Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells

Ireland, Jamie M.; Unanue, Emil R.

doi:10.1084/jem.20110640

Cited by 228 publications

(190 citation statements)

References 30 publications

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“…Similarly, the LC3 lipidation machinery appears to be required for efficient MHC class Ⅱ presentation in vivo (Lee et al, 2010). Moreover, hydrolases that facilitate antigen processing can be transported into lysosomes via autophagy, as shown for peptidylarginine deiminases (PADs) that generate citrullinated peptides, which constitute CD4 + T cell epitopes in rheumatoid arthritis (Ireland and Unanue, 2011). LAP, however, does not seem to affect all phagocytosed cargo similarly.…”

Section: Exogenous Antigen Processing For Mhc Class ⅱ Presentationmentioning

confidence: 99%

Autophagy and autophagy-related proteins in the immune system

et al. 2015

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Autophagy is an intracellular bulk degradation system that is highly conserved in eukaryotes. The discovery of autophagy-related ('ATG') proteins in the 1990s greatly advanced the mechanistic understanding of autophagy and clarified the fact that autophagy serves important roles in various biological processes. In addition, studies have revealed other roles for the autophagic machinery beyond autophagy. In this Review, we introduce advances in the knowledge of the roles of autophagy and its components in immunity, including innate immunity, inflammatory responses and adaptive immunity. AbstractAutophagy is an intracellular bulk degradation system that is highly conserved in eukaryotes.The discovery of Atg proteins in the 1990s has greatly advanced our mechanistic understanding of autophagy, which allowed us to understand that autophagy plays important roles in various biological processes. In addition, recent studies revealed other roles of the autophagic machinery beyond autophagy. In this review, we introduce recent advances in our knowledge of the roles that autophagy and its components play in immunity, including innate immunity, inflammation responses, and adaptive immunity.

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Section: Exogenous Antigen Processing For Mhc Class ⅱ Presentationmentioning

confidence: 99%

Autophagy and autophagy-related proteins in the immune system

et al. 2015

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“…81 Additionally, in TNF transgenic mice, autophagy-deficient macrophages caused less joint destruction due to decreased osteoclast differentiation. 82 Also, autophagy is important in presenting pathogenic citrullinated antigens by macrophages and dendritic cells to CD4 C T cells, 83 which may be an important mechanism in the pathogenesis of RA. Whether the increased expression of SNA-PIN as observed in RA macrophages protects or promotes disease pathogenesis remains to be determined.…”

Section: Ramentioning

confidence: 99%

SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages

et al. 2016

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We previously observed that SNAPIN, which is an adaptor protein in the SNARE core complex, was highly expressed in rheumatoid arthritis synovial tissue macrophages, but its role in macrophages and autoimmunity is unknown. To identify SNAPIN's role in these cells, we employed siRNA to silence the expression of SNAPIN in primary human macrophages. Silencing SNAPIN resulted in swollen lysosomes with impaired CTSD (cathepsin D) activation, although total CTSD was not reduced. Neither endosome cargo delivery nor lysosomal fusion with endosomes or autophagosomes was inhibited following the forced silencing of SNAPIN. The acidification of lysosomes and accumulation of autolysosomes in SNAPINsilenced cells was inhibited, resulting in incomplete lysosomal hydrolysis and impaired macroautophagy/ autophagy flux. Mechanistic studies employing ratiometric color fluorescence on living cells demonstrated that the reduction of SNAPIN resulted in a modest reduction of H C pump activity; however, the more critical mechanism was a lysosomal proton leak. Overall, our results demonstrate that SNAPIN is critical in the maintenance of healthy lysosomes and autophagy through its role in lysosome acidification and autophagosome maturation in macrophages largely through preventing proton leak. These observations suggest an important role for SNAPIN and autophagy in the homeostasis of macrophages, particularly long-lived tissue resident macrophages.

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“…27 The important role of autophagy induction in antigen presentation and adaptive immune responses has been established. 28,29 We previously reported that meningococcal vaccine nanoparticles induced dose-dependent autophagy in macrophages. 14 The observed large cytosolic autophagic vacuoles are induced by vaccine nanoparticles but not by empty nanoparticles.…”

Section: Antigenicity Profiling Of Meningococcal Vaccine Formulationsmentioning

confidence: 99%

Analysis of novel meningococcal vaccine formulations

Zughaier

2017

Human Vaccines & Immunotherapeutics

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The protective effect of meningococcal vaccines targeting disease causing serogroups exemplified by the introduction of MenAfriVac TM in Africa, is well established and documented in large population-based studies. Due to the emergence of other meningococcal disease causing serogroups, novel vaccine formulations are needed. There is a high potential for novel nanotechnology-based meningococcal vaccine formulations that can provide wider vaccine coverage. The proposed meningococcal vaccine formulation contains spherical shaped micro and nanoparticles that are biological mimics of Niesseria meningitidis, therefore present to immune system as invader and elicit robust immune responses. Vaccine nanoparticles encapsulate meningococcal CPS polymers in a biodegradable material that slowly release antigens, therefore enhance antigen presentation by exerting antigen depot effect. The antigenicity of meningococcal vaccine delivered in nanoparticles is significantly higher when compared to vaccine delivered in solution. Preclinical studies are required to assess the immunogenicity of novel vaccine formulations. Therefore, implementing various in-vitro human immune cell-based assays that mimic invivo interactions, would provide good insight on optimal antigen dose, effective antigen presentation, facilitate screening of various vaccine and adjuvant combinations and predict in-vivo immunogenicity. This rapid approach is cost-effective and provides data required for the preclinical immunogenicity assessment of novel meningococcal vaccine formulations.

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Autophagy in antigen-presenting cells results in presentation of citrullinated peptides to CD4 T cells

Abstract: Citrullinated peptide presentation by DCs and macrophages is constitutive, whereas B cells present modified peptides only with autophagy induced by serum starvation or BCR ligation.

Cited by 228 publications

References 30 publications

Autophagy and autophagy-related proteins in the immune system

Autophagy and autophagy-related proteins in the immune system

SNAPIN is critical for lysosomal acidification and autophagosome maturation in macrophages

Analysis of novel meningococcal vaccine formulations

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