Construction of a T cell receptor signaling range for spontaneous development of autoimmune disease.

Thymic selection and peripheral activation of conventional T (Tconv) and regulatory T (Treg) cells depend on TCR signaling, whose anomalies are causative of autoimmunity. Here, we expressed in normal mice mutated ZAP-70 molecules with different affinities for the CD3 chains, or wild type ZAP-70 at graded expression levels under tetracycline-inducible control. Both manipulations reduced TCR signaling intensity to various extents and thereby rendered those normally deleted self-reactive thymocytes to become positively selected and form a highly autoimmune TCR repertoire.

Dispensable roles of Gsdmd and Ripk3 in sustaining IL-1β production and chronic inflammation in Th17-mediated autoimmune arthritis.

Programmed necrosis, such as necroptosis and pyroptosis, is a highly pro-inflammatory cellular event that is associated with chronic inflammation. Although there are various triggers of pyroptosis and necroptosis in autoimmune tissue inflammation and subsequent lytic forms of cell death release abundant inflammatory mediators, including damage-associated molecular patterns and IL-1β, capable of amplifying autoimmune Th17 effector functions, it remains largely unclear whether the programs play a crucial role in the pathogenesis of autoimmune arthritis. We herein report that Gasdermin D (Gsdmd) and receptor interacting serine/threonine kinase 3 (Ripk3)-key molecules of pyroptosis and necroptosis, respectively-are upregulated in inflamed synovial tissues, but dispensable for IL-1β production and the development of IL-17-producing T helper (Th17) cell-mediated autoimmune arthritis in SKG mice.

Macrophage activation syndrome in adult dermatomyositis: a case-based review.

Macrophage activation syndrome (MAS) is a severe and life-threatening syndrome associated with autoimmune diseases, characterized by fever, hepatosplenomegaly, and pancytopenia. Dermatomyositis (DM) is one of the causes of MAS; however, its clinical characteristics in DM patients remain unclear. This study aimed to present a case of anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive DM complicated by MAS in a 29-year-old woman and to review the literatures including similar cases.

Strain-Specific Manifestation of Lupus-like Systemic Autoimmunity Caused by Mutation.

A defect in TCR-proximal signaling is a major characteristic of CD4 T cells in systemic lupus erythematosus; however, it is not fully known how defects in TCR signaling lead to lupus-like systemic autoimmunity characterized by germinal center development and autoantibody production against nuclear Ags. In this study, we show that SKG mice, which develop autoimmune arthritis in a BALB/c background due to defective TCR signaling by a mutation, develop lupus-like systemic autoimmune disease in the C57BL/6 (B6) background (B6SKG mice). B6SKG mice showed multiorgan inflammation with immune complex deposition and anti-dsDNA Ab production.

Autoimmune Th17 Cells Induced Synovial Stromal and Innate Lymphoid Cell Secretion of the Cytokine GM-CSF to Initiate and Augment Autoimmune Arthritis.

Despite the importance of Th17 cells in autoimmune diseases, it remains unclear how they control other inflammatory cells in autoimmune tissue damage. Using a model of spontaneous autoimmune arthritis, we showed that arthritogenic Th17 cells stimulated fibroblast-like synoviocytes via interleukin-17 (IL-17) to secrete the cytokine GM-CSF and also expanded synovial-resident innate lymphoid cells (ILCs) in inflamed joints. Activated synovial ILCs, which expressed CD25, IL-33Ra, and TLR9, produced abundant GM-CSF upon stimulation by IL-2, IL-33, or CpG DNA.

Identification of Novel and Noninvasive Biomarkers of Acute Cellular Rejection After Liver Transplantation by Protein Microarray.

Background: Acute cellular rejection (ACR) is one of the main factors in transplanted organ failure in liver transplantation. A precise marker for diagnosing or predicting rejection is not currently available; therefore, invasive liver biopsy is standard procedure. To develop a noninvasive method for precise diagnosis of ACR, we evaluated autoantibodies from patient sera as potential biomarkers using protein microarrays (seromics).

