated with multidrug resistance. Here we present a case of a 47 year old Caucasian female with a prior medical history of azathioprine treated ulcerative colitis who developed EBV-negative form of ANKL. The patient presented with hepatosplenomegaly, fever and nausea with peripheral blood and bone marrow infiltration with up to 70% of atypical lymphoid cells positive for cCD3, CD2, CD7, CD56, CD38, CD45, TIA1 and granzyme B, and negative for sCD3, CD4, CD5, CD8, CD34 and CD123 indicative of ANKL. Neoplastic CD56(+) NK-cells showed high level of P-glycoprotein expression and activity, but also strong expression of phosphorylated extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) MAP kinase. The patient was treated with an intensive polychemotherapy regimen designed for treatment of acute lymphoblastic leukaemia, but one month after admission developed sepsis, coma and died of cardiorespiratory arrest. We present additional evidence that, except for the immunophenotype, leukaemic NK-cells resemble normal NK-cells in terms of P-gp functional capacity and expression of phosphorylated ERK1/2 signalling molecule. In that sense drugs that block P-glycoprotein activity and activated signalling pathways might represent new means for targeted therapy. |
| 2011 | Dengue-2 and yellow fever 17DD viruses infect human dendritic cells, resulting in an induction of activation markers, cytokines and chemokines and secretion of different TNF-α and IFN-α profiles. | Mem Inst Oswaldo Cruz | Flaviviruses cause severe acute febrile and haemorrhagic infections, including dengue and yellow fever and the pathogenesis of these infections is caused by an exacerbated immune response. Dendritic cells (DCs) are targets for dengue virus (DENV) and yellow fever virus (YF) replication and are the first cell population to interact with these viruses during a natural infection, which leads to an induction of protective immunity in humans. We studied the infectivity of DENV2 (strain 16681), a YF vaccine (YF17DD) and a chimeric YF17D/DENV2 vaccine in monocyte-derived DCs in vitro with regard to cell maturation, activation and cytokine production. Higher viral antigen positive cell frequencies were observed for DENV2 when compared with both vaccine viruses. Flavivirus-infected cultures exhibited dendritic cell activation and maturation molecules. CD38 expression on DCs was enhanced for both DENV2 and YF17DD, whereas OX40L expression was decreased as compared to mock-stimulated cells, suggesting that a T helper 1 profile is favoured. Tumor necrosis factor (TNF)-α production in cell cultures was significantly higher in DENV2-infected cultures than in cultures infected with YF17DD or YF17D/DENV. In contrast, the vaccines induced higher IFN-α levels than DENV2. The differential cytokine production indicates that DENV2 results in TNF induction, which discriminates it from vaccine viruses that preferentially stimulate interferon expression. These differential response profiles may influence the pathogenic infection outcome. |
| 2011 | Primary effusion lymphoma associated with Human Herpes Virus-8 and Epstein Barr virus in an HIV-infected woman from Kampala, Uganda: a case report. | J Med Case Rep | Primary effusion lymphoma is a recently recognized entity of AIDS related non-Hodgkin lymphomas. Despite Africa being greatly affected by the HIV/AIDS pandemic, an extensive MEDLINE/PubMed search failed to find any report of primary effusion lymphoma in sub-Saharan Africa. To our knowledge this is the first report of primary effusion lymphoma in sub-Saharan Africa. We report the clinical, cytomorphologic and immunohistochemical findings of a patient with primary effusion lymphoma.A 70-year-old newly diagnosed HIV-positive Ugandan African woman presented with a three-month history of cough, fever, weight loss and drenching night sweats. Three weeks prior to admission she developed right sided chest pain and difficulty in breathing. On examination she had bilateral pleural effusions.Haematoxylin and eosin stained cytologic sections of the formalin-fixed paraffin-embedded cell block made from the pleural fluid were processed in the Department of Pathology, Makerere University, College of Health Sciences, Kampala, Uganda. Immunohistochemistry was done at the Institute of Haematology and Oncology "L and A Seragnoli", Bologna University School of Medicine, Bologna, Italy, using alkaline phosphatase anti-alkaline phosphatase method. In situ hybridization was used for detection of Epstein-Barr virus.The tumor cells were CD45+, CD30+, CD38+, HHV-8 LANA-1+; but were negative for CD3-, CD20-, CD19-, and CD79a- and EBV RNA+ on in situ hybridization. CD138 and Ki-67 were not evaluable. Our patient tested HIV positive and her CD4 cell count was 127/μL.A definitive diagnosis of primary effusion lymphoma rests on finding a proliferation of large immunoblastic, plasmacytoid and anaplastic cells; HHV-8 in the tumor cells, an immunophenotype that is CD45+, pan B-cell marker negative and lymphocyte activated marker positive. It is essential for clinicians and pathologists to have a high index of suspicion of primary effusion lymphoma when handling HIV positive patients who have effusions without palpable tumor masses. Basic immunohistochemistry is essential for definitive diagnosis. |
