Human osteoclastogenesis in Epstein-Barr virus-induced erosive arthritis in humanized NOD/Shi-scid/IL-2Rγnull mice.

Many human viruses, including Epstein-Barr virus (EBV), do not infect mice, which is challenging for biomedical research. We have previously reported that EBV infection induces erosive arthritis, which histologically resembles rheumatoid arthritis, in humanized NOD/Shi-scid/IL-2Rγnull (hu-NOG) mice; however, the underlying mechanisms are not known. Osteoclast-like multinucleated cells were observed during bone erosion in this mouse model, and therefore, we aimed to determine whether the human or mouse immune system activated bone erosion and analyzed the characteristics and origin of the multinucleated cells in hu-NOG mice. Sections of the mice knee joint tissues were immunostained with anti-human antibodies against certain osteoclast markers, including cathepsin K and matrix metalloproteinase-9 (MMP-9). Multinucleated cells observed during bone erosion stained positively for human cathepsin K and MMP-9. These results indicate that human osteoclasts primarily induce erosive arthritis during EBV infections. Human osteoclast development from hematopoietic stem cells transplanted in hu-NOG mice remains unclear. To confirm their differentiation potential into human osteoclasts, we cultured bone marrow cells of EBV-infected hu-NOG mice and analyzed their characteristics. Multinucleated cells cultured from the bone marrow cells stained positive for human cathepsin K and human MMP-9, indicating that bone marrow cells of hu-NOG mice could differentiate from human osteoclast progenitor cells into human osteoclasts. These results indicate that the human immune response to EBV infection may induce human osteoclast activation and cause erosive arthritis in this mouse model. Moreover, this study is the first, to our knowledge, to demonstrate human osteoclastogenesis in humanized mice. We consider that this model is useful for studying associations of EBV infections with rheumatoid arthritis and human bone metabolism.

Viperin controls chikungunya virus-specific pathogenic T cell IFNγ Th1 stimulation in mice.

Chikungunya virus (CHIKV) has been a worldwide threat since its reemergence in La Reunion Island in 2004. Expression of the interferon-stimulated protein Viperin correlates with viral load burden in patients, and studies in mice have demonstrated its role to limit disease severity against CHIKV infection. Using Viperin -/- mice, we aimed to understand the contribution of Viperin to the T-cell immune response against CHIKV. CD4 T-cell depletion in Viperin -/- mice showed that increased late acute joint inflammation (5-8 d postinfection) was exclusively mediated by T cells. Specifically, CHIKV-infected Viperin -/- mice showed an increased INFγ Th1 profile of CD4 T cells, enhanced INFγ stimulation by APCs, an increased INFγ secretion profile in the joint microenvironment, and increased numbers of inflammatory monocytes in virus-infected joints compared with WT mice. Bone marrow grafting experiments showed that Viperin expression in both hematopoietic and non-hematopoietic cells is instrumental in reducing disease severity associated with a CD4 T-cell response.

Treatment of chikungunya chronic arthritis: A systematic review.

INTRODUCTION: Chikungunya (CHIK) is a tropical arbovirus, transmitted by the female mosquito Aedes aegypti and Aedes albopictus. In Brazil, there have been cases reported since 2014. The initial manifestations of this virus are sudden onset high fever, headache, chills, rashes, myalgia and intense joint pain. Usually, CHIK presents the acute and chronic phases, the latter characterized by bilateral polyarthralgia, which can last for months or even years. During this period, autoimmune diseases can be triggered, making the picture even more complicated. METHOD: A systematic review was performed on the PubMed and Scielo databases in January 2017. Clinical trials, cohorts, case-control and case reports were included in the study. Expert opinions, societal consensuses and literary reviews were exclusion criteria. Studies were conducted in English, Spanish and Portuguese. The studies were descriptively analyzed and the data was grouped according to methodological similarity. RESULTS: Twenty-four (24) articles were selected and, in compliance with the inclusion and exclusion criteria, 18 were eliminated, with six studies remaining in the present review: five clinical trials and one case report. CONCLUSION: When the manifestations of CHIK become chronic and, the longer they last, more complications arise. Polyarthralgia can be immaterial, distancing individuals from their daily-life activities. Anti-inflammatory drugs (either steroid or not), in addition to immunosuppressants, homeopathy and physiotherapy are measures of treatment that, according to the literature, have been successful in relieving or extinguishing symptoms. However, it is fundamental that studies of CHIK treatment be further developed.

