Academic literature on the topic 'Arthritogenic'

ABSTRACT To study what determines the arthritogenicity of bacterial cell walls, cell wall-induced arthritis in the rat was applied, using four strains of Lactobacillus. Three of the strains used proved to induce chronic arthritis in the rat; all were Lactobacillus casei. The cell wall of Lactobacillus fermentum did not induce chronic arthritis. All arthritogenic bacterial cell walls had the same peptidoglycan structure, whereas that of L. fermentum was different. Likewise, all arthritogenic cell walls were resistant to lysozyme degradation, whereas the L. fermentum cell wall was lysozyme sensitive. Muramic acid was observed in the liver, spleen, and lymph nodes in considerably larger amounts after injection of an arthritogenicL. casei cell wall than following injection of a nonarthritogenic L. fermentum cell wall. The L. casei cell wall also persisted in the tissues longer than theL. fermentum cell wall. The present results, taken together with those published previously, underline the possibility that the chemical structure of peptidoglycan is important in determining the arthritogenicity of the bacterial cell wall.

In the past two decades Old World and arthritogenic alphavirus have been responsible for epidemics of polyarthritis, causing high morbidity and becoming a major public health concern. The multifunctional arthritogenic alphavirus capsid protein is crucial for viral infection. Capsid protein has roles in genome encapsulation, budding and virion assembly. Its role in multiple infection processes makes capsid protein an attractive target to exploit in combating alphaviral infection. In this review, we summarize the function of arthritogenic alphavirus capsid protein, and describe studies that have used capsid protein to develop novel arthritogenic alphavirus therapeutic and diagnostic strategies.

Arthritogenic alphaviruses are a group of medically important arboviruses that cause inflammatory musculoskeletal disease in humans with debilitating symptoms, such as arthralgia, arthritis, and myalgia. The arthritogenic, or Old World, alphaviruses are capable of causing explosive outbreaks, with some viruses of major global concern. At present, there are no specific therapeutics or commercially available vaccines available to prevent alphaviral disease. Infected patients are typically treated with analgesics and non-steroidal anti-inflammatory drugs to provide often inadequate symptomatic relief. Studies to determine the mechanisms of arthritogenic alphaviral disease have highlighted the role of the host immune system in disease pathogenesis. This review discusses the current knowledge of the innate immune response to acute alphavirus infection and alphavirus-induced immunopathology. Therapeutic strategies to treat arthritogenic alphavirus disease by targeting the host immune response are also examined.

Alphaviruses are members of the Togaviridae family that are mainly transmitted by arthropods such as mosquitoes. In the last decades, several alphaviruses have re-emerged, causing outbreaks worldwide. One example is the re-emergence of chikungunya virus (CHIKV) in 2004, which caused massive epidemics in the Indian Ocean region after which the virus dramatically spread to the Americas in late 2013. Besides CHIKV, other alphaviruses, such as the Ross River virus (RRV), Mayaro virus (MAYV), and Venezuelan equine encephalitis virus (VEEV), have emerged and have become a serious public health concern in recent years. Infections with the Old World alphaviruses (e.g., CHIKV, RRV) are primarily associated with polyarthritis and myalgia that can persist for months to years. On the other hand, New World alphaviruses such as VEEV cause mainly neurological disease. Despite the worldwide (re-)emergence of these viruses, there are no antivirals or vaccines available for the treatment or prevention of infections with alphaviruses. It is therefore of utmost importance to develop antiviral strategies against these viruses. We here provided an overview of the reported antiviral strategies against arthritogenic alphaviruses. In addition, we highlighted the future perspectives for the development and the proper use of such antivirals.

