Interleukin-17 and -22 synergy linking inflammation and EMT-dependent fibrosis in Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic inflammatory, autoimmune and systemic disorder commonly associated with dry eyes and a dry mouth. Recently, the hypothetical link between epithelial-mesenchymal transition (EMT)-dependent salivary gland (SG) fibrosis and chronic inflammatory conditions has been suggested. In this study, we present data demonstrating a negative correlation of the epithelial marker E-cadherin expression and a positive correlation of mesenchymal vimentin and collagen type I expression with increasing degrees of tissue inflammation in pSS SG specimens. In addition, as it is not clear whether dysregulated cytokines in pSS, interleukin (IL)-17 and IL-22 may also contribute to the EMT-dependent fibrosis process, the effect of IL-17 and IL-22 treatment on EMT-dependent SG fibrosis was evaluated in primary human salivary gland epithelial cells (SGEC) isolated from healthy subjects. Here we present data demonstrating that IL-17 and IL-22 can induce SGEC to undergo a morphological and phenotypical transition to a mesenchymal phenotype. In support of this, vimentin and collagen type I were up-regulated while a decreased expression of E-cadherin occurs after interleukin treatment, and co-operation between IL-17 and Il-22 was required to induce the EMT.

Downstream activation of NF-κB in the EDA-A1/EDAR signalling in Sjögren's syndrome and its regulation by the ubiquitin-editing enzyme A20.

Sjögren's syndrome (SS) is an autoimmune disease and the second most common chronic systemic rheumatic disorder. Prevalence of primary SS in the general population has been estimated to be approximately 1-3%, whereas secondary SS has been observed in 10-20% of patients with rheumatoid arthritis, systemic lupus erythematosus (SLE) and scleroderma. Despite this, its exact aetiology and pathogenesis are largely unexplored. Nuclear factor-kappa B (NF-κB) signalling mechanisms provide central controls in SS, but how these pathways intersect the pathological features of this disease is unclear. The ubiquitin-editing enzyme A20 (tumour necrosis factor-α-induced protein 3, TNFAIP3) serves as a critical inhibitor on NF-κB signalling. In humans, polymorphisms in the A20 gene or a deregulated expression of A20 are often associated with several inflammatory disorders, including SS. Because A20 controls the ectodysplasin-A1 (EDA-A1)/ectodysplasin receptor (EDAR) signalling negatively, and the deletion of A20 results in excessive EDA1-induced NF-κB signalling, this work investigates the expression levels of EDA-A1 and EDAR in SS human salivary glands epithelial cells (SGEC) and evaluates the hypothesis that SS SGEC-specific deregulation of A20 results in excessive EDA1-induced NF-κB signalling in SS. Our approach, which combines the use of siRNA-mediated gene silencing and quantitative pathway analysis, was used to elucidate the role of the A20 target gene in intracellular EDA-A1/EDAR/NF-κB pathway in SS SGEC, holding significant promise for compound selection in drug discovery.

Transcatheter closure of an unligated vertical vein with an Amplatzer Vascular Plug-II device.

: The usual surgical practice after repair of a Total Anomalous Pulmonary Venous Connection (TAPVC) is to ligate the vertical vein (VV). Many surgeons find it expedient to leave the VV unligated to reduce pulmonary arterial pressure, decrease perioperative pulmonary hypertensive crisis, provide better hemodynamics postoperatively (1), and enable the adaptation of cardiac chambers to a new workload. Afterwards, the unligated VV may cause significant left-to-right shunt, likewise an atrial septal defect, mandating later surgical ligation or device closure (2). This report details transcatheter occlusion of a patent VV using a device Amplatzer Vascular Plug II, after TAPVC repair in early infancy. The transcatheter occlusion of an unligated VV after repair of supracardiac TAPVC represents an effective alternative to surgical redo. The device Amplatzer Vascular Plug II achieves great results.

Possible role of oral ibandronate administration in Osteonecrosis of the Jaw: a case report.

