scholarly journals AB0058 ASSOCIATION BETWEEN HLA-DRB1*04:01, RHEUMATOID NODULES AND PARTICULAR EPITOPES OF CITRULLINATED FIBRIN IN PATIENTS WITH RHEUMATOID ARTHRITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1061.1-1061
Author(s):  
G. Larid ◽  
M. Pancarte ◽  
G. Offer ◽  
C. Clavel ◽  
M. Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Antigen Processing ◽  
Rheumatoid Factors ◽  
Post Translational Modification ◽  
Human Fibrinogen ◽  
Rheumatoid Nodules ◽  
Genes Encoding ◽  
High Level ◽  
Almost All

Background:Rheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding the shared epitope (SE), a 5 amino acid motive. RA is usually preceded by the emergence of anti-citrullinated protein antibodies (ACPAs) detected by anti-CCP2 tests. Citrullin is a neutral amino acid resulting from post translational modification of arginin by Peptidyl Arginyl Deiminases (PADs). ACPAs recognize epitopes from citrullinated human fibrinogen (Fib-cit) and can be specifically detected by the AhFibA assay. Five peptides derived from Fib-cit together represent almost all of the epitopes recognized by patients with ACPA-positive RA: β60–74cit, α36–50cit, α621–635cit, α501–515cit and α171–185cit. As RA is a pleiomorphic disease, whose evolution is difficult to predict, the use of antibody fine specificity as a marker of clinical phenotypes has become a major challenge.Objectives:Our objective was to study whether clinical characteristics and HLA-DRB1 genetic background were associated with a specific reactivity against these epitopes.Methods:184 ACPA positive RA patients fulfilling the 2010 ACR/EULAR criteria were studied. Patients characteristics, including HLA-DRB1 genotype, were collected from their medical files. Anti-CCP2, AhFibA, Rheumatoid Factors (RF), and antibodies against the five major Fib-cit peptides were analyzed using ELISA assays.Results:Anti-CCP2 and AhFibA titres were strongly correlated (rs: 0.7037; p = 5.69x10-29, Pearson’s). Anti-α505-515cit antibodies were associated with HLA-DRB1*04:01 (OR = 5.52 [2.00 – 13.64]; p = 0.0003). High level anti-α505-515cit antibodies were significantly associated with rheumatoid nodules (OR = 2.71 [1.00 – 7.16], p= 0.044). Anti α501–515cit antibodies were associated with RF (OR=2.31 [1.10 – 4.78], p= 0.026).Conclusion:Immune complexes containing anti-α501–515cit antibodies and rheumatoid factors might be involved in the development of rheumatoid nodules on the HLA-DRB1*04:01 background. These findings highlight the role played by the HLA-DRB1*04:01 molecule and its rapid intracellular route into the lysosomes, enabling original antigen processing. Finally, purifying these epitope specific antibodies might be a new therapeutic opportunity for rheumatoid nodules.Disclosure of Interests:None declared

scholarly journals In Rheumatoid Arthritis Patients, HLA-DRB1*04:01 and Rheumatoid Nodules Are Associated With ACPA to a Particular Fibrin Epitope

2021 ◽  
Vol 12 ◽  
Author(s):  
Guillaume Larid ◽  
Mikael Pancarte ◽  
Géraldine Offer ◽  
Cyril Clavel ◽  
Marielle Martin ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Patient Characteristics ◽  
Post Translational Modification ◽  
Rheumatoid Nodules ◽  
Genes Encoding ◽  
Therapeutic Opportunity ◽  
Specific Reactivity ◽  
High Level ◽  
Almost All

