Retinoids induce Fas(CD95) ligand cell surface expression via RARgamma and nur77 in T cells

Cells from the CD4+ murine T hybridoma line IP-12-7 enter the apoptotic suicide program via the Fas ligand (FasL)/Fas-mediated pathway upon TCR stimulation. This stimulus regulates the sensitization of the Fas death pathway and the cell surface appearance of preformed FasL. The apoptosis is dependent on new mRNA and protein synthesis and involves up-regulation of nur77.Two groups of nuclear receptors for retinoic acids (RA) have been identified: retinoic acid receptors (RAR) and retinoid X receptors. IP-12-7 cells express RARalpha and RARgamma. Here we show that,in the IP-12-7 T cells, RA also induced the expression and DNA binding of nur77, and the cell surface appearance of FasL. The induction was mediated via RARgamma. Despite the induced expression of cell surface FasL, only two structurally related RARgamma-selective compounds, CD437 and CD2325, initiated apoptosis in these cells. The lack of apoptosis induction by natural RA was related to the inability of RARgamma to sensitize the Fas death-pathway. Cell surface FasL, however, was able to induce cell death in Fas-bearing target cells. Natural RA also induced the expression of FasL in phytohemagglutinin-activated peripheral murine T cells. It is proposed that therapeutically administered RA might induce apoptosis in Fas-sensitive cells via induction of FasL expression in activated Tcells.     

13-cis retinoic acid inhibits development and progression of chronic allograft nephropathy

Chronic allograft nephropathy is characterized by chronic inflammation and fibrosis. Because retinoids exhibit anti-proliferative, anti-inflammatory, and anti-fibrotic functions, the effects of low and high doses of 13-cis-retinoic acid (13cRA) were studied in a chronic Fisher344-->Lewis transplantation model. In 13cRA animals, independent of dose (2 or 20 mg/kg body weight/day) and start (0 or 14 days after transplantation) of 13cRA administration, serum creatinine was significantly lower and chronic rejection damage was dramatically reduced, including subendothelial fibrosis of preglomerular vessels and chronic tubulointerstitial damage. The number of infiltrating mononuclear cells and their proliferative activity were significantly diminished. The mRNA expression of chemokines (MCP-1/CCL2, MIP-1alpha/CCL3, IP-10/CXCL10, RANTES/CCL5) and proteins associated with fibrosis (plasminogen activator inhibitor-1, transforming growth factor-beta1, and collagens I and III) were strikingly lower in treated allografts. In vitro, activated peritoneal macrophages of 13cRA-treated rats showed a pronounced decrease in protein secretion of inflammatory cytokines (eg, tumor necrosis factor-alpha, interleukin-6). The suppression of the proinflammatory chemokine RANTES/CCL5 x 13cRA in fibroblasts could be mapped to a promoter module comprising IRF-1 and nuclear factor-kappaB binding elements, but direct binding of retinoid receptors to promoter elements could be excluded. In summary, 13cRA acted as a potent immunosuppressive and anti-fibrotic agent able to prevent and inhibit progression of chronic allograft nephropathy.     

Human chromosome 3: high-resolution fluorescencein situ hybridization mapping of 40 uniqueNotl linking clones homologous to genes and cDNAs

Forty newNotl linking clones representing sequence tagged sites (STSs) were mapped by fluorescencein situ hybridization (FISH) to different regions of human chromosome 3 (HSA3). Clone NL1-245, containing human aminoacylase 1, was localized to 3p21.2–p21.1. Our previous localization of the CLC-2 chloride channel protein gene was refined to 3q27. Clone NL2-316 most likely contains a translocon-associated protein -subunit gene and was mapped to 3q23–q24. To our knowledge, this is the first time this gene has been mapped. OneNoti linking clone (NL1-229) probably contains a new protein phosphatase gene. This clone was mapped to 3p25. FiveNoti linking clones probably contain human expressed sequence tags (ESTs), as they possess sequences with a high level of identity (>90%) to cDNA clones. Other clones show 56–85% homology to known mammalian and human genes with various functions, including oncogenes and tumour-suppressor genes. These clones might represent new genes.accepted for publication by M. Schmid     

Alpha-adrenergic receptor (alpha(2 A )) is colocalized in basal forebrain cholinergic neurons: a light and electron microscopic double immunolabeling study

