ABSTRACT
Pancreatic islet inflammation plays a crucial role in the etiology of type 2 diabetes (T2D). Macrophages residing in pancreatic islets have emerged as key players in islet inflammation. Macrophages express a plethora of innate immune receptors that bind to environmental and metabolic cues and integrate these signals to trigger an inflammatory response that contributes to the development of islet inflammation. One such receptor, Dectin-2, has been identified within pancreatic islets; however, its role in glucose metabolism remains largely unknown. Here we have demonstrated that mice lacking Dectin-2 exhibit local inflammation within islets, along with impaired insulin secretion and ß-cell dysfunction. Our findings indicate that these effects are mediated by proinflammatory cytokines, such as interleukin (IL)-1α and IL-6, which are secreted by macrophages that have acquired an inflammatory phenotype because of the loss of Dectin-2. This study provides novel insights into the mechanisms underlying the role of Dectin-2 in the development of islet inflammation.
Subject(s)
Diabetes Mellitus, Type 2 , Islets of Langerhans , Animals , Mice , Cytokines/metabolism , Diabetes Mellitus, Type 2/metabolism , Inflammation , Insulin/metabolism , Insulin Secretion , Islets of Langerhans/metabolism , Macrophages/metabolismABSTRACT
BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a useful tool for the treatment of hematologic malignancies. However, transplantation-related complications are the main cause of non-relapse mortality. Previous reports suggest that endothelial damage is related to early complications after HSCT. Non-invasive reactive hyperemia peripheral arterial tonometry (RH-PAT) was performed to evaluate endothelial function as a predictive marker for these complications. METHODS: The reactive hyperemia index (RHI) obtained from RH-PAT was evaluated before the conditioning regimen. The relationship between the RHI and the appearance of engraftment syndrome, thrombotic microangiopathy, and acute graft-versus-host disease (aGVHD) was assessed. Receiver operating characteristic curve analysis showed that an RHI value of 1.58 was the optimal cut-off for predicting transplantation-related complications. RESULTS: In total, 49 patients (22 acute myelogenous leukemia, 7 acute lymphocytic leukemia, 6 myelodysplastic syndrome, 6 adult T-cell leukemia, 6 non-Hodgkin lymphoma, and 2 others) were enrolled; 34 had a normal RHI (≥ 1.59), and 15 had an abnormally low RHI (≤ 1.58). Thrombotic microangiopathy (20.2% vs 0.0%, P = 0.025) and aGVHD (80.0% vs 41.2%, P = 0.015) were significantly more frequent in patients with a low RHI. CONCLUSION: Endothelial dysfunction assessed by RH-PAT before HSCT was able to predict transplantation-related complications.
Subject(s)
Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Hyperemia , Leukemia, Myeloid, Acute , Adult , Humans , Hyperemia/complications , Leukemia, Myeloid, Acute/therapy , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Behavior Therapy , Transplantation Conditioning/adverse effectsABSTRACT
C-type lectin receptors (CLRs) elicit immune responses upon recognition of glycoconjugates present on pathogens and self-components. While Dectin-1 is the best-characterized CLR recognizing ß-glucan on pathogens, the endogenous targets of Dectin-1 are not fully understood. Herein, we report that human Dectin-1 is a ligand for CLEC-2, another CLR expressed on platelets. Biochemical analyses revealed that Dectin-1 is a mucin-like protein as its stalk region is highly O-glycosylated. A sialylated core 1 glycan attached to the EDxxT motif of human Dectin-1, which is absent in mouse Dectin-1, provides a ligand moiety for CLEC-2. Strikingly, the expression of human Dectin-1 in mice rescued the lethality and lymphatic defect resulting from a deficiency of Podoplanin, a known CLEC-2 ligand. This finding is the first example of an innate immune receptor also functioning as a physiological ligand to regulate ontogeny upon glycosylation.
Subject(s)
Blood Platelets , Lectins, C-Type , Humans , Mice , Animals , Ligands , Glycosylation , Blood Platelets/metabolism , Lectins, C-Type/metabolismABSTRACT
Despite recent therapeutic advances for multiple myeloma (MM), relapse is very common. Here, we conducted longitudinal single-cell transcriptome sequencing (scRNA-seq) of MM cells from a patient with relapsed MM, treated with multiple anti-myeloma drugs. We observed five subclusters of MM cells, which appeared and/or disappeared in response to the therapeutic pressure, and identified cluster 3 which emerged during lenalidomide treatment and disappeared after proteasome inhibitor (PI) treatment. Among the differentially expressed genes in cluster 3, we found a candidate drug-response gene; pellino E3 ubiquitin-protein ligase family member 2 (PELI2), which is responsible for PI-induced cell death in in vitro assay. Kaplan-Meier survival analysis of database revealed that higher expression of PELI2 is associated with a better prognosis. Our integrated strategy combining longitudinal scRNA-seq analysis, in vitro functional assay, and database analysis would facilitate the understanding of clonal dynamics of MM in response to anti-myeloma drugs and identification of drug-response genes.