ObjectivesRheumatoid arthritis (RA) is associated with HLA-DRB1 genes encoding the shared epitope (SE), a 5-amino acid motive. RA is usually preceded by the emergence of anti-citrullinated protein/peptide antibodies (ACPAs). Citrulline is a neutral amino acid resulting from post-translational modification of arginine involved in peptidic bounds (arginyl residue) by PeptidylArginine Deiminases (PADs). ACPAs recognize epitopes from citrullinated human fibrin(ogen) (hFib) and can be specifically detected by the AhFibA assay. Five citrullinated peptides derived from hFib together represent almost all of the epitopes recognized by patients with ACPA-positive RA, namely: α36–50cit, α171–185cit, α501–515cit, α621–635cit, and β60–74cit. The use of antibody fine specificities as markers of clinical phenotypes has become a major challenge. Our objective was to study whether RA clinical characteristics and HLA-DRB1 genetic background were associated with a specific reactivity against the epitopes borne by the five peptides.Methods184 ACPA-positive RA patients fulfilling the 2010 ACR/EULAR criteria were studied. Patient characteristics including HLA-DRB1 genotype, were collected from their medical files. Anti-CCP2 antibodies, AhFibA, and antibodies against the five citrullinated hFib (hFib-cit) peptides were analyzed by ELISA.ResultsAnti-α505-515cit antibodies were associated with HLA-DRB1*04:01 (OR = 5.52 [2.00 – 13.64]; p = 0.0003). High level anti-α505-515cit antibodies were associated with rheumatoid nodules (OR = 2.71 [1.00 – 7.16], p= 0.044).ConclusionImmune complexes containing anti-α501-515cit antibodies and rheumatoid factors might be involved in the development of rheumatoid nodules on the HLA-DRB1*04:01 background. Apheresis of these epitope-specific antibodies might be a new therapeutic opportunity for patients with rheumatoid nodules.

scholarly journals Non-Penicillin-Susceptible Streptococcus suis Isolated from Humans

Pathogens ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1178
Author(s):  
Nichari Bamphensin ◽  
Peechanika Chopjitt ◽  
Rujirat Hatrongjit ◽  
Parichart Boueroy ◽  
Nahuel Fittipaldi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Antimicrobial Resistance ◽  
Resistance Genes ◽  
Streptococcus Suis ◽  
Amino Acid Substitutions ◽  
Continuous Control ◽  
Antimicrobial Resistance Genes ◽  
Genes Encoding ◽  
Invasive Infections ◽  
Almost All

Streptococcus suis is a pathogen that causes invasive infections in humans and pigs. In this study, 448 S. suis isolates recovered from human infections in Thailand were characterized with regard to their antimicrobial susceptibility and antimicrobial resistance genes, including, for non-penicillin-susceptible isolates, sequence analyses of five genes encoding penicillin-binding proteins (pbp1a, pbp1b, pbp2a, pbp2b, and pbp2x). All 448 isolates were susceptible to cefepime and ceftriaxone, whereas 99.6%, 91.7%, and 72.9% of the isolates were susceptible to levofloxacin, penicillin, and chloramphenicol, respectively. Almost all isolates were resistant to tetracycline (98.2%), clindamycin (94%), erythromycin (92.4%), and azithromycin (82.6%). Genes tet(O) and ermB were the predominant resistance genes detected among macrolide- and tetracycline-resistant isolates. A total of 37 out of 448 isolates (8.2%) showed intermediately resistance to penicillin. Most of these isolates (59.5%) belonged to serotype 2-ST233. Comparison of the predicted translated sequences of five PBP proteins of a penicillin-susceptible isolate (strain P1/7) to the respective PBP sequences of ten non-penicillin-susceptible isolates revealed multiple amino acid substitutions. Isolates of CC221/234 showed highly variable amino acid substitutions in all PBP proteins. An ST104 isolate had a higher number of amino acid substitutions in PBP2X. Isolates belonging to CC233/379 had numerous substitutions in PBP2B and PBP2X. ST25 isolates exhibited fewer amino acid substitutions than isolates of other STs in all five PBPs. The antimicrobial resistance of S. suis is increasing worldwide; therefore, restrictions on antimicrobial use, continuous control, and the surveillance of this bacterium throughout the pork supply chain are crucial for ensuring public health and must be a priority concern.

scholarly journals Fluoroquinolone resistance in Clostridium difficile isolates from a prospective study of C. difficile infections in Europe

