Márta Brózik

Genetic Background of Anticyclic Citrullinated Peptide Autoantibody Production in Hungarian Patients with Rheumatoid Arthritis

Abstract:  Polymorphisms of the peptidylarginine deiminase 4 (PADI4) gene encoding for the isoenzyme that converts arginyl into citrullyl residues have been shown to contribute to susceptibility to rheumatoid arthritis (RA), depending on the population studied. We aimed at determining whether PADI4 single nucleotide polymorphisms (SNPs) are associated with RA in a Hungarian population. The relationship between anticyclic citrullinated peptide (anti‐CCP) production and HLA‐DRB1 alleles encoding the shared epitope (SE) was also investigated. DNA samples were obtained from RA (n= 261) patients and from control donors (n= 120). HLA‐DRB1 genotyping was carried out by polymerase chain reaction (PCR) with sequence‐specific priming. PAD4_92 G/C and PAD4_104 T/C SNPs were genotyped using real‐time PCR allele discrimination. Autoantibodies against CCP were detected by ELISA. All healthy controls tested anti‐CCP negative, whereas 171 (66%) RA patients were anti‐CCP positive. No significant difference in allele or genotype frequencies were found between RA patients and controls for any of the PADI4 SNPs. Anti‐CCP seropositivity was unrelated to these two SNPs. No association was found between any of the PADI4 SNPs and HLA‐DRB1 subtypes. Presence of the HLA‐RB1 SE alleles was significantly associated with anti‐CCP seropositivity; HLA‐DRB1*0401 and HLA‐DRB1*1001 carriers showed the strongest association. In conclusion, our data suggest that polymorphisms of the PADI4 gene are not associated with rheumatoid arthritis and are unlikely to be responsible for the presence of anti‐CCP autoantibodies in a white Hungarian population. HLA‐DRB1 SE alleles, however, may significantly contribute to the genetic determination of anti‐CCP production in Hungarian patients with RA.

Hepatic regeneration induces transient acute phase reaction: systemic elevation of acute phase reactants and soluble cytokine receptors.

The growth factors present during liver regeneration partially overlap with the regulators of the hepatic acute phase response. We analysed the acute phase reaction and changes in soluble cytokine receptors after partial hepatectomy, when tissue injury inducing acute phase reaction and major reduction of liver mass occur simultaneously. Three acute phase proteins and mRNAs were determined by ELISA and northern blot hybridisation in rats. Serum levels of IL‐6 and three soluble cytokine receptors (sTNF‐αR I and II, sIL‐6R) were detected by ELIBA or dot‐blot assay. Time‐course profiles of fibrinogen, α2‐macroglobulin and haptoglobin proteins and mRNA are presented. Elevation of IL‐6, soluble TNF‐α receptors and soluble IL‐6 receptor levels were also detected. The time‐course of changes in haptoglobin concentration and elevation of soluble cytokine receptors is described by this in vivo experimental system. The results show good correlation with (post)transcriptional activation of immediate and delayed early gene products. These data suggest the involvement of both acute phase proteins and soluble cytokine receptors in the regulation of liver regeneration.

In vivo pulmonary toxicity of cellulose in rats.

Cellulose after a single intratracheal dose (15 mg per animal) brought about fibrosing granulomatous alveobronchiolitis and an increase of IgA production in the bronchoalveolar lavage. Fibrosing alveolitis showed moderate progression as a function of time. With different morphological methods, injury of type I pneumocytes and the incomplete repair of type II pneumocytes were detected. The damage of the alveolar epithelium initiated and activated a series of processes that led to definite pulmonary alterations: pulmonary fibrosis leading to the disintegration of the alveolo‐capillary morphological functional unit.

Combined pulmonary toxicity of diethyldithiocarbamate and lead (II) oxide in rats

The pulmonary toxicity of sodium diethyldithiocarbamate and lead(II) oxide alone or in combination was studied in rats after a single intratracheal instillation. The lead content in the lungs and the whole blood was determined and it has been found that the clearance of lead from the lung was delayed by dithiocarbamate complex formation, which probably had a role in increased IgA levels in the bronchoalveolar fluid and the induction of local immune response. The combined exposure gave rise to calcium deposits in the lungs both extra‐ and intracellularly after 1 month of exposure. Both separate and combined exposure invoked permanent injury in membranes or dystrophic changes in the cytoplasm of pneumocytes, which may initiate and generate a series of events leading to fibrosing alveolitis.