| 2010 | Timing of CD8+ T cell responses in relation to commencement of capillary leakage in children with dengue. | J Immunol | Immune activation is a feature of dengue hemorrhagic fever (DHF) and CD8+ T cell responses in particular have been suggested as having a role in the vasculopathy that characterizes this disease. By phenotyping CD8+ T cells (CD38+/HLA-DR+, CD38+/Ki-67+, or HLA-DR+/Ki-67+) in serial blood samples from children with dengue, we found no evidence of increased CD8+ T cell activation prior to the commencement of resolution of viremia or hemoconcentration. Investigations with MHC class I tetramers to detect NS3(133-142)-specific CD8+ T cells in two independent cohorts of children suggested the commencement of hemoconcentration and thrombocytopenia in DHF patients generally begins before the appearance of measurable frequencies of NS3(133-142)-specific CD8+ T cells. The temporal mismatch between the appearance of measurable surface activated or NS3(133-142)-specific CD8+ T cells suggests that these cells are sequestered at sites of infection, have phenotypes not detected by our approach, or that other mechanisms independent of CD8+ T cells are responsible for early triggering of capillary leakage in children with DHF. |
| 2010 | Maxillofacial mass as the first presentation of acute lymphoblastic leukemia in a nine-year-old girl. | Auris Nasus Larynx | A nine-year-old girl complained of a maxillofacial mass and mild fever lower than 37.5 degrees C. A solid mass was detected in the right maxillary fossa by CT and sonographic examination, and the tumor extended backward into the infratemporal fossa without bony destruction. Laboratory studies showed a white blood cell (WBC) count of 31.6x10(9)/L, which increased progressively to 50.0x10(9)/L over the next several days. Peripheral blood smear revealed 92% lymphoblast with uneven bulk. A biopsy through the right labiogingival groove disclosed a submucosal homogeneous mass. Histologic examination under the microscope revealed atypical mononuclear cells with obvious atypia and nuclear divisions. Bone marrow puncture showed atypical lymphocytes with active proliferation. Immune phenotypic analysis by flow cytometry showed that malignant cells were positive for CD19, CD34, HLA-DR, CD38, CD22, CD58, CD45 and CD56. Real time RT-PCR revealed positive BCR/ABL arrangement. High-risk ALL was diagnosed and four stages of chemotherapies were given for nearly three years. After the induction of the chemotherapy, the facial mass disappeared. A bone marrow biopsy revealed that CR had been achieved since a month after chemotherapy's onset. The initial presentation of ALL as a maxillofacial mass is exceedingly rare. To the best of the authors' knowledge, this is the first reported case of ALL presenting as a maxillofacial lesion. |
| 2009 | [High-dose methylprednisolone for the treatment of refractory chronic lymphocytic leukemia]. | Zhongguo Shi Yan Xue Ye Xue Za Zhi | To investigate the curative effects of high-dose methylprednisolone (HDMP) in the treatment of refractory chronic lymphocytic leukemia (CLL), 5 patients with CLL who poorly reacted to several cycles of fludarabine based protocols with or without rituximab were treated with 1 to 6 cycles of HDMP with 1 g/(m(2)xd) for d1-5. All the patients were at Binet stage C. 3 patients were at Rai stage IV and 2 were at Rai stage III. 2 patients were diagnosed as Richter syndrome. CD38 and ZAP-70 were expressed in 5 and 3 patients respectively. All the patients developed with B group symptoms including fever, night sweat and/or weight loss and so on. Clinical manifestations and complete blood cell count, peripheral blood smear, bone marrow aspirate, hepatic and renal function, blood serum electrolytes, blood glucose were examined, CD5(+)CD19(+) lymphocytes of peripheral blood and bone marrow were determined by flow cytometry. The results showed that B group symptoms disappeared in 4 patients at 2 - 4 weeks after therapy. The size of enlarged lymph nodes was reduced in all the 5 patients. In 1 patient spleen was not palpable from 10 cm below costal margin at 2 weeks after therapy, and his hemafecia was alleviated. The renal function in another patient with renal failure recovered to normal after two cycles of therapy. Pancytopenia improved in 3 patients after therapy. CD5(+)CD19(+) lymphocytes decreased in all the patients. 4 patients acquired partial remission and 1 patient acquired stable status of disease. The side effects became mild. In conclusion, the therapeutic results preliminarily show that HDMP is an effective and safe protocol for the treatment of refractory CLL. |
| 2009 | TLR expression and NK cell activation after human yellow fever vaccination. | Vaccine | The yellow fever vaccine is very effective with a single injection conferring protection for at least 10 years. Recent evidence suggests that the innate immune cells activated through Toll-like receptors (TLRs), are critical determinants of the robustness of the adaptive response. Therefore, we investigated the NK cell status in eight healthy volunteers after vaccination with YF 17DD virus. Shortly after vaccination, we observed increased expression of TLR-3 and TLR-9 in NK cells and markers such as CD69, HLA-DP-DQ-DR, CD38 and CD16. The up-regulation of CD69 was positively correlated with the presence of TLRs throughout the post-vaccination period and the circulating IFN-gamma was significantly augmented. These results suggest that TLRs may play an important role in NK cell activation during the immune response to vaccination, indicating a potential role for NK cells in helping the development of long-lasting protective memory. |
