Apoptosis plays a role in pemphigus IgG-dependent acantholysis; theoretically, the blockade of the caspase pathway could prevent the blistering that is caused by pemphigus autoantibodies. Using this strategy, we attempted to block the pathogenic effect of pemphigus IgG in Balb/c mice by using the caspase inhibitor Ac-DEVD-CMK. This inhibitor was administrated before the injection of pemphigus IgG into neonatal mice. The main results of the present investigation are as follows: (1) pemphigus IgG induces intraepidermal blisters in Balb/c neonatal mice; (2) keratinocytes around the blister and acantholytic cells undergo apoptosis; (3) the caspases inhibitor Ac-DEVD-CMK prevents apoptosis; (4) the inhibition of the caspase pathway prevents blister formation. In conclusion, inhibition of the caspase pathway may be a promising therapeutic tool that can help in the treatment of pemphigus flare ups.
Fibrodysplasia ossificans progressiva (FOP) is an exceptionally rare genetic disease that is characterised by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomical areas. This disease is caused by a mutation in activin receptor IA/activin-like kinase-2 (ACVR1/ALK2). A Mexican family with one member affected by FOP was studied. The patient is a 19-year-old female who first presented with symptoms of FOP at 8 years old; she developed spontaneous and painful swelling of the right scapular area accompanied by functional limitation of movement. Mutation analysis was performed in which genomic DNA as PCR amplified using primers flanking exons 4 and 6, and PCR products were digested with Cac8I and HphI restriction enzymes. The most informative results were obtained with the exon 4 flanking primers and the Cac8I restriction enzyme, which generated a 253 bp product that carries the ACVR1 617G>A mutation, which causes an amino acid substitution of histidine for arginine at position 206 of the glycine-serine (GS) domain, and its mutation results in the dysregulation of bone morphogenetic protein (BMP) signalling that causes FOP.
The present study investigated posttranslational reactions in the salivary glands of patients with Sjögren's syndrome. We analysed the biopsies of primary Sjögren's patients using immunohistochemistry and a tag-purified anticyclic citrullinated protein (CCP) antibody to detect citrullinated peptides, and the presence of peptidylarginine deiminase 2 (PAD2) was assessed simultaneously. The present work demonstrated the weak presence of the PAD2 enzyme in some normal salivary glands, although PAD2 expression was increased considerably in Sjögren's patients. The presence of citrullinated proteins was also detected in the salivary tissues of Sjögren's patients, which strongly supports the in situ posttranslational modification of proteins in this setting. Furthermore, the mutual expression of CCP and PAD2 suggests that this posttranslational modification is enzyme dependent. In conclusion, patients with Sjögren's syndrome expressed the catalytic machinery to produce posttranslational reactions that may result in autoantigen triggering.
The goal of the present study was to determine whether peptidylarginine deiminase PAD2 and PAD4 enzymes are present in Balb/c mouse salivary glands and whether they are able to citrullinate Ro and La ribonucleoproteins. Salivary glands from Balb/c mice were cultured in DMEM and supplemented with one of the following stimulants: ATP, LPS, TNF, IFNγ, or IL-6. A control group without stimulant was also evaluated. PAD2, PAD4, citrullinated peptides, Ro60, and La were detected by immunohistochemistry and double immunofluorescence. PAD2 and PAD4 mRNAs and protein expression were detected by qPCR and Western blot analysis. PAD activity was assessed using an antigen capture enzyme-linked immunosorbent assay. LPS, ATP, and TNF triggered PAD2 and PAD4 expression; in contrast, no expression was detected in the control group (p < 0.001). PAD transcription slightly increased in response to stimulation. Additionally, PAD2/4 activity modified the arginine residues of a reporter protein (fibrinogen) in vitro. PADs citrullinated Ro60 and La ribonucleoproteins in vivo. Molecular stimulants induced apoptosis in ductal cells and the externalization of Ro60 and La ribonucleoproteins onto apoptotic membranes. PAD enzymes citrullinate Ro and La ribonucleoproteins, and this experimental approach may facilitate our understanding of the role of posttranslational modifications in the pathophysiology of Sjögren's syndrome.
Evaluation of: Lian S, Fritzler M, Katz J et al. Small interfering RNA-mediated silencing induces target-dependent assembly of GW/P bodies. Mol. Biol. Cell 18, 3375-3387 (2007). GW bodies (GWBs) are also known as mammalian processing bodies and are involved in 5 -3 mRNA degradation. Conversely, siRNA is a powerful tool for silencing genes. Recently, components of RNAi have been associated with GWBs, but as more components of this complex pathway become known, such relationships remain to be clarified. This paper evaluates the induction of GWBs by siRNA transfection. The main results of these studies indicate that siRNA increased the GWBs, such an increase is also dependent on the endogenous expression of the target mRNA; siRNA increases require GW182 or Ago-2 proteins, but not rck/p54 or LSm1. Results of the present studies propose a regulatory function of RNAi in GWB assembly; therefore, cell biology implications of GWBs may open a new area in pathogenic mechanisms of autoimmunity.
Paraneoplastic pemphigus is a rare and severe autoimmune blistering disease characterized by a recalcitrant and severe mucositis, and polymorphic cutaneous lesions, associated with benign and malignant neoplasms. Paraneoplastic pemphigus is caused by production of autoantibodies against various epidermal proteins involved in cell adhesion. Bronchiolitis obliterans (BO) is one of the leading causes of mortality in these patients. Recent advances have associated the presence of anti-epiplakin antibodies with the development of BO in adult patients. Here we describe the first pediatric patient in whom the association of anti-epiplakin antibodies and BO have been reported so far.
Background: The autoimmunity associated with environmental pollutants such as heavy metals is a phenomenon that has been described previously. The aim of the present study investigated the relationship between autoimmunity and lead pollutants in a cohort of children who lived in a mining settlement. Methods: Children were studied clinically and serologically. The serum lead concentration was measured by atomic absorption spectrometry, and antinuclear antibodies were analysed by immunofluorescence, ELISA and Western blot. Results: None of the studied children displayed any autoimmune disease. The lead concentration in the control group was negligible, at 0.10 ± 011 µg. L -1 . In contrast, the study group had values of 12.72 ± 0.5 µg. L -1 . The differences between the groups were significant (p< 0.0001). In addition, control sera were negative for antinuclear antibodies (ANA), while the sera of children living near the mining settlement showed ANA-positive titres (p< 0.001). These autoantibodies mainly recognized antigens associated with dividing cells, such as the mitotic apparatus and centrioles. Conclusion: The present results show how metallic pollutants induce environmentally associated autoimmunity and are reflected by antinuclear antibodies. This research should prompt us to take greater caution and implement permanent monitoring to ensure a healthy environment.
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