Regulation Of Autoimmune Diseases Research Articles

B cells expressing CD11b effectively inhibit CD4+ T-cell responses and ameliorate experimental autoimmune hepatitis in mice.

Increasing evidence in recent years has suggested that B cells act as a crucial regulator in autoimmune diseases. However, little is known about their role in autoimmune hepatitis (AIH) and the underlying regulatory mechanisms. In this study, we show that B cells ameliorated experimental AIH (EAH) by suppressing CD4+ T-cell responses and that CD11b expression on B cells was required for the regulatory function of B cells. In vitro studies reveal that the suppressive function of CD11b was mediated by the impairment of T-cell antigen receptor (TCR) signaling transduction and the promotion of TCR down-regulation. Moreover, we show that the increased CD11b expression on B cells was interleukin (IL)-10 dependent and that additional IL-10 stimulation promoted CD11b expression on B cells, thereby enhancing B-cell regulatory effects. These findings reveal a previously unrecognized role for CD11b in B-cell regulatory function and its protective effect on EAH.

Role of myeloid-derived suppressor cells in autoimmune disease

Myeloid-derived suppressor cells (MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-based cell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.

MAIT cells in autoimmunity

Mucosal associated invariant T (MAIT) cells express a semi-invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. They are restricted by a nonpolymorphic MHC-related molecule-1 (MR1), and cells are selected in the thymus. Interestingly, MAIT cells require B cells as well as commensal flora for their peripheral expansion. MAIT cells display antimicrobial capacity. Recently, vitamin metabolites were demonstrated as antigens created by intestinal flora for MAIT cells. MAIT cells play a protective role against autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), wheras they play a pathogenic role in murine models of arthritis. In patients with autoimmune diseases, the frequency of MAIT cells in peripheral blood was significantly reduced. The frequency of MAIT cells reflected the disease activity in MS patients, suggesting the involvement of MAIT cells in the regulation of autoimmune diseases.

PReS-FINAL-2342: Anti-TNFALPHA therapy targeys PKB/C-AKT induced resistance of effector cells to suppression in juvenile arthritis

Resistance of effector T cells (Teff) to suppression contributes to disturbed immune regulation in autoimmune disease. Targeting this unresponsiveness to suppression might therefore have beneficial effects in autoimmune inflammation. In juvenile idiopathic arthritis (JIA) we have recently shown that Teff from inflamed joints are refractory to suppression, which was associated with enhanced PKB/c-akt activation in these cells.

OP0057 Anti-TNFΑ Therapy Targets PKB/C-AKT Induced Resistance of Effector Cells to Suppression in Juvenile Idiopathic Arthritis

BackgroundResistance of effector T cells (Teff) to suppression contributes to disturbed immune regulation in autoimmune disease. Targeting this unresponsiveness to suppression might therefore have beneficial effects in autoimmune inflammation1. In...

IL-22+CD4+ T-cells in patients with active systemic lupus erythematosus

Interleukin-22 (IL-22) is a regulator of autoimmune diseases. However, the role of IL-22(+)CD4(+) T-cells in the pathogenesis of systemic lupus erythematosus (SLE) remains unclear. This study is aimed at elucidating the potential role of IL-22 and IL-22(+)CD4(+) T-cells in patients with SLE. A total of 22 patients with freshly diagnosed SLE and 18 age-/gender-matched healthy controls (n = 18) were evaluated for the frequency of different types of IL-22-producing CD4(+) T-cells by flow cytometry analysis following in vitro stimulation. The concentrations of plasma IL-22, IL-17A, IFNγ, serum complement factors (C3, C4), C-reactive protein (CRP), antidouble-stranded (ds) DNA and anti-Smith (Sm) antibodies were measured. The potential association among these measures was analyzed. The percentages of IL-22(+)IL-17(-)IFNγ(-), IL-22(+)IL-17A(-)IFN-γ(+), IL-22(-)IL-17(+)IFN-γ(-) and IL-22(+)IL-17(+)IFN-γ(-) CD4(+) T-cells and the levels of plasma IL-22 and IL-17A in the patients were significantly higher than that in the healthy controls (P < 0.01). The frequency of Th22 cells was correlated positively with that of Th17 and IL-22(+)IL-17(+) CD4(+) T-cells, and the frequency of Th17 and IL-22(+)CD4(+) T-cells was correlated positively with the values of SLE disease activity index (SLEDAI), but not with the values of CRP, ERS and C3 in SLE patients. Our data suggest that both Th17 and IL-22(+)CD4(+) T-cells may participate in the pathogenesis of SLE.

