Lupus Regulator Peptide P140 Represses B Cell Differentiation by Reducing HLA Class II Molecule Overexpression

Wilhelm, Maud; Wang, Fengjuan; Schall, Nicolas; Kleinmann, Jean-François; Faludi, Michael; Nashi, Emil; Sibilia, Jean; Martin, Thierry; Schaeffer, Evelyne; Muller, Sylviane

doi:10.1002/art.40470

Cited by 30 publications

(35 citation statements)

References 48 publications

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“…An interesting clinical outlook on the modulation of autophagy in B cells comes from the studies of Phosphopeptide P140 (Lupuzor), an inhibitor of autophagy currently evaluated in late‐stage clinical trials for the treatment of lupus. This compound increases the accumulation of the autophagy markers p62/SQSTM1 and LC3‐II, consistent with a downregulated lysosomal degradation during autophagic flux . It displays no direct effect on BCR signaling of transitional, mature naive, or memory B cells, as well as of B1 cells.…”

Section: Adaptive Immunitymentioning

confidence: 67%

“…Lupus nephritis remains a major cause of morbidity and mortality in SLE. As discussed above, variants of APOL1 and MTMR3 have been identified as associated with the susceptibility to lupus nephritis [22,97]. In a previous report focusing on murine macrophages, it was shown that proteinuria levels, immune complex deposition, as well as renal pathological changes are alleviated after adoptive transfer of Beclin-1knockdown macrophages [77].…”

Section: Renal Impairmentmentioning

confidence: 99%

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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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Section: Adaptive Immunitymentioning

confidence: 67%

Section: Renal Impairmentmentioning

confidence: 99%

Autophagy and immunological aberrations in systemic lupus erythematosus

Zhou

Zhang

2019

Eur J Immunol

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“…P140 peptide reduces the excessive expression of HSPA8 and LAMP2A observed in lupus mice, alters the (auto)antigen presentation by MHCII molecules in the MIIC compartment and, consequently, attenuates the activation of autoreactive T cells 92 . A significant diminution of MHC molecule expression at the surface of antigen presenting cells was measured in mice that received the P140 peptide intravenously and on patient's peripheral cells treated ex vivo with the peptide 92,101,314 . As a downstream consequence, the activation of auto reactive B cells and their differentiation into autoantibody secreting cells is repressed 101,314 .…”

Section: Box 2 | Methods To Examine Lysosomal Dysfunction In Diseasementioning

confidence: 99%

“…A significant diminution of MHC molecule expression at the surface of antigen presenting cells was measured in mice that received the P140 peptide intravenously and on patient's peripheral cells treated ex vivo with the peptide 92,101,314 . As a downstream consequence, the activation of auto reactive B cells and their differentiation into autoantibody secreting cells is repressed 101,314 . T cells from patients with lupus are no longer responders ex vivo to peptides encompassing CD4 + T cell epitopes 315 .…”

Section: Box 2 | Methods To Examine Lysosomal Dysfunction In Diseasementioning

confidence: 99%

Lysosomes as a therapeutic target

Bonam

Wang

Muller

2019

Nat Rev Drug Discov

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552

374

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| Lysosomes are membrane-bound organelles with roles in processes involved in degrading and recycling cellular waste, cellular signalling and energy metabolism. Defects in genes encoding lysosomal proteins cause lysosomal storage disorders, in which enzyme replacement therapy has proved successful. Growing evidence also implicates roles for lysosomal dysfunction in more common diseases including inflammatory and autoimmune disorders, neurodegenerative diseases, cancer and metabolic disorders. With a focus on lysosomal dysfunction in autoimmune disorders and neurodegenerative diseases -including lupus, rheumatoid arthritis, multiple sclerosis, Alzheimer disease and Parkinson disease -this Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs.

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“…Additionally, some peptides derived from other self-antigens have also been explored as candidate therapeutic vaccines for SLE. For instance, a phosphorylated spliceosomal epitope, the P140 peptide, could repress B cell differentiation and ameliorate lupus [169,177,178]. Subsequent clinical studies further showed that the P140 peptide could improve the clinical and immune status of SLE patients [179][180][181].…”

Section: Journal Of Immunology Researchmentioning

confidence: 99%

Peptide-Based Vaccination Therapy for Rheumatic Diseases

Wang

Chen

Zheng

et al. 2020

Journal of Immunology Research

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Rheumatic diseases are extremely heterogeneous diseases with substantial risks of morbidity and mortality, and there is a pressing need in developing more safe and cost-effective treatment strategies. Peptide-based vaccination is a highly desirable strategy in treating noninfection diseases, such as cancer and autoimmune diseases, and has gained increasing attentions. This review is aimed at providing a brief overview of the recent advances in peptide-based vaccination therapy for rheumatic diseases. Tremendous efforts have been made to develop effective peptide-based vaccinations against rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), while studies in other rheumatic diseases are still limited. Peptide-based active vaccination against pathogenic cytokines such as TNF-α and interferon-α (IFN-α) is shown to be promising in treating RA or SLE. Moreover, peptide-based tolerogenic vaccinations also have encouraging results in treating RA or SLE. However, most studies available now have been mainly based on animal models, while evidence from clinical studies is still lacking. The translation of these advances from experimental studies into clinical therapy remains impeded by some obstacles such as species difference in immunity, disease heterogeneity, and lack of safe delivery carriers or adjuvants. Nevertheless, advances in high-throughput technology, bioinformatics, and nanotechnology may help overcome these impediments and facilitate the successful development of peptide-based vaccination therapy for rheumatic diseases.

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Lupus Regulator Peptide P140 Represses B Cell Differentiation by Reducing HLA Class II Molecule Overexpression

Cited by 30 publications

References 48 publications

Autophagy and immunological aberrations in systemic lupus erythematosus

Autophagy and immunological aberrations in systemic lupus erythematosus

Lysosomes as a therapeutic target

Peptide-Based Vaccination Therapy for Rheumatic Diseases

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