2008 ◽  
Vol 57 (6) ◽  
pp. 784-789 ◽  
Author(s):  
Patrizia Spigaglia ◽  
Fabrizio Barbanti ◽  
Paola Mastrantonio ◽  
Jon S. Brazier ◽  
Frédéric Barbut ◽  
...  
Keyword(s):  
Amino Acid ◽  
Clostridium Difficile ◽  
Prospective Study ◽  
Amino Acid Substitution ◽  
Amino Acid Change ◽  
Fluoroquinolone Resistance ◽  
Genes Encoding ◽  
High Level ◽  
A Prospective Study

The European Study Group on Clostridium difficile (ESGCD) conducted a prospective study in 2005 to monitor and characterize C. difficile strains circulating in European hospitals, collecting 411 isolates. Eighty-three of these isolates, showing resistance or intermediate resistance to moxifloxacin (MX), were selected for this study to assess susceptibility to other fluoroquinolones (FQs) and to analyse the gyr genes, encoding the DNA gyrase subunits GyrA and GyrB. Twenty MX-susceptible isolates from the surveillance study were included for comparison. Overall, one amino acid substitution in GyrA (Thr82 to Ile) and four different substitutions in GyrB (Ser416 to Ala, Asp426 to Asn, Asp426 to Val and Arg447 to Lys) were identified. A high level of resistance (MIC ≥32 μg ml−1) to MX, ciprofloxacin (CI), gatifloxacin (GA) and levofloxacin (LE) was found in 68 isolates showing the amino acid substitution Thr82 to Ile in GyrA, in eight isolates with the substitutions Thr82 to Ile in GyrA and Ser416 to Ala in GyrB, in two isolates showing the substitution Asp426 to Asn in GyrB and in one isolate with Asp426 to Val in GyrB. The remaining four isolates showed high MICs for CI and LE, but different MIC levels for MX and GA. In particular, intermediate levels of resistance to MX were shown by two isolates, one with the substitution Thr82 to Ile in GyrA, and one showing Asp426 to Asn in GyrB. The substitution Arg447 to Lys in GyrB was found in two strains resistant to MX, CI and LE but susceptible to GA. No substitutions in GyrA were found in the FQ-susceptible strains, whereas two strains showed the amino acid change Ser416 to Ala in GyrB. Thr82 to Ile was the most frequent amino acid change identified in the C. difficile isolates examined. In contrast to previous observations, 10 % of the isolates showed this substitution in association with Ser416 to Ala in GyrB. The other amino acid changes found were characteristic of a few strains belonging to certain types and/or countries. Two new substitutions for C. difficile, Ser416 to Ala and Arg447 to Lys, were found in GyrB. Whereas the former does not seem to have a key role in resistance, since it was also detected in susceptible strains, the latter substitution occurred in the same position where other amino acid variations take place in resistant Escherichia coli and other C. difficile strains. A large number of C. difficile isolates now show an alarming pattern of resistance to the majority of FQs currently used in hospitals and outpatient settings, therefore judicious use of these antibiotics and continuous monitoring of in vitro resistance are necessary.

scholarly journals IgG rheumatoid factors and staphylococcal protein A bind to a common molecular site on IgG.

1985 ◽  
Vol 162 (6) ◽  
pp. 1811-1824 ◽  
Author(s):  
F A Nardella ◽  
D C Teller ◽  
C V Barber ◽  
M Mannik
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Binding Site ◽  
Antigenic Determinant ◽  
Protein A ◽  
Side Chains ◽  
Staphylococcal Protein A ◽  
Rheumatoid Factors ◽  
Ph Titration ◽  
Staphylococcal Protein

