El papel del microbioma humano en las enfermedades autoinmunes

With the advent of new diagnostic techniques for microbiological identification, there has been new and growing interest in the relationship between the intestinal microbiome and the development of inflammatory and autoimmune disorders as well as other pathologies. There is a complex relationship between commensal bacteria and host cells, whose delicate balance is threatened by several external factors. The study of the composition and exact proportion of these microorganisms in sick patients compared to healthy controls is aimed at finding therapeutic alternatives for diseases whose definite cure remains unknown. In this paper, we review the most recent studies related to the association between the human microbiome and rheumatologic diseases.En los últimos años y gracias a nuevas técnicas diagnósticas de identificación microbiológica, ha cobrado importancia el estudio de la asociación de la composición bacteriana intestinal y el desarrollo posterior de enfermedades inflamatorias, del sistema inmunológico y otras. Se trata de una relación compleja entre las bacterias comensales y las células del huésped, cuyo delicado equilibrio se ve amenazado por diversos factores externos. El estudio de la composición y proporción exacta de estos microorganismos en pacientes enfermos en comparación con individuos sanos, tiene como objetivo último el poder encontrar alternativas terapéuticas a patologías que hoy no tienen una cura definitiva. En este trabajo se pretende hacer una revisión de los más recientes estudios sobre la asociaciónde las alteraciones en el microbioma humano y las enfermedades autoinmunes más frecuentes

Anti-TNF alpha active immunization is effective in chronic established inflammatory disease: long term study in a TNFalpha transgenic model of arthritis

Premesse: L\u2019immunoterapia passiva contro la citochina proinfiammatoria tumor necoris factor alfa (TNFa) con anticorpi monoclonali o recettori solubili ha dimostrato la sua efficacia nelle malattie infiammatorie croniche, come l\u2019artrite reumatoide; tuttavia una percentuale consistente di pazienti mostra una resistenza primitiva o secondaria a questi trattamenti, i cui costi sanitari sono peraltro molto elevati. Fra le strategie alternative per bloccare il TNFa vi \ue8 l\u2019immunoterapia attiva (vaccinazione ) anti-TNFa. Questo lavoro mira a dimostrare l\u2019efficacia terapeutica e a studiare le conseguenze a lungo termine della vaccinazione anti-TNFa nel modello di artrite sperimentale del topo transgenico per il TNFa umano (TTg), che sviluppa un\u2019artrite spontanea a partire dalle 8 settimane di et\ue0 Materiali e Metodi: i topi TTg sono stati immunizzati con un eterocomplesso TNF\u3b1- enocianina di keyhole limpet detto ChinoideTNF\u3b1, dopo lo sviluppo dell\u2019artrite. Le artriti sono state valutate sul piano clinico ed istologico e i titoli e la capacit\ue0 neutralizzante degli anticorpi anti-TNF\u3b1 mediante metodica ELISA e L929 rispettivamente. Risultati: I topi immunizzati con ChinoideTNF\u3b1 hanno mostrato un drammatico miglioramento dell\u2019artrite rispetto ai topi di controllo. Fra le settimane 27 e 45 i topi immunizzati mostrarono un aggravamento dell\u2019artrite e una parallela diminuzione del titolo di anticorpi anti-TNF\u3b1. Una dose di richiamo di ChinoideTNF\u3b1 invert\uec l\u2019aggravamento clinico incrementando il titolo di anticorpi anti-TNF\u3b1. Alla settimana 45 l\u2019istologia conferm\uf2 la minore progressione dell\u2019artrite nei topi immunizzati con il ChinoideTNF\u3b1. L\u2019iniezione di TNF\u3b1 umano non complessato nel chinoide non fu in grado di indurre una risposta contro il TNF\u3b1 nei topi immunizzati Conclusioni L\u2019immunizzazione attiva (vaccinazione ) contro il TNF\u3b1 umano mediante ChinoideTNF\u3b1 dimostra un\u2019efficacia terapeutica duratura ma reversibile in un modello di artrite gi\ue0 sviluppata, ponendo le basi per una potenziale applicazione nella patologia umana.Background. . Passive blockade of Tumor Necrosis Factor \u3b1 (TNF-\u3b1) has demonstrated high therapeutic efficacy in chronic inflammatory diseases, such as Rheumatoid Arthritis (RA), although some concerns remain such as occurrence of resistance and high cost. These limitations prompted investigations of an alternative strategy to target TNF-\u3b1. This study sought to demonstrate a long-lasting therapeutic effect on established arthritis of an active immunotherapy to human (h) TNF-\u3b1, and to evaluate the long-term consequences of an endogenous anti-TNF-\u3b1 response. Methods. hTNF-\u3b1 transgenic (TTg) mice, which spontaneously develop arthritis from 8 weeks of age, were immunized with a heterocomplex (TNF-K) composed of hTNF-\u3b1 and Keyhole Limpet Hemocyanin (KLH), after the disease onset. We evaluated arthritides by clinical and histological assessment, and titers of neutralizing anti-hTNF\u3b1 antibody by ELISA and L929 assay. Results. Arthritides were dramatically improved compared to control mice at week 27. TNF-K treated mice exhibited high levels of neutralizing anti-hTNF-\u3b1 antibodies. Between weeks 27 and 45, all immunized mice exhibited symptoms of clinical deterioration, and a parallel decrease in anti-hTNF-\u3b1 neutralizing antibodies. A maintenance dose of TNF-K reversed the clinical deterioration and increased the anti-hTNF-\u3b1 antibody titer. At 45 weeks TNF-K long-term efficacy was confirmed by low clinical and mild histological scores for the TNF-K treated mice. Injections of unmodified hTNF-\u3b1 did not induce a recall response to hTNF-\u3b1 in TNF-K immunized mice. Conclusions. Anti-TNF-\u3b1 immunotherapy with TNF-K has a sustained but reversible therapeutic efficacy in an established disease model, supporting the potential suitability of this approach in treating human disease