| 2007 | [Evaluation for two-year highly active antiretroviral therapy in Chinese HIV-1 infection patients]. | Zhonghua Yi Xue Za Zhi | To observe that antiretroviral efficacy, immune reconstitution of two-year HAART, and evaluate its side effect in Chinese HIV-1-infected patients.Three drug regimen composed of didanosine (ddI), stavudine (d4T), and nevirapine (NVP) was used on 27 HIV-1 infected patients, Within 2 weeks before treatment, and 3, 6, 12, 18, and 24 months after the beginning of treatment peripheral blood samples were collected to measure the HIV-RNA viral load (VL) by fluorescent quantitative polymerase chain reactions (FQ-PCR), and the counts of CD3+CD4+ cells, CD3+CD8+ cells, CD4+CD45RA+CD62L+ cells, CD4+CD45RO+ cells, CD8+CD38+ cells, and CD8+CD38+/CD3+CD8+ percentage. The side effects, blood routine, main biochemical parameters, and other disadvantageous accidents were monitored during the 24-mouth treatment period. 17 males and 10 females, aged 33 +/- 11. Thirty-one sex- and age-matched healthy persons were used as controls.FQ-PCR showed that the plasma HIV-1 RNA levels 2 weeks before treatment, and 3, 6, 12, 18, and 24 months after the beginning of treatment were 5.15 logs (copies/ml), 3.37 logs, 2.24 logs, 2.02 logs, 1.97 logs, and 2.15 logs respectively. 24 months after the treatment. In 56.6% (13/24) of the patients the HIV-1 VL was < 50 copies/ml 24 months after treatment, and the counts of CD3+CD4+ cells, CD4+CD45RA+62L+ cells (nave cells), and CD4+CD45RO+ cells (memory cells) 24 months after treatment were (317 +/- 175) cells/microl, (133 +/- 65) cells/microl, and (207 +/- 85) cells/microl respectively, all significantly hoi/higher than the baseline levels [(185 +/- 73) cells/microl, (51 +/- 21) cells/microl, and (115 +/- 57) cells/microl respectively]. And the CD3+CD8+ cell count, CD8+CD38+ cell count, and CD8+CD38+/CD3+CD8+ percentage decreased from (907 +/- 435) cells/microl, (614 +/- 299) cells/microl, and 67.7% to (775 +/- 303) cells/microl, (385 +/- 131) cells/microl, and 49.7% respectively, with the lowest values in the months 3 and 6. But by the month 24, all of the parameters failed to reach the normal level. 19 of the 27 patients had side effects, such as peripheral polyneuropathy, various rashes, central nervous system disorders, abdominal pain, fullness or bloating, fever, and baldness, 21 showed abnormalities in blood routine, liver function, renal function, or lipid tests and increased gamma glutamyl transferase (GGT) and amylase. The regimen had to be changed for 3 of these patients because of paresthesia and suspected lactic acidosis.The regimen with ddI, d4T and NVP foe 24 months showed a good antiretroviral effect and immune reconstitution on the HIV-1 infected persons. However, there are side effects, especially in the respect of gastrointestinal disorder and peripheral neuritis, decrease of WBC and increase of GGT and amylase. |
| 2007 | Activation/modulation of adaptive immunity emerges simultaneously after 17DD yellow fever first-time vaccination: is this the key to prevent severe adverse reactions following immunization? | Clin Exp Immunol | Over past decades the 17DD yellow fever vaccine has proved to be effective in controlling yellow fever and promises to be a vaccine vector for other diseases, but the cellular and molecular mechanisms by which it elicits such broad-based immunity are still unclear. In this study we describe a detailed phenotypic investigation of major and minor peripheral blood lymphocyte subpopulations aimed at characterizing the kinetics of the adaptive immune response following primary 17DD vaccination. Our major finding is a decreased frequency of circulating CD19+ cells at day 7 followed by emerging activation/modulation phenotypic features (CD19+interleukin(IL)10R+/CD19+CD32+) at day 15. Increased frequency of CD4+human leucocyte antigen D-related(HLA-DR+) at day 7 and CD8+HLA-DR+ at day 30 suggest distinct kinetics of T cell activation, with CD4+ T cells being activated early and CD8+ T cells representing a later event following 17DD vaccination. Up-regulation of modulatory features on CD4+ and CD8+ cells at day 15 seems to be the key event leading to lower frequency of CD38+ T cells at day 30. Taken together, our findings demonstrate the co-existence of phenotypic features associated with activation events and modulatory pathways. Positive correlations between CD4+HLA-DR+ cells and CD4+CD25high regulatory T cells and the association between the type 0 chemokine receptor CCR2 and the activation status of CD4+ and CD8+ cells further support this hypothesis. We hypothesize that this controlled microenviroment seems to be the key to prevent the development of serious adverse events, and even deaths, associated with the 17DD vaccine reported in the literature. |
