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[PMID]: 29367523 [Au] Autor: Umeda N; Matsumoto I; Sumida T [Ad] Endereço: Department of Rheumatology, Tsuchiura Kyodo General Hospital. [Ti] Título: [The pathogenic role of ACPA in rheumatoid arthritis]. [So] Source: Nihon Rinsho Meneki Gakkai Kaishi;40(6):391-395, 2017. [Is] ISSN: 1349-7413 [Cp] País de publicação: Japan [La] Idioma: jpn [Ab] Resumo:   In rheumatoid arthritis (RA), ACPA (anti-citrullinated protein/peptide antibody) is elevated with high specificity, and clinically, anti-CCP (cyclic citrullinated peptide) antibody is widely used for diagnosis of RA. It is thought ACPAs are produced with genetic background such as HLA-DR, environmental factors such as periodontal disease and smoking, however, the pathogenic role of ACPA in RA has not been elucidated. These were showed immune complexes including ACPA or ACPA itself promoted inflammatory cytokine production such as TNF. PADs (peptidylarginine deiminases) were expressed and citrullinated proteins existed in RA synovium. ACPAs were deposited on the site of citrulline in CD68 positive cells of RA synovium. The damage of bone and cartilage is observed in RA. It was also suggested that deposition of ACPAs caused osteoclastogenesis and bone loss. We introduce several findings about the pathogenic role of ACPA in RA. [Mh] Termos MeSH primário: Anticorpos Anti-Proteína Citrulinada/efeitos adversos Anticorpos Anti-Proteína Citrulinada/imunologia Artrite Reumatoide/imunologia [Mh] Termos MeSH secundário: Antígenos CD Antígenos de Diferenciação Mielomonocítica Artrite Reumatoide/diagnóstico Artrite Reumatoide/metabolismo Artrite Reumatoide/patologia Reabsorção Óssea/imunologia Osso e Ossos/patologia Cartilagem/patologia Citrulina/imunologia Citrulina/metabolismo Antígenos HLA-DR Seres Humanos Mediadores da Inflamação/metabolismo Osteogênese/imunologia Doenças Periodontais Desiminases de Arginina em Proteínas/metabolismo Fumar Membrana Sinovial/citologia Membrana Sinovial/metabolismo Fator de Necrose Tumoral alfa/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Anti-Citrullinated Protein Antibodies); 0 (Antigens, CD); 0 (Antigens, Differentiation, Myelomonocytic); 0 (CD68 antigen, human); 0 (HLA-DR Antigens); 0 (Inflammation Mediators); 0 (Tumor Necrosis Factor-alpha); 29VT07BGDA (Citrulline); EC 3.5.3.15 (Protein-Arginine Deiminases) [Em] Mês de entrada: 1802 [Cu] Atualização por classe: 180227 [Lr] Data última revisão: 180227 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 180126 [St] Status: MEDLINE [do] DOI: 10.2177/jsci.40.391

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[PMID]: 28748834 [Au] Autor: Awasthi V; Chauhan R; Chattopadhyay D; Das J [Ad] Endereço: Immunology Division, ICMR-National Institute of Malaria Research, New Delhi, India. [Ti] Título: Effect of L-arginine on the growth of and immune modulation of host cells. [So] Source: J Vector Borne Dis;54(2):139-145, 2017 Apr-Jun. [Is] ISSN: 0972-9062 [Cp] País de publicação: India [La] Idioma: eng [Ab] Resumo: BACKGROUND & OBJECTIVES: Malaria is a life-threatening disease caused by Plasmodium parasites. The life-cycle of Plasmodium species involves several stages both in mosquito and the vertebrate host. In the erythrocytic stage, Plasmodium resides inside the red blood cells (RBCs), where it meets most of its nutritional requirement by degrad- ing host's haemoglobin. L-arginine is required for growth and division of cells. The present study was aimed to demonstrate the effect of supplementation of different concentrations of L-arginine and L-citrulline on the growth of parasite, and effect of the culture supernatant on the host's peripheral blood mononuclear cells (PBMCs). METHODS: To examine the effect of supplementation of L-arginine and L-citrulline, Plasmodium falciparum (3D7 strain) was cultured in RPMI 1640, L-arginine deficient RPMI 1640, and in different concentrations of L-arginine, and L-citrulline supplemented in arginine deficient RPMI 1640 medium. To have a holistic view of in vivo cell activation, the PBMCs isolated from healthy human host were cultured in the supernatant collected from P. falciparum culture. RESULTS: Growth of the parasite was greatly enhanced in L-arginine supplemented media and was found to be concentration dependent. However, parasite