A variety of data suggest that noradrenaline and acetylcholine may interact in the basal forebrain, however no morphological studies have addressed whether indeed cholinergic neurons express adrenergic receptors. We have investigated the presence of alpha-adrenergic receptor subtype alpha2A-AR in cholinergic neurons of the basal forebrain. Cholinergic neurons were identified with an antibody against choline acetyltransferase and the receptor with a polyclonal antibody raised against a 47 amino acid fragment of the third intracellular loop of the alpha2A-AR. For double labeling at the light microscopic level the Ni-DAB/DAB technique was used, and for electron microscopy an immunoperoxidase/immunogold method was applied. We detected the alpha2A-AR protein in cholinergic as well as in non-cholinergic neurons. Almost half of all cholinergic neurons contained this adrenergic receptor. Double-labeled neurons were distributed throughout the rostro-caudal extent of the basal forebrain cholinergic continuum, including the medial septum, vertical and horizontal diagonal band nuclei, pallidal regions, substantia innominata and the internal capsule. Non-cholinergic neurons that expressed the alpha2A-AR outnumbered cholinergic/alpha2A-AR neurons by several factors. Electron microscopy confirmed the presence of alpha2A-AR in cholinergic neurons in the medial septum, vertical and horizontal diagonal band nuclei. Gold particles (10 nm) indicative of alpha2A-AR were diffusely distributed in the cytoplasm and accumulated in cytoplasmic areas near the Golgi complex and cysterns of the endoplasmic reticulum and were associated with the cellular membranes at synaptic and non-synaptic locations. Since many of the alpha2A-AR+/non-cholinergic neurons we detected are likely to be GABAergic cells, our data support the hypothesis that noradrenaline may act via basal forebrain cholinergic and non-cholinergic neurons to influence cortical activity.     

The Role of Apoptosis Proteins and Complement Components in the Etiopathogenesis of Systemic Lupus Erythematosus

Systemic lupus erythematosus is a prototypical autoimmune disease characterized by the deregulation of T and B cells, tissue infiltration by mononuclear cells, tissue damage and the production of autoantibodies. There is a consensus that accelerated apoptosis of circulating lymphocytes and/or impaired clearance of apoptotic bodies may increase the amount of nuclear antigens presented to T lymphocytes. This process is accompanied by autoimmune responses that can lead to the development of lupus. The dysfunction of apoptosis may be a direct consequence of alterations in proteins/genes such as Fas, Bcl-2 and C1q. Increased expression of Fas antigen could intensify the exposure of hidden antigens. The overexpression of Bcl-2 protein might inhibit the removal of auto-reactive cells, and the lack of C1q could impair the clearance of self-antigens. The complete knowledge of the role of apoptosis components in the etiopathogenesis of lupus could lead to the development of new therapies targeting the apoptotic threshold, which could result in a more specific and effective disease response compared to global immunosuppression. This review summarizes the role of each component of the apoptotic process in the pathogenesis of lupus.     

Autoinflammatory Diseases: Mimics of Autoimmunity or Part of its Spectrum? Case Presentation

Introduction:

Autoinflammatory diseases are very rare diseases presenting within a wide clinical spectrum. Recognition of the main clinical features are challenging due to overlapping or mimicking with autoimmune diseases.

Discussion:

A case series is reviewed to illustrate typical and atypical features and the difficulties of these diagnoses in the low prevalence areas—a typical unrecognized case of familial Mediterranean fever (FMF) in a youngster, an atypical adult case with overlapping of FMF with Behçet disease, and an early presentation of FMF in infant presenting with inflammatory colitis, as well as the overlapping features within the cryopirin diseases spectrum in an 8-year-old boy who presented with systemic onset arthritis.

Conclusion:

These cases may represent examples of a very puzzling relationship among disorders of innate and adaptive immune systems and inflammation.