| 2007 | The sample processing time interval as an influential factor in flow cytometry analysis of lymphocyte subsets. | Mem Inst Oswaldo Cruz | The objective of this paper is to propose a protocol to analyze blood samples in yellow fever 17DD vaccinated which developed serious adverse events. We investigated whether or not the time between sample collection and sample processing could interfere in lymphocyte subset percentage, for it is often impossible to analyze blood samples immediately after collection due to transport delay from collection places to the flow cytometry facility. CD4+CD38+ T, CD8+CD38+ T, CD3+ T, CD19+ B lymphocyte subsets were analyzed by flow cytometry in nine healthy volunteers immediately after blood collection and after intervals of 24 and 48 h. The whole blood lysis method and gradient sedimentation by Histopaque were applied to isolate peripheral blood mononuclear cells for flow cytometry analyses. With the lysis method, there was no significant change in lymphocyte subset percentage between the two time intervals (24 and 48 h). In contrast, when blood samples were processed by Histopaque gradient sedimentation, time intervals for sample processing influenced the percentage in T lymphocyte subsets but not in B cells. From the results obtained, we could conclude that the whole blood lysis method is more appropriate than gradient sedimentation by Histopaque for immunophenotyping of blood samples collected after serious adverse events, due to less variation in the lymphocyte subset levels with respect to the time factor. |
| 2005 | Lymphocyte subset analyses in healthy adults vaccinated with yellow fever 17DD virus. | Mem Inst Oswaldo Cruz | In this study the kinetics of humoral and cellular immune responses in first-time vaccinees and re-vaccinees with the yellow fever 17DD vaccine virus was analyzed. Flow cytometric analyses were used to determine percentual values of T and B cells in parallel to the yellow fever neutralizing antibody production. All lymphocyte subsets analyzed were augmented around the 30th post vaccination day, both for first-time vaccinees and re-vaccinees. CD3+ T cells increased from 30.8% (SE +/- 4%) to 61.15% (SE +/- 4.2%), CD4+ T cells from 22.4% (SE +/- 3.6%) to 39.17% (SE +/- 2%) with 43% of these cells corresponding to CD4+CD45RO+ T cells, CD8+ T cells from 15.2% (SE +/- 2.9%) to 27% (SE +/- 3%) with 70% corresponding to CD8+CD45RO+ T cells in first-time vaccinees. In re-vaccinees, the CD3+ T cells increased from 50.7% (SE +/- 3%) to 80% (SE +/- 2.3%), CD4+ T cells from 24.9% (SE +/- 1.4%) to 40% (SE +/- 3%) presenting a percentage of 95% CD4+CD45RO+ T cells, CD8+ T cells from 19.7% (SE +/- 1.8%) to 25% (SE +/- 2%). Among CD8+CD38+ T cells there could be observed an increase from 15 to 41.6% in first-time vaccinees and 20.7 to 62.6% in re-vaccinees. Regarding neutralizing antibodies, the re-vaccinees presented high titers even before re-vaccination. The levels of neutralizing antibodies of first-time vaccinees were similar to those presented by re-vaccinees at day 30 after vaccination, indicating the success of primary vaccination. Our data provide a basis for further studies on immunological behavior of the YF 17DD vaccine. |
| Assessment of selected co-stimulatory, adhesion and activatory molecules and cytokines of Th(1)/Th(2) balance in acute lymphoblastic leukemia in children. | Arch Immunol Ther Exp (Warsz) | Recent years have seen a rise in the importance of cytokine production and co-stimulatory/activatory molecule expression in the immune response in leukemia. The aim of our study was to assess the function of T lymphocytes in children with acute lymphoblastic leukemia (ALL) during remission induction based on selected cytokine and co-stimulatory/activatory molecule expression.The study group consisted of 50 children with ALL (B cell precursor). Peripheral blood samples were taken before treatment (day 0), after the prednisone prophase (day 8), and during (day 15) and after (day 33) remission induction. The percentages of T cells with interferon (IFN)-gamma (Th(1)), interleukin (IL)-4 (Th(2)) and IL-2 receptor (IL-2R), CD28, CTLA-4, CD38, ICAM-1, and HLA-DR expression were assessed by tricolor flow cytometry.At the time of diagnosis we noted higher percentages of T cells with adhesion molecule ICAM-1, activation molecule CD38 expression, and an increased population of Th(2 )cells (IL-4) compared with the control group. During and after remission induction we observed a decreased population of CD38(+) T cells, elevated percentages of helper T lymphocytes with IL-2R expression, and a rise in helper T lymphocytes producing IFN-gamma (Th(1)). During fever/infection, higher levels of activated T lymphocytes (CD4(+)HLA-DR(+), CD8(+)HLA-DR(+)), a rise in Th1, and no change in Th(2 )populations were observed.The results suggest T cell activation and Th(2 )predominance at the time of diagnosis and during remission induction in ALL in children. These results confirm the involvement of cellular immunity in the leukemic process and can be used in immune therapy in leukemia. |
