Zur Tuberkulose der knöchernen Schädeldecke

Ohne Zusammenfassung     

Mask face: Bilateral simultaneous facial palsy in an 11‐year‐old boy

Bilateral facial paralysis is an uncommon clinical entity especially in the pediatric age group and occurs frequently as a manifestation of systemic disease. The most important causes are trauma, infectious diseases, neurological diseases, metabolic, neoplastic, autoimmune diseases and idiopathic disease (Bell's palsy). We report a case of an 11‐year‐old boy presenting with bilateral simultaneous peripheral facial paralysis. All possible infectious causes were excluded and the patient was diagnosed as having Bell's palsy (idiopathic). The most important approach in these cases is to rule out a life‐threatening disease.     

Immune dysregulation caused by homozygous mutations in CBLB

CBL-B is an E3 ubiquitin ligase that ubiquitinates proteins downstream of immune receptors to downregulate positive signaling cascades. Distinct homozygous mutations in CBLB were identified in 3 unrelated children with early-onset autoimmunity, one of whom also had chronic urticaria. Patient T cells exhibited hyperproliferation in response to anti-CD3 cross-linking. One of the mutations, p.R496X, abolished CBL-B expression, and a second mutation, p.C464W, resulted in preserved CBL-B expression. The third mutation, p.H285L in the SH2 domain of CBL-B, was expressed at half the normal level in the patient’s cells. Mice homozygous for the CBL-B p.H257L mutation, which corresponds to the patient’s p.H285L mutation, had T and B cell hyperproliferation in response to antigen receptor cross-linking. Cblb^H257L mice had increased percentages of T regulatory cells (Tregs) that had normal in vitro suppressive function. However, T effector cells from the patient with the p.H285L mutation and Cblb^H257L mice were resistant to suppression by WT Tregs. Bone marrow–derived mast cells from Cblb^H257L mice were hyperactivated after FcεRI cross-linking, and Cblb^H257L mice demonstrated exaggerated IgE-mediated passive anaphylaxis. This study establishes CBL-B deficiency as a cause of immune dysregulation.     

Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

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17β-Estradiol prevents mesenteric injury induced by occlusion of the proximal descending aorta in male rats

Objective

In surgical aortic repair or cardiac surgery with aorta occlusion, the occurrence of mesenteric ischemia and bowel injury has been associated with higher short-term mortality. The vascular protection of estrogens has been investigated and is mainly mediated by increasing the availability of nitric oxide (NO). Therefore, this study investigated the role of 17β-estradiol on visceral ischemia-reperfusion (I/R) injury after descending aorta occlusion in male rats.

Leucine-rich repeat containing 8A (LRRC8A) is essential for T lymphocyte development and function