Les anticorps monoclonaux dans les maladies immunes inflammatoires chroniques

Les maladies inflammatoires chroniques, polyarthrite rhumatoïde, spondylarthrite ankylosante, lupus érythémateux systémique, psoriasis, maladie de Crohn, ou sclérose en plaques, ont en commun l’implication de cytokines proinflammatoires dans les manifestations systémiques et articulaires. Ces molécules constituent autant de cibles pour le développement de molécules antagonistes thérapeutiques, dont les anticorps monoclonaux (Acm). La polyarthrite rhumatoïde est à ce titre emblématique puisqu’elle représente le premier exemple de maladie non cancéreuse dans laquelle un Acm thérapeutique dirigé contre le TNFα (tumor necrosis factor alpha) a été utilisé. Depuis, d’autres Acm ont été proposés, ciblant d’autres cytokines, ou depuis récemment, les cellules effectrices immunes et leurs voies de communication, dont les lymphocytes T. Si un bénéfice à long terme de tels traitements est souvent acquis, il doit être confronté à l’évaluation d’autres paramètres comme le risque infectieux, la hiérarchie d’utilisation par rapport aux autres thérapeutiques disponibles, ou encore leur coût

Corneal and scleral involvement in inflammatory rheumatic disease: Rheumatologists and ophthalmologists exchanging views

International audienc

Could omega-3 fatty acids prevent rheumatoid arthritis?

International audienceRheumatoid arthritis (RA) is a systemic inflammatory disease in which both genetics and environment play a role. Diet is an environmental factor that has been studied in other inflammatory conditions [1], [2], [3]. Particularly, omega-3 essential fatty acids (omega-3 FA) have been found to have a suppressive action on inflammation and are thought to modulate immune response [4], [5], [6]. New data showed that omega-3 FA may also interfere in the pathophysiology of rheumatoid arthritis, namely in the steps that lead from the pre-clinical phase to established disease, which may open new perspectives for the prevention of this disease

Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

Tumor necrosis factor-alpha (TNF-α) blockade is an effective treatment for rheumatoid arthritis (RA) and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi) composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA) as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept