Metabolic Reprogramming Commits Differentiation of Human CD27+IgD+ B Cells to Plasmablasts or CD27-IgD- Cells.

B cells play a crucial role in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE). However, the relevance of the metabolic pathway in the differentiation of human B cell subsets remains unknown. In this article, we show that the combination of CpG/TLR9 and IFN-α markedly induced the differentiation of CD27+IgD+ unswitched memory B cells into CD27hiCD38hi plasmablasts. The response was accompanied by mammalian target of rapamycin complex 1 (mTORC1) activation and increased lactate production, indicating a shift to glycolysis. However, CpG alone induced the differentiation of unswitched memory B cells into CD27-IgD- memory B cells with high cytokine production, but such differentiation was suppressed by IFN-α. AMP-activated protein kinase activation enhanced the differentiation to CD27-IgD- B cells, but it attenuated mTORC1 activation and differentiation into plasmablasts. High mTORC1 activation was noted in CD19+ B cells of patients with SLE and correlated with plasmablast differentiation and disease activity. Taken together, differential metabolic reprogramming commits the differentiation of human unswitched memory B cells into plasmablasts (the combination of CpG and IFN-α amplifies mTORC1-glycolysis pathways) or CD27-IgD- memory B cells (CpG alone amplifies the AMP-activated protein kinase pathway). The former metabolic pathway may play a pivotal role in SLE.

l-Leucine influx through Slc7a5 regulates inflammatory responses of human B cells via mammalian target of rapamycin complex 1 signaling.

Objectives: Increasing evidence has revealed the close correlation between immune cell functions and their intracellular metabolism. Mammalian target of rapamycin complex 1 (mTORC1) is the important metabolism-modulating signal that regulates cellular activities. In certain types of cell, it is known that mTORC1 activation depends on influx of l-leucine through an amino acid transporter, Slc7a5. In B cells, however, the expression and the role of Slc7a5 have never been investigated. Methods: CD19+ B cells were obtained from peripheral blood of healthy adults and stimulated by a toll-like receptor 9 ligand, CpG oligodeoxynucleotides. The expression of Slc7a5 and l-leucine uptake were evaluated by RT-PCR, flow cytometry and radioisotope assay. Then the effect of Slc7a5 inhibition on mTORC1 activity, plasmablast differentiation and production of IgG and inflammatory cytokines were analyzed. Results: CpG stimulation significantly induced the expression of Slc7a5 in B cells, resulting in l-leucine influx. Furthermore, inhibition of Slc7a5 abrogated mTORC1 activation, plasmablast differentiation, and production of IgG and inflammatory cytokines in CpG-stimulated B cells. Conclusion: l-leucine influx through Slc7a5 critically regulates mTORC1 activity and the immunological responses of human B cells. Slc7a5-mTORC1 pathway may provide a novel therapeutic strategy for autoimmune diseases.

Hydroxychloroquine efficiently suppresses inflammatory responses of human class-switched memory B cells via Toll-like receptor 9 inhibition.

Hydroxychloroquine is widely used for autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. Although B cells contribute to the pathogenesis of these diseases, the action of hydroxychloroquine on B cells remains unclear. Here we examined the effects of hydroxychloroquine on functions of B cell subsets. Hydroxychloroquine efficiently inhibited the mammalian target of rapamycin complex 1, differentiation of CD19+IgD-CD27+ class-switched memory B cells to plasmablasts and their IgG production, under stimulation with CpG, a Toll-like receptor (TLR)-9 ligand. Hydroxychloroquine also inhibited CpG-induced production of interleukin-6 and tumor necrosis factor-α in B cell subsets. Taken together, hydroxychloroquine markedly suppresses the TLR9-mediated human B cell functions during inflammatory processes. Based on our results, we believe that hydroxychloroquine can be beneficial in the treatment of B cell-mediated autoimmune diseases.

Large-vessel involvement in granulomatosis with polyangiitis successfully treated with rituximab: A case report and literature review.

Granulomatosis with polyangiitis (GPA) is primary necrotizing vasculitis, which predominantly affects small to medium vessels. Herein, we describe a case of a 60-year-old female with GPA who developed inflammatory wall thickening localized in the aortic arch, upper abdominal aorta, and pulmonary artery. The wall thickening in the large vessels and other GPA lesions such as lung nodules and orbital mass had failed to respond to high-dose glucocorticoids combined with cyclophosphamide; however, all were successfully treated with rituximab. Our literature review identified 24 cases of large-vessel involvement associated with GPA. Luminal stenosis, occlusion, or wall thickening were observed in 8, periaortitis in 11, and aneurysms in 5 cases. The most commonly affected vessel was the abdominal aorta (12 cases), followed by the thoracic aorta (6 cases), subclavian artery (4 cases), and internal carotid artery (4 cases). Glucocorticoids were used in 23 cases, 20 of which received combination therapy with cyclophosphamide. Surgical or endovascular therapies were performed in 10 cases with aneurysmal dilatation. This is the first case showing the potential efficacy of rituximab for refractory large-vessel involvement associated with GPA.

Successful leukocytapheresis therapy in a patient with rheumatoid arthritis on maintenance hemodialysis.