| 2004 | [Costimulatory and activation molecules of lymphocytes T in acute lymphoblastic leukemia in children]. | Przegl Lek | In the last years one rises importance of costimulatory molecules in immune response in leukemias. Aim of the study was to assess lymphocytes T function in children with acute lymphoblastic leukemia during remission induction on the grounds of chosen costimulatory and activatory molecules expression. To assess percentages of lymphocytes subpopulations we used tricolor flow cytometry.1. In the moment of diagnosis and remission induction we noted higher percentages of lymphocytes T with adhesion molecule ICAM-1; 2. During remission induction we observed lower percentage values of lymphocytes T with CD38 coexpression; 3. In the end of remission induction rised the percentage values of lymphocytes T helper with IL-2 receptor expression; 4. In the group of patients with fever/infection we observed higher percentage of activated lymphocytes T (CD3-HLA-DR) comparing to non-infected patients. Summarizing, we suggest lymphocytes T activation during appearance and remission induction of acute lymphoblastic leukemia in children. This confirms participation of cellular immunity in leukemic process. |
| 2003 | A case of HLA-DR negative B-precursor acute lymphoblastic leukemia. | J Exp Clin Cancer Res | We present the case of a 9-year-old girl from northwestern Greece admitted to our Hospital because of malaise, low-grade fever, intermittent hip joint pain, anemia, leukopenia and thrombocytopenia. The examination of a bone marrow aspirate revealed the predominance of blast cells (97%) with FAB L1 morphology, immunopheno-typically positive for CD19 (95%), CD10 (95%), CD22 (95%), CD13 (82%), CD34 (95%) and CD38 (72%), with dim expression of CD45 and of the intracellular antigen terminal deoxynucleotidyl transferase (Tdt). Only 10% of the blasts expressed HLA-DR. Staining for CD2, CD3, CD5, CD7, CD20, CD23, CD33, CD14, CD15, AC133 and KOR-SA3544 was negative. Blast cells were lacking surface immunoglobulin expression and bcr/abl rearrangements were not detected. Cell cycle analysis revealed a diploid cell population. Karyotypic abnormalities were not identified. The lack of expression of HLA-DR and the presence of myeloid antigen CD13 indicated that it was a rare case of B-precursor ALL with aberrant immunophenotypic characteristics. |
| 2003 | B-cell lymphoproliferative syndrome and peripheral blood CD20+ cells expansion after hematopoietic stem cell transplantation: association with fludarabine and anti-thymocyte globulin containing conditioning regimen. | Transplant Proc | Fifty-eight patients who received hematopoietic stem cell transplants during a 3-year period in our unit were followed for the symptoms of posttransplant B-cell lymphoproliferative syndrome (B-cell PTLD). Three cases showed lymph node enlargement; in 14, there was an excess of B cells in the blood. Histochemical staining of lymph nodes revealed CD20+ cell expansion in two cases, and in one, CD38+ and CD138+ cells. Kappa and lambda staining revealed poly- or oligoclonal expansion, which was characterized by the presence of Ki67+ cells in 10% to 50% of cells. In 14 cases, an excess of CD20+ cells were observed in blood. Clinical analysis revealed that patients with B-cell expansion in blood and/or in lymph nodes frequently showed fever and that some subjects displayed arthralgia, hemolytic anemia, and hepatitis. LMP-1-positive cells were observed in lymph nodes as well as EBV copies, whereas only a proportion of patients with the excessive CD20+ cells in blood were EBV positive. Notably, lymph node enlargement and CD20+ blood excess occurred significantly more frequently among patients receiving a Fludarabine (Flu) and anti-thymocyte globulin (ATG) conditioning regimen than those whose treatment lacked Flu independent of whether they received ATG (0.80 vs 0.44; P =.036). |
| 2003 | High-dose epirubicin, preceded by dexrazoxane, given in combination with paclitaxel plus filgrastim provides an effective mobilizing regimen to support three courses of high-dose dense chemotherapy in patients with high-risk stage II-IIIA breast cancer. | Bone Marrow Transplant | We verified the possibility of collecting large amounts of peripheral blood stem cells (PBSCs) to support three courses of adjuvant high-dose dense chemotherapy (HDDC) with high-dose epirubicin, preceded by dexrazoxane, and high-dose paclitaxel, in patients with high-risk breast cancer (>/=9 positive nodes). The mobilizing regimen consisted of high-dose epirubicin 150 mg/m(2), preceded by dexrazoxane 1000 mg/m(2) (day 1), given in combination with paclitaxel 175 mg/m(2) (day 2), plus filgrastim. Of the 25 patients enrolled, one went off study due to a severe hypersensitivity reaction to paclitaxel, another did not undergo leukapheresis due to fever persistent after hematological recovery, while in 23 patients an adequate number of PBSCs was collected by a single leukapheresis. The median number of CD34+, CD34+/CD33-, and CD34+/CD38- cells collected per patient was 17 x 10(6)/kg, 13.4 x 10(6)/kg, and 1.5 x 10(6)/kg, respectively. Neutropenia was the only grade 4 toxicity and lasted a median of 3 days. High-dose epirubicin, preceded by dexrazoxane for the first time used in mobilizing regimen, and paclitaxel plus filgrastim are effective in releasing large amounts of PBSCs, which can then be safely employed to support multiple courses of HDDC. |
