Search

We present a principled technique for reducing the lattice and matrix size in some applications of Coppersmith's lattice method for finding roots of modular polynomial equations. It relies on extrapolating patterns from the actual behavior of Coppersmith's attack for smaller parameter sizes, which can be thought of as "focus group" testing. When applied to the small-exponent RSA problem, our technique reduces lattice dimensions and consequently running times, and hence can be applied to a wider range of exponents. Moreover, in many difficult examples our attack is not only faster but also more successful in recovering the RSA secret key. We include a discussion of subtleties concerning whether or not existing metrics (such as enabling condition bounds) are decisive in predicting the true efficacy of attacks based on Coppersmith's method. Finally, indications are given which suggest certain lattice basis reduction algorithms (such as Nguyen-Stehlé's L2) may be particularly well-suited for Coppersmith's method. [ABSTRACT FROM AUTHOR]

Text This paper concerns some novel features of maximal parabolic Eisenstein series at certain special values of their analytic parameter, s . These series arise as coefficients in the R 4 and ∂ 4 R 4 interactions in the low energy expansion of the scattering amplitudes in maximally supersymmetric string theory reduced to D = 10 − d dimensions on a torus, T d ( 0 ⩽ d ⩽ 7 ). For each d these amplitudes are automorphic functions on the rank d + 1 symmetry group E d + 1 . Of particular significance is the orbit content of the Fourier modes of these series when expanded in three different parabolic subgroups, corresponding to certain limits of string theory. This is of interest in the classification of a variety of instantons that correspond to minimal or “next-to-minimal” BPS orbits. In the limit of decompactification from D to D + 1 dimensions many such instantons are related to charged 1 2 -BPS or 1 4 -BPS black holes with euclidean world-lines wrapped around the large dimension. In a different limit the instantons give non-perturbative corrections to string perturbation theory, while in a third limit they describe non-perturbative contributions in eleven-dimensional supergravity. A proof is given that these three distinct Fourier expansions have certain vanishing coefficients that are expected from string theory. In particular, the Eisenstein series for these special values of s have markedly fewer Fourier coefficients than typical maximal parabolic Eisenstein series. The corresponding mathematics involves showing that the wavefront sets of the Eisenstein series in question are supported on only a limited number of coadjoint nilpotent orbits – just the minimal and trivial orbits in the 1 2 -BPS case, and just the next-to-minimal, minimal and trivial orbits in the 1 4 -BPS case. Thus as a byproduct we demonstrate that the next-to-minimal representations occur automorphically for E 6 , E 7 , and E 8 , and hence the first two nontrivial low energy coefficients in scattering amplitudes can be thought of as exotic θ -functions for these groups. The proof includes an appendix by Dan Ciubotaru and Peter E. Trapa which calculates wavefront sets for these and other special unipotent representations. Video For a video summary of this paper, please click here or visit http://youtu.be/QHhgpfOy_ww . [ABSTRACT FROM AUTHOR]

Monocyte development is a tightly regulated and multi-staged process, occurring through several defined progenitor cell intermediates. The key transcription factors, including PU.1, IRF8 and KLF4, growth factors, such as M-CSF and IL-34 and cytokines that drive monocyte development from hematopoietic progenitor cells are well defined. However, the molecular controls that direct differentiation into the Ly6C hi inflammatory and Ly6C lo monocyte subsets are yet to be completely elucidated. This review will provide a summary of the transcriptional regulation of monocyte development. We will also discuss how these molecular controls are also critical for microglial development despite their distinct haematopoetic origins. Furthermore, we will examine recent breakthroughs in defining mechanisms that promote differentiation of specific monocyte subpopulations. [ABSTRACT FROM AUTHOR]

Abstract: Text: We consider the Fourier expansions of automorphic forms on general Lie groups, with a particular emphasis on exceptional groups. After describing some principles underlying known results on , , and , we perform an analysis of the expansions on split real forms of and where simplifications take place for automorphic realizations of real representations which have small Gelfand–Kirillov dimension. Though the character varieties are more complicated for exceptional groups, we explain how the nonvanishing Fourier coefficients for small representations behave analogously to Fourier coefficients on . We use this mechanism, for example, to show that the minimal representation of either or never occurs in the cuspidal automorphic spectrum. We also give a complete description of the internal Chevalley modules of all complex Chevalley groups – that is, the orbit decomposition of the Levi factor of a maximal parabolic on its unipotent radical. This generalizes classical results on trivectors and in particular includes a full description of the complex character variety orbits for all maximal parabolics. The results of this paper have been applied in the string theory literature to the study of BPS instanton contributions to graviton scattering (Green et al., 2011, ). Video: For a video summary of this paper, please click here or visit http://www.youtube.com/watch?v=ELkyOT8c28I. [Copyright &y& Elsevier]

