The value of animal models in predicting genetic susceptibility to complex diseases such as rheumatoid arthritis

For a long time, genetic studies of complex diseases were most successfully conducted in animal models. However, the field of genetics is now rapidly evolving, and human genetics has also started to produce strong candidate genes for complex diseases. This raises the question of how to continue gene-finding attempts in animals and how to use animal models to enhance our understanding of gene function. In this review we summarize the uses and advantages of animal studies in identification of disease susceptibility genes, focusing on rheumatoid arthritis. We are convinced that animal genetics will remain a valuable tool for the identification and investigation of pathways that lead to disease, well into the future

A New Arthritis Therapy with Oxidative Burst Inducers

BACKGROUND: Despite recent successes with biological agents as therapy for autoimmune inflammatory diseases such as rheumatoid arthritis (RA), many patients fail to respond adequately to these treatments, making a continued search for new therapies extremely important. Recently, the prevailing hypothesis that reactive oxygen species (ROS) promote inflammation was challenged when polymorphisms in Ncf1, that decrease oxidative burst, were shown to increase disease severity in mouse and rat arthritis models. Based on these findings we developed a new therapy for arthritis using oxidative burst-inducing substances. METHODS AND FINDINGS: Treatment of rats with phytol (3,7,11,15-tetramethyl-2-hexadecene-1-ol) increased oxidative burst in vivo and thereby corrected the effect of the genetic polymorphism in arthritis-prone Ncf1 (DA) rats. Importantly, phytol treatment also decreased the autoimmune response and ameliorated both the acute and chronic phases of arthritis. When compared to standard therapies for RA, anti-tumour necrosis factor-α and methotrexate, phytol showed equally good or better therapeutic properties. Finally, phytol mediated its effect within hours of administration and involved modulation of T cell activation, as injection prevented adoptive transfer of disease with arthritogenic T cells. CONCLUSIONS: Treatment of arthritis with ROS-promoting substances such as phytol targets a newly discovered pathway leading to autoimmune inflammatory disease and introduces a novel class of therapeutics for treatment of RA and possibly other chronic inflammatory diseases

Role of endogenous and exogenous female sex hormones in arthritis and osteoporosis development in B10.Q-ncf1*/* mice with collagen-induced chronic arthritis

<p>Abstract</p> <p>Background</p> <p>Collagen-induced arthritis (CIA) is an often-used murine model for human rheumatoid arthritis (RA). Earlier studies have shown potent anti-arthritic effects with the female sex hormone estradiol and the selective estrogen receptor modulator (SERM) raloxifene in CIA in DBA/1-mice. B10.Q-ncf1^*/*mice are B10.Q mice with a mutated Ncf1 gene. In B10.Q-ncf1^*/*mice, CIA develops as a chronic relapsing disease, which more accurately mimics human RA. We investigated the role of endogenous and exogenous sex steroids and raloxifene in the course of this model of chronic arthritis. We also examined whether treatment would prevent the development of inflammation-triggered generalized osteoporosis.</p> <p>Methods</p> <p>Female B10.Q-ncf1^*/*mice were sham-operated or ovariectomized, and CIA was induced. 22 days later, when 30% of the mice had developed arthritis, treatment with raloxifene, estradiol or vehicle was started, and the clinical disease was evaluated continuously. Treatment was continued until day 56 after immunization. At termination of the experiment (day 73), bone mineral density (BMD) was analyzed, paws were collected for histological examination, and sera were analyzed for markers of cartilage turnover and pro-inflammatory cytokines.</p> <p>Results</p> <p>Raloxifene and estradiol treatment, as well as endogenous estrogen, decreased the frequency of arthritis, prevented joint destruction and countered generalized osteoporosis. These effects were associated with lower serum levels of the pro-inflammatory cytokine IL-6.</p> <p>Conclusions</p> <p>This is the first study to show that raloxifene and estradiol can ameliorate established erosive arthritis and inflammation-triggered osteoporosis in this chronic arthritis model. We propose that treatment with raloxifene could be a beneficial addition to the treatment of postmenopausal RA.</p

The Role of Reactive Oxygen Species in Animal Models of Autoimmunity

Reactive oxygen species (ROS) produced by the phagocyte NADPH oxidase complex are important in the killing of invading pathogens. Lately, a role of ROS has been suggested in regulation of the immune system. This was further highlighted when the Ncf1 gene, encoding a subunit of the NADPH oxidase complex, was found to regulate arthritis severity in rats. Interestingly, the fact that increased arthritis susceptibility was mediated by a lowered ROS production diverged from the general dogma that ROS in general promotes inflammation. The studies included in this thesis aimed to further investigate and characterize the influence of Ncf1 and ROS in autoimmune diseases such as arthritis and encephalomyelitis. By using animal models of the human Rheumatoid Arthritis (RA) and Multiple Sclerosis (MS), we could confirm the importance of decreased ROS production in development of autoimmunity. This was validated by identification of a mouse Ncf1 mutation that also decreased ROS production and resulted in enhanced arthritis. In addition, we found that T cell reactivity was altered in animals with impaired ROS production, presumably through interaction with antigen presenting cells. We found that the redox level on T cell membranes was the determinant for arthritogenicity. Interestingly, we could also reverse the genetic effect by administrate NADPH oxidase activating oils into rats, thereby preventing and ameliorating disease. This is promising as these findings provide a novel pathway to target therapeutically in complex inflammatory diseases. In summary, this thesis describes a pathway in the pathology of arthritis and encephalomyelitis that reveals a new way to treat autoimmunity