ABSTRACT
Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML). However, TKI-related chronic renal toxicity has been reported, particularly in patients with hypertension. We assessed whether incidental use of specific types of antihypertensive drugs, including renin-aldosterone-angiotensin system inhibitors (RAASis), affects the change in estimated glomerular filtration rate (eGFR) during TKI treatment. We retrospectively analyzed all eGFR measurements during TKI treatment for 142 CML patients at Kyushu University Hospital, estimating the rate of eGFR change using a mixed-effects model. Overall, a significant interaction was found between the type of antihypertensive medication used and the yearly change in eGFR (P < 0.01), with RAASi users exhibiting the most rapid decrease in eGFR (- 5.5%/year). The analysis by TKI used showed that the interaction was significant only in imatinib and bosutinib users (P < 0.01 and P = 0.04, respectively). The yearly rate of eGFR decrease was the most notable in RAASi users, at - 5.7 (- 6.6, - 4.9) and - 10.1 (- 12.3, - 7.9) for imatinib and bosutinib users, respectively. Our findings indicate that eGFR should be carefully monitored in patients taking these TKIs.
Subject(s)
Antihypertensive Agents , Leukemia, Myelogenous, Chronic, BCR-ABL Positive , Humans , Imatinib Mesylate/adverse effects , Glomerular Filtration Rate , Antihypertensive Agents/pharmacology , Antihypertensive Agents/therapeutic use , Aldosterone/pharmacology , Aldosterone/therapeutic use , Renin/pharmacology , Renin/therapeutic use , Retrospective Studies , Protein Kinase Inhibitors/adverse effects , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/complications , Enzyme Inhibitors/therapeutic use , Angiotensins/pharmacology , Angiotensins/therapeutic useABSTRACT
OBJECTIVE: Acute graft-versus-host disease (aGVHD) is a major cause of treatment-related mortality after allogeneic hematopoietic stem cell transplantation. Endothelial cell damage may trigger the initiation of aGVHD. METHODS: Endothelial damage and repair were evaluated by counting circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) in 17 allogeneic hematopoietic stem cell transplantation patients at pre-conditioning, day 0, day 7, day 14, day 30, and day 60 by multicolor flow cytometry. Von Willebrand factor activity was simultaneously measured. RESULTS: Eight patients developed aGVHD and were compared to non-aGVHD patients. Patients' characteristics were not different, except for previous treatment courses. There was no difference in von Willebrand factor activity between the two groups. Both CEC and EPC counts were decreased on day 7 and day 14 and then increased thereafter. The CEC count on day 7 was significantly lower in the aGVHD group than in the non-aGVHD group (p = .0401). Restoration of the EPC count on day 60 was significantly suppressed in the aGVHD group (p = .0464). The CEC count on day 7 could predict aGVHD development (AUC 0.8214, p = .0372). CONCLUSION: The present results showed that CEC count on day 7 could be a predictor of aGVHD.
Subject(s)
Endothelial Progenitor Cells , Graft vs Host Disease , Hematopoietic Stem Cell Transplantation , Acute Disease , Graft vs Host Disease/diagnosis , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , von Willebrand FactorABSTRACT
Helicobacter pylori causes gastritis, which has been attributed to the development of H. pylori-specific T cells during infection. However, the mechanism underlying innate immune detection leading to the priming of T cells is not fully understood, as H. pylori evades TLR detection. Here, we report that H. pylori metabolites modified from host cholesterol exacerbate gastritis through the interaction with C-type lectin receptors. Cholesteryl acyl α-glucoside (αCAG) and cholesteryl phosphatidyl α-glucoside (αCPG) were identified as noncanonical ligands for Mincle (Clec4e) and DCAR (Clec4b1). During chronic infection, H. pylori-specific T cell responses and gastritis were ameliorated in Mincle-deficient mice, although bacterial burdens remained unchanged. Furthermore, a mutant H. pylori strain lacking αCAG and αCPG exhibited an impaired ability to cause gastritis. Thus H. pylori-specific modification of host cholesterol plays a pathophysiological role that exacerbates gastric inflammation by triggering C-type lectin receptors.