Abstract: Many important analytic statements about automorphic forms, such as the analytic continuation of certain -functions, rely on the well-known rapid decay of -finite cusp forms on Siegel sets. We extend this here to prove a more general decay statement along sets much larger than Siegel sets, and furthermore state and prove the decay for smooth but not necessarily -finite cusp forms. We also state a general theorem about the convergence of Rankin–Selberg integrals involving unipotent periods, closing a gap in the literature on -functions. These properties serve as the analytic basis (Miller and Schmid, 2009 ) of a new method to establish holomorphic continuations of Langlands -functions, in particular the exterior square -functions (Miller and Schmid, 2009 ) on . [Copyright &y& Elsevier]

Abstract: Text: We present a construction of expander graphs obtained from Cayley graphs of narrow ray class groups, whose eigenvalue bounds follow from the Generalized Riemann Hypothesis. Our result implies that the Cayley graph of with respect to small prime generators is an expander. As another application, we show that the graph of small prime degree isogenies between ordinary elliptic curves achieves nonnegligible eigenvalue separation, and explain the relationship between the expansion properties of these graphs and the security of the elliptic curve discrete logarithm problem. Video: For a video summary of this paper, please visit http://www.youtube.com/watch?v=7jwxmKWWsyM. [Copyright &y& Elsevier]

Abstract: The probability that epitope spreading occurs in multiple sclerosis (MS) and the fact that patients have been shown to respond to multiple myelin epitopes concurrently makes the use of peptide-specific tolerance therapies targeting single epitopes problematic. To attempt to overcome this limitation, we have employed cocktails of peptides in the ECDI coupled-APC tolerance system in mice to determine if T cell responses to multiple autoepitopes can be targeted simultaneously. Preventative tolerance induced with splenocytes coupled with a peptide cocktail of four distinct encephalitogenic epitopes (PLP139–151, PLP178–191, MBP84–104, and MOG92–106) inhibited initiation of active EAE induced with each individual peptide and by a mixture of the four peptides by preventing activation of autoreactive Th1 cells and subsequent infiltration of inflammatory cells into the CNS. Most relevant to treatment of clinical MS, therapeutic tolerance initiated by splenocytes coupled with the peptide cocktail administered at the peak of acute disease prevented clinical relapses due to epitope spreading and ameliorated a diverse disease induced with a mixture of the four peptides. Interestingly, therapeutic tolerance appeared to be mediated by a mechanism distinct from preventative tolerance, i.e. by significantly increasing the levels of production of the anti-inflammatory cytokines TGF-β and/or IL-10 in both the periphery and the CNS. [Copyright &y& Elsevier]

This is the second in a series of three papers; the other two are “Summation Formulas, from Poisson and Voronoi to the Present” [Progr. Math. 220 (2004) 419–440] and “Automorphic Distributions, L-functions, and Voronoi Summation for GL(3)” (preprint). The first paper is primarily expository, while the third proves a Voronoi-style summation formula for the coefficients of a cusp form on GL(3,Z)&z.drule;GL(3,R). The present paper contains the distributional machinery used in the third paper for rigorously deriving the summation formula, and also for the proof of the GL(3)×GL(1) converse theorem given in the third paper. The primary concept studied is a notion of the order of vanishing of a distribution along a closed submanifold. Applications are given to the analytic continuation of Riemann''s zeta function, degree 1 and degree 2 L-functions, the converse theorem for GL(2), and a characterization of the classical Mellin transform/inversion relations on functions with specified singularities. [Copyright &y& Elsevier]