| 2002 | Aggressive primary plasma cell leukemia with skin manifestations, trisomy 8 and molecular oligoclonal features. | Leuk Lymphoma | Plasma cell leukemia (PCL) is a very rare variant of multiple myeloma (MM) occurring in about 2% of newly diagnosed patients. Plasma cell leukemia may develop during the course of MM (secondary PCL) or it can occur without any prior sign of MM (primary PCL). We report a case of aggressive primary PCL with unusual clinical, cytogenetic and molecular features. A 36-year-old male patient was first seen because of fever and bone pain. On the skin of his chest, back, abdomen, and palpebras, there were nodular infiltrations resembling urticaria. White blood cell count was 10.8 x 10(9)/l with 41% plasmacytes. Bone marrow aspiration was hypercellular, 93.5% of cells were atypical plasmacytes and plasmablasts. The cytogenetic analysis of G-banded chromosomes in bone marrow cells yielded the trisomy 8. The skin biopsy specimen showed intensive infiltrates of uninucleated blastic cells similar to those found in the bone marrow. Immunophenotyping of bone marrow and skin neoplastic cells showed CD45+, CD45Ro+, CD68+, CD38+ and cytoplasmic kappa light chain +. The neoplastic cells stained negatively for lambda light chain, CD3, CD20, CD30, EMA, CD15, CD34, CD56 and factor VIII. The pattern of IgL genes rearrangement in the bone marrow aspirate, peripheral blood mononuclear cells, and skin specimens was examined by PCR analysis. All studied specimens showed three different IgK gene configurations suggesting that the neoplastic cells originated as a result of oligoclonal lymphoproliferation process. The patient received two courses of VAD (vincristine, doxorubicin, dexamethasone) without improvement and three courses of CHOP with only temporary stabilization of the disease. He died 5 months after the diagnosis of PCL because of disease progression and pneumonia. |
| 2000 | [Aggressive transformation and extramedullary tumor formation in IgA-lambda multiple myeloma]. | Rinsho Ketsueki | A 52-year-old woman complained of lower back pain and gluteal pain in April 1997, and was found to have anemia, hypercalcemia and renal disorder. In September of the same year, she was diagnosed as having IgA-lambda myeloma (stage IIIA). VMMD-IFN therapy was started in November, 1997, and this resulted in improvement of the M-protein level, and relief of the pain in the lower back and gluteal region. A second course of VMMD-IFN therapy was also effective. In April 1998, however, the back pain worsened, and in July the patient suffered a fall and fractured her left femur. Upon readmission to our hospital, the level of M-protein was lower, and high fever, hypercalcemia, renal disorder, elevation of the LDH level, anemia and thrombocytopenia were observed. Bone marrow examination revealed 30% atypical large-sized CD19-, CD38+, CD56+ myeloma cells and chromosomal abnormalities. Although the symptoms were improved temporarily after a third course of VMMD therapy, disease aggravation occurred again, and extramedullary masses appeared on the head, face and pelvis. VAD therapy was performed without effect, and the patient died about 2 months after recurrence. This was a comparatively rare case of fulminant multiple myeloma occurring in the terminal stage. |
| 1998 | Randomized, controlled phase II trial of subcutaneous interleukin-2 in combination with highly active antiretroviral therapy (HAART) in HIV patients. | AIDS | To determine the immunological, virological and clinical effects of subcutaneous IL-2 in 44 HIV-patients in conjunction with pre-existing tri-therapy (zidovudine, 3TC, saquinavir).Partially randomized, controlled, prospective trial.Single center study at tertiary care center.Sixty four patients (CD4 count 200-500 x 10(6)/l).Fourty four patients were randomized to receive 5-day cycles of IL-2 (9 Mio IU/d) every 6 weeks (Group A) or whenever the CD4 cell count dropped below the 1.25-fold of baseline (Group B), whereas 20 control patients received the same HAART without IL-2.The optimal individual treatment interval and the immunological and virological effects of subcutaneously administered IL-2 were analysed. Importantly, the level of cellular in vivo immunity and the frequency of dermatological marker diseases and infectious complications were assessed.IL-2 was well tolerated although fever, influenza-like symptoms and indurated injection sites were commonly encountered. After 1 year of IL-2, there was a median increase of more than 100 x 10(6)/l CD4 cells in both IL-2 groups in contrast to the controls (P < 0.01, 0.01 and not significant). The median HIV load did not increase either in plasma or in lymph nodes. Lymphocyte activation decreased as assessed by MHC class II (P < 0.001), CD25 (P < 0.001) and CD38 expression (P < 0.005). Although delayed type hypersensitivity against common recall antigens increased in both IL-2 groups, it did not reach statistical significance. However, it is of note, that in 7 of 11 (63.6%) patients delayed type hypersensitivity against recombinant HIV antigens improved significantly. Whereas there was no opportunistic infection in either IL-2 group, three cases of Kaposi's sarcoma occurred in the controls. Dermatological indicator diseases (thrush, condyloma, herpes simplex) were found to occur more frequently in the control group.Subcutaneous IL-2 in addition to HAART was safe and led to sustained qualitative and quantitative immunological improvements in the majority of patients. Individualisation of therapy intervals further improved the efficacy and tolerance of IL-2. |