growth was compromised in L-citrulline supplemented and L-arginine deficient media. The supernatant collected from L-arginine supplemented parasite media (sArg) showed increased FOXP3 and interleukin-10 (IL-10) expression as compared to the supernatant collected from L-citrulline supple- mented parasite media (sCit). INTERPRETATION & CONCLUSION: The in vitro culture results showed, decreased parasite growth, and decreased expression of programmed cell death-1 (PD-1) (a coinhibitory molecule) and IL-10 in the L-citrulline supplemented media as compared to L-arginine supplemented media. Hence, it was concluded that L-citrulline supplementation would be a better alternative than L-arginine to inhibit the parasite growth. [Mh] Termos MeSH primário: Arginina/metabolismo Leucócitos Mononucleares/imunologia Plasmodium falciparum/crescimento & desenvolvimento Plasmodium falciparum/imunologia [Mh] Termos MeSH secundário: Células Cultivadas Citrulina/metabolismo Meios de Cultivo Condicionados Seres Humanos Plasmodium falciparum/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Culture Media, Conditioned); 29VT07BGDA (Citrulline); 94ZLA3W45F (Arginine) [Em] Mês de entrada: 1801 [Cu] Atualização por classe: 180129 [Lr] Data última revisão: 180129 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170728 [St] Status: MEDLINE

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[PMID]: 28977504 [Au] Autor: Falkenburg WJJ; Kempers AC; Dekkers G; Ooijevaar-de Heer P; Bentlage AEH; Vidarsson G; van Schaardenburg D; Toes REM; Scherer HU; Rispens T [Ad] Endereço: Amsterdam Rheumatology and Immunology Center, Reade. [Ti] Título: Rheumatoid factors do not preferentially bind to ACPA-IgG or IgG with altered galactosylation. [So] Source: Rheumatology (Oxford);56(11):2025-2030, 2017 Nov 01. [Is] ISSN: 1462-0332 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Objectives: Recent reports describe interactions between the two most prominent RA-related autoantibodies, RFs and ACPAs. The main aim of the present study was to investigate whether RFs preferentially interact with ACPA-IgG over non-ACPA IgG. Additionally, interactions of RFs with IgG with altered galactose content in the Fc domain were examined, since ACPA-IgGs have been shown to have decreased Fc galactose content in RF+ patients. Methods: (Auto)antibody interactions were studied in a surface plasmon resonance imaging assay and with ELISA. Target antibodies were isolated from RA patient plasma (polyclonal ACPA- and non-ACPA-IgG) or recombinantly produced to obtain monoclonal IgG with well-defined Fc galactose content. Interacting autoantibodies were studied using autoantibody positive patient sera and two recombinantly produced IgM-RFs. Results: The sera from 41 RF+ RA patients showed similar RF binding to ACPA- and non-ACPA-IgG and no differences in binding to IgG with normal, high or low levels of Fc galactosylation. Two monoclonal IgM-RFs, one interacting with the CH2-CH3 interface and one binding close to the C-terminal end of the CH3 domain showed no influence of the Fc glycan on IgG binding by IgM-RF. Conclusion: Although interactions between RF and ACPA may play a role in inflammatory processes in RA, RFs do not preferentially interact with ACPA-IgG over non-ACPA-IgG nor with agalatosylated IgG over IgG with normal or high galactosylation. [Mh] Termos MeSH primário: Artrite Reumatoide/metabolismo Citrulina/metabolismo Galactose/metabolismo Imunoglobulina G/metabolismo Fator Reumatoide/metabolismo [Mh] Termos MeSH secundário: Sítios de Ligação de Anticorpos Ensaio de Imunoadsorção Enzimática Seres Humanos Domínios de Imunoglobulina Imunoglobulina M/metabolismo Ligação Proteica Processamento de Proteína Pós-Traducional [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Immunoglobulin G); 0 (Immunoglobulin M); 29VT07BGDA (Citrulline); 9009-79-4 (Rheumatoid Factor); X2RN3Q8DNE (Galactose) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171106 [Lr] Data última revisão: 171106 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 171005 [St] Status: MEDLINE [do] DOI: 10.1093/rheumatology/kex284