Dynamic regulatory mechanisms prevent autoreactive T cell activation. Upon T cell receptor crosslinking, CD4+CD25+T regulatory (TR) cells block both the proliferation and cytokine production of CD4+CD25−effector cells in an apparent antigen non-specific manner. Within the TRpopulation, l-selectin (CD62L)hiTRcells have been described as more efficient suppressors of T cell proliferation than CD62LlowTRcells. We have previously reported that CD4+CD25+CD62LhiTRcells express elevated levels of two additional adhesion molecules, ICAM-1 (CD54) and P-selectin (CD62P) in comparison to non-TRcells. In the current study, we investigated the functional contribution of CD54 and CD62P expression to the suppressive phenotype of TRcells both in vitro and in vivo. While the CD4+CD25+TRcell population was demonstrated to be significantly larger in CD62P−/−mice than in wild-type C57BL/6 mice, CD62P−/−TRcell function was deficient in vitro, but not in vivo. Interestingly, we detected no deficiencies in TRcell numbers or effector function in CD54−/−mice suggesting that TRcells may differ from effector CD4+T cells in the requirement for CD54 expression within the immunological synapse. Collectively, these findings indicate that CD62P may influence TRcell differentiation/development and that TRcell activation occurs independently of CD54 expression. [Copyright &y& Elsevier]

We introduce a new type of summation formula for central values of GL (4) × GL (2) L -functions, when varied over Maaß forms. By rewriting such a sum in terms of GL (4) × GL (1) L -functions and applying a new "balanced" Voronoi formula, the sum can be shown to be equal to a differently-weighted average of the same quantities. By controlling the support of the spectral weighting functions on both sides, this reciprocity formula gives estimates on spectral sums that were previously obtainable only for lower rank groups. The "balanced" Voronoi formula has Kloosterman sums on both sides, and can be thought of as the functional equation of a certain double Dirichlet series involving Kloosterman sums and GL (4) Hecke eigenvalues. As an application we show that for any self-dual cusp form Π for SL (4 , Z) , there exist infinitely many Maaß forms π for SL (2 , Z) such that L (1 / 2 , Π × π) ≠ 0. [ABSTRACT FROM AUTHOR]

Abstract: Pro-inflammatory CD4+ T cell-mediated autoimmune diseases, such as multiple sclerosis, are hypothesized to be initiated and maintained by self-reactive interferon-gamma (IFN-γ) and interleukin-17 (IL-17) producing CD4+ T cells. Previous studies have shown moderate to significant alterations in inflammatory T cell responses and potentially treatment of autoimmune disease by administration of antihistamine or tricyclic antidepressants alone. The goal of the present study was to determine if treatment of PLP139–151-induced relapsing–remitting experimental autoimmune encephalomyelitis (R-EAE) in SJL/J mice with a combination of two FDA approved drugs for other indications could decrease R-EAE disease. The findings show that combination treatment with desloratadine and nortriptyline decreases the mean clinical score, disease relapse frequency, and number of CD4+ T cells infiltrating into the CNS. In addition, combination treatment of PLP139–151 primed mice decreases the level of IFN-γ and IL-17 secreted via a decrease in both the number of cells secreting and the amount of cytokine secreted per cell following PLP139–151 reactivation ex vivo. This is in contrast to an increase in the level of IL-4 produced and the number of IL-4 secreting cells. The data also show that combination treatment with desloratadine and nortriptyline inhibits the production of IFN-γ and IL-17 produced by naive CD4+ T cells activated in the presence of Th1 cell- and Th17 cell-promoting conditions, while increasing the level of IL-4 produced by naive CD4+ T cells activated in the presence of Th2 cell-promoting conditions. The present findings suggest a novel method for the development of a putative autoimmune therapy. [Copyright &y& Elsevier]

Abstract: Theiler''s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a relevant mouse model of multiple sclerosis. Infection of susceptible SJL/J mice leads to life-long CNS virus persistence and development of a chronic T cell-mediated autoimmune demyelinating disease triggered via epitope spreading to endogenous myelin epitopes. Potent CNS-infiltrating CD8+ T cell responses to TMEV epitopes have previously been shown to be induced in both disease-susceptible SJL/J and resistant C57BL/6 mice, in which the virus is rapidly cleared. Specific tolerization of SJL CD8+ T cells specific for the immunodominant TMEV VP3159 – 166 epitope has no effect on viral load or development of clinical TMEV-IDD, but adoptive transfer of activated CD8+ VP3159 – 166-specific T cell blasts shortly after TMEV infection to boost the early anti-viral response leads to clearance of CNS virus and protection from subsequent TMEV-IDD. These studies have important implications for vaccine strategies and treatment of chronic infections in humans. [Copyright &y& Elsevier]

