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Nora Sarvetnick

Publications and source records attributed to Nora Sarvetnick.

At least 19 recordsLinked to original sources
PubMed2005

RNase L and double-stranded RNA-dependent protein kinase exert complementary roles in islet cell defense during coxsackievirus infection.

Coxsackievirus (CV) is an important human pathogen that has been linked to the development of autoimmunity. An intact pancreatic beta cell IFN response is critical for islet cell survival and protection from type 1 diabetes following CV infection. In this study, we show that IFNs trigger an antiviral state in beta cells by inducing the expression of proteins involved in intracellular antiviral defense. Specifically, we demonstrate that 2',5'-oligoadenylate synthetases (2-5AS), RNase L, and dsRNA-dependent protein kinase (PKR) are expressed by pancreatic islet cells and that IFNs (IFN-alpha and IFN-gamma) increase the expression of 2-5AS and PKR, but not RNase L. Moreover, our in vitro studies uncovered that these pathways play important roles in providing unique and complementary antiviral activities that critically regulate the outcome of CV infection. The 2-5AS/RNase L pathway was critical for IFN-alpha-mediated islet cell resistance from CV serotype B4 (CVB4) infection and replication, whereas an intact PKR pathway was required for efficient IFN-gamma-mediated repression of CVB4 infection and replication. Finally, we show that the 2-5AS/RNase L and the PKR pathways play important roles for host survival during a challenge with CVB4. In conclusion, this study has dissected the pathways used by distinct antiviral signals and linked their expression to defense against CVB4.

2',5'-Oligoadenylate Synthetase↗
PubMed2004

B7-2 (CD86) controls the priming of autoreactive CD4 T cell response against pancreatic islets.

The B7-1/2-CD28 system provides the critical signal for the generation of an efficient T cell response. We investigated the role played by B7-2 in influencing pathogenic autoimmunity from islet-reactive CD4 T cells in B7-2 knockout (KO) NOD mice which are protected from type 1 diabetes. B7-2 deficiency caused a profound diminishment in the generation of spontaneously activated CD4 T cells and islet-specific CD4 T cell expansion. B7-2 does not impact the effector phase of the autoimmune response as adoptive transfer of islet Ag-specific BDC2.5 splenocytes stimulated in vitro could easily induce disease in B7-2KO mice. CD4 T cells showed some hallmarks of hyporesponsiveness because TCR/CD28-mediated stimulation led to defective activation and failure to induce disease in NODscid recipients. Furthermore, CD4 T cells exhibited enhanced death in the absence of B7-2. Interestingly, we found that B7-2 is required to achieve normal levels of CD4+CD25+CD62L+ T regulatory cells because a significant reduction of these T regulatory cells was observed in the thymus but not in the peripheral compartments of B7-2KO mice. In addition, our adoptive transfer experiments did not reveal either pathogenic or regulatory potential associated with the B7-2KO splenocytes. Finally, we found that the lack of B7-2 did not induce a compensatory increase in the B7-1 signal on APC in the PLN compartment. Taken together these results clearly indicate that B7-2 plays a critical role in priming islet-reactive CD4 T cells, suggesting a simplified, two-cell model for the impact of this costimulatory molecule in autoimmunity against islets.

Adoptive Transfer↗
PubMed2004

Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice.

The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.

Animals↗
PubMed2004

Homeostatic expansion of T cells during immune insufficiency generates autoimmunity.

During illness and stress, the immune system can suffer a considerable loss of T cells (lymphopenia). The remaining T cells undergo vigorous compensatory expansion, known as homeostatic proliferation, to reconstitute the immune system. Interestingly, human diseases of autoimmune etiology often present with immune deficiencies such as lymphopenia. In this study, we show that reduced T cell numbers and the resulting exaggerated homeostatic-type proliferation of T cells generate autoimmunity. The cycling T cell population is short lived, and the depleted memory compartment fuels the generation of new effector T cells. A catalyst for these phenomena is the increased responses to the cytokine IL-21, a mediator that regulates T cell turnover. We conclude that poor T cell survival and lymphopenia precipitate autoimmune disease.

