Browsing by Subject "Autoimmunity"
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Item Epistatic Interactions in the Suppression of Autoimmunity(2005-08-11) Subramanian, Srividya; Wakeland, Edward K.Sle1 is a susceptibility locus for autoimmunity derived from the lupus-prone NZM2410 mouse. The NZW-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of anti-chromatin autoantibodies mediated by Sle1 on the B6 background. Fine-mapping of Sles1 with truncated congenic intervals localized it to a ~956 KB segment on mouse chromosome 17. Sles1 completely abrogated the development of activated lymphocyte populations in B6.Sle1, but splenic B cells from B6.Sle1|Sles1 still exhibited intrinsic ERK phosphorylation. Classic genetic complementation tests using the non-autoimmmune 129/SvJ mouse, suggests that this strain possesses a Sles1 allele complementary to NZW, as evidenced by the lack of autoimmunity in [129 XB6.Sle1|Sles1]F1s. These findings localized and characterized the suppressive properties of Sles1 and implicated 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene. In contrast, introduction of the suppressive modifiers Sles2 and Sles3 onto B6.Sle1 led to a decrease in the penetrance and mean titres of autoantibody production, but not complete suppression. These results suggested that genes, such as Sles1, which can specifically modify the effects of susceptibility alleles causing a breach in tolerance, could prevent systemic autoimmunity, even in the presence of additional susceptibility genes. To test this hypothesis we introduced the Sle1-specific suppressive locus Sles1 onto two different lupus-prone models: B6.Sle1|yaa and B6.Sle1|Sle2|Sle3/5, to determine whether and how Sles1 mediated suppression of Sle1 impacts the highly penetrant systemic autoimmunity characteristic of these two mouse strains. Comparing the development of a variety of pathological, immunological, functional and molecular phenotypes between the B6.Sle1|yaa and 6.Sle1|Sles1|yaa strains at different ages, revealed that Sles1 mediated a profound and complete suppression of systemic autoimmunity in this model. In contrast, the introduction of Sles1 onto the B6.Sle1|Sle2|Sle3/5 strain improved survival, and altered the kinetics of disease, but did not completely suppress disease in this model. These data suggest that the nature of the additional susceptibility loci interacting with Sle1 influences the degree of Sles1-mediated epistatic suppression of Sle1. Further characterization of these different models will help identify specific pathways Sles1 impacts, and provide insight into potential therapeutic strategies.Item Haplotype-Specific Effects of the Slam/Cd2 Family on the Immune Response(2007-05-22) Nguyen, Charles Minh; Wakeland, Edward K.The Sle1b susceptibility interval mediates a breach in tolerance to nuclear antigens in the NZM2410 model of systemic lupus erythematosus (SLE). Congenic B6 mice carrying the Sle1b locus produce anti-nuclear autoantibodies (ANAs) but do not develop lupus nephritis as seen in the parental NZM2410 strain. Fine mapping of the Sle1b locus placed it within a 900kb interval between 171.3 and 172.2Mb on chromosome 1. A Bacterial Artificial Chromosome (BACs) contig that spanned the interval was constructed, and a tiling pathway comprised of six BACs was sequenced. Sequence analysis revealed a dense region of 24 expressed genes. Expression studies determined numerous polymorphisms between B6 and the B6.Sle1b congenic and identified a cluster of genes known as the Slam/CD2 family as the primary candidates for Sle1b. These immunoregulatory receptors play a role in intercellular interactions and regulate function in several immune cell lineages. Of the seven family members within the locus, Ly108 appears to be the strongest candidate as B6.Sle1b shows a differential expression in isoforms. Ly108-1 is highly expressed, while Ly108-2 is expressed at much lower level in the congenic when compared to B6. When lymphocytes are stimulated, Ly108-2 is strongly up-regulated in B6, but not B6.Sle1b. Sequence analysis of the extra-cellular immunoglobulin domains of the Slam/CD2 family revealed two stable haplotypes in a panel of 33 common inbred strains of mice. The first haplotype is only found in B6 and other C57- related strains. The more common second haplotype is found in Sle1b and other autoimmune