Molecular mechanisms of autoimmunity triggered by microbial infection

Autoimmunity can be triggered by microbial infection. In this context, the discovery of Toll-like receptors (TLRs) provides new insights and research perspectives. TLRs induce innate and adaptive antimicrobial immune responses upon exposure to common pathogen-associated molecules, including lipopeptides, lipopolysaccharides, and nucleic acids. They also have the potential, however, to trigger autoimmune disease, as has been revealed by an increasing number of experimental reports. This review summarizes important facts about TLR biology, available data on their role in autoimmunity, and potential consequences for the management of patients with autoimmune disease

Energy Deposition of Energetic Silicon Atoms Within a Silicon Lattice

The energy dependence of the ionization produced in silicon by recoiling silicon atoms was measured in the 4–54-keV energy interval. It is found that the fraction of the recoil energy that is dissipated as ionization follows an E1/2 dependence which agrees well with the predictions of the theory of Lindhard et al. [Mat. Fys. Medd. 33, 10 (1963)]

SICANE: a Detector Array for the Measurement of Nuclear Recoil Quenching Factors using Monoenergetic Neutron Beam

SICANE is a neutron scattering multidetector facility for the determination of the quenching factor (ratio of the response to nuclear recoils and to electrons) of cryogenic detectors used in direct WIMP searches. Well collimated monoenergetic neutron beams are obtained with inverse (p,n) reactions. The facility is described, and results obtained for the quenching factors of scintillation in NaI(Tl) and of heat and ionization in Ge are presented.Comment: 30 pages, Latex, 11 figures. Submitted to NIM

Vector boson pair production at the LHC

We present phenomenological results for vector boson pair production at the LHC, obtained using the parton-level next-to-leading order program MCFM. We include the implementation of a new process in the code, pp -> \gamma\gamma, and important updates to existing processes. We incorporate fragmentation contributions in order to allow for the experimental isolation of photons in \gamma\gamma, W\gamma, and Z\gamma production and also account for gluon-gluon initial state contributions for all relevant processes. We present results for a variety of phenomenological scenarios, at the current operating energy of \sqrt{s} = 7 TeV and for the ultimate machine goal, \sqrt{s} = 14 TeV. We investigate the impact of our predictions on several important distributions that enter into searches for new physics at the LHC.Comment: 35 pages, 14 figure

Low-Energy Direct Capture in the 8Li(n,gamma)9Li and 8B(p,gamma)9C Reactions

The cross sections of the 8Li(n,gamma)9Li and 8B(p,gamma)9C capture reactions have been analyzed using the direct capture model. At low energies which is the astrophysically relevant region the capture process is dominated by E1 transitions from incoming s-waves to bound p-states. The cross sections of both mirror reactions can be described simultaneously with consistent potential parameters, whereas previous calculations have overestimated the capture cross sections significantly. However, the parameters of the potential have to be chosen very carefully because the calculated cross section of the 8Li(n,gamma)9Li reaction depends sensitively on the potential strength.Comment: 6 pages, 5 figures, Phys. Rev. C, accepte

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Background & aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC

HLA-DP on Epithelial Cells Enables Tissue Damage by NKp44+ Natural Killer Cells in Ulcerative Colitis

Background & aims: Ulcerative colitis (UC) is characterized by severe inflammation and destruction of the intestinal epithelium, and is associated with specific risk single nucleotide polymorphisms in HLA class II. Given the recently discovered interactions between subsets of HLA-DP molecules and the activating natural killer (NK) cell receptor NKp44, genetic associations of UC and HLA-DP haplotypes and their functional implications were investigated.Methods: HLA-DP haplotype and UC risk association analyses were performed (UC: n = 13,927; control: n = 26,764). Expression levels of HLA-DP on intestinal epithelial cells (IECs) in individuals with and without UC were quantified. Human intestinal 3-dimensional (3D) organoid cocultures with human NK cells were used to determine functional consequences of interactions between HLA-DP and NKp44.Results: These studies identified HLA-DPA1∗01:03-DPB1∗04:01 (HLA-DP401) as a risk haplotype and HLA-DPA1∗01:03-DPB1∗03:01 (HLA-DP301) as a protective haplotype for UC in European populations. HLA-DP expression was significantly higher on IECs of individuals with UC compared with controls. IECs in human intestinal 3D organoids derived from HLA-DP401pos individuals showed significantly stronger binding of NKp44 compared with HLA-DP301pos IECs. HLA-DP401pos IECs in organoids triggered increased degranulation and tumor necrosis factor production by NKp44+ NK cells in cocultures, resulting in enhanced epithelial cell death compared with HLA-DP301pos organoids. Blocking of HLA-DP401-NKp44 interactions (anti-NKp44) abrogated NK cell activity in cocultures.Conclusions: We identified an UC risk HLA-DP haplotype that engages NKp44 and activates NKp44+ NK cells, mediating damage to intestinal epithelial cells in an HLA-DP haplotype-dependent manner. The molecular interaction between NKp44 and HLA-DP401 in UC can be targeted by therapeutic interventions to reduce NKp44+ NK cell-mediated destruction of the intestinal epithelium in UC

NKp44/HLA-DP-dependent regulation of CD8 effector T cells by NK cells

Although natural killer (NK) cells are recognized for their modulation of immune responses, the mechanisms by which human NK cells mediate immune regulation are unclear. Here, we report that expression of human leukocyte antigen (HLA)-DP, a ligand for the activating NK cell receptor NKp44, is significantly upregulated on CD8+ effector T cells, in particular in human cytomegalovirus (HCMV)+ individuals. HLA-DP+ CD8+ T cells expressing NKp44-binding HLA-DP antigens activate NKp44+ NK cells, while HLA-DP+ CD8+ T cells not expressing NKp44-binding HLA-DP antigens do not. In line with this, frequencies of HLA-DP+ CD8+ T cells are increased in individuals not encoding for NKp44-binding HLA-DP haplotypes, and contain hyper-expanded CD8+ T cell clones, compared to individuals expressing NKp44-binding HLA-DP molecules. These findings identify a molecular interaction facilitating the HLA-DP haplotype-specific editing of HLA-DP+ CD8+ T cell effector populations by NKp44+ NK cells and preventing the generation of hyper-expanded T cell clones, which have been suggested to have increased potential for autoimmunity