Autophagy: highlighting a novel player in the autoimmunity scenario.

Autophagy is a physiological cellular mechanism that degrades and recycles proteins and other molecules to maintain an adequate amino acid level during nutritional starvation of the cell. Autophagy is involved in cellular homeostasis and differentiation, as well as in tissue remodeling, aging, cancer, and other diseases. Under particular environmental conditions, autophagy can also be a contributor to programmed cell death, or can act as a defense mechanism for the elimination of intracellular bacteria and viruses. According to recent experimental data, autophagy may be implicated in autoimmunity by promotion of major histocompatibility complex (MHC) class II presentation of cytosolic antigens and control of T lymphocyte homeostasis, and its induction by Th1 cytokines and perhaps by specific serum autoantibodies. We review herein the role of autophagy in immune function and its possible contribution to breakdown of tolerance and development of autoimmunity.

[1]  Kirsten Lauber,et al.  Clearance deficiency and systemic lupus erythematosus (SLE). , 2007, Journal of autoimmunity.

[2]  R. Gottlieb,et al.  The Interplay between Pro-Death and Pro-Survival Signaling Pathways in Myocardial Ischemia/Reperfusion Injury: Apoptosis Meets Autophagy , 2006, Cardiovascular Drugs and Therapy.

[3]  R. Coppel,et al.  Phylogenetic and immunological definition of four lipoylated proteins from Novosphingobium aromaticivorans, implications for primary biliary cirrhosis. , 2005, Journal of autoimmunity.

[4]  Melissa R. Jeddeloh,et al.  Identification of 2-nonynoic acid, a cosmetic component, as a potential trigger of primary biliary cirrhosis. , 2006, Journal of autoimmunity.

[5]  Kevin M. Ryan,et al.  DRAM, a p53-Induced Modulator of Autophagy, Is Critical for Apoptosis , 2006, Cell.

[6]  B. Levine,et al.  Cell biology: Autophagy and cancer , 2007, Nature.

[7]  A. Strawbridge,et al.  Autophagy in MHC class II antigen processing. , 2007, Current opinion in immunology.

[8]  S. Emr,et al.  Autophagy as a regulated pathway of cellular degradation. , 2000, Science.

[9]  J. Westwick,et al.  Activation of Phosphatidylinositol 3-Kinase by Interleukin-13 , 1997, The Journal of Biological Chemistry.

[10]  J. Chatham,et al.  IGF-I promotes a shift in metabolic flux in vascular smooth muscle cells. , 2002, American journal of physiology. Endocrinology and metabolism.

[11]  H. Rammensee,et al.  Autophagy promotes MHC class II presentation of peptides from intracellular source proteins , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[12]  Peter Walter,et al.  Autophagy Counterbalances Endoplasmic Reticulum Expansion during the Unfolded Protein Response , 2006, PLoS biology.

[13]  K. Hall,et al.  Serum from patients with type 2 diabetes with neuropathy induces complement-independent, calcium-dependent apoptosis in cultured neuronal cells. , 1998, The Journal of clinical investigation.

[14]  Takeshi Tokuhisa,et al.  The role of autophagy during the early neonatal starvation period , 2004, Nature.

[15]  Simon C Watkins,et al.  Autophagy Is Induced in CD4+ T Cells and Important for the Growth Factor-Withdrawal Cell Death1 , 2006, The Journal of Immunology.

[16]  L. Cantley,et al.  Ras, PI(3)K and mTOR signalling controls tumour cell growth , 2006, Nature.

[17]  Joo‐Hang Kim,et al.  Essential Roles of Atg5 and FADD in Autophagic Cell Death , 2005, Journal of Biological Chemistry.

[18]  S. Ikehara,et al.  Comparative immunobiology of thymic DC mRNA in autoimmune-prone mice. , 2007, Journal of autoimmunity.

[19]  A. Cuervo,et al.  A Receptor for the Selective Uptake and Degradation of Proteins by Lysosomes , 1996, Science.

[20]  Sudeshna Dutta,et al.  Autophagic programmed cell death by selective catalase degradation. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[21]  V. Deretic,et al.  Autophagy Is a Defense Mechanism Inhibiting BCG and Mycobacterium tuberculosis Survival in Infected Macrophages , 2004, Cell.

[22]  Ana Maria Cuervo,et al.  When lysosomes get old☆ , 2000, Experimental Gerontology.

[23]  J. Lohr,et al.  Balancing autoaggressive and protective T cell responses. , 2007, Journal of autoimmunity.

[24]  Hiroshi Sagara,et al.  Escape of Intracellular Shigella from Autophagy , 2005, Science.