Detection of T cell responses to a ubiquitous cellular protein in autoimmune disease.

T cells that mediate autoimmune diseases such as rheumatoid arthritis (RA) are difficult to characterize because they are likely to be deleted or inactivated in the thymus if the self antigens they recognize are ubiquitously expressed. One way to obtain and analyze these autoimmune T cells is to alter T cell receptor (TCR) signaling in developing T cells to change their sensitivity to thymic negative selection, thereby allowing their thymic production. From mice thus engineered to generate T cells mediating autoimmune arthritis, we isolated arthritogenic TCRs and characterized the self antigens they recognized.

Thymus, innate immunity and autoimmune arthritis: interplay of gene and environment.

A hypomorphic mutation of the gene encoding zeta-associated protein-70 (ZAP-70), a signaling molecule in T cells, produces autoimmune arthritis in mice under a microbially conventional condition but not in a clean environment. The genetic anomaly alters thymic selection of self-reactive T cells as well as natural regulatory T cells and their respective functions. Highly self-reactive polyclonal T cells, including arthritogenic ones, thus produced by the thymus strongly recognize self-antigens presented by antigen-presenting cells, stimulate them to up-regulate co-stimulatory molecules and secrete cytokines that drive naïve self-reactive T cells to differentiate into autoimmune effector Th17 cells.

Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function.

Mice with a mutation of the zeta-associated protein of 70 kDa gene (skg mutation) are genetically prone to develop autoimmune arthritis, depending on the environment. In a set of mice with the mutation, the amount of zeta-associated protein of 70 kDa protein as well as its tyrosine phosphorylation upon TCR stimulation decreased from +/+, skg/+, skg/skg, to skg/- mice in a stepwise manner. The reduction resulted in graded alterations of thymic positive and negative selection of self-reactive T cells and Foxp3(+) natural regulatory T cells (Tregs) and their respective functions.

Complement drives Th17 cell differentiation and triggers autoimmune arthritis.

Activation of serum complement triggers Th17 cell-dependent spontaneous autoimmune disease in an animal model. In genetically autoimmune-prone SKG mice, administration of mannan or beta-glucan, both of which activate serum complement, evoked Th17 cell-mediated chronic autoimmune arthritis. C5a, a chief component of complement activation produced via all three complement pathways (i.

Reduction of opioid side effects by prophylactic measures of palliative care team may result in improved quality of life.

Purpose: In February 2002, the palliative care team was established in Ikeda Municipal Hospital to improve palliative care. We investigated changes in the incidences of side effects related to opioids, and evaluated palliative care team activities.

Methods: Regarding inpatients for whom narcotics were prescribed in our hospital in the years of 2002 (from October 1, 2002 until September 30, 2003), 2004 (from October 1, 2004 until September 30, 2005), and 2006 (from October 1, 2006 until September 30, 2007), we surveyed the rates at which laxatives or antiemetics were prescribed, frequency of defecation/its state before and after the start of narcotic therapy, frequency of nausea/vomiting, and dietary intake.

Gamma/delta T cells are the predominant source of interleukin-17 in affected joints in collagen-induced arthritis, but not in rheumatoid arthritis.

Objective: Although interleukin-17 (IL-17)-producing gamma/delta T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristics remain unknown. The aim of this study was to clarify whether gamma/delta T cells or CD4+ T cells are the predominant IL-17-producing cells, and to determine what stimulates gamma/delta T cells to secret IL-17 in mice with CIA. The involvement of IL-17-producing gamma/delta T cells in SKG mice with autoimmune arthritis and patients with rheumatoid arthritis (RA) was also investigated.

Arthritis and pneumonitis produced by the same T cell clones from mice with spontaneous autoimmune arthritis.

