Autophagy: A new concept in autoimmunity regulation and a novel therapeutic option
Introduction
Autoimmunity occurs in all of us at a harmless level. It corresponds to a “normal” component of the general immune response able to build up an arsenal of potent cellular and molecular tools to destroy an infectious agent, to wipe tumor cells out or to eliminate abnormal (non-self) cellular or tissue constituents. This “natural” autoimmunity is therefore a first barrier to protect the organism from internal and external danger [1]. Above a certain limit of “basal” response, however, abnormal immune reactions can develop against individual's own healthy cells, tissues and organs. The activating factors that are involved in this misdirected and excessive responses can be linked to internal (genetic predisposition, metabolism dysfunction, hormonal changes) or external (pollution, diet, infections, smoke) elements. The threshold above which the organism can eventually generate autoimmune symptoms is not a pre-set activity limit. It is highly individual, but this limit is likely lowered in genetically-predisposed families where it is not rare to observe several sick propositi. Early development of autoimmunity is usually imperceptible, but this status become quite real when in patients, a phenotypically blatant autoimmune disease appears. This process is long to establish and progresses with periodic fluctuations in certain settings. Some molecular and cellular indicators already appear in the very first phases of the still clinically silent process [2,3], but in general, they are not noticed since apart from exception (e.g. familial context), these markers are not systematically searched.
The US National Institute of Health (NIH) estimates up to 23.5 million American are affected by an autoimmune disease. Other Organisms publish some figures that are close to 50 million patients just in the US, in integrating more diseases. Around 80–100 different autoimmune diseases have been identified (24 officially listed by NIH) but others are suspected. In general, autoimmune diseases are chronic and can present a wide spectrum from subclinical to life-threatening disorders. They affect more women than men.
Due to the diversity and complexity of autoimmune diseases, emergence of potent targeted therapeutics is slow. Even a clear diagnosis has been posed, for example in some cases of systemic lupus erythematosus (SLE), multiple sclerosis (MS) or Crohn's disease (CD), the symptoms can be variable (in a list of possible criteria) and unpredictable in affected patients. In addition, patients can cumulate several autoimmune diseases, as for example Sjögren's syndrome (SjS) and SLE or rheumatoid arthritis (RA), or inflammatory bowel diseases (IBDs) and SLE. A better knowledge of fundamental aspects involved in the loss of tolerance of immune functions in these patients and above all, a finer understanding of the elements prevailing in the tropism of organs, tissues or cells that are affected in individual persons, are central in our quest of adapted specific treatments, which would target the causes and not the symptoms of these complex disorders.
Section snippets
Current strategies applied to treat autoimmune diseases
In contrast to diseases as infections or cancer in which the challenge aims at eliminating or eradicating a foreign or transformed invader (virus, bacteria, parasites, tumor cells), the objectives pursued in autoimmune settings aims at immunomodulating the immune system, which over-responds to antigens, and this without destroying its protecting resources. Until now, however, most of the efficient drugs are immunosuppressants that alter the whole immune system without discerning the “good” and
Targeted therapies under clinical developments for autoimmune diseases
In the panel of new strategies developed to generate more potent and specific drugs to treat autoinflammatory diseases, most of them are directed to cell-surface molecules, the expression of which is pathologically elevated in B lymphocytes and/or plasma cells, T cells, plasmacytoid dendritic cells or other key cells [36] (Table 1; [[100], [101], [102], [103], [104], [105], [106], [107], [108], [109], [110], [111], [112], [113], [114], [115], [116], [117], [37], [38], [39], [40], [41], [42],
Autophagy in autoimmune diseases
Autophagy is a vital catabolic process in which cells degrade self-content through lysosomes [[166], [167], [168]]. There are several forms of autophagy, depending on the substrates (cargos) that are engaged and processed and, on the formation, or not of double-membrane vesicles. The most prominent autophagic pathway is macroautophagy, in which double-membrane autophagosomes are formed around a portion of cytosol and its content, which thus remain included within these vesicles before being
Modulators of autophagy and their applications for controlling autoimmune diseases
A number of activators and inhibitors of autophagy have been described (Fig. 2) [166,190,[216], [217], [218], [219], [220], [221]]. On almost all cases, their fine specificity is not known. Few of them, if any, interact with one single target of a specific autophagic process (e.g. CMA, mitophagy, others). A number of limitations still hamper their development as druggable compounds [166] but recent progresses lead us to envisage that strategies based on autophagy as therapeutic target might
The P140 peptide, an inhibitor of autophagy that reduces clinical symptoms in autoinflammatory diseases
The U1-70 K small nuclear ribonucleoprotein protein is one of the major spliceosomal autoantigen recognized in lupus and mixed connective tissue disease. This nuclear protein plays eminent role in the recognition of the pre-mRNA 5′ splice-site and the subsequent assembly of the spliceosome. By testing a series of overlapping peptides covering the whole protein, we identified an epitope in residues 131–151 present within the RNA recognition motif of the protein. We found that this antigenic
Final conclusions and perspectives
The force of therapeutic strategies as the one we shortly describe with P140 peptide comes from the fact that they target a precise cellular mechanism, the activity of which is altered in pathophysiological context. This notion is central to avoid a general weakening of immune system, with all the adverse effects that it creates. In this setting, modulating the autophagic activity seems a target of choice as autophagy is implicated in various metabolic pathways that are central for the
Take-home messages
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Autophagy, a central mechanism that delivers cytoplasmic material and organelles to lysosomes for degradation is often deregulated in autoinflammatory diseases.
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Therapeutic targeting of autophagy processes might be a target of choice to immunoregulate immunologic diseases.
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As there is an intense crosstalk between autophagy and virtually most of the survival/death pathways of the cell, designing selective molecules that correct autophagy defects is of prime importance.
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The P140 peptide directly
Conflicts of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could construed as a potential conflict of interest.
Author contribution
All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication.
Acknowledgments
This research was funded by the French Centre National de la Recherche Scientifique, Région Alsace, the Laboratory of Excellence Medalis (ANR-10-LABX-0034), Initiative of Excellence (IdEx), Strasbourg University, and ImmuPharma France. SM is most grateful to the University of Strasbourg Institute for Advanced Study (USIAS) for funding FW and acknowledges the support of the TRANSAUTOPHAGY COST Action, CA15138 and the Club francophone de l'autophagie (CFATG).
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