[25]  M. Prescott,et al.  Different Fates of Mitochondria: Alternative Ways for Degradation? , 2007, Autophagy.

[26]  Ana Maria Cuervo,et al.  Autophagy: Many paths to the same end , 2004, Molecular and Cellular Biochemistry.

[27]  S. Hamada,et al.  Autophagy Defends Cells Against Invading Group A Streptococcus , 2004, Science.

[28]  G. Gores,et al.  T cell targeting and phagocytosis of apoptotic biliary epithelial cells in primary biliary cirrhosis. , 2006, Journal of autoimmunity.

[29]  L. Morel,et al.  Role of B-1a cells in autoimmunity. , 2006, Autoimmunity reviews.

[30]  B. Shapiro,et al.  The role of cytokine mRNA stability in the pathogenesis of autoimmune disease. , 2006, Autoimmunity reviews.

[31]  Delu Zhou,et al.  Lamp-2a facilitates MHC class II presentation of cytoplasmic antigens. , 2005, Immunity.

[32]  D. Agrawal,et al.  Insulin‐like growth factor‐1 and TNF‐α regulate autophagy through c‐jun N‐terminal kinase and Akt pathways in human atherosclerotic vascular smooth cells , 2006, Immunology and cell biology.

[33]  P. Codogno,et al.  Autophagy is involved in T cell death after binding of HIV-1 envelope proteins to CXCR4. , 2006, The Journal of clinical investigation.

[34]  M. Hall,et al.  TOR Signaling in Growth and Metabolism , 2006, Cell.

[35]  Craig B. Thompson,et al.  Role of Bcl-2 family proteins in a non-apoptotic programmed cell death dependent on autophagy genes , 2004, Nature Cell Biology.

[36]  D. Sabatini,et al.  Stress and mTORture signaling , 2006, Oncogene.

[37]  T. Tuschl,et al.  Endogenous MHC Class II Processing of a Viral Nuclear Antigen After Autophagy , 2005, Science.

[38]  S. Price,et al.  Suppression of chaperone-mediated autophagy in the renal cortex during acute diabetes mellitus. , 2004, Kidney international.

[39]  T. Noda,et al.  Starvation Triggers the Delivery of the Endoplasmic Reticulum to the Vacuole via Autophagy in Yeast , 2005, Traffic.

[40]  Hideyuki Okano,et al.  Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice , 2006, Nature.

[41]  Vojo Deretic,et al.  Autophagy as an immune defense mechanism. , 2006, Current opinion in immunology.

[42]  S. Korsmeyer,et al.  Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death , 2001, Science.

[43]  S. Fisher,et al.  A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. , 2007, Gastroenterology.

[44]  M. Pypaert,et al.  Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. , 2007, Immunity.

[45]  You-Wen He,et al.  A critical role for the autophagy gene Atg5 in T cell survival and proliferation , 2007, The Journal of experimental medicine.

[46]  P. Rovere-Querini,et al.  Environmental adjuvants, apoptosis and the censorship over autoimmunity. , 2005, Autoimmunity reviews.

[47]  B. Levine.  Eating Oneself and Uninvited Guests Autophagy-Related Pathways in Cellular Defense , 2005, Cell.

[48]  Y. Ueno,et al.  B cells and autoimmune liver diseases. , 2006, Autoimmunity reviews.

[49]  B. Lu,et al.  Autophagy Induction and Autophagic Cell Death in Effector T Cells , 2007, Autophagy.

[50]  S. Rodríguez-Enríquez,et al.  Selective degradation of mitochondria by mitophagy. , 2007, Archives of biochemistry and biophysics.

[51]  Daniel J Klionsky,et al.  Sera from patients with type 2 Diabetes and Neuropathy Induce Autophagy and Colocalization with Mitochondria in SY5Y cells , 2005, Autophagy.

[52]  Jacques Neefjes,et al.  Autophagy in MHC class II presentation: sampling from within. , 2007, Immunity.

[53]  M. Gershwin,et al.  The X and why of xenobiotics in primary biliary cirrhosis. , 2007, Journal of autoimmunity.

[54]  Francesco Scaravilli,et al.  Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease , 2004, Nature Genetics.

[55]  D. Owen,et al.  A novel protein expressed in mammalian cells undergoing apoptosis. , 1995, Experimental cell research.

[56]  D. Béchet,et al.  Leucine Limitation Induces Autophagy and Activation of Lysosome-dependent Proteolysis in C2C12 Myotubes through a Mammalian Target of Rapamycin-independent Signaling Pathway* , 2000, The Journal of Biological Chemistry.

[57]  Michael D. Schneider,et al.  Bcl-2 Antiapoptotic Proteins Inhibit Beclin 1-Dependent Autophagy , 2005, Cell.