The gut is a unique tissue where a refined balance is maintained between immune responses and tolerance to a variety of foreign antigens including food and commensal bacteria. Although activation of T helper (Th) cells, such as Th1 and Th17 cells, is responsible for the host defense against invading pathogens in the gut, inappropriate Th1/Th17 responses cause onset and/or progression of inflammatory bowel disease (IBD) comprised of two major disorders; ulcerative colitis and Crohn's disease. Therefore, the inflammatory responses by Th1/Th17 cells in the gut are tightly regulated through a number of mechanisms. In the human intestine, several innate immune cell subsets play important roles in the maintenance of the gut homeostasis by controlling adaptive immune responses. We recently identified CD14⁺ CD163^low cells and CD14⁺ CD163^high CD160^high cells as Th17-inducing dendritic cells and anti-inflammatory phagocytes, respectively. In addition, the dysfunction of these cell subsets was observed in the patients with IBD. Therefore, it would be an important future issue to analyze the mechanisms underlying regulation of intestinal innate immune cell homeostasis for the development of a novel therapeutic intervention for IBD.

  The skin is one of the largest organs in the human body, which acts as the primary interface with the external world. In view of its protective role, mammalian skin consists of physical and immunological barriers. The water-impermeable stratum corneum and the tight junctions in the granular layer work at the epidermal level work as the most important first and second “physical” barriers. Upon antigen invasion to the skin, the integrated innate and acquired immune systems in both the epidermis and dermis are activated in a coordinated manner to neutralize the external intruder as the strong third “immunological” barriers. Dendritic cells and macrophages are known to play pivotal roles in such immunological barriers. Intra-vital analysis of the murine skin by two-photon microscopy enabled us to assess the habituate and the direct interactions of various cells in the skin in situ, which reside or infiltrate upon inflammation. We introduce the recent works how dendritic cells and macrophages orchestrate the skin immunity, highlighting the importance of sequential leucocyte cluster formation in the efficient activation of memory T cells in the skin, which can be attributed as ‘inducible skin-associated lymphoid tissue (iSALT)’.

  In the pathogenesis of rheumatoid arthritis (RA), TNFα and IL-6 are proved to be crucial cytokines. Monocyte and macrophage are thought to produce these cytokines, as well as the source of cells becoming osteoclast in RA. In this review, I will discuss the role of monocyte/macrophage and the recent topic of negative regulator of arthritis such as TNFα-induced adipose related protein in RA.

  It is widely known that a variety of immune cells in the liver contribute to the pathogenesis of liver diseases. Recently, roles of chemokines/chemokines receptors axes regarding the migration of immune competent cells to the inflamed liver have been reported as possible therapeutic targets. We here showed that CCR9⁺ CD11b⁺ macrophages play an important role during the course of Concanavalin A-induced murine acute liver injury as well as human acute hepatitis via the production of inflammatory cytokines and the Th1 induction. Further analysis using liver-shielded radiation and bone marrow (BM) transplantation model mice revealed that these CCR9⁺ CD11b⁺ macrophages are originated from BM-derived monocytes, but not liver resident macrophages (Kupffer cells). Furthermore, these CD11b⁺ inflammatory macrophages in contact with hepatic stellate cells contribute to the pathogenesis of murine experimental liver fibrosis via CCR9/CCL25 axis. Collectively, these results with further verification in human samples clarify the pathogenic role of CCR9/CCL25 axis as therapeutic target of a variety of liver diseases.

  Extensive research over 100 years has clarified that cancers are surely suppressed by human immune system. Unfortunately, a number of clinical trials with various approaches have fallen short of clinical application because of the lack of significant anti-tumor effect. However, recent approved immune checkpoint inhibitors, namely PD-1 and CTLA-4 blockers, provide even better prognosis than existing chemotherapy in patients with certain types of cancer. There is no doubt that immunotherapy is becoming a standard treatment as well as surgery, chemotherapy and radiotherapy. Dendritic cells express a variety of immune checkpoint molecules including one with unknown function. In addition, accumulating evidence reported that already known molecules might have alternative functions. Further investigation of this field would lead to development of more effective treatments for cancer with less adverse effects. In this short review, we introduce some immune checkpoint molecules expressed in dendritic cells from the point of view of cancer immunotherapy.

  Objective: Th17 cells, which mainly produce interleukin (IL)-17, have been suggested to play a critical role in the pathogenesis of autoimmune diseases. The plasticity of Th17 cells, in which these cells shift to a Th1 phenotype in the presence of IL-12, has recently been reported. However, the role of IL-17 in Sjögren's syndrome (SS) and Mikulicz's disease (MD) currently remains unknown. Patients and Methods: The submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients were collected. IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected by immunohistochemical staining. Results: IFN-γ+ cells, IL-17+ cells, and IFN-γ+IL-17+ cells were detected in the submandibular salivary gland and lymph node of the MD patient and salivary glands of the 15 SS patients. Discussion: IFN-γ+IL-17+cells in the salivary glands of patients were speculated to be Th1/Th17 cells in the present study. Th1/Th17 cells are known to be derived from Th17 cells and differentiate into Th1 cells, and IL-17-derived Th1 cells have been suggested to induce the deterioration of juvenile idiopathic arthritis (JIA). Thus, Th1/Th17 cells may play an important role in the pathogenesis of SS and MD. Conclusion: IFN-γ+, IFN-γ+IL-17+, and IL-17+ cells were detected in the submandibular salivary gland and lymph node of a MD patient and the salivary glands of 15 SS patients.

  A 25-year-old woman diagnosed 1 year earlier with Primary Sjogren's syndrome was admitted to a nearby hospital with fever of unknown origin. Examination revealed anasarca, systemic lymphadenopathy, hepatosplenomegaly and high C-reactive protein level. The patient's symptoms were initially suspected to be caused by severe bacterial infection with Sjogren's syndrome flare. She was given antibiotics and prednisolone (PSL) at 50 mg/day. However, the patient developed anemia and thrombocytopenia and was transferred to our hospital for further care. Histological examination of the right inguinal lymph node showed neutrophilic infiltration. Bone marrow aspiration revealed a normocellular marrow with increased megakaryocytes and mild reticulin fiber hyperplasia. After initiation of minocycline hydrochloride, the patient's symptoms improved. However, as PSL was tapered, her symptoms worsened. The patient's clinical symptoms and laboratory data improved again with initiation of intravenous steroid pulse therapy and cyclosporine. TAFRO syndrome is characterized by a constellation of symptoms: Thrombocytopenia, Anasarca, Fever, Reticulin fibrosis and Organomegaly. Although histological findings of the lymph node in this case differed from previous reports, the patient's other symptoms and clinical course were similar to TAFRO syndrome. TAFRO syndrome can occur with several diseases, including infection, rheumatic disease and malignancies. We report a case in which infection might have triggered TAFRO syndrome.