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[PMID]: 28943354 [Au] Autor: Taga Y; Tanaka K; Hamada C; Kusubata M; Ogawa-Goto K; Hattori S [Ad] Endereço: Nippi Research Institute of Biomatrix, 520-11 Kuwabara, Toride, Ibaraki 302-0017, Japan. Electronic address: y-taga@nippi-inc.co.jp. [Ti] Título: Hydroxyhomocitrulline Is a Collagen-Specific Carbamylation Mark that Affects Cross-link Formation. [So] Source: Cell Chem Biol;24(10):1276-1284.e3, 2017 Oct 19. [Is] ISSN: 2451-9456 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Carbamylation is a non-enzymatic post-translational modification that physiologically occurs during aging and is a risk factor for various diseases. The most common product of carbamylation is homocitrulline (HCit), where a lysine (Lys) amino group has reacted with urea-derived cyanate. HCit has recently been detected in collagen; however, given that 15%-90% of total Lys in collagen is hydroxylated, it is unclear how hydroxylation affects collagen carbamylation. Here, we identified a collagen-specific carbamylation product, hydroxyhomocitrulline (HHCit), and showed that high levels of HHCit are correlated with age in rat tissue collagen and in vivo carbamylation in mice, as well as with the decline of kidney function in the serum of dialysis patients. Proteomic analysis of the carbamylated collagens identified α2(I) Lys , a major cross-linking site, as a preferential HHCit site. Furthermore, our results suggest that hydroxylysine carbamylation affects the mechanical properties of connective tissue by competitively inhibiting collagen cross-link formation. [Mh] Termos MeSH primário: Citrulina/análogos & derivados Colágeno/química Colágeno/metabolismo Processamento de Proteína Pós-Traducional Ureia/metabolismo [Mh] Termos MeSH secundário: Envelhecimento/metabolismo Animais Fenômenos Biomecânicos Citrulina/metabolismo Seres Humanos Camundongos Especificidade de Órgãos Diálise Renal [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 1190-49-4 (homocitrulline); 29VT07BGDA (Citrulline); 8W8T17847W (Urea); 9007-34-5 (Collagen) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171030 [Lr] Data última revisão: 171030 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170926 [St] Status: MEDLINE

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[PMID]: 28873421 [Au] Autor: Timofeev V; Bakhteeva I; Titareva G; Kopylov P; Christiany D; Mokrievich A; Dyatlov I; Vergnaud G [Ad] Endereço: State Research Center for Applied Microbiology and Biotechnology (SRCAMB), Obolensk, Moscow Region, Russia. [Ti] Título: Russian isolates enlarge the known geographic diversity of Francisella tularensis subsp. mediasiatica. [So] Source: PLoS One;12(9):e0183714, 2017. [Is] ISSN: 1932-6203 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Francisella tularensis, a small Gram-negative bacterium, is capable of infecting a wide range of animals, including humans, and causes a plague-like disease called tularemia-a highly contagious disease with a high mortality rate. Because of these characteristics, F. tularensis is considered a potential agent of biological terrorism. Currently, F. tularensis is divided into four subspecies, which differ in their virulence and geographic distribution. Two of them, subsp. tularensis (primarily found in North America) and subsp. holarctica (widespread across the Northern Hemisphere), are responsible for tularemia in humans. Subsp. novicida is almost avirulent in humans. The fourth subspecies, subsp. mediasiatica, is the least studied because of its limited distribution and impact in human health. It is found only in sparsely populated regions of Central Asia. In this report, we describe the first focus of naturally circulating F. tularensis subsp. mediasiatica in Russia. We isolated and characterized 18 strains of this subspecies in the Altai region. All strains were highly virulent in mice. The virulence of subsp. mediasiatica in a vaccinated mouse model is intermediate between that of subsp. tularensis and subsp. holarctica. Based on a multiple-locus variable number tandem repeat analysis (MLVA), we show that the Altaic population of F. tularensis subsp. mediasiatica is genetically distinct from the classical Central Asian population, and probably is endemic to Southern Siberia. We propose to subdivide the mediasiatica subspecies into three phylogeographic groups, M.I, M.II and M.III. [Mh] Termos MeSH primário: Biodiversidade Francisella tularensis/genética Francisella tularensis/patogenicidade Tularemia/microbiologia [Mh] Termos MeSH secundário: Alelos Animais Citrulina/química Análise por Conglomerados Feminino Genótipo Geografia Glicerol/química Seres Humanos Masculino Camundongos Camundongos Endogâmicos BALB C Repetições Minissatélites Filogeografia Polimorfismo de Nucleotídeo Único Federação Russa Células-Tronco Vacinação Virulência [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 29VT07BGDA (Citrulline); PDC6A3C0OX (Glycerol) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171025 [Lr] Data última revisão: 171025 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170906 [St] Status: MEDLINE [do] DOI: 10.1371/journal.pone.0183714