strains such as MRL, NOD, and NZB, as well as non-autoimmune strains such as 129Sv and Balb/c. The presence of this haplotype on B6 mediates autoimmunity as B6 congenics carrying the Sle1b locus from 129Sv also produce ANAs. Signaling studies on both B6.Sle1b and B6.129 reveal an altered pattern of calcium mobilization upon stimulation in T cells. In addition, CD4 T cells from B6.Sle1b demonstrate a reduction in IL-4 expression and secretion upon activation, suggesting that haplotype 2 of the Slam/CD2 family alters the immune response in T cells. Studies to understand the mechanisms by which this haplotype mediates autoimmunity are in progress.Item Inborn errors of immunity: clinical immunology at UT Southwestern(2023-03-03) Wysocki, ChristianItem Inflammasome-Independent Interleukin-1 Beta Drives CD4 T Cell Effector Function and Autoimmune Inflammation(2019-03-26) Jain, Aakanksha; Hooper, Lora V.; Pasare, Chandrashekhar; Malter, James; Conrad, Nicholas; Satterthwaite, Anne B.Successful generation of protective immunity is a result highly orchestrated interactions between the innate and the adaptive arms of the immune system. Innate immune cells sense the infectious threat to the host and convert it into meaningful information that is relayed to T and B cells. This relaying of information is the fundamental principle that forms the basis of all protective immune responses and is referred to as the innate control of adaptive immunity. For naïve CD4 T cell activation, innate control is exerted by the three-signal paradigm which dictates that a productive naïve CD4 T cell response requires TCR activation, co-stimulation and innate cytokine cues. The present work uncovers two consequential yet previously unknown aspects of the innate and adaptive immune, specifically dendritic cell (DC)-T cell, crosstalk. First, I found that in addition to naïve CD4 T cell activation, the three-signal paradigm continue to operate during the reactivation phase of memory CD4 T cells. Memory CD4 T cell reactivation was presumed to be independent of innate cytokine cues however, I found that signaling through interleukin (IL)-1 receptor family is required for effector cytokine production by memory CD4 T cells. Mechanistically, IL-1R signaling provides post-transcriptional stability to T cell cytokine transcripts thereby enabling productive secretion of these cytokines. Second, I discovered that DC-T cell interaction is significantly more bidirectional than previously appreciated. Innate cells such as DCs, have evolved to sense "non-self" or "altered-self" ligands via pattern recognition receptors (PRRs) and get activated only in case of pathogen invasion or tissue damage. Surprisingly, I found that autoreactive T cells can also instruct DCs to become activated independent of PRR activation. During their cognate interaction, T cell engage Tumor necrosis factor superfamily (TNFRSF) signaling in DCs to trigger innate cytokine secretion. I particularly, focused on the mechanism of IL-1β production during DC-T cell interaction as IL-1β is mediator of several autoimmune and autoinflammatory diseases. While IL-1β production is commonly attributed to inflammasome activation in autoimmune diseases, I show that that autoreactive T cells elicit IL-1β production by DCs in an inflammasome-independent manner via TNFR-Fas signaling pathway. Furthermore, this novel mechanism of IL-1β secretion drives CD4 T cell effector function, systemic leukocyte infiltration as well as autoimmune inflammation. Altogether, the findings in this dissertation provide a conceptual leap in our understanding of innate and adaptive immune cross-talk, and necessitates revisiting the established paradigm of innate signaling requirements for myeloid cell activation as well as CD4 T cell function. In addition, this work has vast implications on human health as it sheds light on the previously poorly understood mechanism of action of IL-1R blockade therapy as well as offers novel targets for therapeutic intervention of IL-1β mediated autoimmune inflammation.Item The molecular basis of autoimmunity(1987-04-30) Smiley, J. DonaldItem Multiple Toll-Like Receptor Agonists Act as Potent Adjuvants in the Induction of Autoimmunity(2005-12-20) Hansen, Baranda Santeri; Racke, Michael K.Multiple sclerosis (MS) is an inflammatory disease of the CNS. Infections can trigger or