Erratum to: [Japanese Journal of Clinical Immunology, 30(6): 503-510 (2012)]
incorrect: MINORU MAKAMURA
correct: MINORU NAKAMURA

View full abstract

  Immunosuppressive cells have been reported to contribute to the inflammatory diseases in various organs. Interferon (IFN)-γ stimulations skew macrophages (Mφ) toward classically activated (M1) phenotype and interleukin (IL)-4, IL-13, IL-10 skew toward alternatively activated (M2) phenotypes. M2 polarized Mφhas immune regulatory function via various mechanisms, such as cytokine/chemokine expression, high activity of scavenging and interaction with other type of cells. Recently, another type of immunosuppressive myeloid cells, myeloid derived suppressor cells (MDSC), have been explored not only in tumor immunology, but also in inflammatory diseases. Orchestration of inflammation by these immunosuppressive cells with inflammatory cells has impact on progressive kidney diseases as well as inflammatory diseases.

View full abstract

  Innate Lymphoid cells (ILCs) are recently defined lymphocytes composed of several subsets such as Natural Killer (NK), Natural Helper (NH) and RORγt⁺ cells, which have no antigen receptors but exhibit rapid cytokine production after stimulation. Murine RORγt⁺ ILCs can be classified either as CCR6⁺c-kit^highIL-7Rα^high or CCR6⁻NKp46⁺ cells. The former ones play roles on the formation of secondary lymphoid tissues and the later ones contribute to the maintenance of intestinal epithelial integrity by producing IL-22. Human fetal intestine, tonsil and lympho nodes harbor both NKp44 positive and negative RORγt⁺ ILC subsets. Since human Crohn's disease patients have increased number of RORγt⁺ ILCs in the inflamed intestine, roles of RORγt⁺ ILCs on the pathogenesis of Crohn's disease became of great interest.

View full abstract

  Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by excessive fibrosis and microvasculopathy, along with poor vascular formation and repair. The maintenance of the postnatal vascular system requires constant remodeling through vasculogenesis, which is mediated by the de novo differentiation of mature endothelial cells from endothelial progenitor cells (EPCs). However, a great deal of controversy about EPCs and their roles in postnatal vascular formation has arisen because of discrepancies in how EPCs are defined. The current consensus is that EPCs are heterogeneous cell population containing an extremely small count of “true EPCs”, and pro-angiogenic hematopoietic cells (PHCs) that promotes vascular formation and repair through secretion of pro-angiogenic factors, and differentiation into endothelial cells and mural cells. In 2004, we reported a reduced number and impaired function of circulating CD34⁺CD133⁺CD309⁺CD45^dimCD14⁻ EPCs, which are now regarded as an immature subset of PHCs, in patients with SSc, and proposed a theory that defective vascular repair machinery as one of important mechanisms contributing to SSc vasculopathy. In addition, we showed that in SSc patients, circulating monocytic PHCs were increased and have enhanced angiogenic potency and differentiation potential to fibroblast-like cells. In summary, EPCs are involved in the pathogenesis of SSc by participating in two major pathological features, microvasculopathy and excessive fibrosis. Understanding the roles of EPCs in disease process of SSc may be key to dissecting its pathogenesis and to developing novel therapeutic strategies for this intractable condition.

View full abstract

  We have adopted DNA-microarray technology to analyze gene expression profiles in patients with Kawasaki Disease (KD). The results demonstrated that neutrophils in acute KD patients were not only expanded in number but also activated through the expression of a variety of late-stage granulocyte-specific genes such as polycythemia rubra vera 1 (PRV-1) and haptoglobin compared with febrile controls. In accordance with these findings, serum granulocyte colony-stimulating factor (G-CSF) levels were also higher in IVIG-resistant patients than those in responsive patients. These results might indicate evidences for dysregulated immunological pathways in KD patients and provide possible tools for diagnosis and prognostics of KD. We also found that high-dose IgG specifically and completely inhibited accelerated expression of KD-related cytokines such as G-CSF, IL-6 and IL-1β by HCAEC in response to TNF-α. The suppression of these cytokine genes correlated closely with functional inhibition of a transcription factor, C/EBP-δ. These findings suggest that the clinical effects of IVIG on KD patients are at least in part due to its direct anti-inflammatory effects on the coronary endothelium, which is a major lesion site in the pathogenesis of KD.

View full abstract

  Although the central nervous system and the neurotransmitters are known to control not only the immune system but also the homeostasis of bone mass, their pathological relevance to bone disorders remains unclear. Osteoclasts in the synovium of rheumatoid arthritis (RA) play an important role in bone destruction. It is known that increased sympathetic nervous activity increases both differentiation and function of osteoclasts, which leads to bone loss. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. We previously reported that dopamine plays an important role in IL-6-IL-17 axis and subsequent joint destruction in RA. The major source of dopamine in the synovial tissue of RA was dendritic cells (DCs) that stored and secreted dopamine. Dopamine released by DCs bounded to D1-like dopamine receptors on T cells and induced activation of cAMP and differentiation to Th17 cells via IL-6 production We here overview the interplay among the immune system, bone metabolism and neurologic system shedding light upon dopaminergic signals upon osteoclastogenesis.