Subject(s)
Cholesterol/metabolism , Gastritis/metabolism , Helicobacter Infections/metabolism , Helicobacter pylori/metabolism , Lectins, C-Type/metabolism , Membrane Proteins/metabolism , Receptors, Immunologic/metabolism , Animals , Cholesterol/genetics , Chronic Disease , Gastritis/genetics , Gastritis/microbiology , Helicobacter Infections/genetics , Lectins, C-Type/genetics , Membrane Proteins/genetics , Mice , Mice, Knockout , Receptors, Immunologic/geneticsABSTRACT
BACKGROUND: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. PATIENTS AND METHODS: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. RESULTS: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation. CONCLUSION: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leukemia-Lymphoma, Adult T-Cell/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Cyclophosphamide/pharmacology , Cyclophosphamide/therapeutic use , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Etoposide/pharmacology , Etoposide/therapeutic use , Female , Humans , Leukemia-Lymphoma, Adult T-Cell/mortality , Leukemia-Lymphoma, Adult T-Cell/pathology , Male , Middle Aged , Prednisone/pharmacology , Prednisone/therapeutic use , Progression-Free Survival , Retrospective Studies , Vincristine/pharmacology , Vincristine/therapeutic useABSTRACT
Although gamma heavy chain disease (γ-HCD) lesions occasionally morphologically resemble angioimmunoblastic T-cell lymphoma (AITL), no association has been described in detail due to the rarity of the disease. In this report, we present a rare manifestation of methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) with AITL-like features accompanied by γ-HCD in a 75-year-old man with rheumatoid arthritis (RA). A biopsy specimen was evaluated using immunohistochemistry, clonal analyses of immunoglobulin VH and T-cell receptor γ gene rearrangements by polymerase chain reaction, and Sanger sequencing for confirmation of the structure of deleted γ-HCD clones. The histological features characterized by proliferation of CD4- and PD-1-positive medium-sized T cells and arborizing high endothelial venules together with numbers of small lymphocytes, eosinophils, plasma cells, and histiocytes in the background mimicked those of AITL, but did not completely fulfill the diagnostic criteria. Clonal analysis demonstrated that the specimen contained multiple LPDs of both B-cell and T-cell lineages. Sequence analysis confirmed the co-existence of a clone responsible for production of the abnormal heavy chain. This report provides new insights into the pathology of γ-HCD. Multiple host-derived factors (e.g., RA and/or use of MTX) may be responsible for the occurrence of LPDs of multiple lineages within a single lymph node.
ABSTRACT
A case of acquired hemophilia A (AHA) that developed in a patient with autoimmune pancreatitis (AIP) is presented. A 64-year-old woman was diagnosed with AIP in 2007. The symptoms resolved with prednisolone (PSL). Although the dose of PSL was tapered to 7.5 mg/day for maintenance, serum IgG4 levels remained high. She suddenly presented with subcutaneous bleeding in 2015. Her activated partial thromboplastin time was prolonged (80.0 s). A mixing test showed an inhibitor pattern, factor VIII (FVIII) activity was less than 1%, and FVIII inhibitor was 290 BU/mL. She was diagnosed with AHA. Her serum IgG4 was elevated to 133 mg/dL. She was treated first with PSL alone, but she developed bladder tamponade. Cyclophosphamide and activated prothrombin complex concentrate were combined with PSL. She then achieved hemostasis, and FVIII inhibitor disappeared. FVIII inhibitor had been detected since PSL was tapered and AHA recurred two months later. An enzyme-linked immunosorbent assay showed that the inhibitor was mainly IgG4 and IgG1. This case suggests that elevation of IgG4 may be associated with the development of both AHA and AIP.
Subject(s)
Autoimmune Diseases/etiology , Blood Coagulation Factor Inhibitors/blood , Hemophilia A/etiology , Immunoglobulin G/blood , Pancreatitis/etiology , Autoimmune Diseases/blood , Autoimmune Diseases/drug therapy , Autoimmune Diseases/immunology , Biomarkers/blood , Factor VIII , Female , Hemophilia A/diagnosis , Hemophilia A/drug therapy , Humans , Middle Aged , Pancreatitis/blood , Pancreatitis/drug therapy , Pancreatitis/immunology , Prednisolone/administration & dosageABSTRACT
Aggressive NK-cell leukemia (ANKL) is characterized by systemic infiltration of Epstein-Barr virus (EBV)-associated natural killer cells and poor prognosis. We report a case of ANKL in which EBV-specific cytotoxic T lymphocytes (CTLs) were induced. A 41-year-old male suffered from fever, pancytopenia, and hepatosplenomegaly. The number of abnormal large granular lymphocytes in the bone marrow was increased and the cells were positive for CD56 and EBV-encoded small nuclear RNAs. The patient was diagnosed with ANKL and achieved a complete response following intensive chemotherapy. He then underwent allogeneic peripheral blood stem cell transplantation from his sister. Conditioning therapy consisted of total body irradiation and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. On day 31, complete donor chimerism was achieved and no acute graft-versus-host disease developed. The ANKL relapsed on day 80, and cyclosporine was rapidly tapered and chemotherapy was started. During hematopoietic recovery, the number of atypical lymphocytes increased, but they were donor-derived EBV-specific CTLs. The patient achieved a partial response and EBV viral load decreased to normal range. Unfortunately, ANKL worsen again when the CTLs disappeared from his blood. This is the first case report of ANKL in which induced EBV-specific CTLs may have contributed to disease control.