exacerbate the course of MS, and many agents, both bacterial and viral, have been implicated. These agents are recognized by the innate immune system via pathogen-associated molecular patterns (PAMPs) activating Toll-like receptors (TLRs) on host cells. I investigated the role that PAMPs play in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS. Both genetic and environmental influences contribute to the pathogenesis of MS. I used various PAMPs as the environmental input to imitate infection and activate TLRs in an effort to induce EAE in a resistant mouse strain. To further elucidate the impact of infection on EAE, I examined the role of various TLR agonists in the development of autoimmunity using direct immunization and adoptive transfer of encephalitogenic T cells. Mice developed EAE following immunization with myelin antigen emulsified in IFA with various PAMPs, indicating that various PAMPs can participate as the adjuvant necessary to induce EAE. I also examined the effect of PAMPs on APC activation and found that DCs pulsed with antigen and activated with the TLR agonist LPS enhanced the stimulation of antigen-specific immune cells. Conversely, tolerizing mice to a particular PAMP inhibited the ability of those mice to develop EAE following direct immunization with that PAMP and Ag. To determine the role of the Toll/IL-1 pathway in the target organ, Myelin Basic Protein (MBP) Ac1-11-specific T cells were adoptively transferred into both wild type and IRAK1-deficient mice and disease was monitored in both groups, with the results suggesting that signaling through TLR is not required in the target organ to develop disease. These results suggest that PAMPs play an important role in priming of autoreactive T cells in EAE and potentially MS.Item The non-calciotropic actions of vitamin D: modulation of cardiovascular, immune and proliferative disorders(2007-11-30) Maalouf, NaimItem Item NZB/BINJ and NZW/LACJ Embryonic Chimeras Develop Strong Autoimmunity Dependent on NZB/BINJ T Cells(2018-09-25) Hankins, Julia Dee; Satterthwaite, Anne B.; Beutler, Bruce; Monson, Nancy L.; Theofilopoulos, ArgyriosThe NZB/NZW F1 hybrid develops systemic lupus erythematosus (SLE), displaying features of human disease including spontaneous anti-nuclear antibodies, glomerulonephritis, earlier and more penetrant expression of disease in females, and polygenic etiology. The autoimmunity that develops in these mice must result from epistatic interactions between NZB and NZW alleles at specific loci in the hybrid mice. However, the causative alleles and pathways have remained elusive. In the present study we sought to determine whether incompatibility between cells of the two parental strains causes autoimmunity. We generated chimeras (here designated NZB;NZW) by injecting embryonic stem cells from NZB/BINJ (NZB) mice into NZW/LacJ (NZW) blastocysts. These chimeras developed an accelerated form of autoimmunity characterized by the presence of autoantibodies 3 months earlier, and at titers 10-fold greater, than the NZB/NZW F1 hybrids. The chimeras also developed mild glomerulonephritis and severe lymphadenopathy and splenomegaly. The observed cellular incompatibility was specific for the NZB;NZW combination (not observed in NZB;C57BL/6J or NZW;C57BL/6J), and occurred despite the fact that each parental type does not develop SLE features in a non-chimeric environment. Within each chimera, an expansion of activated T cells from the NZB strain and a predominance of B cells from NZW were observed. Furthermore, the expanded NZB T cells correlated with autoimmunity, and removing these T cells in NZB(Cd3e-/-);NZW chimeras prevented disease. Thus, NZB and NZW cells are inherently incompatible with one another, though compatible with C57BL/6J cells. Pathogenic intercellular transactions cause this strong autoimmunity in chimeric mice, dependent upon the presence of NZB T cells.Item The Roles of Ly108, the Genetic Susceptibility Loci Sle3, and CXCR4/CXCL12 in Systemic Lupus Erythematosus(2011-08-10) Wang, Andrew; Wakeland, Edward K.Ly108, in the NZM2410-derived Sle1b locus, was identified to play a key role in thymic selection. B6.Sle1b thymocytes displayed aberrant cell-surface Ly108 expression and decreased sensitivity to CD3-induced cell-death. Significant V-ß usage was found in B6.Sle1b versus B6 thymocytes. Simultaneous