View full abstract

  IL-10 is an anti-inflammatory cytokine with an important role in preventing inflammatory and autoimmune responses. IL-10 is also important for suppressive function of inducible regulatory T (iTreg) cells, several types of which were reported in succession. Type1 regulatory T (Tr1) cell is a representative of IL-10-prroducing regulatory T cells. Although specific surface markers or origin of Tr1 cells have not fully been clarified yet, IL-27 was recently reported to induce IL-10 production in T cells and be an inducer of Tr1 cells. We previously reported that CD4⁺CD25⁻lymphocyte activation gene (LAG-3)⁺ Treg (LAG3⁺ Treg) is one of the peripherally inducible Tregs and functions as an immune-regulator through IL-10 production. We found that the expression level of Egr-2, a transcription factor required for T cell anergy induction, is elevated in LAG3⁺ Treg and that forced expression of Egr-2 induces LAG-3 expression and IL-10 production. Egr-2 has been suggested to be a key player of regulatory function in LAG3⁺ Treg. In this study, we review Tr1 cells and the mechanism of IL-10 induction by IL-27 in T cells. Also, we introduce LAG3⁺ Treg and discuss the therapeutic potential of these regulatory T cells.

View full abstract

  The patient was a 34-year-old woman who, at age 23, was diagnosed with rheumatoid arthritis (RA) presenting with morning stiffness, swelling and tenderness of bilateral knee joints and metacarpophalangeal (MP) joints of the right second and third fingers, increased C-reactive protein (CRP) levels, and a high level of rheumatoid factor (RF). The patient was maintaining remission with oral dose of bucillamine (BUC; 300 mg/day); however, due to the deterioration of arthralgia at age 26, she was additionally administered 8 mg/week of methotrexate (MTX), which improved the symptoms. Thereafter, the prescription of BUC was discontinued. At age 31, she experienced onsets of swelling and tenderness in both the knee joints and wrists and in MP joints of the right second and third fingers; further, CRP levels increased to 5.44 mg/dL, resulting in increased RA activity. The concomitant administration of infliximab was started at a dose of 3 mg/kg, which helped achieve favorable RA control. At age 32, approximately 2 years before childbirth, the prescription of infliximab was changed to 25 mg/dose of etanercept administered twice a week because the patient wished to conceive. Remission was maintained even after the drug change; therefore, MTX was discontinued and the patient was treated with etanercept alone. After she was confirmed to be pregnant in March of the following year, administration of etanercept was continued for treating of RA even during pregnancy. During that time, RA was favorably controlled, and the patient gave birth to a baby boy weighing 3192 g in October of the same year. The Apgar score of the baby was favorable. This case is considered important because, to the best of our knowledge, this may be the first report of a planned pregnancy and childbirth in a patient under administration of a biological preparation.

View full abstract

  Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious disorder of skeletal system mainly seen in children. We report a case of CRMO presenting with fever and leg pain. The patient was an 11-year-old boy complaining of a fever, swelling and pain on his right foot, and pain on both legs. Although serum levels of CK and aldolase were not increased, MRI imaging suggested polymyositis. Muscle biopsy showed interstitial infiltration of inflammatory cells without any evidences of dermatomyositis or polymyositis. One month later, he complained of a swelling, pain and redness of his left clavicle as recurrently experienced during the recent 6 months, and MRI investigation indicated the diagnosis of osteomyelitis. Bone biopsy was performed and showed chronic inflammatory changes with negative bacterial culture. Multiple bone lesions and muscle uptake of FDG in his legs were revealed by whole body FDG-PET/CT, and he was diagnosed as having CRMO with interstitial myositis. The combinatorial administration of non-steroidal anti-inflammatory drugs and bisphosphonate successfully improved his clinical symptoms and laboratory abnormalities. To our knowledge, there is no report of a patient of CRMO associated with interstitial myositis.

View full abstract

  A 46-year-old man, who had had sinusitis, developed bilateral omalgia, petechiae on his lower extremities and a congested right eye. A blood test detected elevated serum C-reactive protein level. Computed tomography incidentally found an acute lesion of thalamic hemorrhage without neurological symptoms and no specific therapy was given at the time. Thereafter, he developed vertigo, vomiting and pneumonia for which antibiotics were ineffective. He was referred and admitted to our hospital. Further, aural and renal lesions, and presence of serum proteinase 3-antineutrophil cytoplasmic antibody (PR3-ANCA) confirmed his diagnosis of granulomatosis with polyangiitis (Wegener's) (GPA). With corticosteroid and cyclophosphamide therapy, his symptoms disappeared in two months along with faded PR3-ANCA. Afterward he showed neither new cerebral lesion nor symptom. This is a rare case of GPA manifested with asymptomatic intracerebral hemorrhage. It should be noted that GPA could cause various manifestations in central nervous system such as a fatal or an asymptomatic hemorrhagic lesion, which might respond to immunosuppressive therapy.

View full abstract