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[PMID]: 28835673 [Au] Autor: Potempa J; Mydel P; Koziel J [Ad] Endereço: University of Louisville School of Dentistry, Department of Oral Immunology and Infectious Diseases, 501 South Preston Street, Louisville, Kentucky 40202, USA. [Ti] Título: The case for periodontitis in the pathogenesis of rheumatoid arthritis. [So] Source: Nat Rev Rheumatol;13(10):606-620, 2017 Oct. [Is] ISSN: 1759-4804 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Rheumatoid arthritis (RA), an autoimmune disease that affects ∼1% of the human population, is driven by autoantibodies that target modified self-epitopes, whereas ∼11% of the global adult population are affected by severe chronic periodontitis, a disease in which the commensal microflora on the tooth surface is replaced by a dysbiotic consortium of bacteria that promote the chronic inflammatory destruction of periodontal tissue. Despite differences in aetiology, RA and periodontitis are similar in terms of pathogenesis; both diseases involve chronic inflammation fuelled by pro-inflammatory cytokines, connective tissue breakdown and bone erosion. The two diseases also share risk factors such as smoking and ageing, and have strong epidemiological, serological and clinical associations. In light of the ground-breaking discovery that Porphyromonas gingivalis, a pivotal periodontal pathogen, is the only human pathogen known to express peptidylarginine deiminase, an enzyme that generates citrullinated epitopes that are recognized by anti-citrullinated protein antibodies, a new paradigm is emerging. In this Review, the clinical and experimental evidence supporting this paradigm is discussed and the potential mechanisms involved in linking periodontitis to RA are presented. [Mh] Termos MeSH primário: Artrite Reumatoide/epidemiologia Epitopos/metabolismo Hidrolases/metabolismo Periodontite/epidemiologia [Mh] Termos MeSH secundário: Artrite Reumatoide/imunologia Proteínas de Bactérias/metabolismo Citrulina/metabolismo Epitopos/química Epitopos/imunologia Feminino Seres Humanos Masculino Periodontite/microbiologia Porphyromonas gingivalis/enzimologia Porphyromonas gingivalis/isolamento & purificação Processamento de Proteína Pós-Traducional Desiminases de Arginina em Proteínas [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Bacterial Proteins); 0 (Epitopes); 29VT07BGDA (Citrulline); EC 3.- (Hydrolases); EC 3.5.3.15 (Protein-Arginine Deiminases) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170825 [St] Status: MEDLINE [do] DOI: 10.1038/nrrheum.2017.132

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[PMID]: 28801345 [Au] Autor: Scally SW; Law SC; Ting YT; Heemst JV; Sokolove J; Deutsch AJ; Bridie Clemens E; Moustakas AK; Papadopoulos GK; van der Woude D; Smolik I; Hitchon CA; Robinson DB; Ferucci ED; Bernstein CN; Meng X; Anaparti V; Huizinga T; Kedzierska K; Reid HH; Raychaudhuri S; Toes RE; Rossjohn J; El-Gabalawy H; Thomas R [Ad] Endereço: Department of Biochemistry and Molecular Biology, Infection and Immunity Program, Biomedicine Discovery Institute Monash University, Clayton, Australia. [Ti] Título: Molecular basis for increased susceptibility of Indigenous North Americans to seropositive rheumatoid arthritis. [So] Source: Ann Rheum Dis;76(11):1915-1923, 2017 11. [Is] ISSN: 1468-2060 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: OBJECTIVE: The pathogenetic mechanisms by which alleles are associated with anticitrullinated peptide antibody (ACPA)-positive rheumatoid arthritis (RA) are incompletely understood. RA high-risk alleles are known to share a common motif, the 'shared susceptibility epitope (SE)'. Here, the