The antigenic determinant on the Fc region of human IgG for two IgG rheumatoid factors (IgG-RF) from patients with rheumatoid arthritis were investigated in detail. The RF did not interact with IgG fragments that contained the C gamma 2 or C gamma 3 region alone, but required the presence of both regions for binding. The RF binding to solid-phase IgG were poorly inhibited by the IgG3 subclass and strongly inhibited by staphylococcal protein A (SPA) (42 kD), and fragment D of SPA (7 kD), indicating that the binding site is most likely the same as the Ga antigenic determinant described for IgM-RF, and is in the same location as the site on IgG that binds SPA. pH titration studies of the RF binding to IgG indicated the involvement of histidine and lysine or tyrosine side chains. Chemical modification studies showed the histidines were involved on the Fc side of the interactions, and tyrosines were involved on both the antigenic and antibody sides of the interactions. Lysines were not involved. The above information, and the knowledge of the number and position in space of the amino acid residues involved in the C gamma 2-C gamma 3 interface region of IgG, the binding site for SPA, and the amino acid substitutions in IgG3 that account for its inability to bind protein A, allowed the identification of the site on IgG that bind IgG-RF. This binding site involves some of the same amino acid side chains, His 435, Tyr 436, and one or both His 433 and 310, and is in the same location as the site that binds SPA. The same site is likely to be a common antigenic determinant for other RF. Furthermore, the described molecular mimicry suggests a biological relationship between bacterial Fc-binding proteins and the production of RF in rheumatoid arthritis.

scholarly journals Sequences of the Genes for the TEM-20, TEM-21, TEM-22, and TEM-29 Extended-Spectrum β-Lactamases

1999 ◽  
Vol 43 (4) ◽  
pp. 969-971 ◽  
Author(s):  
Guillaume Arlet ◽  
Sylvie Goussard ◽  
Patrice Courvalin ◽  
Alain Philippon
Keyword(s):  
Amino Acid ◽  
Promoter Region ◽  
Amino Acid Sequences ◽  
Extended Spectrum ◽  
Genes Encoding ◽  
High Level ◽  
Level Production

ABSTRACT The sequences of the bla TEM genes encoding TEM-20, TEM-21, TEM-22, and TEM-29 extended-spectrum β-lactamases were determined. Analysis of the deduced amino acid sequences indicated that TEM-20 and TEM-29 were derived from TEM-1 and that TEM-21 and TEM-22 were derived from TEM-2. The substitutions involved were Ser-238 and Thr-182 for TEM-20; His-164 for TEM-29; Lys-104, Arg-153, and Ser-238 for TEM-21; and Lys-104, Gly-237, and Ser-238 for TEM-22. The promoter region of the bla TEM-22 gene was identical to that of bla TEM-3. High-level production of TEM-20 could result from a 135-bp deletion which combined the −35 region of the Pa promoter with the −10 region of the P3 promoter and a G→T transition in the latter motif.

In Vitro and In Vivo Evaluation of Amino Acid-Functionalized Cellulose Beads for Whole Blood Hemoperfusion

2005 ◽  
Vol 288-289 ◽  
pp. 393-396 ◽  
Author(s):  
Yong Jian Wang ◽  
Yao Ting Yu
Keyword(s):  
Rheumatoid Arthritis ◽  
Amino Acid ◽  
Whole Blood ◽  
Blood Perfusion ◽  
In Vitro Test ◽  
Rheumatoid Factors ◽  
In Vivo Evaluation ◽  
Vitro Test

Phenylalanine linked to cellulose beads was designed as an adsorbent in whole blood hemoperfusion for the therapy of rheumatoid arthritis. In whole blood perfusion tests, the adsorbent adsorbed rheumatoid factors directly from whole blood. In vitro test showed that the adsorbent had good biocompability properties. No acute systemic toxicity and dermal irritancy with extremely low skin sensitizing activity were observed. In vivo animal test with satisfactory results was perfumed with rabbits. Experimental results show that the adsorbent holds promise as a highly effective and safe hemoadsorbent in clinical therapy for rheumatoid arthritis patients by hemoperfusion.

Benign Rheumatoid Nodules

PEDIATRICS ◽  
1975 ◽  
Vol 56 (1) ◽  
pp. 29-33
Author(s):  
F. Estelle ◽  
R. Simons ◽  
Jane G. Schaller
Keyword(s):  
Rheumatoid Arthritis ◽  
Antinuclear Antibodies ◽  
Systemic Disease ◽  
Skin Grafting ◽  
Surgical Excision ◽  
Rheumatoid Factors ◽  
Adult Onset ◽  
Rheumatoid Nodules ◽  
Large Size ◽  
Asymptomatic Children