Dissertação de Mestrado em Biologia Celular e Molecular apresentada à Faculdade de Ciências e Tecnologia
A artrite reumatóide (AR) é a doença autoimune reumática crónica mais comum, afectando 0,5-1% da população mundial. A incidência desta doença autoimune é três vezes superior nas mulheres do que nos homens, com idades entre 40-70 anos. A etiologia da doença permanece desconhecida, embora a combinação de factores hormonais, genéticos, sexuais e ambientais sejam importantes contribuintes para o desenvolvimento de AR. Várias evidências apoiam o envolvimento directo das células T na patogénese da AR, nomeadamente i) a correlação da susceptibilidade e severidade da AR com os genes associados à activação das células T e a diferenciação de células T anormal, como o antígeno leucocitário humano - antígeno D relacionado (HLA- DR) e a proteína tirosina fosfatase não receptora do tipo 22 (PTPN22); ii) o recrutamento e activação contínua de células T nas articulações de pacientes com AR; iii) a transferência de células T CD4 do sinóvio dos pacientes é suficiente para induzir AR em ratos imunes deficientes. No entanto, a base molecular da desregulação das células T nesta doença permanece indescritível. Os tratamentos biológicos actuais são bem-sucedidos no controlo de AR num subconjunto de pacientes, neutralizando a resposta inflamatória global sem ter como alvo as causas subjacentes que geram inflamação crónica. Embora os tratamentos biológicos tenham aumentado a qualidade de vida de alguns pacientes, nem todos os pacientes respondem à terapia (50%), os tratamentos biológicos têm sérios efeitos colaterais imunossupressores e perdem a eficácia ao longo do tempo. Portanto, existe uma necessidade de desenvolvimento de novas terapias que sejam direccionadas precisamente para os mecanismos subjacentes à desregulação das células T CD4 em vez da activação geral das células T ou dos produtos finais, citoquinas inflamatórias. Apesar do seu papel primordial, muito pouco se sabe sobre a base molecular da desregulação de células T na AR. Este estudo pretende elucidar os circuitos moleculares que controlam a desregulação das células T, bem como, esclarecer como é possível desactivá-las, um conhecimento em última instância necessário para induzir a remissão da AR.No meu trabalho experimental, através da análise de amostras de sangue de pacientes com AR e do uso da técnica de citometria, foi feita uma caracterização das células T existentes. Particularmente, a produção de citoquinas inflamatórias foi medida para caracterizar a resposta das células T na patologia AR. Adicionalmente, alguns circuitos moleculares foram avaliados para fornecer informação sobre a resposta patogénica das células T. O impacto da identificação do circuito molecular das células T envolvidas estende-se muito além da patogénese. Assim, poderá representar um ponto de partida para novas imunoterapias de precisão capazes de reverter a AR sem imunossupressão dos pacientes. A nível clínico, este projeto poderia fornecer biomarcadores para serem usados no diagnóstico pré-sintomático e na monitorização da progressão da doença e da eficiência do tratamento.
Rheumatoid arthritis (RA) is the most common chronic rheumatic autoimmune disease, affecting 0,5-1% of worldwide population. The incidence of this autoimmune disease is three times greater in females than in males, with an age at onset between 40-70 years. The aetiology of the disease remains unknown although the combination of hormonal, genetic, sex and environmental factors are important contributors to the development of RA. Distinct evidence supports the direct involvement of T cells in the pathogenesis of RA, namely i) the correlation of RA susceptibility and severity with genes associated with T cell activation and abnormal T cell differentiation, such as human leukocyte antigen – antigen D related (HLA-DR) and protein tyrosine phosphatase non-receptor type 22 (PTPN22); ii) the continuous recruitment and activation of T cells into the joints of patients with RA; iii) transfer of CD4 T cells from patients synovium is sufficient to induce RA in immune deficient mice. However, the molecular basis of T cell dysregulation in this disease remains elusive.Current biological treatments are successful at managing RA in a subset of patients by quenching the overall inflammatory response without targeting the underlying causes driving chronic inflammation. Even though biological treatments have increased the quality of life of some patients, not all patients respond to therapy (50%), biological treatments have serious immunocompromising side effects and they lose efficiency over time. Therefore, there is an unmet need for therapies that precisely target the mechanisms underpinning CD4 T cell dysregulation rather than overall T cell activation or the end products, inflammatory cytokines. Despite their primordial role, very little is known about the molecular basis of T cell dysregulation in RA. This study aims to elucidate the molecular circuits that control T cell dysregulation and to clarify how to turn them off, a knowledge ultimately necessary to induce RA remission.In my experimental work, by analyzing blood samples from RA patients and by using flow cytometry technique a characterization of existing T cells was made. Particularly, inflammatory cytokines production was measured to characterize the responsiveness of T cells in RA pathology. Additionally, some molecular circuits were evaluated to provide some insights of the pathogenic responses of T cells.The impact of identifying the molecular circuitry of T cells driving RA is well beyond pathogenesis. It could represent the starting ground for new precision immunotherapies capable of reverting RA without immunocompromising the patients. At clinical level, this project could provide biomarkers to be used in pre-symptomatic diagnosis and in monitoring disease progression and treatment efficiency.