| 1995 | Characterization and transfusion of in vitro cultivated hematopoietic progenitor cells. | Transfus Sci | Our study is to show the safety of transfusion and the number, phenotype, and proliferative potential of in vitro cultivated autologous hematopoietic peripheral blood progenitor/stem cells (PBPCs). An in vitro long-term liquid culture using PBPC suspension from consenting patients with metastatic breast cancer was established. The medium was supplemented with a variety of hematopoietic growth factors. The mononuclear cells (MNCs), their viability, CD34+ subsets, clonogenic cells, and neutrophil function were measured prior to, during, and after liquid culture for 14 days. The total cell number increased during incubation in vitro from 2.5 x 10(8) to 5 x 10(9). The clonogenic and CD34+ cells increased during the first week 6- and 3.5-fold, respectively, and were almost undetectable after 2 weeks. Maturation into the myeloid cell series was demonstrated by standard cytology and increase of CD33+ and CD38+ cell numbers. On average, 1.5 x 10(9) cells were transfused to consenting patients with metastatic breast cancer after high-dose chemotherapy and PBPC transplantation at nadir of WBC < or = 0.1/nL. One hour later, the mean WBC was measurable at 0.3/nL. Subsequently, WBC counts dropped to 0.2/nL and 0.1/nL at 6 and 24 h post transfusion. No side effects and complications were observed. In summary, an in vitro expansion can produce a > or = 20-fold increase of maturing PBPCs for an effective and safe autologous transfusion. This unique approach, when refined, could lead to a safer post-transplant period and a decrease of complications due to neutropenic fever. |
| 1994 | Immunological abnormalities in patients with chronic fatigue syndrome. | Scand J Immunol | Between January 1991 and January 1993, 265 patients who fulfilled the CDC criteria of the working case definition of Chronic Fatigue Syndrome (CFS) have been observed at our Institution and submitted for clinical and laboratory evaluation. One hundred and sixty-three patients were females and 102 males, the median age was 35 years (range 4-55 years); all patients reported profound and prolonged fatigue, lasting for a median of 3 years (range 6 months-10 years), preceded or accompanied at appearance by fever in 185 cases, and neuropsychologic problems including inability to concentrate, difficulty in thinking, confusion, irritability, forgetfulness, and depression. The fatigue was so severe that it required 102 patients to stop their working activities for a period of time ranging from 3 months to 2 years (range 7 months). In 40 consecutive patients a comprehensive immunologic testing by single and two-colour flow cytometry was performed and results compared with a group of 35 healthy, age- and sex-matched controls. Whilst no significant differences were found in the absolute numbers of circulating total T cells (CD3+) and of total helper/inducer (CD4+) or suppressor/cytotoxic (CD8+) T cells, an evident reduction in CD3-/CD16+ and CD57+/CD56+ NK lymphocytes along with an expansion of the CD8+/CD56+ and CD16-/CD56+ NK subsets, were found in the CFS group. In addition, CD56+ NK cells from CFS subjects were found to express an increased amount of cell adhesion molecules (CD11b, CD11c, CD54) and activation antigens (CD38). Both the percentage and absolute numbers of CD4+ T cells bearing the CD45RA antigen appeared significantly reduced in CFS patients, and CD4+ T lymphocytes from CFS subjects displayed an increased expression of the intercellular adhesion molecule-1 (ICAM-1/CD54). Finally, the total numbers of circulating (CD19+) B lymphocytes, were significantly higher in CFS cases than in controls, and in 11 out of 30 CFS patients the increase in circulating B cells was sustained by the expansion of the CD5+/CD19+ subset of B lymphocytes. We conclude that CFS is a syndrome not previously described in Italy, with already known clinical characteristics and appears to be associated with several immunologic abnormalities, including those reported previously in cohort of patients from different countries. We also show for the first time that CD56- NK cell subsets from CFS patients display an abnormally increased expression of cell adhesion molecules and activation markers. |