Abstract: Intracerebral infection of susceptible strains of mice, e.g. SJL/J, with Theiler''s murine encephalomyelitis virus (TMEV) leads to a persistent CNS infection accompanied by development of a chronic-progressive inflammatory CNS autoimmune demyelinating disease which is clinically and pathologically similar to human multiple sclerosis. In contrast, resistant strains of mice, e.g. C57BL/6 (B6), effectively clear TMEV from the CNS and do not develop demyelinating disease. Although CD8+ T cells are crucial for viral clearance in B6 mice, SJL mice also mount potent CD8+ T cell responses against virus, thus the reason for the viral persistence in the CNS in these mice is unclear. Here, we examined innate anti-viral responses of CNS-resident astrocytes as a potential determinant of viral persistence and disease susceptibility. We demonstrate that B6 astrocytes produce significantly higher levels of cytokines, chemokines and adhesion molecules in response to TMEV infection, or stimulation with IFN-γ and TNF-α or poly I:C than SJL mice. In addition, TMEV more effectively induces MHC I molecules on B6 astrocytes than SJL, corresponding with an increased ability to activate TMEV-specific CD8+ T cells directly ex vivo. These results suggest that enhanced anti-viral responses of B6 astrocytes contribute to the ability of these mice to clear TMEV from the CNS and therefore to their resistance to the development of autoimmune demyelinating disease. [Copyright &y& Elsevier]

Abstract: Innate immunity in the CNS depends primarily on the functions of glial cells, astrocytes and microglia, which are important for the early control of pathogen replication and direct the recruitment and activation of cells of the adaptive immune system required for pathogen clearance. Efficient immune responses are required for clearance of an invading pathogen, but dysregulation of a pro-inflammatory response in the CNS could lead to the development of autoimmunity. This review summarizes the activation of toll-like receptors (TLRs) expressed on glial cells and the functional outcome of these interactions for CNS health and disease which depends on a delicate balance of the protective and toxic effects of molecules induced in the CNS following TLR ligation. [Copyright &y& Elsevier]

CD28 provides a co-stimulatory signal critical for optimal T cell activation. We and others have shown that the B7/CD28 co-stimulatory pathway is a major regulatory pathway for the control of immune responses. Experimentally induced models of autoimmunity have been shown to be prevented or reduced in intensity in mice deficient for CD28. Here, we show that EAE and accompanying neuroantigen-specific immune responses are drastically reduced in the absence of CD28. However, we go on to show that EAE can be induced in CD28-deficient mice following two immunizations. After re-immunization, CD28-deficient mice develop severe EAE with myelin-specific responses equal to those of wildtype controls, and extensive demyelination in the spinal cord. Treatment of CD28-deficient mice with anti-CD40L at the time of immunization significantly reduced DTH responses and prevented the development of EAE following two immunizations, indicating a critical role for CD40/CD40L signaling in the absence of CD28. Taken together, our results indicate that CD28-mediated co-stimulation does not regulate immunological anergy. Instead, CD28 appears to adjust the threshold for activation and expansion of autoreactive cells. [Copyright &y& Elsevier]

Type 1 diabetes (T1D) is mediated by destruction of pancreatic β cells by autoantigen-specific CD4 + and CD8 + T cells, thus the ideal solution for T1D is the restoration of immune tolerance to β cell antigens. We demonstrate the ability of carboxylated 500 nm biodegradable poly(lactide- co -glycolide) (PLG) nanoparticles PLG nanoparticles (either surface coupled with or encapsulating the cognate diabetogenic peptides) to rapidly and efficiently restore tolerance in NOD.SCID recipients of both activated diabetogenic CD4 + BDC2.5 chromagranin A-specific and CD8 + NY8.3 islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)-specific TCR transgenic T cells in an antigen-specific manner. Further, initiation and maintenance of Ag-PLG tolerance operates via several overlapping, but independent, pathways including regulation via negative-co-stimulatory molecules (CTLA-4 and PD-1) and the systemic induction of peptide-specific Tregs which were critical for long-term maintenance of tolerance by controlling both trafficking of effector T cells to, and their release of pro-inflammatory cytokines within the pancreas, concomitant with selective retention of effector cells in the spleens of recipient mice. [ABSTRACT FROM AUTHOR]

