Nod2 Suppresses Borrelia burgdorferi Mediated Murine Lyme Arthritis and Carditis through the Induction of Tolerance

The internalization of Borrelia burgdorferi, the causative agent of Lyme disease, by phagocytes is essential for an effective activation of the immune response to this pathogen. The intracellular, cytosolic receptor Nod2 has been shown to play varying roles in either enhancing or attenuating inflammation in response to different infectious agents. We examined the role of Nod2 in responses to B. burgdorferi. In vitro stimulation of Nod2 deficient bone marrow derived macrophages (BMDM) resulted in decreased induction of multiple cytokines, interferons and interferon regulated genes compared with wild-type cells. However, B. burgdorferi infection of Nod2 deficient mice resulted in increased rather than decreased arthritis and carditis compared to control mice. We explored multiple potential mechanisms for the paradoxical response in in vivo versus in vitro systems and found that prolonged stimulation with a Nod2 ligand, muramyl dipeptide (MDP), resulted in tolerance to stimulation by B. burgdorferi. This tolerance was lost with stimulation of Nod2 deficient cells that cannot respond to MDP. Cytokine patterns in the tolerance model closely paralleled cytokine profiles in infected Nod2 deficient mice. We propose a model where Nod2 has an enhancing role in activating inflammation in early infection, but moderates inflammation after prolonged exposure to the organism through induction of tolerance

Type IV Secretion-Dependent Activation of Host MAP Kinases Induces an Increased Proinflammatory Cytokine Response to \u3cem\u3eLegionella pneumophila\u3c/em\u3e

The immune system must discriminate between pathogenic and nonpathogenic microbes in order to initiate an appropriate response. Toll-like receptors (TLRs) detect microbial components common to both pathogenic and nonpathogenic bacteria, whereas Nod-like receptors (NLRs) sense microbial components introduced into the host cytosol by the specialized secretion systems or pore-forming toxins of bacterial pathogens. The host signaling pathways that respond to bacterial secretion systems remain poorly understood. Infection with the pathogen Legionella pneumophila, which utilizes a type IV secretion system (T4SS), induced an increased proinflammatory cytokine response compared to avirulent bacteria in which the T4SS was inactivated. This enhanced response involved NF-κB activation by TLR signaling as well as Nod1 and Nod2 detection of type IV secretion. Furthermore, a TLR- and RIP2-independent pathway leading to p38 and SAPK/JNK MAPK activation was found to play an equally important role in the host response to virulent L. pneumophila. Activation of this MAPK pathway was T4SS-dependent and coordinated with TLR signaling to mount a robust proinflammatory cytokine response to virulent L. pneumophila. These findings define a previously uncharacterized host response to bacterial type IV secretion that activates MAPK signaling and demonstrate that coincident detection of multiple bacterial components enables immune discrimination between virulent and avirulent bacteria

Fermion Mass Hierarchies and Small Mixing Angles from Extra Dimensions

In this paper we study renormalization-group evolutions of Yukawa matrices enhanced by Kaluza-Klein excited modes and analyze their infrared fixed-point structure. We derive necessary conditions to obtain hierarchies between generations on the fixed point. These conditions restrict how the fields in the models can extend to higher dimension. Several specific mechanisms to realize the conditions are presented. We also take account of generation mixing effects and find a scenario where the mixing angles become small at low energy even with large initial values at high-energy scale. A toy model is shown to lead realistic quark mass matrices.Comment: 23 pages, 7 figures, LaTeX, a supplementary explanation and references adde

IL-1 receptor–associated kinase M is a central regulator of osteoclast differentiation and activation

Osteoporosis is a serious problem worldwide; it is characterized by bone fractures in response to relatively mild trauma. Osteoclasts originate from the fusion of macrophages and they play a central role in bone development and remodeling via the resorption of bone. Therefore, osteoclasts are important mediators of bone loss that leads, for example, to osteoporosis. Interleukin (IL)-1 receptor (IL-1R)–associated kinase M (IRAK-M) is only expressed in cells of the myeloid lineage and it inhibits signaling downstream of IL-1R and Toll-like receptors (TLRs). However, it lacks a functional catalytic site and, thus, cannot function as a kinase. IRAK-M associates with, and prevents the dissociation of, IRAK–IRAK-4–TNF receptor–associated factor 6 from the TLR signaling complex, with resultant disruption of downstream signaling. Thus, IRAK-M acts as a dominant negative IRAK. We show here that mice that lack IRAK-M develop severe osteoporosis, which is associated with the accelerated differentiation of osteoclasts, an increase in the half-life of osteoclasts, and their activation. Ligation of IL-1R or TLRs results in hyperactivation of NF-κB and mitogen-activated protein kinase signaling pathways, which are essential for osteoclast differentiation. Thus, IRAK-M is a key regulator of the bone loss that is due to osteoclastic resorption of bone