The dual roles of inflammatory cytokines and chemokines in the regulation of autoimmune diseases and their clinical implications

Cytokines and chemokines are secreted, small cell-signaling protein molecules, whose receptors are expressed on immune cells. These factors play a critical role in immune cell differentiation, migration, and polarization into functional subtypes and in directing their biological functions. Much attention has been devoted to exploring the role of key inflammatory cytokines and promigratory chemokines in autoimmune, autoinflammatory, and allergic diseases, leading to development of therapeutic strategies that are based on their targeted neutralization. Recent studies, including those coming from our groups, show that several major proinflammatory cytokines and chemokines, including IFN-γ, IL-2, CCL2, and CXCL12, may also function as anti-inflammatory mediators and therefore, may have potential as anti-inflammatory drugs. Likewise, major anti-inflammatory mediators, such as TGF-β, may under certain conditions, in combination with other cytokines, exhibit proinflammatory function and direct the polarization of the highly inflammatory CD4(+) Th17 cells. We show here that the biological function of pro- and anti-inflammatory cytokines is dependent on three key parameters: the local concentration of a given cytokine, the stage of disease in which it is administered, and its combination with other cytokines. The therapeutic implications of these findings are discussed, including two very recent studies summarizing clinical trials, in which low-dose administration of IL-2 was used to successfully suppress HCV and GVHD.

Rapid, column-free two-step procedure for the enrichment of human Th17 Cells from peripheral blood (56.13)

Abstract Human Th17 cells play a critical role in the regulation of autoimmune disease and antimicrobial host defenses through production of pro-inflammatory cytokines IL17A and IL-17F. They can be characterized by expression of surface receptors including IL-23R, CCR6, CD161 and lineage-specific transcription factor RORC, but lack of CXCR3 expression. The major disadvantages of current isolation methods are the requirement for in vitro stimulation and the co-secretion of IFN-γ. We have developed a 2-step EasySepTM immunomagnetic column-free method for the enrichment of CD4+CXCR3-CCR6+ cells from fresh peripheral blood nucleated cells (PBNC). First, non-CD4 T cells and CXCR3+ cells are targeted for depletion using dextran-coated magnetic particles and a cocktail of antibody complexes. Labeled cells are separated using an EasySepTM magnet, and pre-enriched CD4 T-cells are poured off. Next, CCR6+ cells are positively selected from the pre-enriched fraction. The procedure can be automated using RoboSepTM. Starting with a frequency of 5 ± 2% CD4+CXCR3-CCR6+ cells, purities of 94 ± 3% (n=10) can be obtained. The resulting cells produce high levels of IL-17 with minimal IFN-γ when measured by ELISA and intracellular staining and increased RORC mRNA expression over total CD4 T cells and CD4+CXCR3+ T cells (Th1 cells). Enrichment of unstimulated human Th17 cells enables the investigation of adaptive immune responses and regulation mechanisms required for the development of future therapies.

Role of Inhibitory BCR Co-Receptors in Immunity

B lymphocytes (B cells) express a variety of membrane molecules containing immunoreceptor tyrosine-based inhibition motifs (ITIMs) in the cytoplasmic region such as FcγRIIB, FCRLs, CD22, mouse Siglec-G/human Siglec-10, PECAM-1, mouse PIR-B/human LIRB1 and LIRB2PD-1 and CD72. When phosphorylated, ITIMs in these molecules recruit and activate phosphatases such as SH2 domain-containing protein tyrosine phosphatase 1 (SHP-1), SHP-2, SH2 domain- containing inositol 5-phosphatase 1 (SHIP1) and SHIP2 depending on receptors. These phosphatases then negatively regulate B cell antigen receptor (BCR) signaling. Because of their ability to inhibit BCR signaling, these ITIMcontaining molecules are called inhibitory BCR co-receptors. Studies on mice deficient in an inhibitory co-receptor have demonstrated that the inhibitory co-receptors regulate B cell development, antibody responses and development of autoimmune diseases. Moreover, polymorphisms in some inhibitory co-receptors such as FcγRIIB, FCRL3 and CD72 are associated with autoimmune diseases, suggesting a crucial role of inhibitory co-receptor polymorphisms in the regulation of autoimmune diseases. The ligands for inhibitory co-receptors regulate their inhibitory activity by inducing co-ligation of the co-receptors with BCR or some other regulatory mechanisms. Inhibitory co-receptors and their ligands are therefore good targets for controlling antibody responses and autoimmune diseases.