Treatment of chikungunya chronic arthritis: A systematic review / Tratamento de artralgia crônica da chikungunya: uma revisão sistemática

Summary Introduction: Chikungunya (CHIK) is a tropical arbovirus, transmitted by the female mosquito Aedes aegypti and Aedes albopictus. In Brazil, there have been cases reported since 2014. The initial manifestations of this virus are sudden onset high fever, headache, chills, rashes, myalgia and intense joint pain. Usually, CHIK presents the acute and chronic phases, the latter characterized by bilateral polyarthralgia, which can last for months or even years. During this period, autoimmune diseases can be triggered, making the picture even more complicated. Method: A systematic review was performed on the PubMed and Scielo databases in January 2017. Clinical trials, cohorts, case-control and case reports were included in the study. Expert opinions, societal consensuses and literary reviews were exclusion criteria. Studies were conducted in English, Spanish and Portuguese. The studies were descriptively analyzed and the data was grouped according to methodological similarity. Results: Twenty-four (24) articles were selected and, in compliance with the inclusion and exclusion criteria, 18 were eliminated, with six studies remaining in the present review: five clinical trials and one case report. Conclusion: When the manifestations of CHIK become chronic and, the longer they last, more complications arise. Polyarthralgia can be immaterial, distancing individuals from their daily-life activities. Anti-inflammatory drugs (either steroid or not), in addition to immunosuppressants, homeopathy and physiotherapy are measures of treatment that, according to the literature, have been successful in relieving or extinguishing symptoms. However, it is fundamental that studies of CHIK treatment be further developed.

Resumo Introdução: A chikungunya é uma arbovirose tropical, transmitida pela fêmea dos mosquitos Aedes aegypti e Aedes albopictus. No Brasil, existem casos relatados desde 2014. As manifestações iniciais dessa virose são: febre alta de início súbito, cefaleia, calafrios, erupções cutâneas, mialgia e dor articular intensa. Normalmente, a chikungunya apresenta as fases aguda e crônica, sendo a última caracterizada pela poliartralgia bilateral, que pode durar meses e até anos. Durante esse período, doenças autoimunes podem ser desencadeadas, tornando o quadro ainda mais complicado. Método: Foi realizada uma revisão sistemática nos bancos de dados PubMed e Scielo em janeiro de 2017. Ensaios clínicos, coortes, casos-controle e relatos de caso foram incluídos na pesquisa. Opiniões de especialista, consensos de sociedades e revisões literárias foram critérios de exclusão. Foram avaliados estudos nas línguas inglesa, espanhola e portuguesa. Os estudos foram analisados descritivamente, e os dados agrupados, conforme semelhança metodológica. Resultados: Foram selecionados 24 artigos; em obediência aos critérios de inclusão e exclusão, 18 foram eliminados, restando seis estudos na presente revisão: cinco ensaios clínicos e um relato de caso. Conclusão: Quando as manifestações da chikungunya se tornam crônicas, quanto mais tempo duram, mais complicações surgem. A poliartralgia pode ser incapacitante, afastando os indivíduos das suas atividades de vida diária. Anti-inflamatórios (esteroides ou não), somados a imunossupressores, homeopatia e fisioterapia são medidas de tratamento que, conforme a literatura, têm alcançado êxito no alívio ou na extinção dos sintomas. Todavia, é fundamental que os estudos do tratamento da chikungunya sejam mais aprofundados.