The inoculation of a single dose of Complete Freund's Adjuvant (CFA) in Dark Agouti rats induces a polyarthritis that resembles rheumatoid arthritis (RA) in humans. The specific role of T cells in the pathogenesis of RA is controversial but a considerable body of evidence suggests that the joint destruction is mediated by T cells within the synovium, which may activate other cells such as macrophages and fibroblasts that are more directly implicated in articular damage. To gain a further understanding of the mechanisrns involved in the development of T cell-mediated polyarthritis, the activation and phenotype of CD4⁺ T cells during the prodrome of adjuvant-induced arthritis (AA) has been investigated in rats. Research in the Arthritis Research Laboratory has demonstrated previously that activated CD4⁺ T cells in the thoracic duct (TD) lymph of rats during the late prodromal phase of AA (9 days after inoculation) have the capacity to enter both normal and inflamed joints after the adoptive transfer to syngeneic recipients. Furthermore, these activated CD4⁺ T cells can transfer disease to naive recipient rats. The arthritogenic population is contained within a subset of CD4⁺ T cells that expresses CD25, MHC class II, CD134and CD7l. The delay in onset of AA after inoculation with adjuvant (9-10 days) or adoptive transfer of arthritogenic TD lymphocytes (4-6 days) suggests that progressive differentiation or selection of effector cells is required before disease can be expressed. This study has charted the emergence of activated and arthritogenic CD4⁺ T cells in the inguinal and popliteal lymph nodes draining the site of inoculation, in the TD lymph and in the joints of the hind paws. In the lymph nodes and TD lymph, the proportion of CD4⁺ T cells expressing activation markers such as CD25, MHC class II, CD134 and CD71 and adhesion molecules such as ICAM-1 increased within 3 days following inoculation of CFA and these levels remained elevated throughout the early stages of AA. Arthritogenic lymphocytes were present in the TD lymph by the fourth day after inoculation of CFA. Interestingly, the disease transferred to recipients by lymphocytes from a donor on the fourth day post-inoculation followed similar kinetics to that transferred by TD lymphocytes harvested from donors at later time points. Very few CD4⁺ T cells were detected in the hind paws during the prodrome of AA, whereas a dramatic influx was observed by day 9 and even more so at day 12 post-inoculation, when joint inflammation was usually moderate to severe. These CD4⁺ T cells in the inflamed hind paws had effector phenotype. A method was developed for detecting the cytokine production by individual T lymphocytes under conditions that reflected the cytokine production by these cells in vivo. This technique revealed that CD4⁺ T cells from arthritic rats produced more interferon (IFN)-γ than interleukin (IL)-4, suggesting that this disease was mediated by T helper type -1 cells. CD4⁺ T cells from inflamed joints were prolific producers of IFN-γ, suggesting that this pro-inflammatory cytokine may have played a crucial role in disease pathology. However, when a monoclonal antibody was used to block IFN-γ produced by either transferred arthritogenic lymphocytes or host cells in the active disease, the arthritis was markedly exacerbated, indicating that this cytokine also has down-regulatory effects at an important stage during the development of the inflammatory response.
Thesis (Ph.D.) -- University of Adelaide, Dept. of Molecular Biosciences, 2002

Family and twin studies have long suggested a large genetic component in ankylosing spondylitis (AS). The genetic association with HLA-B27 remains one of the strongest single gene variant associations reported in any complex polygenic disease. The exact mechanism by which HLA-B27 contributes to AS remains unknown, with three main theories proposed: the arthritogenic peptide, endoplasmic reticulum stress with unfolded protein response, and homodimerization theories. Genome-wide association studies have identified a number of other important susceptibility genes for AS, several of which overlap with other spondyloarthritis conditions. Of these, ERAP1 and IL-23R, are covered in more detail, highlighting their functional importance.

