T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy

Alessandri, Cristiano; Barbati, Cristiana; Vacirca, Davide; Piscopo, Paola; Confaloni, Annamaria; Sanchez, Massimo; Maselli, Angela; Colasanti, Tania; Conti, Fabrizio; Truglia, S.; Perl, András; Valesini, Guido; Malorni, Walter; Ortona, Elena; Pierdominici, Marina

doi:10.1096/fj.12-206060

Cited by 137 publications

(127 citation statements)

References 62 publications

(84 reference statements)

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“…[16][17][18] This deregulation could contribute to autoreactive T-cell survival and can be put in line with the deregulation of both macroautophagy and chaperone-mediated autophagy (CMA) in B cells that has been recently described to occur in lupus. 19,20 To date, however, these data remain correlative and no study has been published describing an in vivo model, prone to systemic autoimmunity, with specific autophagy deletion in B cells.…”

mentioning

confidence: 71%

Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

Arnold¹,

Murera²,

Arbogast³

et al. 2015

Cell Death Differ

101

113

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To gain new insight into the role of B-cell autophagy, we generated two novel mouse models deficient for the autophagy-related gene (Atg)5, one from the outset pro-B cell stage (Atg5 f/ − Mb1 cre) and the other in mature B cells only (Atg5 f/ − CD21 cre). We show that autophagy is dispensable for pro-to pre-B cell transition, but necessary at a basal level to maintain normal numbers of peripheral B cells. It appears non-essential for B-cell activation under B-cell receptor stimulation but required for their survival after lipopolysaccharide stimulation that drives plasmablast differentiation and for specific IgM production after immunization. Results obtained using Atg5 f/ − CD21 cre × C57BL/6 lpr/lpr autoimmune-prone mice show that B-cell autophagy is involved in the maintenance of anti-nuclear antibody secretion, elevated number of long-lived plasma cells, and sustains IgG deposits in the kidneys. Thus, treatments specifically targeting autophagy might be beneficial in systemic autoimmune diseases. Cell Death and Differentiation (2016) 23, 853-864; doi:10.1038/cdd.2015 published online 20 November 2015 Macroautophagy is a catabolic process allowing the degradation of cytoplasmic material in double membrane vesicles, ultimately fusing with lysosomes. Macroautophagy, initially implicated in the generation of nutrients under metabolic stress, is known to have multiple roles, in different physiologic compartments, such as in vacuole trafficking, cell signalling, and cell death. Macroautophagy is deeply involved in the regulation of immunity.1 It has been shown that autophagy can regulate inflammation related to inflammasome activation and to type I interferon secretion. Moreover, it contributes to antigen presentation by both major histocompatibility complex (MHC) class I and class II molecules. 2Macroautophagy is also tightly linked to lymphocyte activation and survival. It has central roles in T-cell basal homeostasis, survival, and polarization.3 It is also involved in the regulation of T-cell signalling by downregulating the NF-κB pathway 4 and apoptosis processes through the procaspases 3 and 8 degradation. 5 Macroautophagy has additionally been described to regulate B-cell lineage, in particular during B-cell development. Thus, it has been shown that B cells generated from fetal liver chimaeras, with a complete deletion of the essential autophagy-related gene (Atg)5, exhibited a block at the proto pre-B stage transition.6,7 However, as the genetic deletion is systemic and occurs very early during development, the question remains over whether the developmental blockade could be due to defects resulting from early haematopoietic development. Indeed, macroautophagy has been shown to be fundamental to haematopoietic stem cell survival and renewal.8 Moreover, conditional deletion of Atg5 under the control of CD19 promoter expressed from the pre-B stage does not lead to major developmental breaks, except a decrease in B-1a B-cell population. 6 The contrast with results obtained with chimaeric mice could be due...

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mentioning

confidence: 71%

Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

Arnold¹,

Murera²,

Arbogast³

et al. 2015

Cell Death Differ

101

113

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“…C'est le cas de l'hydroxychloroquine, utilisée en routine, ou la rapamycine et le peptide P140 [45,46] qui sont en essais cliniques. De plus, l'autophagie est dérégulée dans les LT, dans des modèles murins de lupus, et chez les patients atteints de LED [28,[47][48][49]. Les LT de ces patients présentent une charge en autophagosomes plus importante que des LT de sujets sains [47].…”

Section: Autophagie Des Lymphocytes Et Physiopathologieunclassified

L’autophagie et l’homéostasie des lymphocytes T et B

et al. 2016

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“…The alteration of mitophagy leads to defective clearance of mitochondria and formation of megamitochondria [55]. Another research showed that T lymphocytes from lupus patients were resistant to autophagic induction and presented up-regulation of genes which negatively regulate autophagy [57]. It suggests that autophagy-resistant T lymphocytes could be selected because of chronic exposure to specific antibodies in SLE.…”

Section: Autophagy In Rheumatic Diseases Systemic Lupus Erythematosusmentioning

confidence: 99%

Pathogenic Role of Autophagy in Rheumatic Diseases

Choi

Yoo

2016

J Rheum Dis

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Autophagy is a principle catabolic process mediated by lysosomes in eukaryotic cells. This is an intracellular homeostatic mechanism crucial for degradation in acidic lysosomal compartments of waste components from the cytoplasm. Autophagy research was initially focused on its degradation mechanism, but focus is now shifting to its effects on immunity. It contributes to detection and removal of pathogens as well as regulation of inflammasomes and neutrophil extracellular traps. Moreover, it is pivotal in antigen presentation and immune cell maturation, survival and homeostasis. The importance of autophagic pathways in normal and dysregulated immunity has become increasingly recognized in the past several years. Dysregulation of the autophagic pathway is implicated in the pathogenesis of several rheumatic diseases. In this review, we summarize the immunological function of autophagy in innate and adaptive immunity, and the functions of autophagy in the pathogenesis of rheumatic diseases. (J Rheum Dis 2016;23:202-211)

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T lymphocytes from patients with systemic lupus erythematosus are resistant to induction of autophagy

Cited by 137 publications

References 62 publications

Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

Autophagy is dispensable for B-cell development but essential for humoral autoimmune responses

L’autophagie et l’homéostasie des lymphocytes T et B

Pathogenic Role of Autophagy in Rheumatic Diseases

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