Editorial
Autoimmune flares. The hows, whens, and whys of killing
Cómo, cuando y por qué matar durante los brotes en las enfermedades autoinmunes
Olga Sánchez-Pernaute
Rheumatology Division, Unit for Autoimmune Diseases, IIS-Fundación Jiménez Díaz University Hospital, Avda Reyes Católicos 2, 28040 Madrid, Spain
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The hows, whens, and whys of killing" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "1" "paginaFinal" => "2" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Olga Sánchez-Pernaute" "autores" => array:1 [ 0 => array:3 [ "nombre" => "Olga" "apellidos" => "Sánchez-Pernaute" "email" => array:1 [ 0 => "osanchez@fjd.es" ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Rheumatology Division, Unit for Autoimmune Diseases, IIS-Fundación Jiménez Díaz University Hospital, Avda Reyes Católicos 2, 28040 Madrid, Spain" "identificador" => "aff0005" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Cómo, cuando y por qué matar durante los brotes en las enfermedades autoinmunes" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Autoimmune diseases are globally regarded as a consequence of the loss of tolerance against self-antigens. This view has guided our therapeutic efforts to increase the auto-reactive threshold using immunosuppressive drugs. This editorial aims at discussing the strategies to treat autoimmune flares from a different perspective, and in the light of recent molecular insights.</p><p id="par0010" class="elsevierStylePara elsevierViewall">At present, the capacity of immunosuppressive drugs to maintain remission in autoimmune conditions is unquestioned. However, during flares of activity there is a completely different scenario, under which our first goal should probably be to kill over-reactive cells. This is because positive selected immune cells cannot easily be switched off, unless they are forced to die. It is, therefore, understandable that cytostatic agents, typically cyclophosphamide, yield so good results dampening severe flares, even when used at low dose to reduce toxicity.<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In contrast, doses of “selective” immunosuppressive drugs required to kill cells can get unacceptably high, in many occasions failing to provide a safer alternative.<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">On the other hand, too much killing could be dangerous. As it happens, not all patients show a good response to the so-called induction therapies, and the line between success and toxicity is very thin. In addition, drug regimens are frequently applied according to fixed protocols, e.g. during an established period of time, although sometimes we really do not know at which point the patient ceases to benefit from the therapy and if it can be safely withdrawn. On the whole, it seems clear that there are two distinct stages of disease that need different approaches, but still we need to decipher mechanisms concurring during flares and find out when to stop cytostatic strategies.</p><p id="par0020" class="elsevierStylePara elsevierViewall">The more we learn about the innate defence system, the more it looks that it greatly contributes to spark the flares of autoimmune diseases. My colleagues at the clinic usually remind me that not all autoimmune deregulation can be explained by germs. However, these provide a fine model to learn what can be going on in our patients during flares. Furthermore, the pathways triggered by the engagement of innate receptors help understand the importance of cell death in shutting down the activation process. Essentially, the debate about presence or absence of inductor pathogens is not so relevant in itself, as far as we accept that the activation of immune cells closely resembles the one evoked by intracellular microorganisms.</p><p id="par0025" class="elsevierStylePara elsevierViewall">In order not to argue with my colleagues, let us consider that not germs in particular, but “perturbations inside immune cells” come to be detected by innate receptors. The latter will then trigger three types of responses: (1) the production of NF-kappaB driven pro-inflammatory genes, (2) the induction of type I interferons, and (3) the initiation of self-destruction programmes. These are straightforward mechanisms intended to erase the disturbing agent, create specific memory against future attacks and eliminate the igniting cell.