We describe a case of Osteonecrosis of the Jaw (ONJ) that developed in a 65-year-old Caucasian woman with osteopenia and other risk factors who was receiving low doses of oral bisphosphonate therapy (ibandronate, 150 mg monthly). Computed tomography (CT), panoramic radiographs (OPT), 99mTc-Sn-MDP scintigraphy, and magnetic resonance imaging (MRI) were performed to study the diseased area; cytological examination also revealed the presence of suppurative material around the area of exposed bone. A diagnosis of bisphosphonate-related osteonecrosis of the jaw complicated by osteomyelitis was made. The patient was prescribed a drug protocol consisting of metronidazole 250 mg 2 times daily, chlorhexidine mouthwashes 3 times daily and chewing exercises for two months. Ibandronate was stopped and replaced with strontium ranelate. The symptoms improved and the patient is still under close follow-up. Assessment of the benefits versus risks is particularly necessary in patients with several risk factors to ascertain their eligibility for treatment with antiresorptive drugs and when this is not possible to choose alternative medications.

Sjögren's syndrome pathological neovascularization is regulated by VEGF-A-stimulated TACE-dependent crosstalk between VEGFR2 and NF-κB.

We explore the involvement of tumor necrosis factor α (TNF-α)-converting enzyme (TACE) in vascular endothelial growth factor (VEGF) and its receptor 2 (VEGFR2) (VEGF-A/VEGFR2)-mediated angiogenesis in Sjögren's syndrome (SS), one of the most common autoimmune rheumatic diseases. To test the hypothesis that SS autoantibodies (Abs) regulate VEGF-A/VEGFR2 expression by a TACE-dependent nuclear factor-κB (NF-κB) activation pathway, their effects on the expression and activation of the VEGF-A/TACE/VEGFR2/NF-κB pathway were determined in human salivary gland epithelial cells (SGEC). An enhanced angiogenesis in SS salivary gland biopsies was observed, associated with an increased VEGF-A expression and activation of VEGF-A/VEGFR2 signaling. Human cytokine array analysis of the pro-inflammatory and pro-angiogenic protein response in SGEC treated with SS Abs revealed an overexpression of multiple pro-angiogenic factors. TACE RNA knockdown, the use of anti-VEGF-A monoclonal antibody and the inhibition of NF-κB activity significantly abrogated the release of pro-angiogenic factors, demonstrating that VEGF-A/TACE/VEGFR2/NF-κB axis dysfunction may be contributory to pathogenesis and exacerbation of this autoimmune condition.

Anti-Ro/SSA autoantibody-mediated regulation of extracellular matrix fibulins in human epithelial cells of the salivary gland.

OBJECTIVES: The fibulins are a family of extracellular matrix (ECM) molecules that regulate the organ shape along with other growth factors and stromal cells and have recently been shown to be involved in a variety of cellular functions including proliferation, migration, differentiation, and survival. Important changes in acinar and ductal morphology and function, together with pronounced ECM remodelling, are detectable in the labial salivary glands (LSGs) of patients with Sjögren's syndrome (SS). Here we report the in vitro expression of the recently identified ECM proteins fibulin-6 and fibulin-7 by human salivary gland epithelial cells (SGECs). The ability of anti-Ro/SSA autoantibodies (Abs) to modulate fibulin-6 and fibulin-7 expression was investigated. METHODS: Semiquantitative reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR were used to analyse fibulin-6 and fibulin-7 mRNA expression. Confocal microscopy and fluorescence-activated cell sorting (FACS) were used to study expression of the proteins in primary human SGEC cultures, established from biopsies of minor LSGs, in both untreated control cells and anti-Ro/SSA Abs-treated cells. RESULTS: The methods used show the expression of fibulin-6 and fibulin-7 in SGECs. Treatment of cells with anti-Ro/SSA Abs results in a down-regulation of fibulin-6 mRNA expression whereas no significant differences were observed in fibulin-7 expression between untreated and treated cells. CONCLUSION: Dysregulation of fibulin expression in SGECs by anti-Ro/SSA Abs may contribute to disorganization of the ECM environment and thus cause injury to the salivary gland architecture and functionality observed in SS.

Hashimoto's thyroiditis in Melkersson-Rosenthal syndrome patient: casual association or related diseases?

Melkersson-Rosenthal syndrome (MRS) is a rare disorder of unknown etiology. MRS is classically defined as a triad of recurrent orofacial edema, relapsing paralysis of the facial nerve, and fissured tongue. The authors present the case of a 52-year-old woman with orofacial swelling and facial pain attacks. The patient reported to suffer of hypothyroidism and laboratory findings disclosed free triiodothyronine (FT(3)), free thyroxine (FT(4)), and thyrotropin (TSH) altered. Endocrinological consult led to the diagnosis of Hashimoto's thyroiditis. Antithyroper-oxidase antibodies (anti-TPO) were highly elevated and thyroid function tests had evidenced a clinically significant hypothyroidism. A link between MRS and immunological disorders such as sarcoidosis, Crohn's disease, unilateral anterior uveitis and multiple sclerosis was documented. The literature did not report any association between Hashimoto's thyroiditis and Melkersson-Rosenthal syndrome. The presence of the anti-TPO antibodies in the case reported here could suggest a possible correlation between immunological alteration characteristic of autoimmune thyroiditis and MRS.