B cells as effectors and regulators of sex-biased arthritis

B cells have been implicated both with pathogenic as well as protective capabilities in induction and regulation of autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease that occurs more often in women than men. A significant role of B cells as antibody producing and antigen-presenting cells has been demonstrated in RA. Predisposition to RA is associated with the presence of certain HLA class II alleles that share sequences with DRB1*0401. To determine the role of HLA genes and B cells in vivo, we have generated transgenic mice carrying HLA genes, DRB1*0401 and DQ8, known to be associated with susceptibility to RA. Humanized mice can be induced to develop arthritis that mimics human disease in clinical, histopathological and sex bias. Effect of hormones on immune cells and their function has been described in humans and mice and has been suggested to be the major reason for female bias of autoimmune diseases. An immune response to an antigen requires presentation by HLA molecules thus suggesting a critical role of MHC in combination with sex hormones in susceptibility to develop rheumatoid arthritis. Based on our observations, we hypothesize that modulation of B cells by estrogen, presentation of modified antigens by DR4 and production of antigen-specific B cell modulating cytokines leads to autoreactivity in females. These data suggest that considering patient's sex may be crucial in selecting the optimal treatment strategy. Humanized mice expressing RA susceptible and resistant haplotype provide a means to investigate mechanism sex-bias of arthritis and future strategies for therapy.

MAIT cells in autoimmunity

Mucosal associated invariant T (MAIT) cells are restricted by a nonpolymorphic MHC-related molecule-1 (MR1), and express an invariant TCRα chain: Vα7.2-Jα33 in humans and Vα19-Jα33 in mice. MAIT cells are selected in the thymus, but, interestingly, MAIT cells require B cells as well as commensal flora for their peripheral expansion. Bourhis et al demonstrated that MAIT cells display antimicrobial capacity. Both human and mouse MAIT cells have been shown to be activated by Escherichia coli-infected antigen presenting cells in an MR1-dependent manner. MAIT cells show a protective role against Mycobacteriu abscessus or E. coli infections in mice. Human MAIT cells are capable of producing IFNγ and IL-17 and are found in Mycobacterium tuberculosis-infected lung tissues. Thus, MAIT cells play an antimicrobial function under these infectious conditions. MAIT cells play a protective role against autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS), whereas they play a pathogenic role in murine models of arthritis. In patients with autoimmune diseases, the frequency of MAIT cells in peripheral blood was significantly reduced. The frequency of MAIT cells reflected the disease activity in MS patients, suggesting the involvement of MAIT cells in the regulation of autoimmune diseases.

In Vivo Induction of Tr1 Cells via Mucosal Dendritic Cells and AHR Signaling

BackgroundType 1 regulatory T (Tr1) cells, characterized by the secretion of high levels of the anti-inflammatory cytokine interleukin-10 (IL-10), play an important role in the regulation of autoimmune diseases and transplantation. However, effective strategies that specifically induce Tr1 cells in vivo are limited. Furthermore, the pathways controlling the induction of these cells in vivo are not well understood.Methodology/Principal FindingsHere we report that nasal administration of anti-CD3 antibody induces suppressive Tr1 cells in mice. The in vivo induction of Tr1 cells by nasal anti-CD3 is dependent on IL-27 produced by upper airway resident dendritic cells (DCs), and is controlled by the transcription factors aryl hydrocarbon receptor (AHR) and c-Maf. Subsequently, IL-21 acts in an autocrine fashion to expand and maintain the Tr1 cells induced in vivo by nasally administered anti-CD3.Conclusions/SignificanceOur findings identify a unique approach to generate Tr1 cells in vivo and provide insights into the mechanisms by which these cells are induced.