Intravenously infused synthetic 500 nm nanoparticles composed of poly(lactide- co -glycolide) are taken up by blood-borne inflammatory monocytes via a macrophage scavenger receptor (macrophage receptor with collagenous structure), and the monocytes no longer traffic to sites of inflammation. Intravenous administration of the nanoparticles after experimental spinal cord injury in mice safely and selectively limited infiltration of hematogenous monocytes into the injury site. The nanoparticles did not bind to resident microglia, and did not change the number of microglia in the injured spinal cord. Nanoparticle administration reduced M1 macrophage polarization and microglia activation, reduced levels of inflammatory cytokines, and markedly reduced fibrotic scar formation without altering glial scarring. These findings thus implicate early-infiltrating hematogenous monocytes as highly selective contributors to fibrosis that do not play an indispensable role in gliosis after SCI. Further, the nanoparticle treatment reduced accumulation of chondroitin sulfate proteoglycans, increased axon density inside and caudal to the lesion site, and significantly improved functional recovery after both moderate and severe injuries to the spinal cord. These data provide further evidence that hematogenous monocytes contribute to inflammatory damage and fibrotic scar formation after spinal cord injury in mice. Further, since the nanoparticles are simple to administer intravenously, immunologically inert, stable at room temperature, composed of an FDA-approved material, and have no known toxicity, these findings suggest that the nanoparticles potentially offer a practical treatment for human spinal cord injury. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), there is a growing interest in inhibiting the pro-inflammatory effects of granulocyte-macrophage colony-stimulating factor (GM-CSF). We sought to evaluate the therapeutic potential and underlying mechanisms of GM-CSF receptor alpha (Rα) blockade in animal models of MS. We show that GM-CSF signaling inhibition at peak of chronic experimental autoimmune encephalomyelitis (EAE) results in amelioration of disease progression. Similarly, GM-CSF Rα blockade in relapsing-remitting (RR)-EAE model prevented disease relapses and inhibited T cell responses specific for both the inducing and spread myelin peptides, while reducing activation of mDCs and inflammatory monocytes. In situ immunostaining of lesions from human secondary progressive MS (SPMS), but not primary progressive MS patients shows extensive recruitment of GM-CSF Rα + myeloid cells. Collectively, this study reveals a pivotal role of GM-CSF in disease relapses and the benefit of GM-CSF Rα blockade as a potential novel therapeutic approach for treatment of RRMS and SPMS. [ABSTRACT FROM AUTHOR]

IL-7 is known to be vital for T cell homeostasis but has previously been presumed to be dispensable for TCR-induced activation. Here, we show that IL-7 is critical for the initial activation of CD4 + T cells in that it provides some of the necessary early signaling components, such as activated STAT5 and Akt. Accordingly, short-term in vivo IL-7Rα blockade inhibited the activation and expansion of autoantigen-specific CD4 + T cells and, when used to treat experimental autoimmune encephalomyelitis (EAE), prevented and ameliorated disease. Our studies demonstrate that IL-7 signaling is a prerequisite for optimal CD4 + T cell activation and that IL-7R antagonism may be effective in treating CD4 + T cell-mediated neuroinflammation and other autoimmune inflammatory conditions. [ABSTRACT FROM AUTHOR]

The induction of donor-specific tolerance to transplanted cells and organs, while preserving immune function as a whole, remains a highly sought after and elusive strategy for overcoming transplant rejection. Tolerance necessitates modulating a diverse array of cell types that recognize and respond to alloantigens, including antigen presenting cells and T lymphocytes. Nanotherapeutic strategies that employ cellular and biomaterial engineering represent an emerging technology geared towards the goal of inducing transplant tolerance. Nanocarriers offer a platform for delivering antigens of interest to specific cell types in order to achieve tolerogenic antigen presentation. Furthermore, the technologies also provide an opportunity for local immunomodulation at the graft site. Nanocarriers delivering a combination of antigens and immunomodulating agents, such as rapamycin, provide a unique technology platform with the potential to enhance outcomes for the induction of transplant tolerance. [ABSTRACT FROM AUTHOR]