Siögren's syndrome: anti-Ro and anti-La autoantibodies trigger apoptotic mechanism in the human salivary gland cell line, A-253.

AIM: The Sjögren's syndrome (SS) is an autoimmune rheumatic disease that targets salivary and lacrimal glands, characterized by a high concentration of autoantibodies in the serum. The anti-Ro and anti-La autoantibodies are present in approximately 70-90% of the patients with primary SS and this presence is correlated to extraglandular manifestations. The objective of this work was to explore the cellular apoptotic pathway triggered by binding and penetration of anti-Ro and anti-La autoantibodies, isolated from the total IgG fraction of patients with primary SS, in the human salivary gland cell line A-253. METHODS: The sera were obtained from 13 healthy volunteers and 13 patients with primary SS. The IgG was obtained from sera through precipitation with ammonium sulfate and the anti-La and anti-Ro autoantibodies were purified using Sepharose 4B-Ro and Sepharose 4B-La affinity columns. The methods used to evaluate the apoptosis were: DNA fragmentation, immunofluorescence and immunoenzymatic tests. RESULTS: In the salivary gland cells, the anti-Ro and anti-La autoantibodies: 1) are able to penetrate; 2) induce DNA fragmentation and cleavage and activation of the effector caspase-3. In the same experimental condition, IgG purified from healthy sera did not have any apoptotic effect on the human salivary gland cell line. CONCLUSION: Anti-Ro and anti-La autoantibodies mediate the apoptosis the human salivary gland cells A-253 in a caspase-3 dependent manner.

Anti-Ro and anti-La autoantibodies induce TNF-alpha production by human salivary gland cells: an in vitro study.

In this report, we demonstrate that both TNFR1 and the TNFR2 are expressed on the salivary gland cell line A-253 cell membrane. Furthermore, cell treatment with anti-Ro and anti-La autoantibodies from Sjögren IgG determined TNF-alpha production, clarifying which could be the inducer of the extrinsic pathway of apoptosis in salivary gland cells.

Modeling of granulocyte cytoskeletal responses following fMLP challenging.

Formyl peptides released from Gram-negative bacteria ligate a group of specific mammalian receptors, expressed mainly on granulocytes, monocytes, and macrophages. Receptor ligation activates different transduction cascades, eventually leading to the release of reactive oxygen species and other bactericidal chemical species, and the activation of the actin cytoskeleton with extension of lamellipodia and migration toward the sites of maximal formyl peptide concentration. In vitro, under conditions of nongradient formyl peptide concentrations, lamellipodia form all around the cell contour (chemokinesis). In granulocytes challenged under these conditions with N-formyl-methionyl-leucyl-phenylalanine, (i) the power spectrum of the contour of activated cells shows a peak at a specific periodicity, indicating that the lamellipodial extension is not completely random but stochastically conforms to a deterministic scheme, and (ii) the morphological response (percent of cells exhibiting chemokinesis) tends to reach a maximum at certain drug concentrations, then declining at higher concentrations. Accordingly, the logarithm of the drug concentration-polarizing effect curve is bell-shaped. Herein we illustrate theoretical models for the simulation of these two components of the chemokinetic responses. We show that the main traits of the general morphology and arrangement of lamellipodia may be simulated by an algorithm that starting from a situation of random distribution of active receptors on the cell membrane, encompasses in the successive calculation cycles both a local autocatalytic enhancement of the actin polymerization and a relative inhibition of the actin polymerization at some distance from the more active polymerization foci. In addition, a drug log concentration-polarizing effect bell-shaped curve may be simulated by assuming that the N-formyl-methionyl-leucyl-phenylalanine, while binding with high affinity to the specific receptor, is also able to bind to another lower affinity receptor that may effect depolarizing actions or, more generally, metabolic blocking effects. Under these conditions, at low drug concentrations the polarizing effect brought about by the ligation of the specific receptor is largely predominant. However, as the drug concentration increases and the specific receptors approach saturation, the inhibitory effects become more and more powerful and the net polarizing effect is reduced.