Innate immune mechanisms are strongly implied in the pathophysiology of spondyloarthritis (SpA). This chapter discusses available data on the role of the innate immune system in relation to HLA-B27, genetic associations, and the cellular and molecular characteristics of disease target tissue. Regarding the linkage with MCH-class I molecule HLA-B27, the chapter discusses the arthritogenic peptide hypothesis and three popular antigen-independent theories. The genetic architecture of the disease argues against a role for the adaptive immune system and identifies cytokine pathways, such as IL-1, TNF, and IL-23/IL-17. In experimental as well as in human SpA, the importance of these cytokine pathways are confirmed by effective reduction of signs and symptoms upon blockade of specific molecules. In-depth cellular and molecular analysis of the target tissue identifies a contribution of cells with strong innate features, rather than cells of the adaptive immune system.

HLA-B27 is present in the majority of patients with ankylosing spondylitis (AS). Although we have learned a considerable amount about the natural immunologic function of HLA class I proteins, this has not provided a definitive mechanism of AS pathogenesis. While HLA-B27 is adept at presenting antigenic peptides to CD8+ T cells, ‘arthritogenic’ peptides targeted by a cross-reactive T or natural killer cell response have not been described, nor have autoreactive T cells been found. Newer concepts have evolved based on the propensity of HLA-B27 to ‘misbehave’, both inside cells and on the cell surface. Misfolded HLA-B27 molecules may stimulate an endoplasmic reticulum stress response, promoting production of IL-23 and then IL-17 and related cytokines. Aberrant cell-surface HLA-B27 molecules are ligands for natural killer and related immunoreceptors, and recognition can lead to IL-17 proinflammatory responses. There is growing evidence to suggest that these aberrant behaviours contribute to AS pathogenesis.

Rheumatoid arthritis (RA) is the most common inflammatory complication and affects approximately 1 % of the global population. It affects three times more women than men. RA is an autoimmune disorder elicited by exposure of genetic factors from the host to unknown antigens causing arthritogenic complaints. It also includes the activation of lymphocytes as well as CD4+ helper T cells along with local release of chronic inflammatory mediators and cytokines like tumor necrosis factor (TNF α) and various cytokines like interleukins (IL) that enormously affect the joints. The available allopathic therapies for RA are not a cure for the complications, and antibody therapy and surgical procedures are expensive. However, in the present era, researchers and healthcare professionals have moved toward natural medicines obtained from plants and other natural sources. Research based on developments in phytomedicine has progressed steadily. Evidence has been collected to show the massive therapeutic potential of medicinal plants used in various traditional systems against many pathological complications. Researchers have focused on the therapeutic potential of natural products used for treatment and counteracting various disorders along with their complications having negligible adverse effects. Natural Products for the Management of Arthritic Disorders compiles current knowledge about the bioactive compounds and herbal formulations useful in the treatment of rheumatoid arthritis. 11 chapters explain the role of natural products in the management of rheumatoid arthritis. Topics have been contributed by experts in medicinal chemistry and rheumatology. The book first introduces the reader to rheumatoid arthritis before delving into conventional and alternative therapies for the disease. The editors have also included special topics such as the biomarkers for RA, cytokines and anti-inflammatory mediators, preclinical and clinical studies. The range of topics should provide a comprehensive overview of natural remedies for arthritis and the role of natural products in anti-arthritic drug development. The information will be useful for many readers including medical and pharmacology students, multidisciplinary research scholars, scientists, pharma / herbal / food industrialists, and policy makers.