Proteinase 3 Mediates Enzyme-Independent Reversible Inhibition of CD4 and CD8 T Cell Proliferation by Blocking G1-S Transition

AbstractAbstract 2099Proteinase 3 (P3), a serine protease found in primary granules in neutrophils, is the target of T cell- and B cell-mediated autoimmunity in Wegener's granulomatosis (WG) and of anti-leukemia immunity mediated by PR1 (VLQELNVTV)-specific cytotoxic T lymphocytes (PR1-CTL). Although aberrant P3 and neutrophil elastase (NE) expression by leukemia targets increases their susceptibility to PR1-CTL-mediated killing, overexpression of P3 also induces apoptosis of the high affinity PR1-CTL leading to deletional tolerance and leukemia outgrowth. Because serum level of P3 in leukemia patients is increased by 5-fold compared to healthy controls, we sought to determine whether such overexpression impairs PR1-CTL immunity to leukemia by a direct effect on T lymphocytes. To study this, T cells from healthy donors were activated by anti-CD3 and anti-CD28 and exposed to increasing concentration of soluble P3 or NE over one to five days, and the percentage of apoptotic cells and cell proliferation were determined by flow cytometry. P3, but not NE, induced dose-dependent T-cell apoptosis and inhibition of proliferation. Specifically, after 24 hours of incubation at a high concentration of P3 ('10 μg/ml), apoptosis of CD4+ and CD8+ T-cells was increased by 50% and 70%, respectively, compared to <10% in controls (p<0.05). No apoptosis of CD4+ or CD8+ T-cells was observed at a P3 concentration ≤ 1 μg/ml. Surprisingly, however, 14% inhibition of proliferation was observed at 0.5 μg/ml of P3, which increased to >90% inhibition at 5 μg/ml and was completely abrogated at 10 μg/ml in both CD4+ and CD8+ T-cells. Inhibition was reversible as T cells proliferated once again after removing P3 from media. These effects on apoptosis or cell proliferation persist after heating of P3 to 95°C or co-incubation with the serine protease inhibitors Elafin or alpha-1 antitrypsin, suggesting enzyme-independent. However, co-incubation of P3 with a molar excess of anti-P3 monoclonal antibody (mAb) reversed P3-mediated inhibition of both CD4+ and CD8+ T cells. Furthermore, P3 mediated cell cycle arrest by maintaining T cells primarily in the G0 phase of the cell cycle and thus blocking the G1-S transition, determined with Propidium Iodide (PI) and Ki-67 labeling of anti-CD3/anti-CD28 stimulated T cells. In contrast, at protein concentrations up to 25 μg/ml, NE showed no effect on apoptosis or cell proliferation. The inhibition is also independent of the tetrapeptide IVGG that suppresses granulopoietic progenitors. Currently, we are analyzing various forms of recombinant P3 to define the structural determinants of P3 responsible for the inhibition of T-cell proliferation. Neutrophils from patients with P3 anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis and some other chronic inflammatory diseases show higher levels of membrane P3 (mP3) expression than neutrophils from healthy controls. The presence of a high proportion of mP3 expressing neutrophils is associated with more frequent relapses of WG. Co-incubation of mP3 expressing neutrophils with T cells at a ratio of 5 to 1 significantly inhibited proliferation of both CD4+ and CD8+ T cells. The inhibition of T cell proliferation by mP3 expressing neutrophils was completely abrogated when anti-P3 mAb was added. Taken together, this data supports a new enzyme-independent function of soluble and membrane-bound P3 expressed on innate immune cells in regulating adaptive T cell immunity. These findings suggest P3 that is observed in myeloid leukemia patients may down-regulate anti-leukemia immunity and may also modulate autoimmunity and inflammation that is common to many cancers. The data will be useful in understanding the biology of immune regulation in autoimmune disease and leukemia, and may be useful in therapy planning and patient monitoring. Additionally, new approaches for targeting serum P3 may provide novel methods for the treatment of leukemia and autoimmune disease. Disclosures:No relevant conflicts of interest to declare.

Identification of variant isoforms of CD44 and their functions in murine immune cells (87.6)

Abstract CD44 is known to be implicated in a variety of immunological processes such as T cell migration, activation and differentiation. CD44 comprises a standard form and a family of isoforms that vary by their degree of post-translational modifications and due to alternative splicing of their primary amino acid sequence encoded by up to 10 variant exons. The isoforms actually determine the differential functions of CD44 in various types of immune cells and immune responses. Upon activation, lymphocytes transiently express certain CD44 splice variants. However, the precise nature of CD44 variant isoforms expressed by various cells types of the immune system has not been studied thus far. In this report, we screened variant exons from exon 1 to 10 using Southern blot hybridization and identified CD44 isoforms on CD4, CD8, FoxP3+ Treg and dendritic cells, either naïve or activated with SRBC, OVA, LPS, anti-CD3 plus anti-CD28, or IL-2 respectively. The results showed distinct isoforms for each cell type that also varied based on naïve or activated status. In experimental autoimmune encephalomyelitis (EAE), targeted deletion of full CD44 sequence prevented EAE whereas sole deletion of variant 7 induced a progressive and non-remitting type of EAE. Our study, has for the first time, identified the unique CD44 isoforms expressed on murine CD4, CD8, Treg and dendritic cells and shown the differential role of CD44 variant isoforms in the regulation of autoimmune disease.