Genetics of autoimmune diseases: a multistep process.

Abstract in UndeterminedIt has so far been difficult to identify genes behind polygenic autoimmune diseases such as rheumatoid arthritis (RA), multiple sclerosis (MS), and type I diabetes (T1D). With proper animal models, some of the complexity behind these diseases can be reduced. The use of linkage analysis and positional cloning of genes in animal models for RA resulted in the identification of one of the genes regulating severity of arthritis in rats and mice, the Ncf1 gene. The Ncf1 gene encodes for the Ncf1 protein that is involved in production of free oxygen radicals through the NADPH oxidase complex, which opens up a new pathway for therapeutic treatment of inflammatory diseases. in most cases, however, a quantitative trait locus (QTL) is the sum effect of several genes within and outside the QTL, which make positional cloning difficult. Here we will discuss the possibilities and difficulties of gene identification in animal models of autoimmune disorders

Samtalsgruppers inverkan i den äldres vardag

Sammanfattning Bakgrund: Att känna social gemenskap är ett mänskligt behov. Studier visar att äldre personer på särskilda boenden upplever ensamhet. Röda Korset anordnarsamtalsgrupper på särskilda boenden där meningen är att bryta ensamheten för den äldre personen. Syfte: Belysa samtalsgrupper på ett särskilt boende och dess inverkan för den äldre personen i dennes vardag med särskilt fokus på det sociala livet. Metod: Kvalitativ intervjustudie, med innehållsanalys inspirerad av Graneheim och Lundmans (2004) sammanfattning. Resultat: De tre kategoriersom identifierades i intervjuerna var vikten av ett socialt liv, kommunikation och ett avbrott i vardagen. De äldre personer som deltar i samtalsgrupperna upplever att tillfällena med gruppen ger dem gemenskap och positiva känslor av att få delta i en social situation. De upplever dock inte detta tillräckligt då de känner en brist på kommunikation samt brist på social samvaro med andra till vardags. Slutsats:Samtalsgrupperna gör en positiv inverkan i den äldre personens vardag men är inte tillräckligt för att helt fylla det sociala behov deltagarna har

Ncf1 (p47phox) polymorphism determines oxidative burst and the severity of arthritis in rats and mice.

Identifying genes that regulate polygenic diseases influenced by the environment such as rheumatoid arthritis (RA), has so far proven to be difficult. By using an alternative approach, i.e., linkage analysis using relevant animal models we succeeded in finding the Ncf1 gene residing in the Pia4 quantitative trait locus to be responsible for the severity of pristane induced arthritis in rats. The influence of another mutation in the mouse Ncf1 gene showed the same association between decreased oxidative burst and enhanced arthritis. In this case the mutation affected a splice site giving a non-detectable oxidative burst response and enhanced collagen induced arthritis as well as myelin oligodendrocyte protein induced experimental autoimmune encephalomyelitis. These findings open up new possibilities for new treatments for autoimmune diseases, i.e., RA, targeting the NADPH oxidase pathway

Samtalsgruppers inverkan i den äldres vardag

Sammanfattning Bakgrund: Att känna social gemenskap är ett mänskligt behov. Studier visar att äldre personer på särskilda boenden upplever ensamhet. Röda Korset anordnarsamtalsgrupper på särskilda boenden där meningen är att bryta ensamheten för den äldre personen. Syfte: Belysa samtalsgrupper på ett särskilt boende och dess inverkan för den äldre personen i dennes vardag med särskilt fokus på det sociala livet. Metod: Kvalitativ intervjustudie, med innehållsanalys inspirerad av Graneheim och Lundmans (2004) sammanfattning. Resultat: De tre kategoriersom identifierades i intervjuerna var vikten av ett socialt liv, kommunikation och ett avbrott i vardagen. De äldre personer som deltar i samtalsgrupperna upplever att tillfällena med gruppen ger dem gemenskap och positiva känslor av att få delta i en social situation. De upplever dock inte detta tillräckligt då de känner en brist på kommunikation samt brist på social samvaro med andra till vardags. Slutsats:Samtalsgrupperna gör en positiv inverkan i den äldre personens vardag men är inte tillräckligt för att helt fylla det sociala behov deltagarna har