Monocytes are no longer regarded as a homogenous cell population but can be divided, both phenotypically and functionally, into different subsets. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocytes is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA). The work at hand shows that the frequency of CD56+ monocytes is also expanded in RA; moreover, this subpopulation seems to increase with age in healthy controls. This age association is completely lost in patients suffering from RA. Further functional investigations could demonstrate a dysregulated cytokine response to lipopolysaccharide (LPS) with an increased production of pro-inflammatory cytokines like TNFα as well as an increased spontaneous reactive oxygen intermediate (ROI) production. A longitudinal treatment study using Etanercept as an established TNFα-blocking agent revealed a decrease of the frequency of that cell population under therapy. This decrease was more pronounced in patients with a good treatment response as judged by the reduction of the disease activity score (DAS) 28. Summing up those results, the CD56+ monocyte subset might be involved in immunosenescence as well as in the pathogenesis of RA.

Submitted by Haroudo Xavier Filho (haroudo.xavierfo@ufpe.br) on 2016-01-08T18:39:56Z No. of bitstreams: 1 Dissertação_Laurindo Ferreira da Rocha Junior_Programa de Pós Graduação em Inovação Terapêutica_2013.pdf: 3307978 bytes, checksum: 5e34b9890902ecde22940446891759b7 (MD5) / Made available in DSpace on 2016-01-08T18:39:56Z (GMT). No. of bitstreams: 1 Dissertação_Laurindo Ferreira da Rocha Junior_Programa de Pós Graduação em Inovação Terapêutica_2013.pdf: 3307978 bytes, checksum: 5e34b9890902ecde22940446891759b7 (MD5) Previous issue date: 2013-02-02 / A artrite reumatoide (AR) é uma doença autoimune inflamatória sistêmica que tem como característica principal o acometimento articular. As citocinas estão diretamente implicadas na patogênese da AR. Este trabalho objetivou determinar os níveis de citocinas da via Th17, particularmente IL-17A e IL-22 e correlacionar seus níveis séricos com dados clínicos, demográficos, radiológicos e laboratoriais de pacientes com AR, bem como avaliar a atividade imunomoduladora do novo derivado tiazolidínico LPSF/TM17. Os pacientes foram provenientes do Hospital das Clínicas da Universidade Federal de Pernambuco (UFPE). A coleta de dados clínico-demográficos foi realizada por questionário específico e os pacientes que preencheram os critérios de inclusão realizaram coleta do sangue periférico. A quantificação de citocinas foi realizada em 83 pacientes e 30 controles saudáveis por ELISA. Os níveis de IL-22 mostraram-se aumentados nos pacientes (média 432,37 pg/ml) quando comparados aos controles (67,45 pg/ml), p<0,001. Houve correlação da IL-22 com os índices clínicos de atividade de doença DAS28 (p = 0.037) e CDAI (p = 0.013). Houve correlação dos níveis desta citocina com a presença de erosões radiográficas (p = 0.0001) e com a presença do autoanticorpo fator reumatoide (p = 0.001). Visando avaliar o efeito imunomodulador do LPSF/TM17, foram dosadas citocinas em sobrenadantes de culturas de células mononucleares periféricas após estimulação com PMA e Ionomicina de parte destes pacientes com AR (IFNγ, IL-17A, IL-6 e IL-22). O LPSF/TM17 inibiu significativamente a produção de IFNγ na concentração de 100μM e de IL-17A e IL-22 nas concentrações de 1, 10 e 100 μM (p<0,05). Este estudo foi pioneiro em associar os níveis de IL-22 com a gravidade da doença implicando importante papel desta citocina na patogênese da AR. O presente estudo mostrou a associação da IL-22 na patogênese da AR e que, nessa doença, o LPSF/TM17 pode ser importante na abordagem terapêutica, uma vez que inibiu citocinas envolvidas na doença (IFNγ, IL-17ª e IL-22). / Rheumatoid Arthritis (RA) is an inflammatory systemic autoimune disease with joint involvement as main clinical feature.Cytokines are directed implicated in RA pathogenesis.This study aimed to assess the citokine profile of Th17 pathway, paticularly IL-17A and IL-22 as well as correlate these cytokines serum levels with clinical, demographic, radiographic e laboratory data from patients with Rheumatoid Arthritis (RA) and we also evaluated the immunomodulatory activity of the new thiazolidinedione LPSF/TM17. The patients were recruited at Hospital das Clínicas of Universidade Federal de Pernambuco (UFPE). Clinical and demographic data were recorded in standard questionnaire and patients who fullfilled the inclusion criteria had their blood collected. Cytokines were assayed with ELISA in 83 RA patients and 30 healthy controls. IL-22 levels were increased in patients with RA compared with controls (mean 432.37 pg/ml and 67.45 pg/ml, respectively; p < 0.001). Levels of IL-22 correlated with the composites indices of disease activity DAS28 (p=0.037) and CDAI (p=0.013). Rheumatoid factor (RF) positivity and the presence of bone erosions correlated with higher levels of IL-22 in patients with RA, p=0.001 and p=0.0001, respectively. The immunomodulatory effect of LPSF/TM17 was assessed in peripheral blood mononuclear cells (PBMCs) from RA patients after cytokines assays (IFNγ, IL-17A e IL-22) in culture supernatants after stimulation with PMA and Ionomycin. This was the first study to associate IL-22 serum levels with disease severity suggesting an important role of this cytokine in RA pathogenesis. Importantly, LPSF/TM17 significantly inhibited IFNγ productionin the concentration of 100 μM and induced lower levels of IL-17A and IL-22 in the concentrations of 1, 10 and 100 μM (p<0,05). The role of the thiazolidinediones, synthetics agonists of PPARγ, in RA and in other autoimmune diseases has been described suggesting that these compounds may be of great importance in the therapeutic approach of theses diseases.

Monocytes are no longer regarded as a homogenous cell population but can be divided, both phenotypically and functionally, into different subsets. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocytes is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA). The work at hand shows that the frequency of CD56+ monocytes is also expanded in RA; moreover, this subpopulation seems to increase with age in healthy controls. This age association is completely lost in patients suffering from RA. Further functional investigations could demonstrate a dysregulated cytokine response to lipopolysaccharide (LPS) with an increased production of pro-inflammatory cytokines like TNFα as well as an increased spontaneous reactive oxygen intermediate (ROI) production. A longitudinal treatment study using Etanercept as an established TNFα-blocking agent revealed a decrease of the frequency of that cell population under therapy. This decrease was more pronounced in patients with a good treatment response as judged by the reduction of the disease activity score (DAS) 28. Summing up those results, the CD56+ monocyte subset might be involved in immunosenescence as well as in the pathogenesis of RA.

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