Lrrc8a is a ubiquitously expressed gene that encodes a leucine-rich repeat (LRR)–containing protein detected at higher levels on the surface of thymocytes than on other immune cells. We generated Lrrc8a^−/− mice to investigate the role of LRRC8A in lymphocyte development and function. Lrrc8a^−/− mice had increased prenatal and postnatal mortality, growth retardation, and multiple tissue abnormalities. Lrrc8a^−/− mice displayed a modest block in B cell development but intact intrinsic B cell function. In contrast, both Lrrc8a^−/− mice and Lrrc8a^−/−→Rag2^−/− bone marrow chimeras exhibited a severe cell-intrinsic block in early thymic development, with decreased proliferation and increased apoptosis of thymocytes, and impaired peripheral T cell function. Thymic epithelial cells expressed an LRRC8A ligand that was critical for double-negative to double-positive thymocyte differentiation and survival in vitro. LRRC8A constitutively associated with the GRB2–GAB2 complex and lymphocyte-specific protein tyrosine kinase (LCK) in thymocytes. LRRC8A ligation activated AKT via the LCK–ZAP–70–GAB2–PI3K pathway, and AKT phosphorylation was markedly reduced in the thymus of Lrrc8a^−/− mice. These findings reveal an essential role for LRRC8A in T cell development, survival, and function.Leucine-rich repeats (LRRs) are 20–29-aa-long sequences that contain a conserved consensus sequence LxxLxLxxN/CxL, where L may be replaced by isoleucine, phenylalanine, or valine (Kobe and Kajava, 2001). LRRs provide a structural framework for protein–protein interactions (Kobe and Kajava, 2001). Several LRR-containing proteins, such as TLRs, NODs, and GP1bβ, are important in innate immunity (Tang et al., 2004; Inohara et al., 2005; Lee and Kim, 2007). Little is known about the role of LRR-containing proteins in adaptive immunity, with the exception of CIITA (MHC class II transactivator), the deficiency of which results in absent expression of MHC class II molecules and severe immunodeficiency (Cressman et al., 1999).LRRC8A (LRR containing 8A) is a 94-kD LRR-containing protein highly conserved between human and mouse (Sawada et al., 2003). LRRC8A spans the cell membrane four times and its extracellular C terminus contains 17 LRRs (Sawada et al., 2003; Smits and Kajava, 2004). A 17-yr-old female patient with congenital facial abnormalities, absent B cells, and agammaglobulinemia, but normal numbers of T cells, had a balanced t(9;20)(q33.2;q12) translocation, resulting in the deletion of the C-terminal two-and-a-half LRRs of LRRC8A (91 aa) and the addition of 35 aa derived from an intronic sequence (Sawada et al., 2003). The truncated LRRC8A product was co-expressed with the intact product of the normal LRRC8A allele at comparable levels (Sawada et al., 2003). Reconstitution of irradiated recipient mice with syngeneic CD34⁺ BM progenitors transduced with a retroviral vector overexpressing the mutant LRRC8A resulted in a severe block in B cell development at the pro–B cell to pre–B cell transition and reduced numbers of T cells (Sawada et al., 2003). The phenotype was attributed to the dominant negative effect of the co-expressed mutant LRRC8A allele (Conley, 2003; Sawada et al., 2003). No developmental or functional analysis of the T cells was conducted in these mice, and the expression level of the mutant protein in hematopoietic cells was not documented (Sawada et al., 2003).To understand the role of LRRC8A in the adaptive immune system, we generated Lrrc8a^−/− mice that expressed no LRRC8A protein. Unlike the patient, Lrrc8a^−/− mice have peripheral B cells and normal immunoglobulin levels but display a severe cell-intrinsic block in thymic development and impaired peripheral T cell function. We demonstrate that thymic epithelial cell (TECs) express ligands for LRRC8A and that LRRC8A ligation activates AKT via the lymphocyte-specific protein tyrosine kinase (LCK)–ZAP-70–GAB2–PI3K pathway. Our work demonstrates an essential role for LRRC8A in T cell development and function.     

CD1d restricted natural killer T cells are not required for allergic skin inflammation

BACKGROUND: Invariant T-cell receptor-positive natural killer (iNKT) cells have been shown to be essential for the development of allergen-induced airway hyperreactivity (AHR). OBJECTIVE: We examined the role of iNKT cells in allergic skin inflammation using a murine model of atopic dermatitis (AD) elicited by epicutaneous sensitization with ovalbumin (OVA). METHODS: Wild-type (WT) and natural killer T-cell-deficient CD1d-/- mice were epicutaneously sensitized with OVA or normal saline and challenged with aerosolized OVA. iNKT cells in skin and bronchoalveolar lavage fluid were analyzed by fluorescence-activated cell sorting, and cytokine mRNA levels were measured by quantitative RT-PCR. AHR to methacholine was measured after OVA inhalation. RESULTS: Skin infiltration by eosinophils and CD4+ cells and expression of mRNA encoding IL-4 and IL-13 in OVA-sensitized skin were similar in WT and CD1d-/- mice. No significant increase in iNKT cells was detectable in epicutaneously sensitized skin. In contrast, iNKT cells were found in the bronchoalveolar lavage fluid from OVA-challenged epicutaneously sensitized WT mice, but not CD1d-/- mice. Epicutaneously sensitized CD1d-/- mice had an impaired expression of IL-4, IL-5, and IL-13 mRNA in the lung and failed to develop AHR in response to airway challenge with OVA. CONCLUSION: These results demonstrate that iNKT cells are not required for allergic skin inflammation in a murine model of AD, in contrast with airway inflammation, in which iNKT cells are essential. CLINICAL IMPLICATIONS: Understanding the potential role of iNKT cells in AD will allow us to have a more specific target for therapeutic use.