Animals↗
PubMed2004

Terminal deoxynucleotidyltransferase deficiency decreases autoimmune disease in diabetes-prone nonobese diabetic mice and lupus-prone MRL-Fas(lpr) mice.

The wide diversity of the T and B Ag receptor repertoires becomes even more extensive postneonatally due to the activity of TdT, which adds nontemplated N nucleotides to Ig and TCR coding ends during V(D)J recombination. In addition, complementarity-determining region 3 sequences formed in the absence of TdT are more uniform due to the use of short sequence homologies between the V, D, and J genes. Thus, the action of TdT produces an adult repertoire that is both different from, and much larger than, the repertoire of the neonate. We have generated TdT-deficient nonobese diabetic (NOD) and MRL-Fas(lpr) mice, and observed a decrease in the incidence of autoimmune disease, including absence of diabetes and decreased pancreatic infiltration in NOD TdT(-/-) mice, and reduced glomerulonephritis and increased life span in MRL-Fas(lpr) TdT(-/-) mice. Using tetramer staining, TdT(-/-) and TdT(+/+) NOD mice showed similar frequencies of the diabetogenic BDC 2.5 CD4(+) T cells. We found no increase in CD4(+)CD25(+) regulatory T cells in NOD TdT(-/-) mice. Thus, TdT deficiency ameliorates the severity of disease in both lupus and diabetes, two very disparate autoimmune diseases that affect different organs, with damage conducted by different effector cell types. The neonatal repertoire appears to be deficient in autoreactive T and/or B cells with high enough affinities to induce end-stage disease. We suggest that the paucity of autoreactive specificities created in the N region-lacking repertoire, and the resultant protection afforded to the newborn, may be the reason that TdT expression is delayed in ontogeny.

Animals↗
PubMed2004

Increased islet antigen presentation leads to type-1 diabetes in mice with autoimmune susceptibility.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is frequently used in preclinical and clinical protocols to modulate autoimmune responses, bone marrow transplants, and recovery from immune ablative therapies. The immunological outcome of such therapies is not fully understood. We tested the hypothesis that GM-CSF would enhance the maturation of antigen-presenting cells, facilitating presentation of beta-cell autoantigens to autoreactive T cells. We found that islet expression of GM-CSF greatly enhanced disease in male mice. Islet-derived APC but not splenic APC showed markedly enhanced capacity to stimulate in vitro proliferative responses of islet-antigen-specific autoreactive T cells. In vivo transfer of CD8(+) and CD4(+) T cells demonstrate that autoreactive T cells undergo extensive division in pancreatic lymph nodes of GM-CSF-transgenic mice compared with wild-type NOD male mice. Together, the results presented here demonstrate that expression of GM-CSF in the pancreas can enhance autoimmunity in disease-susceptible mice.

Adoptive Transfer↗
PubMed2004

Coxsackieviral-mediated diabetes: induction requires antigen-presenting cells and is accompanied by phagocytosis of beta cells.

Epidemiological studies have associated coxsackie B virus (CBV) with the development of insulin-dependent diabetes mellitus (IDDM) in humans. Infections of genetically susceptible mice with CBV strain 4 (CB4) induce autoimmune diabetes. Herein, we demonstrate that in mice, CB4 infection of insulin-producing pancreatic beta cells does not directly cause beta cell death. Instead, we observed the phagocytosis of beta cells by macrophages following infection. Further, antigen-presenting cells isolated from CB4-infected mice induced diabetes upon adoptive transfer. Therefore, the specificity of CB4 for infection of beta cells leads indirectly to the development of IDDM. This generalized mechanism suggests that macrophages are the initiating pathogenic cell type during virus-mediated autoimmune diabetes and that multiple environmental agents specific for beta cells could cause IDDM.

Animals↗
PubMed2004

Peptide specific amelioration of T cell mediated pathogenesis in murine type 1 diabetes.

