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1.  Lupus-Prone Mice Fail to Raise Antigen-Specific T Cell Responses to Intracellular Infection 
PLoS ONE  2014;9(10):e111382.
Systemic lupus erythematosus (SLE) is characterized by multiple cellular abnormalities culminating in the production of autoantibodies and immune complexes, resulting in tissue inflammation and organ damage. Besides active disease, the main cause of morbidity and mortality in SLE patients is infections, including those from opportunistic pathogens. To understand the failure of the immune system to fend off infections in systemic autoimmunity, we infected the lupus-prone murine strains B6.lpr and BXSB with the intracellular parasite Toxoplasma gondii and survival was monitored. Furthermore, mice were sacrificed days post infection and parasite burden and cellular immune responses such as cytokine production and cell activation were assessed. Mice from both strains succumbed to infection acutely and we observed greater susceptibility to infection in older mice. Increased parasite burden and a defective antigen-specific IFN-gamma response were observed in the lupus-prone mice. Furthermore, T cell:dendritic cell co-cultures established the presence of an intrinsic T cell defect responsible for the decreased antigen-specific response. An antigen-specific defect in IFN- gamma production prevents lupus-prone mice from clearing infection effectively. This study reveals the first cellular insight into the origin of increased susceptibility to infections in SLE disease and may guide therapeutic approaches.
PMCID: PMC4216089  PMID: 25360768
2.  CaMK4-dependent activation of AKT/mTOR and CREM-α underlies autoimmunity-associated Th17 imbalance 
The Journal of Clinical Investigation  2014;124(5):2234-2245.
Tissue inflammation in several autoimmune diseases, including SLE and MS, has been linked to an imbalance of IL-17–producing Th (Th17) cells and Tregs; however, the factors that promote Th17-driven autoimmunity are unclear. Here, we present evidence that the calcium/calmodulin-dependent protein kinase IV (CaMK4) is increased and required during Th17 cell differentiation. Isolation of naive T cells from a murine model of lupus revealed increased levels of CaMK4 following stimulation with Th17-inducing cytokines but not following Treg, Th1, or Th2 induction. Furthermore, naive T cells from mice lacking CaMK4 did not produce IL-17. Genetic or pharmacologic inhibition of CaMK4 decreased the frequency of IL-17–producing T cells and ameliorated EAE and lupus-like disease in murine models. Inhibition of CaMK4 reduced Il17 transcription through decreased activation of the cAMP response element modulator α (CREM-α) and reduced activation of the AKT/mTOR pathway, which is known to enhance Th17 differentiation. Importantly, silencing CaMK4 in T cells from patients with SLE and healthy individuals inhibited Th17 differentiation through reduction of IL17A and IL17F mRNA. Collectively, our results suggest that CaMK4 inhibition has potential as a therapeutic strategy for Th17-driven autoimmune diseases.
PMCID: PMC4001553  PMID: 24667640
3.  The Dysregulation of Cytokine Networks in Systemic Lupus Erythematosus 
Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune activation and tissue damage. Organ damage in SLE results from the deposition of immune complexes and the infiltration of activated T cells into susceptible organs. Cytokines are intimately involved in every step of the SLE pathogenesis. Defective immune regulation and uncontrolled lymphocyte activation, as well as increased antigen presenting cell maturation are all influenced by cytokines. Moreover, expansion of local immune responses as well as tissue infiltration by pathogenic cells is instigated by cytokines. In this review, we describe the main cytokine abnormalities reported in SLE and discuss the mechanisms that drive their aberrant production as well as the pathogenic pathways that their presence promotes.
PMCID: PMC3189553  PMID: 21877904
4.  The Role of Platelet Factor 4 in Local and Remote Tissue Damage in a Mouse Model of Mesenteric Ischemia/Reperfusion Injury 
PLoS ONE  2012;7(7):e39934.
The robust inflammatory response that occurs during ischemia reperfusion (IR) injury recruits factors from both the innate and adaptive immune systems. However the contribution of platelets and their products such as Platelet Factor 4 (PF4; CXCL4), during the pathogenesis of IR injury has not been thoroughly investigated. We show that a deficiency in PF4 protects mice from local and remote tissue damage after 30 minutes of mesenteric ischemia and 3 hours of reperfusion in PF4-/- mice compared to control B6 mice. This protection was independent from Ig or complement deposition in the tissues. However, neutrophil and monocyte infiltration were decreased in the lungs of PF4-/- mice compared with B6 control mice. Platelet-depleted B6 mice transfused with platelets from PF4-/- mice displayed reduced tissue damage compared with controls. In contrast, transfusion of B6 platelets into platelet depleted PF4-/- mice reconstituted damage in both intestine and lung tissues. We also show that PF4 may modulate the release of IgA. Interestingly, we show that PF4 expression on intestinal epithelial cells is increased after IR at both the mRNA and protein levels. In conclusion, these findings demonstrate that may PF4 represent an important mediator of local and remote tissue damage.