Formyl peptide receptors on immune and nonimmune cells: analysis of sequence conservation in FPR genes.

Formyl peptides are oligopeptides released by Gram-negative bacteria. So far, specific formyl peptide receptors (FPRs) have been described in mammals only. FPRs are seven-transmembrane G-coupled molecules and make up a relatively homogeneous group, although exhibiting different levels of affinity for the ligands. We examined the patterns of conservation/mutation within the FPR group of genes, as studied in 16 mRNAs from different species. Following alignment of the coding sections, those nucleotides identical in at least 15 sequences were assigned a "conservation index" 2; those with 8-14 identities an index 1; those with less than 8 identities an index zero. The cumulative average conservation index was 1.36. The autocorrelation function and the power spectrum of the whole series of indexes demonstrated a 3-unit periodicity. This periodicity is explained by the fact that the average conservation indexes of the first, second and third nucleotides of the coding triplets were 1.46, 1.55 (both above the mean), and 1.06 (below the mean), respectively, so that correlations at lag 3 tend to be all positive. In mRNAs, regardless of the position in the coding triplets, T is significantly more frequently conserved (average index = 1.60) than A, C, and G (1.21 - 1.38). In the nucleotides with conservation index 1 or zero, we recorded the two more frequently represented bases. In 35% of mRNA nucleotides the two more frequently represented bases were C and T; in 28% of cases the two more frequently represented bases were A and G; other couples occurred with lower frequencies. Both mutations may arise following C methylation with subsequent transformation into T (by deamination), either in the template or the coding DNA strand. Thus, we hypothesized that in FPR mRNAs there is an evolutionary trend of transformation from G to A and from C to T, the latter being the more stable of the bases.

Formyl peptide receptor expression in birds.

N-formyl-methionyl-leucyl-phenylalanine (fMLP) is a major chemotactic factor produced by Escherichia coli and other Gram-negative bacteria. The prototypal human fMLP receptor 1 (FPR1) was cloned in 1990 from a differentiated HL-60 myeloid leukemia cell cDNA library. In transfected cells, FPR1 binds fMLP with high affinity and is activated by picomolar to low nanomolar concentrations of fMLP in chemotaxis and calcium ion mobilization assays. Two additional human genes, designated FPR-like 1 (FPRL1) and FPR-like 2 (FPRL2), were later isolated by low-stringency hybridization using FPR1 cDNA as a probe, and these were shown to cluster with FPR1 on chromosome 19q13.3. In avian models the fMLP effects and the possible expression of FPRs have been poorly investigated. In this study we demonstrated that stimulation with fMLP of cultured cells isolated from the 10-day chick embryo brain causes superoxide anion and nitric oxide release and protein phosphorylation at serine, threonine, and tyrosine residues. These effects were abrogated by pretreatment with pertussis toxin, suggesting the involvement of a G-protein-coupled receptor (GPCR). Although specific N-formyl peptide receptors have so far been demonstrated only in mammals, a specific polyclonal antihuman-FPR1 antibody proved to bind to the membrane of both neurons and glial cells isolated from the chick brain. Immunoblot analysis revealed a single band corresponding to 60 kDa ca. A BLAST search and aa sequence alignments demonstrated that a number of avian 7-transmembrane (7TM) GPCRs share some homologies with the human FPR1. Furthermore, the CXCR4 ligand, SDF-1alpha, seems to compete with the antihuman-FPR1 polyclonal antibody used in our experiments. We thus advance the hypothesis that in birds one (or more) of the expressed 7TM GPCRs, most probably chemokine receptors belonging to the CXCR4 subfamily, also may act as fMLP receptors.

The 18S rRNA is basically composed of two tandem quasirepeats. Insights into the evolution of some innate immunity receptors.

The gene encoding the 18S rRNA is an ancient molecule and its basic structure has been highly conserved from fish to mammals. Recently, we compared the nucleotide sequences of the human 18S rRNA and the human formyl peptide receptor 1 mRNA and concluded that selected segments of the two sequences exhibit similarities that are unlikely to be due simply to chance. Other data suggest the existence of nonrandom similarities between the 18S rRNA and the chemokine CXC receptor 4 mRNA. Therefore we advance the hypothesis that some groups of genes encoding 7-transmembrane G-coupled receptors of immunological interest may be evolutionarily related to the 18S gene. In this article we analyze the base-sequence architecture of the human 18S rRNA in terms of similarities between selected segments within the molecule. The method of study was based on the recording of the positions of 7- to 11-base oligonucleotide repeats, followed by a probabilistic analysis of the random occurrence of the repeats. Herein we show that most of the 18S rRNA molecule appears to be composed of two long tandem quasirepeats. We hypothesize that an ancestral gene structure composed of a chain of about 850 nucleotides duplicated to form a two-unit tandem repeat. Then the two units diverged as a consequence of independent nucleotide mutations, deletions, and insertions, but still retaining recognizable homologies. In addition, further nonduplicated shorter segments were added to build up the complete sequence.