Fifteen asymptomatic children with benign rheumatoid nodules, followed up to 12 years, are described. Nodules are characterized by subcutaneous location with predilection for pretibial regions and scalp, occasional large size, spontaneous regression, and frequent recurrence. Granuloma annulare was present in two patients. All 15 children were healthy and free from rheumatoid arthritis, rheumatic fever, or any other recognizable systemic disease at followup and none had positive tests for antinuclear antibodies or rheumatoid factors. Histologically the nodules closely resembled those seen in adult-onset rheumatoid arthritis. Though biopsy may be useful for confirmation of the clinical diagnosis of benign rheumatoid nodules, wide surgical excision, skin grafting, and treatment with medication are unnecessary in this selflimited syndrome.

scholarly journals Cloning and High-Level Expression of α-Galactosidase cDNA from Penicillium purpurogenum

1998 ◽  
Vol 64 (11) ◽  
pp. 4489-4494 ◽  
Author(s):  
Hajime Shibuya ◽  
Hiroaki Nagasaki ◽  
Satoshi Kaneko ◽  
Shigeki Yoshida ◽  
Gwi Gun Park ◽  
...  
Keyword(s):  
Amino Acid ◽  
Amino Acid Sequence ◽  
Specific Activity ◽  
Amino Acid Residues ◽  
Ph Profile ◽  
Penicillium Purpurogenum ◽  
Mature Enzyme ◽  
Terminal Amino ◽  
High Level ◽  
Almost All

ABSTRACT The cDNA coding for Penicillium purpurogenumα-galactosidase (αGal) was cloned and sequenced. The deduced amino acid sequence of the α-Gal cDNA showed that the mature enzyme consisted of 419 amino acid residues with a molecular mass of 46,334 Da. The derived amino acid sequence of the enzyme showed similarity to eukaryotic αGals from plants, animals, yeasts, and filamentous fungi. The highest similarity observed (57% identity) was toTrichoderma reesei AGLI. The cDNA was expressed inSaccharomyces cerevisiae under the control of the yeast GAL10 promoter. Almost all of the enzyme produced was secreted into the culture medium, and the expression level reached was approximately 0.2 g/liter. The recombinant enzyme purified to homogeneity was highly glycosylated, showed slightly higher specific activity, and exhibited properties almost identical to those of the native enzyme from P. purpurogenum in terms of the N-terminal amino acid sequence, thermoactivity, pH profile, and mode of action on galacto-oligosaccharides.

scholarly journals Blackout in the powerhouse: clinical phenotypes associated with defects in the assembly of OXPHOS complexes and the mitoribosome

2020 ◽  
Vol 477 (21) ◽  
pp. 4085-4132
Author(s):  
Daniella H. Hock ◽  
David R. L. Robinson ◽  
David A. Stroud
Keyword(s):  
Mitochondrial Disease ◽  
Mitochondrial Diseases ◽  
Basic Research ◽  
Post Translational Modification ◽  
Mitochondrial Ribosomes ◽  
Heterogenous Group ◽  
Mitochondrial Ribosome ◽  
Genes Encoding ◽  
Severity Of The Disease ◽  
Almost All

Mitochondria produce the bulk of the energy used by almost all eukaryotic cells through oxidative phosphorylation (OXPHOS) which occurs on the four complexes of the respiratory chain and the F1–F0 ATPase. Mitochondrial diseases are a heterogenous group of conditions affecting OXPHOS, either directly through mutation of genes encoding subunits of OXPHOS complexes, or indirectly through mutations in genes encoding proteins supporting this process. These include proteins that promote assembly of the OXPHOS complexes, the post-translational modification of subunits, insertion of cofactors or indeed subunit synthesis. The latter is important for all 13 of the proteins encoded by human mitochondrial DNA, which are synthesised on mitochondrial ribosomes. Together the five OXPHOS complexes and the mitochondrial ribosome are comprised of more than 160 subunits and many more proteins support their biogenesis. Mutations in both nuclear and mitochondrial genes encoding these proteins have been reported to cause mitochondrial disease, many leading to defective complex assembly with the severity of the assembly defect reflecting the severity of the disease. This review aims to act as an interface between the clinical and basic research underpinning our knowledge of OXPHOS complex and ribosome assembly, and the dysfunction of this process in mitochondrial disease.

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