SKG mice, a newly established model of rheumatoid arthritis (RA), spontaneously develop autoimmune arthritis accompanying extra-articular manifestations, such as interstitial pneumonitis. To examine possible roles of T cells for mediating this systemic autoimmunity, we generated T cell clones from arthritic joints of SKG mice. Two distinct CD8(+) clones were established and both showed in vitro autoreactivity by killing syngeneic synovial cells and a variety of MHC-matched cell lines.

Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model.

This report shows that interleukin (IL) 17-producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor beta and IL-6 additionally need IL-1 and neutralization of interferon (IFN) gamma and IL-4 for CCR6 expression. Forced expression of RORgamma t, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells.

T cell self-reactivity forms a cytokine milieu for spontaneous development of IL-17+ Th cells that cause autoimmune arthritis.

This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17-secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell-derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells.

Boc-Pro-Hyp-Gly-OBzl and Boc-Ala-Hyp-Gly-OBzl, two repeating triplets found in collagen.

The protected tripeptides benzyl N-{2-[N-(tert-butoxycarbonyl)prolyl]-4-hydroxyprolyl}glycinate or Boc-Pro-Hyp-Gly-OBzl, C24H33N3O7, and benzyl N-{2-[N-(tert-butoxycarbonyl)alanyl]-4-hydroxyprolyl}glycinate or Boc-Ala-Hyp-Gly-OBzl, C22H31N3O7, are the minimum repeating triplets found in collagen. Within the crystal structure of each are two independent peptide molecules with similar structures. The peptides are arranged antiparallel to one another and interact through hydrogen bonds involving the main chains and the 4-hydroxyprolyl groups.

Spontaneous development of autoimmune arthritis due to genetic anomaly of T cell signal transduction: Part 1.

A point mutation of the gene encoding ZAP-70, a key signal transduction molecule in T cells, results in spontaneous development of T cell-mediated autoimmune arthritis in mice homozygous for the mutation. The genetic anomaly alters differentiation and selection of T cells in the thymus, leading to thymic production of arthritogenic autoimmune T cells. The arthritogenic T cells persist in the periphery and elicit arthritis when activated by microbial agents that stimulate innate immunity.

Animal models of arthritis caused by systemic alteration of the immune system.

Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of rheumatoid arthritis. Several new mouse models have either been produced, including transgenics, gene-knockouts, and gene knock-ins, or established as a spontaneous disease due to natural gene mutations. These models are suitable for addressing the roles of T cells, autoantibodies, cytokines and innate immunity in the development and progression of rheumatoid arthritis.

Differentiation and elimination of uterine natural killer cells in delayed implantation and parturition mice.

To clarify the roles of uterine natural killer (uNK) cells in implantation and parturition, differentiation and elimination of uNK cells in the pregnant uterus was examined using artificial delayed implantation (DI) and delayed parturition (DP) mice. To prepare DI mice, pregnant mice were ovariectomized on the third day of pregnancy (D3) and treated with 2 mg progesterone daily. The same amount of progesterone was administered on D15 or D17 of normal pregnant mice at 24 h intervals until sampling to prepare DP mice.

Regulatory T cells in immunologic self-tolerance and autoimmune disease.

Naturally arising CD25+ CD4+ regulatory T cells play key roles in the maintenance of immunologic self-tolerance and negative control of various immune responses. The majority, if not all, of them are produced by the normal thymus as a functionally distinct T-cell subpopulation, and their generation is in part developmentally controlled. Genetic abnormality in the development and function of this population can indeed be a cause of autoimmune disease, immunopathology, and allergy in humans.

A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice.

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal beta-glucan, or purified beta-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice.

Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice.

Cytokines play key roles in spontaneous CD4(+) T cell-mediated chronic autoimmune arthritis in SKG mice, a new model of rheumatoid arthritis. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-alpha deficiency retarded the onset of arthritis and substantially reduced its incidence and severity.