The importance of FcRn in neuro-immunotherapies: From IgG catabolism, FCGRT gene polymorphisms, IVIg dosing and efficiency to specific FcRn inhibitors.

The neonatal Fc receptor (FcRn) binds endogenous IgG and protects it from lysosomal degradation by transporting it back to the cell surface to re-enter the circulation, extending the serum IgG life span. FcRn plays a role in the function of IVIg because the supraphysiological IgG levels derived from IVIg administrations saturate the FcRn allowing the endogenous IgG to be degraded, instead of being recycled, resulting in high levels of infused IgG ensuring IVIg efficiency. New data in myasthenia gravis patients suggest that the that the Variable Number of Tandem 3/2 (VNTR3/2) polymorphisms in FCGRT, the gene that encodes FcRn, may affect the duration of infused IgG in the circulation and IVIg effectiveness. This review addresses these implications in the context of whether the FCGRT genotype, by affecting the half-life of IVIg, may also play a role in up to 30% of patients with autoimmune neurological diseases, such as Guillain-Barré syndrome, CIDP or Multifocal Motor Neuropathy, who did not respond to IVIg in controlled trials. The concern is of practical significance because in such patient subsets super-high IVIg doses may be needed to achieve high IgG levels and ensure efficacy. Whether FCGRT polymorphisms affect the efficacy of other therapeutic monoclonal antibodies by influencing their distribution clearance and pharmacokinetics, explaining their variable effectiveness, is also addressed. Finally, the very promising effect of monoclonal antibodies that inhibit FcRn, such as efgartigimod, rozanolixizumab and nipocalimab, in treating antibody-mediated neurological diseases is discussed along with their efficacy in the IgG4 subclass of pathogenic antibodies and their role in the blood-brain barrier endothelium, that abundantly expresses FcRn

Hereditary angioedema (HAE) in children and adolescents : a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis

Protein Kinase C θ Is Critical for the Development of In Vivo T Helper (Th)2 Cell But Not Th1 Cell Responses

The serine/threonine-specific protein kinase C (PKC)-θ is predominantly expressed in T cells and localizes to the center of the immunological synapse upon T cell receptor (TCR) and CD28 signaling. T cells deficient in PKC-θ exhibit reduced interleukin (IL)-2 production and proliferative responses in vitro, however, its significance in vivo remains unclear. We found that pkc-θ−/− mice were protected from pulmonary allergic hypersensitivity responses such as airway hyperresponsiveness, eosinophilia, and immunoglobulin E production to inhaled allergen. Furthermore, T helper (Th)2 cell immune responses against Nippostrongylus brasiliensis were severely impaired in pkc-θ−/− mice. In striking contrast, pkc-θ−/− mice on both the C57BL/6 background and the normally susceptible BALB/c background mounted protective Th1 immune responses and were resistant against infection with Leishmania major. Using in vitro TCR transgenic T cell–dendritic cell coculture systems and antigen concentration-dependent Th polarization, PKC-θ–deficient T cells were found to differentiate into Th1 cells after activation with high concentrations of specific peptide, but to have compromised Th2 development at low antigen concentration. The addition of IL-2 partially reconstituted Th2 development in pkc-θ−/− T cells, consistent with an important role for this cytokine in Th2 polarization. Taken together, our results reveal a central role for PKC-θ signaling during Th2 responses

A Subset of Liver NK T Cells is Activated During \u3cem\u3eLeishmania donovani\u3c/em\u3e Infection by CD1d-Bound Lipophosphoglycan

Natural killer (NK) T cells are activated by synthetic or self-glycolipids and implicated in innate host resistance to a range of viral, bacterial, and protozoan pathogens. Despite the immunogenicity of microbial lipoglycans and their promiscuous binding to CD1d, no pathogen-derived glycolipid antigen presented by this pathway has been identified to date. In the current work, we show increased susceptibility of NK T cell–deficient CD1d−/− mice to Leishmania donovani infection and Leishmania-induced CD1d-dependent activation of NK T cells in wild-type animals. The elicited response was Th1 polarized, occurred as early as 2 h after infection, and was independent from IL-12. The Leishmania surface glycoconjugate lipophosphoglycan, as well as related glycoinositol phospholipids, bound with high affinity to CD1d and induced a CD1d-dependent IFNγ response in naive intrahepatic lymphocytes. Together, these data identify Leishmania surface glycoconjugates as potential glycolipid antigens and suggest an important role for the CD1d–NK T cell immune axis in the early response to visceral Leishmania infection