AIRE deficiency leads to impaired iNKT cell development

Autoimmune Polyendocrine Syndrome type I (APS I) is caused by mutations in the Autoimmune Regulator gene ( AIRE), and results in the immunological destruction of endocrine organs. Herein we have characterized the CD1d-restricted invariant NKT cells ( iNKT) and NK cells in APS I patients and Aire −/− mice, two cell populations known to play a role in the regulation of autoimmune disease. We show that the frequency of circulating iNKT cells is reduced in APS I patients compared to healthy controls. In accordance with this, iNKT cells are significantly reduced in the thymus and peripheral organs of Aire −/− mice. Bone marrow transfer from wild type donors into lethally irradiated Aire −/− recipients led to a decreased iNKT cell population in the liver, suggesting an impaired development of iNKT cells in the absence of Aire expression in radio-resistant cells. In contrast to the iNKT cells, both conventional NK cells and thymus-derived NK cells were unaffected by Aire deficiency and differentiated normally in Aire −/− mice. Our results show that expression of Aire in radio-resistant cells is important for the development of iNKT cells, whereas NK cell development and function does not depend on Aire.

Tracking Differential Gene Expression in MRL/MpJ versus C57BL/6 Anergic B Cells: Molecular Markers of Autoimmunity

BACKGROUND: Anergy is a key mechanism controlling expression of autoreactive B cells and a major site for failed regulation in autoimmune diseases. Yet the molecular basis for this differentiated cell state remains poorly understood. The current lack of well-characterized surface or molecular markers hinders the isolation of anergic cells for further study. Global gene profiling recently identified transcripts whose expression differentiates anergic from naïve B cells in model mouse systems. The objective of the current study was to evaluate the molecular and cellular processes that differentiate anergic cells that develop in the healthy C57BL/6 (B6) milieu from those that develop in the autoimmune-prone MRL/MpJ (MRL) background. This approach takes advantage of B6 and MRL mice bearing an anti-laminin Ig transgene with a well characterized anergic B cell phenotype. RESULTS: Global gene expression was evaluated in purified transgenic B cells using Operon version 3.0 oligonucleotide microarray assaying >31,000 oligoprobes. Genes with a 2-fold expression difference in B6 as compared to MRL anergic B cells were identified. Expression of selected genes was confirmed using quantitative RT-PCR. This approach identified 43 probes corresponding to 37 characterized genes, including Ptpn22, CD74, Birc1f/Naip, and Ctla4, as differentially expressed in anergic B cells in the two strains. Gene Ontology classification identified differentiation, cell cycle, proliferation, development, apoptosis, and cell death as prominently represented ontology groups. Ingenuity Pathway Analysis identified two major networks incorporating 27 qualifying genes. Network 1 centers on beta-estradiol and TP53, and Network 2 encompasses RB1, p38 MAPK, and NFkB cell growth, proliferation, and cell cycle signaling pathways. CONCLUSION: Using microarray analysis we identified 37 characterized genes and two functional pathways engaged in maintenance of B cell anergy for which expression is distorted by underlying autoimmune genetic susceptibility. This approach identifes a new biological role for multiple genes and potential new therapeutic targets in autoimmunity.

Invariant NKT Cells Exacerbate Type 1 Diabetes Induced by CD8 T Cells

Invariant NKT (iNKT) cells have been implicated in the regulation of autoimmune diseases. In several models of type 1 diabetes, increasing the number of iNKT cells prevents the development of disease. Because CD8 T cells play a crucial role in the pathogenesis of diabetes, we have investigated the influence of iNKT cells on diabetogenic CD8 T cells. In the present study, type 1 diabetes was induced by the transfer of CD8 T cells specific for the influenza virus hemagglutinin into recipient mice expressing the hemagglutinin Ag specifically in their beta pancreatic cells. In contrast to previous reports, high frequency of iNKT cells promoted severe insulitis and exacerbated diabetes. Analysis of diabetogenic CD8 T cells showed that iNKT cells enhance their activation, their expansion, and their differentiation into effector cells producing IFN-gamma. This first analysis of the influence of iNKT cells on diabetogenic CD8 T cells reveals that iNKT cells not only fail to regulate but in fact exacerbate the development of diabetes. Thus, iNKT cells can induce opposing effects dependent on the model of type 1 diabetes that is being studied. This prodiabetogenic capacity of iNKT cells should be taken into consideration when developing therapeutic approaches based on iNKT cell manipulation.