PMCID: PMC3391230  PMID: 22792197
5.  Inhibition of Listeria monocytogenes infection by neurological drugs 
To gain insights into the cellular processes required for intracellular bacterial pathogenesis, we previously developed a generalisable screening approach to identify small molecule compounds that alter Listeria monocytogenes infection. In this report, a small molecule library enriched for compounds affecting neurological functions was screened and 68 compounds that disrupted L. monocytogenes infection of macrophages were identified. Many of these compounds were known antimicrobial agents, however 26 compounds were novel inhibitors of intracellular infection. Two of the compounds chosen for further study, the antipsychotic drug thioridazine and the calcium channel blocker bepridil, exhibited dose-dependent inhibition of vacuolar escape and intracellular replication of L. monocytogenes during infection of murine macrophages. These results suggest that clinically approved neurological drugs may provide a novel source of anti-infective agents that are suitable for development as therapeutics against intracellular bacterial infections.
PMCID: PMC2818453  PMID: 20031379
Listeria monocytogenes; Small molecule screen; Intracellular infection; Bepridil; Neurological compounds; Thioridazine
6.  Pathogenesis of human systemic lupus erythematosus: recent advances 
Trends in molecular medicine  2010;16(2):47-57.
Systemic lupus erythematosus (SLE) is an autoimmune disease that predominantly affects women and presents with manifestations derived from the involvement of multiple organs including the kidneys, joints, nervous system, and hematopoietic organs. Immune system aberrations, as well as heritable, hormonal, and environmental factors interplay in the expression of organ damage. Recent contributions from different fields have developed our understanding of SLE and reshaped current pathogenic models. Here, we review novel information that deals with 1) genes associated with disease expression, 2) immune cell molecular abnormalities that lead to autoimmune pathology, 3) the role of hormones and sex chromosomes in the development of disease, 4) environmental and epigenetic factors thought to contribute to the expression of SLE. Finally, we emphasize molecular defects intimately associated with the disease process of SLE that represent ideal therapeutic targets and disease biomarkers.
PMCID: PMC2823952  PMID: 20138006
7.  The IL-2 Defect in Systemic Lupus Erythematosus Disease Has an Expansive Effect on Host Immunity 
IL-2 production is decreased in systemic lupus erythematosus (SLE) patients and affects T cell function and other aspects of host immunity. Transcription factors regulating IL-2 production behave aberrantly in SLE T cells. In addition to IL-2 dysregulation, other IL-2 family members (IL-15 and IL-21) are abnormally expressed in SLE. Decreased IL-2 production in SLE patients leads to many immune defects such as decreased Treg production, decreased activation-induced cell death (AICD), and decreased cytotoxicity. IL-2 deficiency results in systemic dysregulation of host immune responses in patients suffering from SLE disease.
PMCID: PMC2896881  PMID: 20625413
8.  A Small-Molecule Screen Identifies the Antipsychotic Drug Pimozide as an Inhibitor of Listeria monocytogenes Infection▿  
We developed a screening procedure to identify small-molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small-molecule library of 480 compounds with known biological functions was screened, and 21 compounds that altered the L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease the bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as the phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium, and Escherichia coli K12) was significantly inhibited in the presence of pimozide. The invasion and cell-to-cell spread of L. monocytogenes during the infection of nonprofessional phagocytic cells also was decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, the infection of BMM in a calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small-molecule compounds that affect cellular pathways that are required for intracellular bacterial pathogenesis. We also have identified pimozide, a clinically approved antipsychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.
PMCID: PMC2630664  PMID: 19015342
9.  Interleukin-15-Deficient Mice Develop Protective Immunity to Toxoplasma gondii  
Infection and Immunity  2004;72(11):6729-6732.
Previous studies have suggested an important role for interleukin-15 (IL-15) in resistance to and memory for Toxoplasma gondii infection. The studies presented here reveal that IL-15 is not required for infection-induced expansion of NK or CD8+ T cells. Furthermore, IL-15−/− mice develop long-term protective immunity to this pathogen.
PMCID: PMC523054  PMID: 15501812
10.  Susceptibility of Interleukin-2-Deficient Mice to Toxoplasma gondii Is Associated with a Defect in the Production of Gamma Interferon  
Infection and Immunity  2002;70(9):4757-4761.
Costimulation through the B7-CD28 interaction is an important second signal for T-cell activation, and previous studies have shown that CD28−/− mice infected with Toxoplasma gondii generate suboptimal CD4+ T-cell responses, associated with a defect in production of the T-cell growth factor interleukin-2 (IL-2). To address the role of IL-2 in the expansion of T cells during toxoplasmosis, IL-2−/− mice were infected with T. gondii and their ability to generate a protective T-cell response was assessed. Although IL-2−/− mice produced normal levels of IL-12p40, they had reduced levels of gamma interferon (IFN-γ) in serum, had an increased parasite burden, and succumbed to infection with T. gondii within 20 days. Fluorescence-activated cell sorter analysis revealed that, although uninfected IL-2−/− mice had an increased number of activated T cells compared with uninfected IL-2+/+ mice, following infection they were unable to further upregulate this population. Examination of the ability of splenocytes from uninfected and infected mice to produce IFN-γ revealed that IL-2−/− mice were hyporesponsive to stimulation with anti-CD3 or parasite antigen compared with wild-type mice, and the addition of IL-2 alone or in combination with IL-12 or stimulation with phorbol myristate acetate and ionomycin did not restore the production of IFN-γ. Together, these studies reveal that IL-2−/− mice are unable to generate a protective IFN-γ response following infection with T. gondii and suggest that IL-2−/− mice have an intrinsic defect in their ability to activate and expand IFN-γ-producing T cells required for resistance to T. gondii.
PMCID: PMC128219  PMID: 12183516

Results 1-10 (10)