electropositive P4 pocket of HLA-DRB1 accommodates self-peptide residues containing citrulline but not arginine. HLA-DRB1 His/Phe13ß stratifies with ACPA-positive RA, while His13ßSer polymorphisms stratify with ACPA-negative RA and RA protection. Indigenous North American (INA) populations have high risk of early-onset ACPA-positive RA, whereby HLA-DRB1*04:04 and HLA-DRB1*14:02 are implicated as risk factors for RA in INA. However, HLA-DRB1*14:02 has a His13ßSer polymorphism. Therefore, we aimed to verify this association and determine its molecular mechanism. METHODS: HLA genotype was compared in 344 INA patients with RA and 352 controls. Structures of HLA-DRB1*1402-class II loaded with vimentin-64Arg , vimentin-64Cit and fibrinogen ß-74Cit were solved using X-ray crystallography. Vimentin-64Cit -specific and vimentin -specific CD4+ T cells were characterised by flow cytometry using peptide-histocompatibility leukocyte antigen (pHLA) tetramers. After sorting of antigen-specific T cells, TCRα and ß-chains were analysed using multiplex, nested PCR and sequencing. RESULTS: ACPA RA in INA was independently associated with . Consequent to the His13ßSer polymorphism and altered P4 pocket of HLA-DRB1*14:02, both citrulline and arginine were accommodated in opposite orientations. Oligoclonal autoreactive CD4+ effector T cells reactive with both citrulline and arginine forms of vimentin were observed in patients with HLA-DRB1*14:02 RA and at-risk ACPA first-degree relatives. HLA-DRB1*14:02-vimentin -specific and HLA-DRB1*14:02-vimentin-64Cit -specific CD4+ memory T cells were phenotypically distinct populations. CONCLUSION: HLA-DRB1*14:02 broadens the capacity for citrullinated and native self-peptide presentation and T cell expansion, increasing risk of ACPA+ RA. [Mh] Termos MeSH primário: Nativos do Alasca/genética Artrite Reumatoide/etnologia Artrite Reumatoide/genética Predisposição Genética para Doença/etnologia Cadeias HLA-DRB1/genética Índios Norte-Americanos/genética [Mh] Termos MeSH secundário: Alaska/etnologia Alelos Arginina/genética Arginina/imunologia Autoanticorpos/sangue Autoanticorpos/imunologia Linfócitos T CD4-Positivos/imunologia Canadá/etnologia Estudos de Casos e Controles Citrulina/genética Citrulina/imunologia Feminino Citometria de Fluxo Genótipo Seres Humanos Masculino Peptídeos Cíclicos/imunologia Polimorfismo Genético Fatores de Risco Vimentina/genética [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Autoantibodies); 0 (HLA-DRB1 Chains); 0 (Peptides, Cyclic); 0 (Vimentin); 0 (cyclic citrullinated peptide); 29VT07BGDA (Citrulline); 94ZLA3W45F (Arginine) [Em] Mês de entrada: 1710 [Cu] Atualização por classe: 171114 [Lr] Data última revisão: 171114 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170813 [St] Status: MEDLINE [do] DOI: 10.1136/annrheumdis-2017-211300

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[PMID]: 28801099 [Au] Autor: Breier M; Wahl S; Prehn C; Ferrari U; Sacco V; Weise M; Grallert H; Adamski J; Lechner A [Ad] Endereço: Research Unit of Molecular Epidemiology, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Epidemiology II, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health, Neuherberg, Germany; German Center for Diabetes Resear [Ti] Título: Immediate reduction of serum citrulline but no change of steroid profile after initiation of metformin in individuals with type 2 diabetes. [So] Source: J Steroid Biochem Mol Biol;174:114-119, 2017 Nov. [Is] ISSN: 1879-1220 [Cp] País de publicação: England [La] Idioma: eng [Ab] Resumo: Metformin is the most important first-line treatment for type 2 diabetes mellitus (T2DM) but its exact mode of action remains unknown. In this study, we used targeted metabolomics to gain new insights into the metabolic effects of metformin in humans with T2DM. We also examined changes in the serum steroid hormone profile. We quantified 167 serum metabolites and 19 steroid hormones using liquid chromatography-tandem mass spectrometry at three time points in individuals with previously untreated T2DM: before the start of metformin therapy (time point A), after the first dose (B) and after short-term therapy for 4-6 weeks (C). For metabolite analysis, we split the study cohort into a discovery and a replication study of 88 and 45 subjects, respectively. The statistical