Processing of proteins in autophagy vesicles of antigen-presenting cells generates citrullinated peptides recognized by the immune system

Ireland, Jamie M.; Unanue, Emil R.

doi:10.4161/auto.19261

Cited by 51 publications

(40 citation statements)

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“…12, 45) show that LCV-infected B cells have a central pathogenic role in the activation of highly pathogenic MHC-E-restricted effector memory cytotoxic T cells that, upon activation with the MOG34-56 peptide (core epitope [40][41][42][43][44][45][46][47][48], can elicit MS-like pathology and disease. Notably, similar autoaggressive CTLs were found in MS lesions, where they seemed to be engaged in cytotoxic interactions with HLA-E + oligodendrocytes (5).…”

Section: Discussionmentioning

confidence: 99%

“…Citrullination of antigenic peptides is a physiological process that can take place in autophagosomes of APCs (43). If citrullination of the encephalitogenic MOG34-56 peptide played any role in the conversion of destructive processing to productive processing of the MOG40-48 epitope in LCV-infected B cells, we would expect to observe induction of autophagy and concomitant induction of PAD enzymes by the virus.…”

Section: Autophagy Induction In Lcv-infected B Cellsmentioning

confidence: 99%

“…Although CatG of marmosets has a mouse-like narrow specificity for aromatic (chymotryptic) cleavage sites (Trp, Phe, Tyr), a double mutation in the specificity-determining residues (Ala-189-Ser and Glu-226-Ala) broadens the activity of rhesus monkey and human CatG to basic (tryptic) cleavage sites (e.g., Arg and Lys) (42). To test the proteolytic degradation of the pathogenically dominant Mm-MOG34-56 peptide we used the shorter peptide MOG35-51 to avoid interference of the Arg residue at position 52, which is outside the epitope of interest (residues [40][41][42][43][44][45][46][47][48]. The reported in vitro data show that native Mm-MOG35-51 peptide is rapidly degraded in cellfree lysates of noninfected and LCV infected B cells of rhesus monkeys as well as in LCV-infected B cells of marmosets.…”

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

“…Data obtained from mice show that the presence of a Pro or Ser residue on position 42 has a strong influence on the encephalitogenic potency of the MOG34-56 peptide (55). The Arg to Cit substitution is a physiologically relevant modification of antigenic peptides, mediated by the enzyme PAD (43), which can occur in stressed B cells, such as those infected by LCV. The investigators claim that citrullination by PAD occurs in autophagosomes.…”

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

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Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS. We report that B cells infected with EBV-related lymphocryptovirus (LCV) are requisite APCs for MHC-E–restricted autoaggressive effector memory CTLs specific for the immunodominant epitope 40-48 of myelin oligodendrocyte glycoprotein (MOG). These T cells drive the EAE pathogenesis to irreversible neurologic deficit. The aim of this study was to determine why LCV infection is important for this pathogenic role of B cells. Transcriptome comparison of LCV-infected B cells and CD20+ spleen cells from rhesus monkeys shows increased expression of genes encoding elements of the Ag cross-presentation machinery (i.e., of proteasome maturation protein and immunoproteasome subunits) and enhanced expression of MHC-E and of costimulatory molecules (CD70 and CD80, but not CD86). It was also shown that altered expression of endolysosomal proteases (cathepsins) mitigates the fast endolysosomal degradation of the MOG40–48 core epitope. Finally, LCV infection also induced expression of LC3-II+ cytosolic structures resembling autophagosomes, which seem to form an intracellular compartment where the MOG40–48 epitope is protected against proteolytic degradation by the endolysosomal serine protease cathepsin G. In conclusion, LCV infection induces a variety of changes in B cells that underlies the conversion of destructive processing of the immunodominant MOG40–48 epitope into productive processing and cross-presentation to strongly autoaggressive CTLs.

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Section: Discussionmentioning

confidence: 99%

Section: Autophagy Induction In Lcv-infected B Cellsmentioning

confidence: 99%

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

Section: Prolongation Of the Half-life Of The Ctl Epitopementioning

confidence: 99%

See 2 more Smart Citations

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Jagessar

Holtman

Hofman

et al. 2016

The Journal of Immunology

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“…However, recent studies suggested that autophagy is associated with the generation and presentation of citrullinated peptides in APCs. Furthermore, elevated peptidyl arginine deiminase (PAD) activity was also detected in purified autophagosome [73,74]. The role for autophagy in the generation of citrullinated peptides also reported.…”

Section: Rheumatoid Arthritis (Ra)mentioning

confidence: 84%

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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Autophagy and immunological aberrations in systemic lupus erythematosus

Zhou

Zhang

2019

Eur J Immunol

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Systemic lupus erythematosus (SLE) is a complex autoimmune disease, in which immune defects can occur at multiple points of the cascading auto‐aggressive immune reactions, resulting in a striking heterogeneity of clinical presentations. The clinical manifestations of such autoimmune response can be severe: common manifestations symptoms include rash and renal inflammation progressing to kidney failure. Autophagy, the cellular “self‐digestion” process, is a key factor in the interplay between innate and adaptive immunity. Dysregulation of autophagy has been implicated in numerous autoimmune diseases. Several lines of evidence from genomic studies, cell culture systems, animal models, and human patients are emerging to support the role of autophagy in progression and pathogenesis of SLE. In this review, we summarize recent key findings on the aberrations of autophagy in SLE, with a special focus on how deregulated autophagy promotes autoimmunity and renal damage. We will also discuss how the observed findings may be translated into therapeutic settings.

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Processing of proteins in autophagy vesicles of antigen-presenting cells generates citrullinated peptides recognized by the immune system

Cited by 51 publications

References 0 publications

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein

Pathogenic Role of Autophagy in Rheumatic Diseases

Autophagy and immunological aberrations in systemic lupus erythematosus

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