<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> In this regard, the self-destruction programmes of the immune system are a most effective way to terminate the activating signals emitted by disturbed cells. In addition, they eradicate germs that have made a shelter out of the intracellular environment, which the immune cell confers. As a matter of fact, many intracellular pathogens have ideated the so-called immune evasion mechanisms to protect this shelter and remain in latency.<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> If the auto-destruction programmes fail, the carrier cell continues to struggle to get rid of the invader, in this manner adding more wood to the fire.</p><p id="par0030" class="elsevierStylePara elsevierViewall">This rationale challenges the concept of loss of tolerance, suggesting instead that patients with autoimmune diseases probably bear a paradoxical excessive tolerance to own cell internal perturbations. In other words, they could have problems to carry out the programmes designed to erase intracellular pathogens, or to alternatively get the carrier cells killed. All indicates that in autoimmune diseases, the perturbed cells live abnormally long, and so does the invader as well. In this setting, application of cytostatic drugs helps eradicate the niche and break the vicious circle.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Of course, the solution provided by cytostatic strategies is transient, as it is thereafter the immune system from the host, which should add up for a favourable outcome. In this regard, the ability of phagocytes to clear dead cells needs to be intact. Also to consider is the leakage of germs upon cell death and their capacity to resist at the extracellular space until they can find another niche. This means that lymphocytes should be ready to battle an overt infection. Hence, the importance to carefully design our therapies, in order to avoid increasing the patient's vulnerability. At this point, we should acknowledge the drawbacks of selective immunosuppressive drugs. If along with killing cells we add alterations to the normal function of lymphocytes, mechanisms of fighting microorganisms will be at stake. Perhaps, we should reconsider the use of therapies that potentially decrease natural killer (NK) functions, since in fact NK cells are trying to eliminate over-reactive cells and restore the balance.<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> In this sense, it is attractive to suggest that actual targets during flares are over- rather than auto-reactive cells, both populations being not necessarily coincident. Also to bear in mind is that therapies decreasing levels of secreted IgM could hamper the removal of apoptotic cells.<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Thus, not only our strategy might favour overt infections, but also the formation of autoantibodies to epitopes showing up during apoptosis.<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">Since we need to implement mechanisms that are failing and try not to touch those that are working well, we have to learn how and which cell death processes are taking place in a particular setting. Globally, death can be classified into necrosis, heterophagy, and autophagy. The two latter terms imply digestion of the cell components, which can result from apoptosis (first case) or from own programmed destruction, while necrosis is associated to changes in permeability, and cell swelling. All these processes take place in a tightly regulated manner, and an expanding family of death-related terms has emerged as a result of the identification of killing machinery. Among them, RIP-mediated necroptosis, parthanatos, oxytosis, ferroptosis, NETosis, pyronecrosis, or pyroptosis have been coined to underline particular aspects characterising the deadly pathways, as recently reviewed by Vande Berghe.