| 1992 | Gamma delta T cells and the immune response in visceral leishmaniasis. | Eur J Immunol | Visceral leishmaniasis (VL) caused by Leishmania donovani, a protozoan parasite, is a disease of high morbidity associated with hepatosplenomegaly, hypergammaglobulinemia, fever and death. One of the immunological hallmarks of VL is a remarkable increase in serum immunoglobulin levels as a result of polyclonal B cell activation. This study demonstrated that T lymphocytes expressing the T cell receptors (TcR) gamma delta in association with CD3 molecules are increased in circulation of patients with VL. A large proportions of TcR gamma delta-bearing T cells had CD4+ CD8- phenotype, and expressed CD25, CD38, CD71 and HLA-DR activation antigens. Furthermore, we demonstrated wide functional differences in TcR gamma delta and TcR alpha beta T cells in their proliferative response, secretion of interleukin-2 (IL-2), B cell growth factor (BCGF) and B cell differentiation factor (BCDF). It was of interest that the TcR gamma delta T cells from patients with VL could be expanded by in vitro culture with human recombinant IL-2. Although these TcR gamma delta T cells secreted diminished levels of IL-2, they produced highly augmented levels of both BCGF and BCDF, suggesting that secretion of these lymphokines in these T cell subsets is regulated independently. The relative increases in the CD4+ CDw29+ TcR gamma delta T cell subsets and their secretion of highly elevated levels of BCGF and BCDF largely accounted for the humoral immune system abnormality and hypergammaglobulinemia found in this disease. These observations may help to explain that TcR gamma delta T cells might be functional in vivo and are involved in immunological mechanisms of pathogenesis in VL. |
| 1992 | [CD3-negative natural killer cell leukemia with aggressive clinical course]. | Rinsho Ketsueki | The authors report an autopsy case of CD3- large granular cell leukemia with an aggressive clinical course. A 15-year-old male was admitted to our hospital with complaint of high fever. Clinical examination revealed cervical lymphadenopathy and hepatosplenomegaly. His white blood cell count was 7,000/microliters with 45% large granular lymphocytes. A biopsy specimen of the cervical lymph node showed diffuse lymphoma, mixed small and large cells (DM). Surface marker analysis by immunohistochemical technique revealed that neoplastic cells expressed CD2, CD38, CD56 and HLA-DR but lacked CD3, CD4 and CD8. Southern blot analysis of immunoglobulin (Ig) and T cell receptor (TCR) genes showed germ line of Ig and TCR. These findings indicate that this case was a large granular cell leukemia with the natural killer cell phenotype. Despite anti-leukemic therapy, he died of hyperkalemia and acidosis. Autopsy showed a marked swelling of the liver (3,122 g) and spleen (2,434 g) with leukemic cell infiltration. |
| 1990 | [Mollaret benign recurrent aseptic meningitis. Case report, results of cerebrospinal fluid cytology and review of the literature]. | Nervenarzt | Mollaret's recurrent aseptic meningitis is a rare disease of unknown etiology and excellent prognosis, characterized by short attacks of meningeal irritation, fever and pleocytosis with first polymorphonuclear, then mononuclear predominance. A case is reported, in which the characteristic so-called endothelial cells in the CSF were identified as monocytes with immunocytochemic methods. The remaining fraction of CSF cells mainly consisted of T-lymphocytes with a majority of CD4 positive cells and an increased portion of CD38 positive cells. Between attacks, patients are asymptomatic. The course is self-limiting. Specific treatment is unknown. |
| 1989 | [Germ-line configuration of the immunoglobulin heavy chain gene in a case of B cell precursor acute lymphoblastic leukemia]. | Rinsho Ketsueki | A 20-year-old man was admitted to our hospital because of fever and knee joint pain on March 20, 1986. Physical examination revealed generalized lymphadenopathy and hepatomegaly. White blood cell count was 32,800 microliters with 74.4% blast cells. Bone marrow was hypercellular with 93.6% blast cells. Blast cells were weakly positive for acid phosphatase and PAS stainings but were negative for peroxidase, sudan black B and esterase stainings. Cell surface marker analysis of blast cells disclosed that they were positive for anti-HLA-DR, CD19, CD24, CD33 and CD38, but were negative for CD10 and CD20. Cytoplasmic immunoglobulin of blast cells was negative and TdT activity by immunofluorescent method was positive. Chromosomal analysis of bone marrow samples revealed normal karyotype. Therefore, this case was diagnosed as having acute lymphoblastic leukemia (L2) and achieved complete remission with LVP therapy consisting of 1-asparaginase, vincristine and prednisolone. Gene analysis of blast cells disclosed germ-line configuration of both the immunoglobulin heavy chain gene and T cell receptor beta chain gene. We speculated that the phenotype of leukemic cells might precede the genotype in some cases of acute leukemia. |
| 1988 | T lymphocyte subsets in Mediterranean spotted fever. | Acta Trop | Several studies have previously suggested the possible role of a T lymphocyte suppressor population in infections by species of the genus Rickettsia. In 15 patients with Mediterranean spotted fever (MSF), we quantified, during the acute and convalescent phases of the disease, the peripheral blood lymphocyte populations using monoclonal antibodies that recognize CD3+, CD4+, CD8+, CD38+ and CD20+ cells. In three cases a reversal in the normal ratio of T lymphocyte helper-inducer/suppressor-cytotoxic subsets was detected lasting, in two of them, up to the fifth week of the disease. This disturbance was always weak and lacked clinical significance. |