Chemokine CXC receptor 4: an evolutionary approach.

Selected segments of the nucleotide sequences of the human 18S rRNA and the human formyl peptide receptor 1 mRNA exhibit structural similarities that are unlikely to be due simply to chance. Herein we analyze the structural similarities between the human 18S rRNA gene and the vertebrate chemokine CXC receptor 4 (CXCR4) gene that encodes a class A (rhodopsin-like) seven-transmembrane G-protein coupled receptor belonging to the same superfamily of formyl peptide receptors. The method of study was based on the recording of the positions of the 7-or-more-base oligonucleotide identities encountered in the 18S and CXCR4 genes and the construction of scatter-plots (abscissa-18S; ordinate-CXCR4) displaying the identity points positions. Analysis of the distribution of distances between identity points (abscissa-ordinate in the scatter-plot) demonstrated distinct peaks of frequency around 1200. Series of identities arranged near diagonal lines at 45 degrees in the scatter-plot (quasialignments) were evaluated for their probabilistic level of random occurrence. Results of this analysis demonstrated nonrandom quasialignments between (i) a 900-nt ca. section of the human CXCR4 intron that immediately precedes almost the whole of the coding sequence and the 18S gene from nt 125 to 1025 ca.; and (ii) a 425-nt ca. section of the CXCR4 vertebrate genes, corresponding to nt 137-560 of the coding sequence, and the 18S gene from nt 1300 to 1730 ca. In both instances significant quasialignments are evidenced when CXCR4 nt sequences are shifted to the right by about 1200 nt with respect to the 18S nt sequence, as confirmed by analysis of the abscissa - ordinate differences. Taken together, these results indicate that, at least in humans, a continuous nonrandom quasialignment extends for some 1600 nt, from the second part of the (single) intron to the first part of the coding sequence. We hypothesize that the relatively more recent CXCR4 vertebrate gene might be evolutionarily related to the more ancient and highly conserved 18S gene.

Evolution of a "conserved" amino acid sequence: a model study of an in silico investigation of the phylogenesis of some immune receptors.

In this paper we analyze a 55-amino acid (aa) sequence which is relatively well conserved in several seven-transmembrane receptor families (from Insects to Mammals) and in some Viruses. This sequence, which covers the second transmembrane domain, the first extracellular loop and the third transmembrane domain, appears in its complete configuration in most of the seven-transmembrane receptor families, as well as in the protein products of some viruses. Other seven-transmembrane receptors and viruses exhibit reduced configurations of the conserved sequence, lacking either aa 31 or aa 30-31. 53-aa configurations are typically found in most chemokine receptor (CKR) subfamilies, as well as in some viral protein products. However, the CCR1, CCR3, and CCR6 subfamilies comprise a 54-aa configuration and the CKR-related protein products, ChemR23 and RDC1, include the complete 55-aa sequence. For each CKR subfamily the "modal sequence" of the conserved segment was constructed by selecting the most frequently occurring aa at each position. Then, pairwise alignments were made between: (i) the modal CKR sequences, and (ii) the sequence (53-aa) of the Yaba-like disease virus - 7L protein. From the alignments two consensus matrices were derived: (i) the consensus 1 matrix with reference to the whole conserved segment, and (ii) the consensus 2 matrix with reference to aa 22-29, which appear to be the most variable segment of the sequence. Based on the obtained consensus values and with reference to this specific conserved segment, the following conclusions are proposed: (1) ChemR23 and RDC1 are probably the more primitive CKR forms; (2) CCR1 and CCR3 may be grouped in a single cluster; (3) CCRs 2, 4, and 5 are closely related to each other and may be grouped in a cluster; CCR7 is likely to be evolutionarily related to this cluster; (4) CXCRs 2, 3, and 4 and CCX CKR appear to be evolutionarily related to each other and very likely derived from an CCR6-like gene; (5) CCR2/4/5 and CCR7 may have derived either from CCR1/3-like or CCR6-like genes; (6). The Yaba-like disease virus--7L protein most likely derived, through "molecular piracy", from a CCR8-like gene. We also discuss possible, more remote, evolutionary links between CKRs, formylpeptide receptors, and possibly the highly conserved 18S rRNA genes.