We report the case of a 44-year-old female undergoing maintenance hemodialysis in whom early-phase rheumatoid arthritis (RA) was successfully treated by leukocytapheresis (LCAP). The effects of prednisone, tacrolimus, and etanercept were limited, but LCAP was highly effective and its efficacy continued even after cessation of LCAP. Moreover, remission was maintained for 2 years after discontinuation of medication. LCAP may be an important treatment option for RA patients with end-stage renal failure who are on hemodialysis.

Effectiveness of subcutaneous tocilizumab in refractory adult Still's disease: report of three cases and a review of the literature.

Adult Still's disease (ASD) is a systemic inflammatory disorder characterised by spiking fever, skin rash, arthritis, hepatosplenomegaly, and elevated inflammatory markers. Several proinflammatory cytokines, including interleukin (IL)-6, contribute to its pathogenesis. There have been some recent reports on the efficacy of tocilizumab (TCZ), a humanised anti-IL-6 receptor antibody, in the treatment of ASD refractory to conventional therapy. However, most of the evidence is for intravenous administration of TCZ, whereas subcutaneous injection is often preferred in terms of efficiency in cost and labour. We have experienced three patients whose ASD was refractory to corticosteroid and immunosuppressant therapy but showed a marked response to off-label use of subcutaneous TCZ (TCZ-SC). Patient 1 received TCZ-SC 162 mg on days 0 and 14 and every week thereafter. Patients 2 and 3 received TCZ-SC every 2 weeks. At the time of initiation of TCZ-SC, all three patients had elevated inflammatory markers and two had fever despite previous therapy. After the first TCZ-SC injection, the patients became afebrile within one day and inflammatory parameters (i.e. C-reactive protein and erythrocyte sedimentation rate) returned to normal within 2 weeks. None of the patients developed severe infection or other serious side effects during 104 weeks of follow-up. There have been only a limited number of case reports showing that TCZ-SC significantly improves refractory ASD during its active phase. Our experience with these patients suggests that TCZ-SC could, as well as offering cost efficiency in clinical practice, be a potent treatment option for refractory ASD.

Familial Mediterranean Fever with Rheumatoid Arthritis Complicated by Pulmonary Paragonimiasis.

A 42-year-old woman presented with an intermittent fever and chest and back pain, and an abnormal chest shadow was detected. She was diagnosed with paragonimiasis caused by Paragonimus westermani. Praziquantel therapy improved the abnormal chest shadow, but did not relieve her symptoms. She was also diagnosed with familial Mediterranean fever (FMF), and colchicine therapy resolved her symptoms. She subsequently developed arthralgia and morning stiffness in her hands. We also diagnosed the patient with rheumatoid arthritis (RA), and corticosteroid and salazosulfapyridine therapy improved her symptoms. The existence of paragonimiasis complicated the diagnosis of FMF. The coexistence of FMF and RA is very rare, but does exist.

Congenital intrahepatic portosystemic venous shunt presenting with paraparesis as the initial symptom.

An 85-year-old woman was hospitalized with rapidly progressive paraparesis without altered consciousness, although she was not definitively diagnosed. She developed acute drowsiness and disorientation several days later. An intrahepatic portosystemic venous shunt (IPSVS) was observed on enhanced computed tomography, and hyperammonemia suggested leakage of neurotoxins from the shunt as the etiology of the patient's symptoms. Her neurological symptoms and hyperammonemia improved following transcatheter shunt embolization. We diagnosed her with hepatic myelopathy, which is a rare complication of liver cirrhosis and portosystemic venous shunts. Hepatic myelopathy resulting from a congenital IPSVS has not been previously reported. A diagnosis of hepatic myelopathy should be ruled out in diagnostically difficult cases of paraparesis.

[Simultaneous relapse of Basedow's disease in a patient with adult-onset Still's disease].

This report describes a 50-year-old woman with coexisting Basedow's disease and adult-onset Still's disease (AOSD) that relapsed simultaneously. She was diagnosed with Basedow's disease in 1999, and treatment with antithyroid agents was started. However, the treatment was soon stopped because of severe side effects. A partial thyroidectomy was performed and the thyroid function stayed well-controlled after the surgery. In August 2007, she was admitted to our hospital with fever, a sore throat, skin rashes, arthritis and leukocytosis, and was diagnosed with AOSD. At the same time, her laboratory data revealed decreased serum TSH and elevated serum free T4, suggesting a relapse of Basedow's disease. After initiation of steroid pulse therapy accompanied by oral prednisolone, both diseases improved significantly. Prednisolone was gradually reduced, and the disease activity remained in remission. Immediately after prednisolone reached 3 mg/day in November 2009, both diseases relapsed. Prednisolone was increased to 30 mg/day, and the diseases became well-controlled again. In this case, Basedow's disease was aggravated when AOSD was in the active stage. Literature searches revealed five previously reported cases with coexisting Basedow's disease and AOSD. In four of the six cases, including our case, both diseases were activated simultaneously. AOSD in the active stage is known to cause hypercytokinemia and immunological derangement. Our case indicated that the pathogenesis of AOSD might lead to relapse of coexisting Basedow's disease.