<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">The surface receptor MHC class I related chain A (MICA) is induced by stress and intracellular pathogens and makes the cell visible for NK cells. Through the binding of MICA, NK cells help flagged cells undergo apoptosis.<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> This pathway is up-regulated by retinoid acid, a fact that has been advantageously translated to treat cancer. Inactivation of MICA is used as immune evasion system by some pathogens, such as cytomegalovirus,<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> which thus make sterile the efforts of NK cells to erase the infected cell. Interestingly, we have recently observed a suppression of MICA gene expression in peripheral blood mononuclear cells from a subgroup of patients with lupus.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> We are currently trying to decipher the underlying mechanism, but it appears that these patients show some kind of evasion strategy to NK surveillance, promoting the survival of perturbed mononuclear cells.</p><p id="par0050" class="elsevierStylePara elsevierViewall">Autophagy is a homeostatic cell programme that has attracted attention because of its participation in the elimination of intracellular altered products – or sources of intracellular disturbances. Autophagy involves fusion of late phagosomes with lysosomes and endosomal vesicles, and consists in a sequential process of digestion/degradation of unfolded proteins, microbiota, and stress-dependent damaged organelles. The vitamin D receptor pathway and the activation of IL-1β<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a> contribute to the successful progression of autophagy. It turns out that an efficient autophagy usually prolongs cell survival, arrests cell growth at G1, and protects cells from apoptosis. Studies conducted with rapamycin – an activator of autophagy – have shown that the cell growth arrest is responsible both for its antifungal activity and the tolerogenic effect on lymphocytes. In this sense, the integrity of this homeostatic process may not only make the over-activation subside, but rescue the cell as well, a fact that makes it look as a very promising pathway to modulate in autoimmunity.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Intriguingly, some available therapeutic compounds can directly or indirectly affect the progression of autophagy, including estrogens and chloroquine, as well as drugs of common use, such as metformin.</p><p id="par0055" class="elsevierStylePara elsevierViewall">It will take time to take full advantage of these processes at the bedside. First we would need to work out how the pieces fit together in each patient, so it would be necessary to find sensitive markers of the ongoing death pathways. We have already mentioned several candidates, although their utility in clinical practice has not been established so far. Between them, IL-1β appears as a master regulator of cytotoxicity and bactericidal activity. Soluble MICA has been found to act as a decoy receptor, so that its circulating levels could point to deficient NK functions. Important is the awareness of vitamin deficiencies since, as we have mentioned, both vitamin A derivates and 25-hydroxyvitamin D3 fuel regulatory death mechanisms. Our patients are especially prone to deficiencies of these vitamins, because they have been instructed into low-fat diets, the dread of intoxication, and sun protection. Finally, we could more frequently measure serum IgM levels, particularly in patients under B cell depleting strategies, to assess capacity of removal of apoptotic bodies.</p><p id="par0060" class="elsevierStylePara elsevierViewall">In summary, all through these pages, I have argued for killing instead of disarming the immune system. However, not to forget is the fact that cell death is a principal source of inflammation related accrued damage. Killing and rescue should be, therefore, conveniently mixed to protect cells from indirect inflammation-derived injury. I would like to stress the need to consider adjuvant therapies such as the aforementioned vitamins and antimicrobial prophylaxis, whenever we use pure immunosuppressive drugs.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0065" class="elsevierStylePara elsevierViewall">The current work from Dr. Olga Sánchez Pernaute is supported by a grant from the <span class="elsevierStyleGrantSponsor" id="gs1">Spanish Ministry of Health's Fondo de Investigaciones Sanitarias</span> (<span class="elsevierStyleGrantNumber" refid="gs1">FIS PI10/00377</span>).</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "F.A. 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| año/Mes | Html | Total | |