An induction dose of epoetin alpha of 40 000 IU daily for three consecutive days increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy.

BACKGROUND: This pilot study was conducted to evaluate the feasibility, activity, and safety of an induction dose of epoetin alpha in cancer patients with moderate or severe anemia who were receiving chemotherapy. PATIENTS AND METHODS: Thirty patients with solid tumors and hemoglobin (Hb) levels <11.0 g/dl were enrolled. Patients received single s.c. injections of epoetin alpha, 40 000 IU for three consecutive days, and were then observed for the following 30 days. The primary efficacy variable was the response rate (Hb increase > or=1 g/dl) at day 15. Secondary efficacy variables included the proportion of patients given blood transfusions between baseline and the end of study, the duration of response (Hb level > or=1 g/dl), and ability to maintain the planned chemotherapy dose (dose intensity). RESULTS: At day 15, 23 of 30 (77%) patients had achieved increases in Hb levels of at least 1 g/dl. The mean Hb increase in responders was 2.0 g/dl [95% confidence interval (CI) = 1.7-2.3 g/dl]. The Hb increase was 2.3 +/- 0.7 g/dl in responders with baseline Hb levels <9.5 g/dl (median Hb value), and 1.7 +/- 0.6 g/dl in those with higher Hb levels (P = 0.012). The median duration of response was 6.1 weeks (95% CI = 1.6-10.6 weeks). Hematologic parameters were not significantly changed in nonresponders. Multivariate analysis detected no significant differences in Hb increase at day 15 on the basis of age, sex, weight, baseline Hb levels, type or stage of tumor, or treatment with platinum-based chemotherapy. No serious adverse event related to epoetin alpha treatment was observed. CONCLUSIONS: We conclude that a higher initial dosing of epoetin alpha appears to be an efficient schedule for treating anemia in cancer patients undergoing chemotherapy, conferring higher response rates than those seen with standard doses. Further evaluation of these and other epoetin alpha dosage regimens is warranted.

Autoantibodies from Sjögren's syndrome induce activation of both the intrinsic and extrinsic apoptotic pathways in human salivary gland cell line A-253.

Sjögren's syndrome (SS) is an autoimmune rheumatic disease that targets salivary and lachrymal glands, characterized by a high concentration of serum autoantibodies directed against nuclear and cytoplasmic antigens. It is known that autoantibodies can enter viable cells and this phenomenon has functional consequences including activation of apoptotic process. The objective of this work was to explore whether autoantibodies contained in IgG purified from Sjögren sera trigger apoptotic process in an experimental model represented by the human salivary gland cell line A-253. To define if the intrinsic or extrinsic pathways are activated, we examined which caspases are critical for inducing cell death. The results have demonstrated that morphological changes and DNA laddering, consistent with apoptotic cell death, occurred in A-253 cells treated with IgG from Sjögren sera. Sjögren IgG induced cleavage and activation of the effector caspase-3 and degradation of the caspase-3 substrate poly(ADP-ribose)polymerase. Both the intrinsic and extrinsic apoptotic pathways were activated, since both caspase-8 and caspase-9 cleavages occurred. In conclusion, autoantibodies contained in IgG purified from Sjögren sera mediate apoptosis of the A-253 cell line in a caspase-dependent manner.

Biological role of the N-formyl peptide receptors.

Ligation of N-formyl-methionyl-leucyl-phenylalanine (fMLP) to its specific cell surface receptors triggers different cascades of biochemical events, eventually leading to cellular activation. The formyl peptide receptors (FPRs) are members of the seven-transmembrane, G-protein coupled receptors superfamily, expressed at high levels on polymorphonuclear and mononuclear phagocytes. The main responses elicited upon ligation of formylated peptides, referred to as cellular activation, are those of morphological polarization, locomotion, production of reactive-oxygen species and release of proteolytic enzymes. FPRs have in recent years been shown to be expressed also in several non myelocytic populations, suggesting other unidentified functions for this receptor family, independent of the inflammatory response. Finally, a number of ligands acting as exogenous or host-derived agonists for FPRs, as well as ligands acting as FPRs antagonists, have been described, indicating that these receptors may be differentially modulated by distinct molecules.