γδ T cells are resident in cerebrospinal fluid and central nervous system (CNS) lesions of multiple sclerosis (MS) patients, but as multifaceted cells exhibiting innate and adaptive characteristics, their function remains unknown. Previous studies in experimental autoimmune encephalomyelitis (EAE) are contradictory and identified these cells as either promoting or suppressing disease pathogenesis. This study examines distinct γδ T cell subsets during EAE and indicates they mediate differential functions in CNS inflammation and demyelination resulting in pathogenesis or protection. We identified two γδ subsets in the CNS, Vγ1+ and Vγ4+, with distinct cytokine profiles and tissue specificity. Anti-γδ T cell receptor (TCR) monoclonal antibody (mAb) administration results in activation and downregulation of surface TCR, rendering the cells undetectable, but with opposing effects: anti-Vγ4 treatment exacerbates disease whereas anti-Vγ1 treatment is protective. The Vγ4+ subset produces multiple pro-inflammatory cytokines including high levels of IL-17, and accounts for 15-20% of the interleukin-17 (IL-17) producing cells in the CNS, but utilize a variant transcriptional program than CD4+ Th17 cells. In contrast, the Vγ1 subset produces CCR5 ligands, which may promote regulatory T cell differentiation. γδ T cell subsets thus play distinct and opposing roles during EAE, providing an explanation for previous reports and suggesting selective targeting to optimize regulation as a potential therapy for MS. [ABSTRACT FROM AUTHOR]

Abstract: We evaluated the therapeutic efficacy and mechanisms of action of both mouse and human B7-H4 Immunoglobulin fusion proteins (mB7-H4Ig; hB7-H4Ig) in treating EAE. The present data show that mB7-H4Ig both directly and indirectly (via increasing Treg function) inhibited CD4+ T-cell proliferation and differentiation in both Th1- and Th17-cell promoting conditions while inducing production of IL-10. B7-H4Ig treatment effectively ameliorated progression of both relapsing (R-EAE) and chronic EAE correlating with decreased numbers of activated CD4+ T-cells within the CNS and spleen, and a concurrent increase in number and function of Tregs. The functional requirement for Treg activation in treating EAE was demonstrated by a loss of therapeutic efficacy of hB7-H4Ig in R-EAE following inactivation of Treg function either by anti-CD25 treatment or blockade of IL-10. Significant to the eventual translation of this treatment into clinical practice, hB7-H4Ig similarly inhibited the in vitro differentiation of naïve human CD4+ T-cells in both Th1- and Th17-promoting conditions, while promoting the production of IL-10. B7-H4Ig thus regulates pro-inflammatory T-cell responses by a unique dual mechanism of action and demonstrates significant promise as a therapeutic for autoimmune diseases, including MS. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is an autoimmune, demyelinating disease and as such, the gold standard of treatment is to selectively suppress the pathogenic autoimmune response without compromising the entire arm of the adaptive immune response. One target of this strategy lying upstream of the pathologic adaptive immune response is the local, innate immune signaling that initiates and drives autoimmunity and sterile injury. High-mobility group box 1 protein (HMGB1) is a ubiquitous nuclear protein that when released from necrotic cells, such as damaged oligodendrocytes in MS lesions, drives pro-inflammatory responses. Here we demonstrate that HMGB1 drives neuroinflammatory responses in experimental autoimmune encephalomyelitis (EAE), a murine model for MS, and that inhibition of HMGB1 signaling ameliorates disease. Specifically i.v. injection of an HMGB1 neutralizing antibody in the C57BL/6 model of chronic EAE or SJL/J model of relapsing-remitting EAE ameliorated clinical disease prophylactically or during ongoing disease, blocked T cell infiltration of the central nervous system, and inhibited systemic CD4+ T cell responses to myelin epitopes. Additionally, lymphocytes from EAE mice restimulated in vitro in the presence of recombinant HMGB1 exhibited increased proliferation and pro-inflammatory cytokine production, an effect that was blocked by anti-HMGB1 antibody. Similarly recombinant HMGB1 promoted proliferation and pro-inflammatory cytokine production of human peripheral blood mononuclear cells stimulated in vitro, and anti-HMGB1 antibody blocked this effect. These findings indicate that HMGB1 contributes to neuroinflammatory responses that drive EAE pathogenesis and that HMGB1 blockade may be a novel means to selectively disrupt the pro-inflammatory loop that drives MS autoimmunity. [Copyright &y& Elsevier]