analysis was done using linear mixed-effects models. Among the metabolites quantified, citrulline showed the most pronounced changes. Compared to its baseline serum concentration, citrulline was reduced by 17% after the first dose of metformin (p=1.34E-07) and by 24% after short-term therapy (p=2.84E-08) in the discovery study. These results were confirmed in the replication study. The only other metabolite significantly changed after correction for multiple testing was PC ae C36:4 between baseline and 4-6 weeks. The serum steroid hormone profile showed no significant changes after metformin intake. In summary, we observed an immediate and sustained reduction of serum citrulline by metformin in humans. This may be relevant for some of the wanted or unwanted effects of the drug. [Mh] Termos MeSH primário: Citrulina/sangue Diabetes Mellitus Tipo 2/sangue Hipoglicemiantes/farmacologia Metformina/farmacologia Esteroides/sangue [Mh] Termos MeSH secundário: Idoso Diabetes Mellitus Tipo 2/tratamento farmacológico Diabetes Mellitus Tipo 2/metabolismo Feminino Seres Humanos Hipoglicemiantes/uso terapêutico Metabolômica Metformina/uso terapêutico Meia-Idade Esteroides/metabolismo [Pt] Tipo de publicação: JOURNAL ARTICLE; OBSERVATIONAL STUDY [Nm] Nome de substância: 0 (Hypoglycemic Agents); 0 (Steroids); 29VT07BGDA (Citrulline); 9100L32L2N (Metformin) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171113 [Lr] Data última revisão: 171113 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170813 [St] Status: MEDLINE

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[PMID]: 28732135 [Au] Autor: Orr C; Najm A; Biniecka M; McGarry T; Ng CT; Young F; Fearon U; Veale DJ [Ad] Endereço: University College Dublin, Dublin, Ireland. [Ti] Título: Synovial Immunophenotype and Anti-Citrullinated Peptide Antibodies in Rheumatoid Arthritis Patients: Relationship to Treatment Response and Radiologic Prognosis. [So] Source: Arthritis Rheumatol;69(11):2114-2123, 2017 Nov. [Is] ISSN: 2326-5205 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: OBJECTIVE: Serum anti-citrullinated peptide antibodies (ACPAs) may be present before the development of rheumatoid arthritis (RA) and may be predictive of more severe, erosive disease. This study was undertaken to examine the synovial tissue immunophenotype according to ACPA status in patients with RA, as well as the response to treatment and erosion status. METHODS: Consecutive RA patients were prospectively recruited and underwent clinical and serologic assessments before and after treatment. Radiologic assessment was performed at the time of clinical follow-up. Synovial tissue was immunostained for specific markers of B cells (CD19), T cells (CD3, CD4, and CD8), macrophages (CD68), and blood vessels (factor VIII). Serum CXCL13 levels were quantified by enzyme-linked immunosorbent assay. Synovial tissue sections were analyzed for immunophenotype according to ACPA status, using a validated semiquantitative scoring method, and also analyzed for the presence of lymphoid aggregates. Response to treatment with nonbiologic or biologic disease-modifying antirheumatic drugs was assessed using the European League Against Rheumatism (EULAR) response criteria. RESULTS: In total, 123 subjects (78 ACPA+) were included. Compared to ACPA- RA patients, synovium from ACPA+ RA patients was characterized by significantly higher levels of CD19+ B cells and CD3+ and CD8+ T cells (each P < 0.05), and CD19+ B cell levels were significantly higher in patients who were naive to treatment. The CD19+ B cell infiltrate level was higher in patients with erosions at follow-up (P = 0.0128). Levels of lymphoid aggregates of CD19+ B cells were significantly higher in ACPA+ patients (P < 0.05), and this was associated with increased serum CXCL13 levels. The EULAR response was significantly associated with the level of CD3+ T cell infiltrates (P < 0.05), while CD68+ macrophage and CD8+ T cell levels were predictive of the response to tumor necrosis factor inhibitors (P < 0.05). CONCLUSION: The results of this prospective study demonstrate that the levels of synovial B cell infiltrates and lymphoid aggregates were significantly higher in ACPA+ RA patients, especially those who were naive to treatment. In addition, ACPA+ subjects developed more erosions during progression