|---|---|---|---|
| 2024 Noviembre | 3 | 7 | 10 |
| 2024 Octubre | 62 | 34 | 96 |
| 2024 Septiembre | 54 | 18 | 72 |
| 2024 Agosto | 82 | 39 | 121 |
| 2024 Julio | 96 | 28 | 124 |
| 2024 Junio | 106 | 28 | 134 |
| 2024 Mayo | 90 | 25 | 115 |
| 2024 Abril | 81 | 28 | 109 |
| 2024 Marzo | 83 | 32 | 115 |
| 2024 Febrero | 52 | 37 | 89 |
| 2024 Enero | 57 | 19 | 76 |
| 2023 Diciembre | 58 | 34 | 92 |
| 2023 Noviembre | 56 | 27 | 83 |
| 2023 Octubre | 78 | 30 | 108 |
| 2023 Septiembre | 114 | 43 | 157 |
| 2023 Agosto | 98 | 20 | 118 |
| 2023 Julio | 56 | 27 | 83 |
| 2023 Junio | 58 | 29 | 87 |
| 2023 Mayo | 68 | 23 | 91 |
| 2023 Abril | 35 | 9 | 44 |
| 2023 Marzo | 73 | 28 | 101 |
| 2023 Febrero | 72 | 29 | 101 |
| 2023 Enero | 66 | 40 | 106 |
| 2022 Diciembre | 93 | 39 | 132 |
| 2022 Noviembre | 77 | 31 | 108 |
| 2022 Octubre | 86 | 52 | 138 |
| 2022 Septiembre | 72 | 41 | 113 |
| 2022 Agosto | 62 | 40 | 102 |
| 2022 Julio | 48 | 48 | 96 |
| 2022 Junio | 66 | 55 | 121 |
| 2022 Mayo | 73 | 53 | 126 |
| 2022 Abril | 106 | 49 | 155 |
| 2022 Marzo | 115 | 53 | 168 |
| 2022 Febrero | 98 | 31 | 129 |
| 2022 Enero | 85 | 63 | 148 |
| 2021 Diciembre | 69 | 46 | 115 |
| 2021 Noviembre | 49 | 55 | 104 |
| 2021 Octubre | 66 | 50 | 116 |
| 2021 Septiembre | 53 | 49 | 102 |
| 2021 Agosto | 33 | 44 | 77 |
| 2021 Julio | 33 | 36 | 69 |
| 2021 Junio | 55 | 51 | 106 |
| 2021 Mayo | 108 | 50 | 158 |
| 2021 Abril | 164 | 92 | 256 |
| 2021 Marzo | 99 | 43 | 142 |
| 2021 Febrero | 88 | 27 | 115 |
| 2021 Enero | 79 | 27 | 106 |
| 2020 Diciembre | 64 | 32 | 96 |
| 2020 Noviembre | 81 | 28 | 109 |
| 2020 Octubre | 65 | 20 | 85 |
| 2020 Septiembre | 83 | 29 | 112 |
| 2020 Agosto | 64 | 26 | 90 |
| 2020 Julio | 55 | 19 | 74 |
| 2020 Junio | 75 | 45 | 120 |
| 2020 Mayo | 74 | 16 | 90 |
| 2020 Abril | 53 | 23 | 76 |
| 2020 Marzo | 77 | 31 | 108 |
| 2020 Febrero | 74 | 22 | 96 |
| 2020 Enero | 65 | 20 | 85 |
| 2019 Diciembre | 78 | 46 | 124 |
| 2019 Noviembre | 62 | 22 | 84 |
| 2019 Octubre | 72 | 23 | 95 |
| 2019 Septiembre | 73 | 39 | 112 |
| 2019 Agosto | 47 | 29 | 76 |
| 2019 Julio | 59 | 22 | 81 |
| 2019 Junio | 34 | 19 | 53 |
| 2019 Mayo | 56 | 49 | 105 |
| 2019 Abril | 58 | 42 | 100 |
| 2019 Marzo | 44 | 36 | 80 |
| 2019 Febrero | 37 | 25 | 62 |
| 2019 Enero | 36 | 38 | 74 |
| 2018 Diciembre | 75 | 51 | 126 |
| 2018 Noviembre | 134 | 14 | 148 |
| 2018 Octubre | 94 | 9 | 103 |
| 2018 Septiembre | 46 | 12 | 58 |
| 2018 Agosto | 21 | 9 | 30 |
| 2018 Julio | 15 | 6 | 21 |
| 2018 Mayo | 4 | 1 | 5 |
| 2018 Abril | 49 | 7 | 56 |
| 2018 Marzo | 65 | 10 | 75 |
| 2018 Febrero | 27 | 3 | 30 |
| 2018 Enero | 13 | 6 | 19 |
| 2017 Diciembre | 29 | 11 | 40 |
| 2017 Noviembre | 31 | 8 | 39 |
| 2017 Octubre | 19 | 6 | 25 |
| 2017 Septiembre | 22 | 9 | 31 |
| 2017 Agosto | 25 | 9 | 34 |
| 2017 Julio | 24 | 15 | 39 |
| 2017 Junio | 27 | 10 | 37 |
| 2017 Mayo | 34 | 18 | 52 |
| 2017 Abril | 30 | 8 | 38 |
| 2017 Marzo | 33 | 11 | 44 |
| 2017 Febrero | 15 | 7 | 22 |
| 2017 Enero | 19 | 8 | 27 |
| 2016 Diciembre | 58 | 15 | 73 |
| 2016 Noviembre | 36 | 10 | 46 |
| 2016 Octubre | 42 | 12 | 54 |
| 2016 Septiembre | 32 | 4 | 36 |
| 2016 Agosto | 22 | 8 | 30 |
| 2016 Julio | 12 | 11 | 23 |
| 2016 Junio | 1 | 0 | 1 |
| 2016 Abril | 2 | 0 | 2 |
| 2016 Febrero | 1 | 0 | 1 |
| 2015 Diciembre | 2 | 0 | 2 |
| 2015 Noviembre | 1 | 23 | 24 |
| 2015 Octubre | 1 | 12 | 13 |
| 2015 Septiembre | 2 | 0 | 2 |
| 2015 Julio | 26 | 10 | 36 |
| 2015 Junio | 39 | 10 | 49 |
| 2015 Mayo | 68 | 19 | 87 |
| 2015 Abril | 90 | 33 | 123 |
| 2015 Marzo | 58 | 18 | 76 |
| 2015 Febrero | 147 | 63 | 210 |
| 2015 Enero | 231 | 89 | 320 |
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