Abstract: Type 1 diabetes (T1D) is mediated by destruction of pancreatic β-cells by CD4 and CD8 T cells specific for epitopes on numerous diabetogenic autoantigens resulting in loss of glucose homeostasis. Employing antigen-specific tolerance induced by i.v. administration of syngeneic splenocytes ECDI cross-linked to various diabetogenic antigens/epitopes (Ag-SP), we show that epitope spreading plays a functional role in the pathogenesis of T1D in NOD mice. Specifically, Ag-SP coupled with intact insulin, Ins B9-23 or Ins B15-23, but not GAD65509-528, GAD65524-543 or IGRP206-214, protected 4–6 week old NOD mice from the eventual development of clinical disease; infiltration of immune cells to the pancreatic islets; and blocked the induction of DTH responses in a Treg-dependent, antigen-specific manner. However, tolerance induction in 19–21 week old NOD mice was effectively accomplished only by Ins-SP, suggesting Ins B9-23 is a dominant initiating epitope, but autoimmune responses to insulin epitope(s) distinct from Ins B9-23 emerge during disease progression. [Copyright &y& Elsevier]

Abstract: Enhancing the ability of either endogenous or transplanted oligodendrocyte progenitors (OPs) to engage in myelination may constitute a novel therapeutic approach to demyelinating diseases of the brain. It is known that in adults neural progenitors situated in the subventricular zone of the lateral ventricle (SVZ) are capable of generating OPs which can migrate into white matter tracts such as the corpus callosum (CC). We observed that progenitor cells in the SVZ of adult mice expressed CXCR4 chemokine receptors and that the chemokine SDF-1/CXCL12 was expressed in the CC. We therefore investigated the role of chemokine signaling in regulating the migration of OPs into the CC following their transplantation into the lateral ventricle. We established OP cell cultures from Olig2-EGFP mouse brains. These cells expressed a variety of chemokine receptors, including CXCR4 receptors. Olig2-EGFP OPs differentiated into CNPase-expressing oligodendrocytes in culture. To study the migratory capacity of Olig2-EGFP OPs in vivo, we transplanted them into the lateral ventricles of mice. Donor cells migrated into the CC and differentiated into mature oligodendrocytes. This migration was enhanced in animals with Experimental Autoimmune Encephalomyelitis (EAE). Inhibition of CXCR4 receptor expression in OPs using shRNA inhibited the migration of transplanted OPs into the white matter suggesting that their directed migration is regulated by CXCR4 signaling. These findings indicate that CXCR4 mediated signaling is important in guiding the migration of transplanted OPs in the context of inflammatory demyelinating brain disease. [Copyright &y& Elsevier]

Abstract: Theiler’s murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) serves as virus-induced model of chronic progressive multiple sclerosis. Infection of susceptible SJL/J mice leads to life-long CNS virus persistence and a progressive autoimmune demyelinating disease mediated by myelin-specific T cells activated via epitope spreading. In contrast, virus is rapidly cleared by a robust CTL response in TMEV-IDD-resistant C57BL/6 mice. We investigated whether differential induction of regulatory T cells (Tregs) controls susceptibility to TMEV-IDD. Infection of disease-susceptible SJL/J, but not B6 mice, leads to rapid activation and expansion of Tregs resulting in an unfavorable CNS ratio of Treg:Teffector cells. In addition, anti-CD25-induced inactivation of Tregs in susceptible SJL/J, but not resistant B6, mice results in significantly decreased clinical disease concomitant with enhanced anti-viral CD4+, CD8+ and antibody responses resulting in decreased CNS viral titers. This is the first demonstration that virus-induced Treg activation regulates susceptibility to autoimmune disease differentially in susceptible and resistant strains of mice and provides a new mechanistic explanation for the etiology of infection-induced autoimmunity. [Copyright &y& Elsevier]