of the disease and had higher serum levels of CXCL13. The EULAR response to therapy in ACPA+ RA patients was associated with increased levels of T cell and macrophage markers. [Mh] Termos MeSH primário: Artrite Reumatoide/imunologia Peptídeos Cíclicos/imunologia Membrana Sinovial/imunologia [Mh] Termos MeSH secundário: Adulto Idoso Antígenos CD/metabolismo Antígenos CD19/metabolismo Antígenos de Diferenciação Mielomonocítica/metabolismo Antirreumáticos/uso terapêutico Artrite Reumatoide/tratamento farmacológico Autoanticorpos Linfócitos B/imunologia Linfócitos B/metabolismo Complexo CD3/metabolismo Antígenos CD4/metabolismo Antígenos CD8/metabolismo Quimiocina CXCL13/imunologia Citrulina/imunologia Ensaio de Imunoadsorção Enzimática Fator VIII/metabolismo Feminino Seres Humanos Imuno-Histoquímica Imunofenotipagem Macrófagos/imunologia Macrófagos/metabolismo Masculino Meia-Idade Peptídeos/imunologia Fenótipo Prognóstico Estudos Prospectivos Linfócitos T/imunologia Linfócitos T/metabolismo Resultado do Tratamento [Pt] Tipo de publicação: JOURNAL ARTICLE [Nm] Nome de substância: 0 (Antigens, CD); 0 (Antigens, CD19); 0 (Antigens, Differentiation, Myelomonocytic); 0 (Antirheumatic Agents); 0 (Autoantibodies); 0 (CD19 molecule, human); 0 (CD3 Complex); 0 (CD4 Antigens); 0 (CD68 antigen, human); 0 (CD8 Antigens); 0 (CXCL13 protein, human); 0 (Chemokine CXCL13); 0 (Peptides); 0 (Peptides, Cyclic); 0 (cyclic citrullinated peptide); 29VT07BGDA (Citrulline); 9001-27-8 (Factor VIII) [Em] Mês de entrada: 1711 [Cu] Atualização por classe: 171116 [Lr] Data última revisão: 171116 [Sb] Subgrupo de revista: AIM; IM [Da] Data de entrada para processamento: 170722 [St] Status: MEDLINE [do] DOI: 10.1002/art.40218

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MEDLINE

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[PMID]: 28695293 [Au] Autor: Kampstra ASB; Toes REM [Ad] Endereço: Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC, Leiden, The Netherlands. a.s.b.kampstra@lumc.nl. [Ti] Título: HLA class II and rheumatoid arthritis: the bumpy road of revelation. [So] Source: Immunogenetics;69(8-9):597-603, 2017 Aug. [Is] ISSN: 1432-1211 [Cp] País de publicação: United States [La] Idioma: eng [Ab] Resumo: Rheumatoid arthritis (RA) is a chronic auto-immune disease primarily targeting the joints. Approximately 1% of the population is affected by RA, and despite the improvements in therapeutic interventions, elucidation of the disease pathogenesis is still in its infancy. RA patients can be subdivided on basis of the presence of autoantibodies, especially anti-citrullinated protein antibodies (ACPA). ACPA and ACPA disease most likely differ in aetiology, as different genetic and environmental risk factors are associated with these two disease entities. For ACPA RA disease, the genetic factors associating with disease mainly comprised of human leukocyte antigen (HLA) class II molecules. The predisposing HLA-DR alleles have been depicted as the 'HLA Shared Epitope (SE) alleles', as these alleles encode a similar sequence, the shared epitope sequence, within the beta chain of the HLA-DR molecule. In addition to the involvement of the HLA-SE alleles in the development of ACPA RA disease, other HLA-DR molecules have been shown to confer protection against this disease entity. The protective HLA molecules have, instead of the SE-motif, a different but shared sequence at the same location in the beta chain of HLA-DR molecules, consisting of the amino acid residues DERAA. The possible contributions of the predisposing and protective HLA molecules in association with ACPA-positive RA are discussed in this review. [Mh] Termos MeSH primário: Artrite Reumatoide/imunologia Antígenos HLA-DR/genética [Mh] Termos MeSH secundário: Alelos Animais Células Apresentadoras de Antígenos/imunologia Citrulina/imunologia Epitopos Antígenos HLA-DR/fisiologia Seres Humanos Camundongos [Pt] Tipo de publicação: JOURNAL ARTICLE; REVIEW [Nm] Nome de substância: 0 (Epitopes); 0 (HLA-DR Antigens); 29VT07BGDA (Citrulline) [Em] Mês de entrada: 1709 [Cu] Atualização por classe: 170929 [Lr] Data última revisão: 170929 [Sb] Subgrupo de revista: IM [Da] Data de entrada para processamento: 170712 [St] Status: MEDLINE [do] DOI: 10.1007/s00251-017-0987-5

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