NOD mice spontaneously develop insulitis and type 1 diabetes (T1D) mellitus similar to humans. Insulitis without overt disease occurs in the BDC2.5 TCR-transgenic NOD mice that express the rearranged TCR alpha- and beta-chain genes of a diabetogenic T cell clone reactive to an unknown beta cell autoantigen. A previous study identified an extensive panel of peptides that are highly active in stimulating T cells from transgenic BDC2.5 mice in culture. However, none of these peptides cause active disease in NOD and BDC2.5 animals or in NOD recipients of adoptively transferred BDC2.5 T cells following direct immunization in vivo. We show that direct immunization of transgenic BDC2.5 mice causes many BDC2.5 T cells to become activated and apoptotic. Strikingly, soluble peptides administered to recipients of activated, highly pathogenic BDC2.5 T cells results in protection from disease. These results suggest that high affinity peptide analogues of autoimmune epitopes might be useful as therapeutic modulators in active autoimmune disease.

Animals↗
PubMed2004

The role of NK cells and NK cell receptors in autoimmune disease.

Natural killer (NK) cells are the first line of defense against infection and transformation. Additionally, NK cells can play seemingly opposite roles in autoimmune disease. Here, we summarize the functions of NK cells as both regulators and inducers of autoimmune disease. The role NK cells play depends on which cells become targets for NK cell attack. The activity of NK cells is controlled by inhibitory receptors specific for MHC Class I molecules, and by activating receptors with diverse specificities. The ligands for both activating and inhibitory receptors are present on potential target cells. It is the balance in expression of these different ligands that determines NK cell activation and therefore whether the cell becomes a target for NK cell-mediated killing. We further discuss the roles of NK cell receptors and their ligands in autoimmune disease.

Animals↗
PubMed2004

Inhibition of activin signaling induces pancreatic epithelial cell expansion and diminishes terminal differentiation of pancreatic beta-cells.

Activins regulate the growth and differentiation of a variety of cells. During pancreatic islet development, activins are required for the specialization of pancreatic precursors from the gut endoderm during midgestation. In this study, we probed the role of activin signaling during pancreatic islet cell development and regeneration. Indeed, we found that both activins and activin receptors are upregulated in duct epithelial cells during islet differentiation. Interestingly, the expression of endogenous cellular inhibitors of activin signaling, follistatin and Cripto, were also found to be augmented. Inhibition of activins significantly enhanced survival and expansion of pancreatic epithelial cells but decreased the numbers of differentiated beta-cells. Our results suggest that the homeostasis of growth and terminal differentiation requires a precise context-dependent regulation of activin signaling. Follistatin participates in this process by promoting expansion of precursor cells during pancreas growth.

Activin Receptors↗
PubMed2004

Peptides from common viral and bacterial pathogens can efficiently activate diabetogenic T-cells.

Cross-reactivity between an autoantigen and unknown microbial epitopes has been proposed as a molecular mechanism involved in the development of insulin-dependent diabetes (type 1 diabetes). Type 1 diabetes is an autoimmune disease that occurs in humans and the nonobese diabetic (NOD) mouse. BDC2.5 is an islet-specific CD4+ T-cell clone derived from the NOD mouse whose natural target antigen is unknown. A biometrical analysis of screening data from BDC2.5 T-cells and a positional scanning synthetic combinatorial library (PS-SCL) was used to analyze and rank all peptides in public viral and bacterial protein databases and identify potential molecular mimic sequences with predicted reactivity. Selected sequences were synthesized and tested for stimulatory activity with BDC2.5 T-cells. Active peptides were identified, and some of them were also able to stimulate spontaneously activated T-cells derived from young, pre-diabetic NOD mice, indicating that the reactivity of the BDC2.5 T-cell is directed at numerous mouse peptides. Our results provide evidence for their possible role as T-cell ligands involved in the activation of diabetogenic T-cells.

Adoptive Transfer↗
PubMed2003

The stromal cell-derived factor-1alpha/CXCR4 ligand-receptor axis is critical for progenitor survival and migration in the pancreas.