Impaired membrane resealing and autoimmune myositis in synaptotagmin VII–deficient mice

Members of the synaptotagmin family have been proposed to function as Ca2+ sensors in membrane fusion. Syt VII is a ubiquitously expressed synaptotagmin previously implicated in plasma membrane repair and Trypanosoma cruzi invasion, events which are mediated by the Ca2+-regulated exocytosis of lysosomes. Here, we show that embryonic fibroblasts from Syt VII–deficient mice are less susceptible to trypanosome invasion, and defective in lysosomal exocytosis and resealing after wounding. Examination of mutant mouse tissues revealed extensive fibrosis in the skin and skeletal muscle. Inflammatory myopathy, with muscle fiber invasion by leukocytes and endomysial collagen deposition, was associated with elevated creatine kinase release and progressive muscle weakness. Interestingly, similar to what is observed in human polymyositis/dermatomyositis, the mice developed a strong antinuclear antibody response, characteristic of autoimmune disorders. Thus, defective plasma membrane repair in tissues under mechanical stress may favor the development of inflammatory autoimmune disease

Microwave spectroscopic study of the hyperfine structure of antiprotonic helium-3

In this work we describe the latest results for the measurements of the hyperfine structure of antiprotonic helium-3. Two out of four measurable super-super-hyperfine SSHF transition lines of the (n,L)=(36,34) state of antiprotonic helium-3 were observed. The measured frequencies of the individual transitions are 11.12548(08) GHz and 11.15793(13) GHz, with an increased precision of about 43% and 25% respectively compared to our first measurements with antiprotonic helium-3 [S. Friedreich et al., Phys. Lett. B 700 (2011) 1--6]. They are less than 0.5 MHz higher with respect to the most recent theoretical values, still within their estimated errors. Although the experimental uncertainty for the difference of 0.03245(15) GHz between these frequencies is large as compared to that of theory, its measured value also agrees with theoretical calculations. The rates for collisions between antiprotonic helium and helium atoms have been assessed through comparison with simulations, resulting in an elastic collision rate of gamma_e = 3.41 +- 0.62 MHz and an inelastic collision rate of gamma_i = 0.51 +- 0.07 MHz.Comment: 15 pages, 9 figures. arXiv admin note: substantial text overlap with arXiv:1102.528

Interleukin-1 receptor-associated kinase-M suppresses systemic lupus erythematosus

Interleukin-1 receptor-associated kinase (IRAK)-M suppresses Toll-like receptor (TLR)-mediated activation of innate immunity during infection. A similar role was hypothesised for IRAK-M in autoimmunity

Infrared alignment of SUSY flavor structures

The various experimental bounds on flavor-changing interactions severely restrict the low-energy flavor structures of soft supersymmetry breaking parameters. In this work, we show that with a particular assumption of Yukawa couplings, the fermion mass and sfermion soft mass matrices are simultaneously diagonalized by common mixing matrices and we then obtain an alignment solution for the flavor problems. The required condition is generated by renormalization group evolutions and achieved at low-energy scale independently of high-energy structures of couplings. In this case, the diagonal entries of the soft scalar mass matrices are determined by gaugino and Higgs soft masses. We also discuss possible realizations of this scenario and the characteristic sparticle spectrum in the models.Comment: 18 pages, 1 figur

Universal Texture of Quark and Lepton Mass Matrices and a Discrete Symmetry Z_3

Recent neutrino data have been favourable to a nearly bimaximal mixing, which suggests a simple form of the neutrino mass matrix. Stimulated by this matrix form, a possibility that all the mass matrices of quarks and leptons have the same form as in the neutrinos is investigated. The mass matrix form is constrained by a discrete symmetry Z_3 and a permutation symmetry S_2. The model, of course, leads to a nearly bimaximal mixing for the lepton sectors, while, for the quark sectors, it can lead to reasonable values of the CKM mixing matrix and masses.Comment: 24 pages, RevTEX, no figure, some references and comments were adde