A Subset of Liver NK T Cells Is Activated during Leishmania donovani Infection by CD1d-bound Lipophosphoglycan

Natural killer (NK) T cells are activated by synthetic or self-glycolipids and implicated in innate host resistance to a range of viral, bacterial, and protozoan pathogens. Despite the immunogenicity of microbial lipoglycans and their promiscuous binding to CD1d, no pathogen-derived glycolipid antigen presented by this pathway has been identified to date. In the current work, we show increased susceptibility of NK T cell–deficient CD1d−/− mice to Leishmania donovani infection and Leishmania-induced CD1d-dependent activation of NK T cells in wild-type animals. The elicited response was Th1 polarized, occurred as early as 2 h after infection, and was independent from IL-12. The Leishmania surface glycoconjugate lipophosphoglycan, as well as related glycoinositol phospholipids, bound with high affinity to CD1d and induced a CD1d-dependent IFNγ response in naive intrahepatic lymphocytes. Together, these data identify Leishmania surface glycoconjugates as potential glycolipid antigens and suggest an important role for the CD1d–NK T cell immune axis in the early response to visceral Leishmania infection

ASTEC -- the Aarhus STellar Evolution Code

The Aarhus code is the result of a long development, starting in 1974, and still ongoing. A novel feature is the integration of the computation of adiabatic oscillations for specified models as part of the code. It offers substantial flexibility in terms of microphysics and has been carefully tested for the computation of solar models. However, considerable development is still required in the treatment of nuclear reactions, diffusion and convective mixing.Comment: Astrophys. Space Sci, in the pres

lp-Recovery of the Most Significant Subspace among Multiple Subspaces with Outliers

We assume data sampled from a mixture of d-dimensional linear subspaces with spherically symmetric distributions within each subspace and an additional outlier component with spherically symmetric distribution within the ambient space (for simplicity we may assume that all distributions are uniform on their corresponding unit spheres). We also assume mixture weights for the different components. We say that one of the underlying subspaces of the model is most significant if its mixture weight is higher than the sum of the mixture weights of all other subspaces. We study the recovery of the most significant subspace by minimizing the lp-averaged distances of data points from d-dimensional subspaces, where p>0. Unlike other lp minimization problems, this minimization is non-convex for all p>0 and thus requires different methods for its analysis. We show that if 0<p<=1, then for any fraction of outliers the most significant subspace can be recovered by lp minimization with overwhelming probability (which depends on the generating distribution and its parameters). We show that when adding small noise around the underlying subspaces the most significant subspace can be nearly recovered by lp minimization for any 0<p<=1 with an error proportional to the noise level. On the other hand, if p>1 and there is more than one underlying subspace, then with overwhelming probability the most significant subspace cannot be recovered or nearly recovered. This last result does not require spherically symmetric outliers.Comment: This is a revised version of the part of 1002.1994 that deals with single subspace recovery. V3: Improved estimates (in particular for Lemma 3.1 and for estimates relying on it), asymptotic dependence of probabilities and constants on D and d and further clarifications; for simplicity it assumes uniform distributions on spheres. V4: minor revision for the published versio

Linear, Deterministic, and Order-Invariant Initialization Methods for the K-Means Clustering Algorithm

Over the past five decades, k-means has become the clustering algorithm of choice in many application domains primarily due to its simplicity, time/space efficiency, and invariance to the ordering of the data points. Unfortunately, the algorithm's sensitivity to the initial selection of the cluster centers remains to be its most serious drawback. Numerous initialization methods have been proposed to address this drawback. Many of these methods, however, have time complexity superlinear in the number of data points, which makes them impractical for large data sets. On the other hand, linear methods are often random and/or sensitive to the ordering of the data points. These methods are generally unreliable in that the quality of their results is unpredictable. Therefore, it is common practice to perform multiple runs of such methods and take the output of the run that produces the best results. Such a practice, however, greatly increases the computational requirements of the otherwise highly efficient k-means algorithm. In this chapter, we investigate the empirical performance of six linear, deterministic (non-random), and order-invariant k-means initialization methods on a large and diverse collection of data sets from the UCI Machine Learning Repository. The results demonstrate that two relatively unknown hierarchical initialization methods due to Su and Dy outperform the remaining four methods with respect to two objective effectiveness criteria. In addition, a recent method due to Erisoglu et al. performs surprisingly poorly.Comment: 21 pages, 2 figures, 5 tables, Partitional Clustering Algorithms (Springer, 2014). arXiv admin note: substantial text overlap with arXiv:1304.7465, arXiv:1209.196