Th17 cells in inflammation and autoimmunity.

T helper 17 (Th17), a distinct subset of CD4(+) T cells with IL-17 as their major cytokine, orchestrate the pathogenesis of inflammatory and autoimmune diseases. Dysregulated Th17 cells contribute to inflammatory and autoimmune diseases. Candidate biologics are in development for targeting IL-17, IL-17 receptors or IL-17 pathways.

The role of miRNA in inflammation and autoimmunity.

miRNAs are small non-coding RNA molecules that modulate the expression of multiple protein-encoding genes at the post-transcriptional level. They have recently been recognized as powerful regulators of numerous genes and pathways in the pathogenesis of inflammatory and autoimmune diseases. The targets of most miRNAs remain unknown and their roles in biological processes such as cell differentiation, proliferation, and death (apoptosis) are not clearly understood.

PD-1, gender, and autoimmunity.

Programmed death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are responsible for inhibitory T cell signaling that helps mediate the mechanisms of tolerance and immune homeostasis. The PD-1:PD-L signaling pathway has been shown to play an important role in a variety of diseases, including autoimmune conditions, chronic infection, and cancer. Recently, investigators have explored the role of sex hormones in modulating the pathway in autoimmune conditions.

CD8+ Tregs in lupus, autoimmunity, and beyond.

While CD4(+)CD25(high) regulatory T cells (Tregs) have garnered much attention for their role in the maintenance of immune homeostasis, recent findings have shown that subsets of CD8(+) T cells (CD8(+) Tregs) display immunoregulatory functions as well. Both CD4(+) Tregs and CD8(+) Tregs appear impaired in number and/or function in several autoimmune diseases and in experimental animal models of autoimmunity, suggesting the possibility of immunotherapeutic targeting of these cells for improved management of autoimmune conditions. Our group has developed a strategy to induce CD8(+) Tregs in autoimmune mice through the use of a tolerogenic self-peptide, and new information has been gained on the phenotype, function and role of induced CD8(+) Tregs in autoimmunity.

Tuning immune suppression in systemic autoimmunity with self-derived peptides.

A central pathologic mechanism in systemic autoimmune diseases with chronic inflammation such as systemic lupus erythematosus (SLE) is the aberrant production of antibodies against self-components produced by abnormal B cells with the help of hyperactive CD4(+)T cells. One goal for better control of the disease is the limitation of the number of abnormal and hyperactive cells, to prevent and/or attenuate the damaging effects of the pathogenic antibodies on target tissues. Recently, a role of regulatory T cells in the suppression of autoimmune reactivity in diseases including SLE has been recognized.

Induction of immune tolerance by activation of CD8+ T suppressor/regulatory cells in lupus-prone mice.

Multiple CD8(+) suppressive T cell (Ts) subtypes are now recognized as essential regulators of the immune system that prevent autoimmunity through secretion of multiple cytokines and the subsequent inhibition of effector lymphocyte function. CD8(+) Ts are an exciting area of study because of the possible therapeutic implications of inducing suppressive cells that are able to subdue or anergize autoimmune manifestations. Current research in systemic lupus erythematosus (SLE), a disease in which most effective therapies are widely immunosuppressive, is often focused on novel and highly targeted ways in which to treat this multiorgan disease.

pConsensus peptide induces tolerogenic CD8+ T cells in lupus-prone (NZB x NZW)F1 mice by differentially regulating Foxp3 and PD1 molecules.

Systemic lupus erythematosus is an autoimmune disease caused primarily by autoantibodies (including IgG anti-DNA) and immune complexes that cause tissue damage. After tolerization with an artificial peptide (pConsensus, pCons) based on murine anti-DNA IgG sequences containing MHC class I and class II T cell determinants, lupus-prone (NZB x NZW)F(1) female (BWF(1)) mice develop regulatory CD4+CD25+ T cells and inhibitory CD8+ T cells, both of which suppress anti-DNA Ig production and immune glomerulonephritis. In the present work, we show that splenocytes from BWF(1) mice treated with pCons had significant expansion of primarily CD8+ T cells.

CD8+ T cell-mediated suppression of autoimmunity in a murine lupus model of peptide-induced immune tolerance depends on Foxp3 expression.

Systemic lupus erythematosus is an autoimmune disease caused by autoantibodies, including IgG anti-DNA. New Zealand Black/New Zealand White F(1) female mice, a model of spontaneous polygenic systemic lupus erythematosus, tolerized with an artificial peptide (pConsensus) based on anti-DNA IgG sequences containing MHC class I and class II T cell determinants, develop regulatory CD4+CD25+ T cells and CD8+ inhibitory T cells (CD8+ Ti), both of which suppress autoantibody production. CD8+ Ti inhibit primarily via secretion of TGF-beta.

Tolerogenic treatment of lupus mice with consensus peptide induces Foxp3-expressing, apoptosis-resistant, TGFbeta-secreting CD8+ T cell suppressors.

Lupus-prone (NZB x NZW)F1 mice spontaneously develop elevated titers of anti-DNA Abs that contain T cell determinants in their V(H) regions. We have previously shown that tolerization with an artificial peptide based on these T cell determinants (pConsensus (pCons)) can block production of anti-DNA Abs and prolong survival of the mice. In this study, we show that this protection depends in part on the generation of peripheral TGFbeta- and Foxp3-expressing inhibitory CD8+ (Ti) cells.

Mapping behavioral traits by use of genome-tagged mice.

Objective: Complex trait mapping has been widely used to analyze the genetics of behavior. However, the approach has some disadvantages, including poor gene localization and low replicability. Genome-tagged mice (GTMs) are sets of congenic mouse strains that span the entire mouse genome and are a promising reagent for localization of genes contributing to behavior.

Identifying loci for behavioral traits using genome-tagged mice.

Identification of behavioral loci through complex trait mapping remains a widely employed approach but suffers from poor gene localization and low replicability. Genome-tagged mice (GTMs) are overlapping sets of congenic strains spanning the whole genome and offer the possibilities of superior mapping power and reproducibility. In this study, three GTM strains each consisting of an average approximately 27 cM DBA/2J genomic intervals introgressed onto a C57BL/6J background were employed for localization of behavioral traits.

Ligation of HLA class I molecules on endothelial cells induces phosphorylation of Src, paxillin, and focal adhesion kinase in an actin-dependent manner.

The development of chronic rejection is the major limitation to long-term allograft survival. HLA class I Ags have been implicated to play a role in this process because ligation of class I molecules by anti-HLA Abs stimulates smooth muscle cell and endothelial cell proliferation. In this study, we show that ligation of HLA class I molecules on the surface of human aortic endothelial cells stimulates phosphorylation of Src, focal adhesion kinase, and paxillin.

The role of IL-18 in blood-stage immunity against murine malaria Plasmodium yoelii 265 and Plasmodium berghei ANKA.

A possible protective role of IL-18 in host defense against blood-stage murine malarial infection was studied in BALB/c mice using a nonlethal strain, Plasmodium yoelii 265, and a lethal strain, Plasmodium berghei ANKA. Infection induced an increase in mRNA expression of IL-18, IL-12p40, IFN-gamma, and TNF-alpha in the case of P. yoelii 265 and an increase of IL-18, IL-12p40, and IFN-gamma in the case of P.