The SDF-1alpha/CXCR4 ligand/chemokine receptor pair is required for appropriate patterning during ontogeny and stimulates the growth and differentiation of critical cell types. Here, we demonstrate SDF-1alpha and CXCR4 expression in fetal pancreas. We have found that SDF-1alpha and its receptor CXCR4 are expressed in islets, also CXCR4 is expressed in and around the proliferating duct epithelium of the regenerating pancreas of the interferon (IFN) gamma-nonobese diabetic mouse. We show that SDF-1alpha stimulates the phosphorylation of Akt, mitogen-activated protein kinase, and Src in pancreatic duct cells. Furthermore, migration assays indicate a stimulatory effect of SDF-1alpha on ductal cell migration. Importantly, blocking the SDF-1alpha/CXCR4 axis in IFNgamma-nonobese diabetic mice resulted in diminished proliferation and increased apoptosis in the pancreatic ductal cells. Together, these data indicate that the SDF-1alpha-CXCR4 ligand receptor axis is an obligatory component in the maintenance of duct cell survival, proliferation, and migration during pancreatic regeneration.

Animals↗
PubMed2003

Coxsackievirus-mediated hyperglycemia is enhanced by reinfection and this occurs independent of T cells.

The induction of autoimmunity by viruses has been hypothesized to occur by a number of mechanisms. Coxsackievirus B4 (CB4) induces hyperglycemia in SJL mice resembling diabetes in humans. While virus is effectively cleared within 2 weeks, hyperglycemia does not appear until about 8-12 weeks postinfection at a time when replicative virus is no longer detectable. In SJL mice, reinfection with CB4 enhanced the development of hyperglycemia. As predicted, the immune system responded more rapidly to the second infection and virus was cleared more swiftly. However, while infiltrating T cells were found within the pancreas, depletion of the CD4 T cell population prior to secondary infection or use of CD8 knock-out mice had no effect on the development of virus-mediated hyperglycemia. In conclusion, enhanced hyperglycemia induced by CB4 occurs independent of the T cell response.

Animals↗
PubMed2003

Th1 and Th2 pancreatic inflammation differentially affects homing of islet-reactive CD4 cells in nonobese diabetic mice.

The control of lymphocyte recruitment to the site of inflammation is an important component determining the pathogenicity of an autoimmune response. Progression from insulitis to diabetes in the nonobese diabetic mouse is typically associated with Th1 pancreatic inflammation, whereas Th2 inflammation can seemingly be controlled indefinitely. We show that a Th1 (IFN-gamma) pancreatic environment greatly accelerates the recruitment of adoptively transferred islet-specific CD4 T cells to the islets and also accelerates the onset of diabetes. The increased number of islet-reactive T cells in the pancreas does not result from increased proliferation or a decreased rate of apoptosis; instead, it appears to be caused by a greatly facilitated rate of entry to the pancreas. In contrast, a Th2 (IL-4) pancreatic environment does act to enhance Ag-specific proliferation and decrease the rate of apoptosis in islet-specific CD4 T cells. Nonpathogenic/regulatory cells are not preferentially expanded by the presence of IL-4. Increased recruitment to the islets was also observed in the presence of IL-4, but to a lesser extent than in the presence of IFN-gamma, and this lesser increase in the rate of recruitment did not accelerate diabetes onset within the time period examined. Therefore, the production of Th1 cytokines by initial islet-infiltrating cells may cause a greater increase than Th2 cytokines in the rate of recruitment of activated T cells. This difference in rate of recruitment may be critical in determining whether the initial infiltrate proceeds to diabetes or whether a steady state insulitis develops that can be maintained.

Animals↗
PubMed2003

Cytokines and autoimmunity: redundancy defines their complex nature.

Cytokines are critical mediators in autoimmunity and a better understanding of their mode of action should contribute to the development of strategies for controlling harmful autoimmune reactions. Their complicated nature makes it difficult to classify them as pro- or anti-inflammatory mediators; redundancy in their mode of action has been widely reported. Their complexity is further exemplified by the fact that several cytokines display redundancy in their receptor usage, with the recently identified IL-12 and IL-10 families being prototypical examples. Several aspects--including kinetics of expression, mode of induction, regulation of receptor expression and competition for occupancy, and the stage (acute vs chronic) of the disease--are critical to the net effect, and all these aspects need to be understood if we are to define a cytokine's whole nature.

Animals↗
PubMed2003

Autoimmunity.

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Animals↗