Subject(s)
Herpesvirus 4, Human , Leukemia, Large Granular Lymphocytic/therapy , Peripheral Blood Stem Cell Transplantation/adverse effects , T-Lymphocytes, Cytotoxic/virology , Adult , Disease Management , Epstein-Barr Virus Infections/etiology , Epstein-Barr Virus Infections/therapy , Humans , Leukemia, Large Granular Lymphocytic/virology , Male , Peripheral Blood Stem Cell Transplantation/methods , Recurrence , T-Lymphocytes, Cytotoxic/transplantation , Tissue Donors , Transplantation Chimera , Transplantation, HomologousABSTRACT
Light-chain deposition disease (LCDD) is a rare plasma cell neoplasm that secretes an abnormal immunoglobulin light chain, which is deposited in tissues, leading to organ dysfunction. Spontaneous splenic rupture is a rare and life-threatening complication of treatment with granulocyte colony-stimulating factor (G-CSF). Herein, we describe spontaneous splenic rupture after the administration of lenograstim to a patient with LCDD undergoing autologous stem cell transplantation (ASCT). The patient was successfully treated by transcatheter embolization of the splenic artery, and long-term stringent complete remission was attained. Plasma cell neoplasms, including multiple myeloma with amyloidosis, are among the most commonly reported conditions associated with spontaneous splenic rupture in patients undergoing ASCT. This finding suggests that, in addition to the effect of G-CSF on the spleen, a combination of factors, including tissue vulnerability induced by the infiltration of abnormal immunoglobulins, may be involved in the pathogenesis of spontaneous splenic rupture. Notably, splenomegaly is not always evident in these patients. Surgical treatment may not be an option, because of severe myelosuppression, and thus less invasive treatment using transcatheter embolization may be feasible.
Subject(s)
Paraproteinemias/complications , Peripheral Blood Stem Cell Transplantation/adverse effects , Rupture, Spontaneous/etiology , Splenic Rupture/etiology , Female , Humans , Middle Aged , Rupture, Spontaneous/drug therapy , Splenic Rupture/drug therapy , Transplantation, Autologous/adverse effects , Treatment OutcomeABSTRACT
CD 20 positive myeloma with small lymphoplasmacytoid morphology is difficult to differentiate from mature B-cell lymphoma. A 71-year-old male was referred to our hospital because of osteolytic vertebral fractures and anemia. Urine was positive for Bence Jones protein, κ type. Bone marrow consisted of approximately 30% small lymphoplasmacytoid cells with scant cytoplasm, and these cells were positive for CD20, CD23 and CD138. FISH analysis revealed t(11;14)(CCND1/IGH). Myeloma with t(11;14) is closely associated with small lymphoplasmacytoid appearance and CD20 and CD23 expressions. The patient was diagnosed as having myeloma based on clinical and cytogenetic findings, and achieved VGPR (very good partial response) after treatment with lenalidomide.
Subject(s)
Antigens, CD20/immunology , Bone Marrow/pathology , Diagnosis, Differential , Immunoglobulin Heavy Chains/blood , Lymphoma, B-Cell/pathology , Multiple Myeloma/pathology , Waldenstrom Macroglobulinemia/pathology , Aged , Humans , Lymphoma, B-Cell/diagnosis , Male , Multiple Myeloma/diagnosisABSTRACT
Primary effusion lymphoma (PEL) is a rare B-cell lymphoma, characterized by human herpes virus 8 (HHV8) infection and serous effusions without detectable tumor masses. However, cases with HHV8 unrelated PEL have also been reported, mainly in Japan, and these are referred to as PEL-like lymphoma (PEL-LL). We describe a 70-year-old man with cardiac comorbidity who developed PEL-LL with pleural effusion. The patient achieved a complete response (CR) after treatment with oral low-dose sobuzoxane and etoposide combined with rituximab. To date, the patient has been in CR for about 7 months without chemotherapy. PEL-LL reportedly has a better prognosis than PEL. Because PEL-LL is positive for CD20, unlike PEL, combination therapy including rituximab may be effective. PEL-LL mainly affects elderly people, so that further investigation of tolerable and effective regimens is required.