Cytokine signal regulation and autoimmune disorders

Understanding of biological activities of cytokines and exquisite mechanism to regulate their functions has facilitated the therapeutic concept to restore the disequilibrium between pro-inflammatory cytokines and anti-inflammatory cytokines or cytokine inhibitors in some autoimmune inflammatory diseases such as rheumatoid arthritis (RA) and Crohn's disease. The application of molecular biology techniques to design monoclonal antibodies, soluble receptors, or receptor antagonists as therapeutic biologic agents made it possible to regulate the cytokine signals for the treatment of the diseases refractory to conventional therapies.Japanese researchers have contributed considerably to the establishment of cytokine signal regulation in autoimmune diseases. In this article, Japanese studies of cytokine signal regulation, particularly for Interleukin-6 (IL-6) in autoimmune diseases are reviewed.

Immunosteroid as a regulator for Th1/Th2 balance: Its possible role in autoimmune diseases

Immune balance controlled by Th1 and Th2 cells is critical for the protection of host from pathogenic invasion while its imbalance becomes the cause of various immune disorders including autoimmune diseases. Cytokines, such as IL-12 and IL-4, are critical factor to drive the differentiation of naïve CD4+ T cells to Th1 or Th2 cells. In addition to cytokines, steroid hormones have been demonstrated to affect on the control of Th1/Th2 balance and the onset of autoimmune diseases. Here, we will propose a new concept that immunosteroid, which is designated as a steroid produced by immunoregulatory cells, also play a critical role for regulation of Th1/Th2 balance. First example of immunosteroid is Th2-dependently produced progesterone. Th2 cells, but not Th1 cells expressed P450scc and 20α-HSD and produced progesterone from 22R-hydroxycholesterol in cooperation with 3β-HSD-expressing mouse fibroblasts. Th2-dependently produced progesterone induced apoptotic cell death of Th1 cells and inhibited the differentiation of Th1 cells. While Th2 cells were escaped from toxic effect of progesterone by metabolizing it to non-toxic 20α-hydroxyprogesterone with 20α-HSD. Second example of immunosteroid is dendritic cell (DC)-dependently produced 1α,25-dihydroxyvitamin D3 [1,25(OH)2D] secosteroid hormone, which has been demonstrated to inhibit autoimmune diseases. We found that 25-hydroxyvitamin D3 1α-hydroxylase, which metabolize 25-hydroxyvitamin D3 (inactive form) to 1,25(OH)2D was expressed in Th2-cytokine induced bone marrow-derived DC2 but not Th1-cytokine induced DC1. Moreover, 1,25(OH)2D was significantly inhibited DC1-induced type1 immunity.Thus, we initially demonstrated the critical role of immunosteroids in the control of Th1/Th2 balance influencing on the onset of autoimmune diseases. Therefore, it will be an important issue to investigate the possible role of immunosteroids for the regulation of autoimmune diseases.

Infiltration of the inflamed eye by NKT cells in a rat model of experimental autoimmune uveitis

NK and NKT cells play important roles in both the pathogenesis and regulation of autoimmune disease. In this study, NK and NKT cells in the periphery and in the inflamed eyes of Lewis rats developing uveitis were quantified and evaluated for function. The number and phenotype of NK/NKT cells in the inflamed eyes and spleens were determined. The cytotoxic and suppressive activity of the eye-infiltrating NK/NKT cells was also studied. In rats with interphotoreceptor retinoid-binding protein (IRBP)-induced uveitis, the number of NK/NKT cells declined in the periphery, but increased in the eyes. The eye-infiltrating NK/NKT cells inhibited cytokine production by autoreactive T cells in vitro and had a weak cytolytic effect on NK-sensitive YAC-1 cells and NKT-sensitive U937 cells in vitro. Our study shows that the number of NK and NKT cells decreases in the periphery of rats with autoimmune uveitis. It is discussed whether the changing number of NK/NKT cells allows the escape from immune surveillance of uveitogenic (i.e. autoreactive) T cells and the development of intraocular inflammation, and the increased infiltration of the inflamed eye by suppressive NK/NKT cells favors rapid recovery from disease.