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Muller S.,CNRS Immunopathology and Therapeutic Chemistry | Radic M.,University of Tennessee Health Science Center
Clinical Reviews in Allergy and Immunology | Year: 2015

The conversion of an arginine residue in a protein to a citrulline residue, a reaction carried out by enzymes called peptidylarginine deiminases (PADs), is rather subtle. One of the terminal imide groups in arginine is replaced by oxygen in citrulline, thus resulting in the loss of positive charge and the gain of 1 dalton. This post-translational modification by PAD enzymes is conserved in vertebrates and affects specific substrates during development and in various mature cell lineages. Citrullination offers a unique perspective on autoimmunity because PAD activity is stringently regulated, yet autoantibodies to citrullinated proteins predictably arise. Autoantigens recognized by anti-citrullinated protein antibodies (ACPA) include extracellular proteins such as filaggrin, collagen II, fibrinogen, and calreticulin; membrane-associated proteins such as myelin basic protein; cytoplasmic proteins such as vimentin and enolase; and even nuclear proteins such as histones. Some ACPA are remarkably effective as diagnostics in autoimmune disorders, most notably rheumatoid arthritis (RA). Several ACPA can be observed before other clinical RA manifestations are apparent. In patients with RA, ACPA may attain a sensitivity that exceeds 70 % and specificity that approaches 96–98 %. The biological context that may account for the induction of ACPA emerges from studies of the cellular response of the innate immune system to acute or chronic stimuli. In response to infections or inflammation, neutrophil granulocytes activate PAD, citrullinate multiple autoantigens, and expel chromatin from the cell. The externalized chromatin is called a neutrophil extracellular “trap” (NET). Citrullination of core and linker histones occurs prior to the release of chromatin from neutrophils, thus implicating the regulation of citrullinated chromatin release in the development of autoreactivity. The citrullination of extracellular autoantigens likely follows the release of NETs and associated PADs. Autoantibodies to citrullinated histones arise in RA, systemic lupus erythematosus, and Felty’s syndrome patients. The citrullination of linker histone H1 may play a key role in NET release because the H1 histone regulates the entry and exit of DNA from the nucleosome. Juxtaposition of citrullinated histones with infectious pathogens and complement and immune complexes may compromise tolerance of nuclear autoantigens and promote autoimmunity. © 2014, Springer Science+Business Media New York. Source

Jeltsch-David H.,CNRS Immunopathology and Therapeutic Chemistry | Muller S.,CNRS Immunopathology and Therapeutic Chemistry
Autoimmunity Reviews | Year: 2014

Mouse models of autoimmunity, such as (NZB. ×. NZW)F1, MRL/MpJ-Fas. lpr (MRL-. lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models that adequately mimic human autoimmune diseases exist. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease that requires to be better understood at the mechanistic level emerge. This is the case of neuropsychiatric (NP) events that affect 50-60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-. lpr female mice, can be used for studying the pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics. © 2014 The Authors. Source

Schall N.,CNRS Immunopathology and Therapeutic Chemistry | Muller S.,CNRS Immunopathology and Therapeutic Chemistry
Lupus | Year: 2015

Over the last decade there has been a rapid expansion in the use of peptides as drugs. Nowadays, they are being used therapeutically in such diverse areas as endocrinology, neurology, haematology and some types of allergies. In the field of autoimmunity, a few candidates have emerged. Thus, in the pipeline of novel strategies designed to treat patients with systemic lupus erythematosus, the 21-mer peptide P140/Lupuzor raises hopes for the generation of an efficient, specific and safe treatment. This phosphopeptide has successfully completed a phase IIb clinical trial and will enter into a multi-centre, double-blind, placebo-controlled phase III clinical trial. The phase IIb trial showed that after three months of therapy (three subcutaneous injections of 200-μg peptide/patient in addition to standard of care), Lupuzor improved Systemic Lupus Erythematosus Disease Activity Index score of lupus patients under active treatment by 67.6% versus 41.5% in the placebo group (p-<-0.025). After three additional months of follow-up, the improvement rate was 84.2% versus 45.8% (p-<-0.025). The side-effect profile was unproblematic and the drug was well tolerated as evidenced by a very low drop-out rate. P140 does not behave as an immunosuppressant, it acts primarily as a fine immunomodulator of autoreactive CD4+ T cells. Its underlying mechanism of action involves autophagy, a cellular process that implicates lysosomal-dependent recycling of intracellular components and controls the pool of major histocompatibility complex class II-displayed peptides that is presented to CD4+ T cells. © The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav. Source

Muller S.,CNRS Immunopathology and Therapeutic Chemistry | Wallace D.J.,Cedars Sinai Medical Center
Lupus | Year: 2014

Peptide therapeutics hold attractive potential. However, the proper stabilization of such therapeutics remains a major challenge. Some peptides are marginally stable and are prone to degradation. Therefore, in addition to chemical modifications that can be introduced in their sequence, a wide variety of excipients are added in the formulation to stabilize them, as is also done routinely for protein therapeutics. These substances are supposed to suppress peptide/protein aggregation and surface adsorption, facilitate their dispersion and additionally to provide physiological osmolality. Particular attention has to be paid to the choice of such excipients. Here we highlight the observation that in certain clinical situations, an excipient that is not totally inert can play a highly damaging role and mask (or even reverse) the beneficial effect of a molecule in clinical evaluation. This is the case, for instance, of trehalose, a normally safe excipient, which notably has proven to act as an activator of autophagy. This excipient, although used efficiently in several therapeutics, adversely impacted a phase IIb clinical trial for human and murine lupus, a systemic autoimmune disease in which it has been recently discovered that at the base line, autophagy is already abnormally enhanced in lymphocytes. Thus, in this particular pathology, while the peptide that was tested was active in lupus patients when formulated in mannitol, it was not efficient when formulated in trehalose. This observation is important, since autophagy is enhanced in a variety of pathological situations, such as obesity, diabetes, certain neurological diseases, and cancer. © The Author(s), 2014. Source

Jeltsch-David H.,CNRS Immunopathology and Therapeutic Chemistry | Muller S.,CNRS Immunopathology and Therapeutic Chemistry
Nature Reviews Neurology | Year: 2014

Systemic lupus erythematosus (SLE) is a complex clinical syndrome, elements of which remain poorly understood. Although recognized over 140 years ago when Kaposi recorded the systemic nature and manifestations of the disease, CNS involvement represents one of the least understood aspects of SLE. This knowledge gap remains despite the fact that up to 75% of adults and children with SLE will, at some point over the course of the disease and to different extents, experience the various disabling effects of neuropsychiatric SLE (NPSLE). Indeed, after decades of research, our understanding of the underlying pathophysiology of NPSLE, in particular, remains limited. Numerous factors contribute to the immune dysfunction that occurs in SLE, including genetic, environmental and hormonal influences, and the contributory or predisposing components that lead to neurological tropism of disease in some patients have not been clearly demonstrated. Features of NPSLE pathogenesis that might be directly linked to clinical manifestations have been identified; however, the complexity and variety of NPSLE symptoms and the clinical overlap with other psychiatric disorders continue to make accurate diagnosis difficult and time-consuming. Thus, efforts to define biomarkers of NPSLE are needed to improve prediction of disease outcomes and guide treatment. In this article, we review the manifestation and pathogenesis of NPSLE, focusing on the features that might aid identification of potential biomarkers. © 2014 Macmillan Publishers Limited. All rights reserved. Source

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