Abstract: Multiple sclerosis (MS) is a chronic autoimmune neurological disease characterized by infiltration of peripheral inflammatory cells to the central nervous system (CNS) and demyelination of CNS white matter. Epidemiological evidence suggests a possible infectious trigger. One potential mechanism by which an infectious agent may trigger MS is via molecular mimicry wherein T cells generated against foreign epitopes cross-react with self-myelin epitopes, such as myelin basic protein (MBP), with sufficient sequence similarity. It has been previously reported that an MBP85–99-reactive T cell clone derived from an MS patient cross-reacted with multiple bacterial-derived mimic peptides in vitro. We show that the same mimic peptides can induce clinical disease in two different strains of mice transgenic for both a human MBP85–99-specific TCR and HLA-DR2 (MHC II), albeit with different disease patterns – relapsing–remitting vs. monophasic. Interestingly, clinical disease correlates with CNS infiltration of CD4+ T cells and F4/80+ macrophages, but not with in vitro proliferative or cytokine responses of splenocytes in response to either MBP85–99 or its mimics. [Copyright &y& Elsevier]

Abstract: GlsA, a J-protein chaperone, is required for the asymmetric divisions that set aside germ and somatic cell precursors during embryogenesis in Volvox carteri, and previous evidence indicated that this function requires an intact Hsp70-binding site. To determine if Hsp70A, the only known cytoplasmic Hsp70 in V. carteri, is the chaperone partner of GlsA, we investigated the localization of the two proteins during critical stages of embryogenesis and tested their capacity to interact. We found that a substantial fraction of Hsp70A co-localizes with GlsA, both in interphase and mitotic blastomeres. In addition, Hsp70A coimmunoprecipitated with GlsA, and co-expression of GlsA and Hsp70A variants partially rescued the Gls phenotype of a glsA mutant, whereas neither variant by itself rescued the mutant phenotype. Immunofluorescence analysis demonstrated that GlsA is about equally abundant in all blastomeres at all cleavage stages examined but that Hsp70A is more abundant in anterior (asymmetrically dividing) blastomeres than in posterior (symmetrically dividing) blastomeres during the period of asymmetric division. We conclude that Hsp70A and GlsA function as chaperone partners that regulate asymmetric division and that the relative abundance of Hsp70A in asymmetrically dividing embryos may determine which blastomeres divide asymmetrically and which do not. [Copyright &y& Elsevier]

Abstract: The glucocorticoid-induced TNF-related gene receptor (GITR) is the newest member of the costimulatory molecule family and is expressed on both resting CD4+CD25+ regulatory T (TR) cells and activated CD4+ T cells. We investigated the endogenous mechanisms that regulate GITR expression on both TR and CD4+ T cells, as well as the functional interaction between GITR and other costimulatory molecules. CD28 stimulation increased GITR expression on both TR and CD4+ T cells via IL-2-dependent mechanisms. In addition, ligation of GITR and/or CD28 increased the level of CD4+ T cell proliferation and effector function under both APC-dependent and -independent conditions, suggesting that these costimulatory molecules cooperate to regulate CD4+ T cell activation and function by directly signaling to the CD4+ T cell. Thus, GITR may serve opposing functional roles on CD4+ TR and effector cells and alterations in GITR expression and/or function may tip the balance between immune tolerance and effector function. [Copyright &y& Elsevier]

Abstract: The central role of human pancreatic glucokinase in insulin secretion and, consequently, in maintenance of blood glucose levels has prompted investigation into identification of ATP-binding site residues and examination of ATP- and glucose-binding interactions. Because glucokinase has been resistant to crystallization, computer generated homology models were developed based on the X-ray crystal structure of the COOH-terminal domain of human brain hexokinase 1 bound to glucose and ADP or glucose and glucose-6-phosphate. Human pancreatic glucokinase mutants were designed based upon these models and on ATPase domain sequence conservation to identify and characterize potential glucose and ATP-binding sites. Specifically, mutants Asp78Ala, Thr82Ala, Lys90Ala, Lys102Ala, Gly227Ala, Thr228Ala, Ser336Leu, Ser411Ala, and Ser411Leu were constructed, expressed, purified, and kinetically characterized under steady-state conditions. Compared to their respective wild type controls, several mutants demonstrated dramatic changes in Vmax, cooperativity of glucose binding and S0.5 for ATP and glucose. Results suggest a role for Asp78, Thr82, Gly227, Thr228, and Ser336 in ATP binding and indicate these residues are essential for glucose phosphorylation by human pancreatic glucokinase. [Copyright &y& Elsevier]