Fiebre de Chikungunya: reporte de tres casos del Hospital Naval Almirante Nef / Chikungunya fever: report of three cases from Almirante Nef Naval Hospital

Chikungunya fever is an emerging infection in our country due to travelers to endemic areas. It presents acutely with high fever, fatigue, headache, myalgia, skin rash and arthritis, usually as a symmetric polyarthritis compromising the interphalangeal and metacarpophalangeal joints, wrist, elbow, ankle and knee. While most of the symptoms last about a week, arthralgias may become chronic and generate significant functional impairment. Chikungunya has been postulated as a triggering factor for rheumatoid arthritis because of the presence of positive rheumatoid factor. We present the three confirmed cases in Almirante Nef Naval Hospital with the review of the published literature...

La fiebre de Chikungunya es una infección novedosa en nuestro país pues su contagio se produce por viajeros en zonas endémicas. Se presenta generalmente en forma aguda con fiebre alta, astenia, cefalea, mialgia, rash cutaneo y artritis, mayoritariamente como poliartritis simétrica comprometiendo las articulaciones interfalángicas, metacarpofalángicas, muñecas, codos, tobillo y rodillas. Si bien la mayoría de los síntomas duran aproximadamente una semana, las artralgias pueden hacerse crónicas y generar un importante deterioro funcional. Se ha postulado que podría ser un factor gatillante de artritis reumatoide ante la presencia de factor reumatoideo positivo. A continuación se presentan los tres casos confirmados del Hospital Naval Almirante Nef junto a la revisión de la literatura publicada hasta el momento...

Critical role for macrophage migration inhibitory factor (MIF) in Ross River virus-induced arthritis and myositis.

Arthrogenic alphaviruses, such as Ross River virus (RRV), chikungunya, Sindbis, mayaro and o'nyong-nyong viruses circulate endemically worldwide, frequently causing outbreaks of polyarthritis. The exact mechanisms of how alphaviruses induce polyarthritis remain ill defined, although macrophages are known to play a key role. Macrophage migration inhibitory factor (MIF) is an important cytokine involved in rheumatoid arthritis pathogenesis. Here, we characterize the role of MIF in alphavirus-induced arthritides using a mouse model of RRV-induced arthritis, which has many characteristics of RRV disease in humans. RRV-infected WT mice developed severe disease associated with up-regulated MIF expression in serum and tissues, which corresponded to severe inflammation and tissue damage. MIF-deficient (MIF(-/-)) mice developed mild disease accompanied by a reduction in inflammatory infiltrates and muscle destruction in the tissues, despite having viral titers similar to WT mice. In addition, reconstitution of MIF into MIF(-/-) mice exacerbated RRV disease and treatment of mice with MIF antagonist ameliorated disease in WT mice. Collectively, these findings suggest that MIF plays a critical role in determining the clinical severity of alphavirus-induced musculoskeletal disease and may provide a target for the development of antiviral pharmaceuticals. The prospect being that early treatment with MIF-blocking pharmaceuticals may curtail the debilitating arthritis associated with alphaviral infections.

Potential infectious agents in the induction of arthritides.

In the multifactorial etiology of rheumatic diseases, infectious agents are regarded as the major environmental factors that may cause inflammatory arthritides in genetically susceptible hosts. Two not mutually exclusive pathogenetic pathways are hypothesized to explain the initiation and perpetuation of chronic arthritides by infectious agents: persistent infection and induction of immunopathology. In this review we focus on the role of infections in the etiopathogenesis of rheumatoid arthritis. Retroviruses and enteropathogenic bacteria continue to be the most intensively discussed candidates as possible etiologic factors of rheumatoid arthritis. Although there is ample indirect evidence for the involvement of infections in the pathogenesis of autoimmune disease, direct proof is still missing. There may be no single infectious trigger for rheumatoid arthritis, but multiple infectious agents that share antigenic motifs. The "reverse immunology" approach addresses this issue and is discussed in our outlook on future research directions.

Microbiological investigation of polyarthralgia.

Results of serological investigations on patients with joint pain, arthralgia or polyarthritis were analysed and this information was used to develop a diagnostic algorithm to ensure optimal utilisation of laboratory resources. Accordingly, all cases are now examined for parvovirus IgM, mycoplasma IgM and streptococcal antibodies. Further tests are undertaken by following the algorithm after obtaining supplementary information from a questionnaire. This approach is put forward as a preliminary standard which other laboratories may like to evaluate and develop according to local requirements.