administration of OVA and anti-Ly108 antibody led to complete protection of OVA-induced deletion in B6.Sle1b.OTII mice but not in B6.OTII controls. Significant differences between B6 and B6.Sle1b were found in the amount of Ly108 phosphorylation and subsequent SAP-binding. Calm2 was found to be differentially expressed in B6.Sle1b thymocytes following Ly108 cross-linking. B6.Sle1b thymocytes were shown to flux less calcium, as result of modulated intracellular stocks of calcium, and, be more arrested in G1-phase following Ly108 engagement compared to B6, leading to an overall reduction in thymic apoptosis. These data suggest that the autoimmune form of Ly108 impairs thymic tolerance by dampening CD3-signaling and disrupting a G1-S cell-cycle checkpoint. Sle3, an NZM2410-derived susceptibility locus, mediates transition from benign to fatal autoimmunity. Sle3 was mapped to two main sub-loci, Sle3a and Sle3b. Sle3b was mapped to a 3.4 Mb interval containing Klf13, which has a known role in regulating RANTES. We found that Klf13 mRNA expression was significantly increased and that B6.Sle3 macrophages secreted roughly 2-fold more RANTES compared to B6. Co- culture of B6.Sle3 macrophages with blocking antibody to RANTES reversed the hyperactivation phenotype to B6 levels, indicating that increased RANTES secretion due to a genetic lesion in Klf13 could be responsible for the hyperactivation of macrophages seen in B6.Sle3. Polymorphisms in Klf13 were shown to be associated with human SLE. A significant dysregulation of the CXCR4/CXCL12 axis was observed in multiple murine models of spontaneous lupus. Increased CXCR4 expression in lupus mice led to functional differences, including increased migration to positive CXCL12 gradients. Simultaneously, the ligand for CXCR4, CXCL12, was significantly upregulated in the nephritic kidneys. To assess the contribution of CXCR4/CXCL12 upregulation on lupus pathogenesis, mice were treated with a peptide antagonist of CXCR4. Both preventive and therapeutic administration of CXCR4 blockade resulted in reduced renal infiltration by inflammatory myeloid cells and prolonged survival. Finally, increased renal CXCL12 expression and increased immune-cell CXCR4 expression was also observed in human SLE. These findings underscore the pathogenic role of CXCR4/CXCL12 in lupus nephritis and highlight this axis as a new and promising therapeutic target in this disease.Item Soluble Peptide Treatment Reverses CD8 T Cell-Induced Disease in a Mouse Model of Spontaneous Tissue-Selective Autoimmunity(2011-10-25) Paek, So Yeon; Katz, Stephen I.Autoimmunity is a complex process that involves recognition of self antigens by autoreactive T cells or tissue targeting by autoantibodies produced by B cells. Specific molecular targets have been identified in several autoimmune diseases but remain unknown in many others. Transgenic (Tg) mice have been utilized to express model antigens that can be recognized by T cells or by autoantibodies. To identify mechanisms by which CD8+ autoreactive T cells cause inflammation, we generated a double transgenic (DTg) murine model of autoimmunity by crossing K14-sOVA mice, which express soluble chicken ovalbumin (OVA), with OT-1 mice, whose CD8 T cells express V2/V5 regions of the T cell receptor that are specific for SIINFEKL peptide (OVA 257-264) in association with class I MHC molecules. The K14-SOVA/OT-1 (#5 and #17) DTg mice develop normally, except that they undergo a destructive process that selectively targets the external pinnae in the first 6 days of life. The purpose of this study was to elucidate the mechanism and attempt to obviate the resulting tissue-specific destruction. By light microscopy, the ear bud area displayed an intense inflammatory infiltrate of V2/V5+CD8+ OT-1 cells when characterized by FACS. Administration of the TCR-recognized SIINFEKL peptide i.v. to pregnant F1 mice on days E16 and E18 in utero and i.p. to newborn pups on days 2 and 4 prevented the inflammatory response and resulted in development of normal-looking ears in 100% of pups. Treatment with the SIINFEKL peptide was shown to down-regulate the CD8 coreceptor and activate T-cells to differentiate into memory T-cells. This model can inform us about mechanisms of peripheral tolerance and potential therapies for autoimmune diseases in which specific molecular targets are known.