     

Localization of glutamatergic/aspartatergic neurons projecting to the hypothalamic paraventricular nucleus studied by retrograde transport of [3H]D-aspartate autoradiography

Morphological and functional data indicate that glutamatergic innervation of the hypothalamic paraventricular nucleus plays an important role in the control of this prominent cell group. Sources of this neural input are unknown. The present investigations were aimed at studying this question. The retrograde tracer [3H]D-aspartate, which is selectively taken up by the terminals of neurons that use glutamate or aspartate as a neurotransmitter, and is retrogradely transported to their perikarya, was injected into the paraventricular nucleus. The brain was examined for labelled neurons visualized by autoradiography. Labelled neurons were detected in the paraventricular nucleus itself, in several hypothalamic areas including medial and lateral preoptic area, suprachiasmatic nucleus, anterior hypothalamic area, ventromedial nucleus, dorsomedial nucleus, lateral hypothalamic area, posterior part of arcuate nucleus, ventral premammillary nucleus and supramammillary nucleus. Outside the hypothalamus labelled neurons were found in the thalamic paraventricular nucleus and in certain telencephalic regions including lateral septum, bed nucleus of the stria terminalis and amygdala. All of them are known to project to the hypothalamic paraventricular nucleus. We failed to detect labelled neurons in the lower brainstem.From these findings we conclude that firstly, there are glutamatergic/aspartatergic interneurons in the paraventricular nucleus; secondly, all intrahypothalamic and telencephalic, but not lower brainstem afferents to this nucleus contain glutamatergic/aspartatergic fibres; and thirdly, the glutamatergic/aspartatergic innervation of this heterogeneous cell group is extremely complex.     

Complete genome characterization of mosavirus (family Picornaviridae) identified in droppings of a European roller (Coracias garrulus) in Hungary

Mosavirus (mosavirus A1, M-7/2010/USA, JF973687), a novel picornavirus, was found in a canyon mouse (Peromyscus crinitus) in the USA in 2010. It represents a novel species (Mosavirus A) in a novel genus (Mosavirus) in the family Picornaviridae. In this study, the first complete genome sequence of another mosavirus, SZAL6-MoV/2011/HUN (KF958461), was determined from one out of 18 fecal samples from an Afro-Palearctic migratory bird, the European roller (Coracias garrulus). The complete genome of SZAL6-MoV/2011/HUN is 8385 nt long (from poly(C) tract to poly(A) tail), contains a 646-nt-long 5′UTR that forms a type II IRES, and encodes a potential 2550-aa-long polyprotein precursor including an aphthovirus-like L^pro-proteinase, a small aphthovirus-like 2A^NPG↓P, and two 3B^VPg proteins. SZAL6-MoV/2011/HUN has 67 %, 74 %, and 76 % aa sequence identity in the P1, P2, and P3 region, respectively, to M-7/2010/USA and represents a second mosavirus type, mosavirus A2.     

Hyperferritinemia is Associated with Serologic Antiphospholipid Syndrome in SLE Patients

Ferritin may play a direct role on the immune system. We sought to determine if elevated levels of ferritin in lupus patients correlate with disease activity and organ involvement in a large cohort. Ferritin levels (gender and age adjusted) were assessed in 274 lupus serum samples utilizing the LIASON Ferritin automated immunoassay method. Significant disease activity was determined if European Consensus Lupus Activity Index (ECLAM)?>?2 or Systemic Lupus Erythematosus Disease Activity Index (SLEDAI)?>?4. Utilizing an EXCEL database, we compared elevated ferritin levels to manifestations grouped by organ involvement, serology, and previous therapy. The patients were predominantly female (89%), median age was 37 years old, and disease duration was 10.6?±?7.7 years. Hyperferritinemia was found in 18.6% of SLE patients. Compared to subjects with normal ferritin levels, a significantly greater proportion of patients with hyperferritinemia had thrombocytopenia (15.4% vs. 33.3%, p?=?0.003) and lupus anticoagulant (11.3% vs. 29.0%, p?=?0.01). Additionally, compared to normoferritinemic subjects, hyperferritinemic subjects had significantly higher total aCL (99.7?±?369 vs. 30.9?±?17.3 GPI, p?=?0.02) and aCL IgM antibody levels (75.3?±?357.4 vs. 9.3?±?10.3 GPI, p?=?0.02), and marginally lower aCL IgG antibody levels (9.2?±?4.9 vs. 9.7?±?3.9 GPI, p?=?0.096). While the ECLAM score significantly correlated with hyperferritinemia (p?=?0.04), the SLEDAI score was marginally associated with hyperferritinemia (p?=?0.1). Serositis was marginally associated with hyperferritinemia, but not with other manifestations. An association with serologic APS was encountered. Hyperferritinemia was associated with thrombocytopenia, lupus anticoagulant, and anti-cardiolipin antibodies suggest that it may be an early marker for secondary antiphospholipid syndrome in SLE patients.