This report shows that highly self-reactive T cells produced in mice as a result of genetically altered thymic T cell selection spontaneously differentiate into interleukin (IL)-17–secreting CD4+ helper T (Th) cells (Th17 cells), which mediate an autoimmune arthritis that clinically and immunologically resembles rheumatoid arthritis (RA). The thymus-produced self-reactive T cells, which become activated in the periphery via recognition of major histocompatibility complex/self-peptide complexes, stimulate antigen-presenting cells (APCs) to secrete IL-6. APC-derived IL-6, together with T cell–derived IL-6, drives naive self-reactive T cells to differentiate into arthritogenic Th17 cells. Deficiency of either IL-17 or IL-6 completely inhibits arthritis development, whereas interferon (IFN)-γ deficiency exacerbates it. The generation, differentiation, and persistence of arthritogenic Th17 cells per se are, however, insufficient for producing overt autoimmune arthritis. Yet overt disease is precipitated by further expansion and activation of autoimmune Th17 cells, for example, via IFN-γ deficiency, homeostatic proliferation, or stimulation of innate immunity by microbial products. Thus, a genetically determined T cell self-reactivity forms a cytokine milieu that facilitates preferential differentiation of self-reactive T cells into Th17 cells. Extrinsic or intrinsic stimuli further expand these cells, thereby triggering autoimmune disease. Intervention in these events at cellular and molecular levels is useful to treat and prevent autoimmune disease, in particular RA.
A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal β-glucan, or purified β-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major β-glucan receptor, can prevent SKG arthritis triggered by β-glucans, which strongly activate dendritic cells in vitro in a Dectin-1–dependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.
Extremely high pressures ( 10 TPa) and temperatures (5 10 5 K) have been produced using a single laser pulse (100 nJ, 800 nm, 200 fs) focused inside a sapphire crystal. The laser pulse creates an intensity over 10 14 W=cm 2 converting material within the absorbing volume of 0:2 m 3 into plasma in a few fs. A pressure of 10 TPa, far exceeding the strength of any material, is created generating strong shock and rarefaction waves. This results in the formation of a nanovoid surrounded by a shell of shock-affected material inside undamaged crystal. Analysis of the size of the void and the shock-affected zone versus the deposited energy shows that the experimental results can be understood on the basis of conservation laws and be modeled by plasma hydrodynamics. Matter subjected to record heating and cooling rates of 10 18 K=s can, thus, be studied in a well-controlled laboratory environment. DOI: 10.1103/PhysRevLett.96.166101 PACS numbers: 81.07.ÿb, 47.40.Nm, 62.50.+p, 81.40.ÿz The study of matter in conditions of extreme pressure and temperature is an exciting area of condensed matter physics relevant to the formation of new materials and modeling the state of matter inside stars and planets. Creation of such extreme conditions in the laboratory is, however, a formidable experimental task. So far, pressures in excess of 0.1 TPa have been obtained using a diamond anvil in stationary conditions, while transient pressures behind shock waves generated by chemical or nuclear explosions or generated using powerful lasers up to 50 TPa have been reported [1,2]. Here we present experimental evidence that one can create TPa pressures, many times the strength of any material, using low energy pulses from a conventional tabletop laser.Recent studies have demonstrated [3][4][5][6][7][8] that sub-ps laser pulses tightly focused inside transparent dielectrics (glasses, crystals, and polymers) can produce detectable sub-micrometer-sized structural modifications, including voids. This requires intensities in excess of 10 14 W=cm 2 which results in a highly nonlinear light-matter interaction with most dielectrics being ionized early in the laser pulse. To achieve such high intensities the laser beam should be tightly focused using high numerical aperture optics into a spot whose dimensions are of the order of the laser wavelength ( ).Previously the formation of voids in silica was associated with self-focusing of the laser beam [3]. In fact void formation can occur in conditions favorable for selffocusing if the beam is weakly focused into the sample [9]. Previously, however, there has been no systematic study of void formation by single fs pulses in conditions when self-focusing cannot occur. We demonstrate here that in such conditions nanovoids are formed by the extreme temperatures and pressures created by optical breakdown and these drive shock and rarefaction waves in the surrounding material. It is possible that new materials [10 -12] with altered chemical properties [13] could be formed by such micro-explosions.The inte...
The thiol-oxidoreductase ERp57 is an integral component of the peptide-loading complex of the major histocompatibility complex (MHC) class I pathway, but its function is unknown. To investigate its function in antigen presentation, we generated ERp57-deficient mice. Death in utero caused by ubiquitous ERp57 deletion was prevented by specific deletion in the B cell compartment. We demonstrate that ERp57 was central for recruitment of MHC class I molecules into the loading complex. In ERp57-deficient cells, we found short-lived interaction of MHC class I molecules with the loading complex. Thus, in the steady state, very few MHC class I molecules were present in the loading complex. Surface H-2K(b)-peptide expression and stability were reduced, and presentation of a model antigen was decreased. Our results indicate that ERp57 does not influence the redox state of MHC class I molecules but is an essential structural component required for stable assembly of the peptide-loading complex.
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