A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity

Ooi, Joshua D.; Jiang, Jhih-Hang; Eggenhuizen, Peter J.; Chua, Ling Ling; Timmeren, Mirjan van; Loh, Khai Lee; O’Sullivan, Kim M.; Gan, Poh-Yi; Zhong, Yong; Tsyganov, Kirill; Shochet, Lani; Ryan, Jessica; Stegeman, Coen A.; Fugger, Lars; Reid, Hugh Harrington; Rossjohn, Jamie; Heeringa, Peter; Holdsworth, Stephen R.; Peleg, Anton Y.; Kitching, A. Richard

doi:10.1038/s41467-019-11255-0

Cited by 42 publications

(25 citation statements)

References 64 publications

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“…4). Some attention has focused on S. aureus, with reports of increased rates of nasal carriage in relapsing patients with GPA 22 and experimental data implicating a plasmid-encoded 6-phosphogluconate dehydro genase sequence from some S. aureus strains by molecular mimicry in MPO-AAV 46 .…”

Section: Environmental Factors and Infectionsmentioning

confidence: 99%

ANCA-associated vasculitis

Kitching

Anders

Basu

et al. 2020

Nat Rev Dis Primers

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497

409

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The anti-neutrophil cytoplasmic antibody (ANCA)associated vasculitides (AAVs) are diseases characterized by inflammation of blood vessels, endothelial injury and tissue damage. The three types of small-vessel vasculitis, namely granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic GPA (EGPA; previously known as Churg-Strauss syndrome), feature a loss of tolerance to neutrophil primary granule proteins, most often leukocyte proteinase 3 (PR3; also known as myeloblastin) or myeloperoxidase (MPO) (Table 1). The vessels involved in AAV are typically capillaries, arterioles and venules but small arteries and veins may also be affected. Autoimmunity is documented clinically by serum ANCAs to PR3 (PR3-ANCA) or MPO (MPO-ANCA), which are generally associated with the main syndromic AAV presentations (box 1). AAVs collectively represent one of several types of autoimmune vasculitis (Fig. 1). GPA and MPA can involve small blood vessels in any organ or tissue but commonly affect the upper and lower respiratory tract and the kidneys (box 2). Patients with AAV typically present with severe organ-threatening or life-threatening disease, although less severe presentations also occur. GPA is predominantly associated with PR3-ANCA and its clinical features typically include sinonasal disease, lower respiratory tract involvement with pulmonary haemorrhage and granulomatous inflammation, and glomerulonephritis. MPA is usually associated with MPO-ANCA and clinical features include more severe renal disease and some of the manifestations of GPA but without granulomatous inflammation. EGPA is characterized by asthma, eosinophilia and, in many (but not all) cases, vasculitis. EGPA is less common than GPA or MPA and, in some cases, is associated with ANCAs, mainly MPO-ANCA (Table 1). Although categorized as a form of AAV, EGPA has less overlap with the other AAVs than that between GPA and MPA with regard to its genetic, pathogenetic, and clinical features and its management and is typically considered a separate entity. Improvements in treatment and prognosis for patients with AAV have resulted from the translation of both preclinical and clinical research findings. Here, we provide an updated overview of the clinical and

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Section: Environmental Factors and Infectionsmentioning

confidence: 99%

ANCA-associated vasculitis

Kitching

Anders

Basu

et al. 2020

Nat Rev Dis Primers

Self Cite

497

409

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“…Infection may also be associated with loss of tolerance to MPO through molecular mimicry. Immunization of mice with a plasmid-encoded peptide with some sequence homology with the T cell immunodominant MPO epitope, but found only in some strains of Staphylococcus aureus, induced anti-MPO autoimmunity and vasculitis (104).…”

Section: Active Anti-mpo Glomerulonephritis In Micementioning

confidence: 99%

Animal Models of ANCA Associated Vasculitis

2020

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“…High affinity TCRs on Treg cells are known to elicit a strong response to self-peptides as a result of thymic T cell selection selecting for Tregs with high-affinity, self-peptide recognising TCRs. Conversely, CD4+ T conventional cells (Tconvs) possess TCRs that have a lower affinity for their cognate peptide-MHC, are more flexible in their cross-reactivity, and possess a higher specificity to foreign peptides, which aligns with their T effector functions [ 25 , 26 , 27 ]. After recessive immune tolerance deleting most self-reactive TCRs in the thymus, a subset of those that remain obtain FOXP3 expression and nTreg phenotype, which is promoted through the autoimmune regulator transcription factor AIRE [ 28 , 29 , 30 , 31 ].…”

Section: The Regulatory T Cellmentioning

confidence: 99%

Treg Enhancing Therapies to Treat Autoimmune Diseases

Eggenhuizen

Ooi

2020

IJMS

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125

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Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

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A plasmid-encoded peptide from Staphylococcus aureus induces anti-myeloperoxidase nephritogenic autoimmunity

Cited by 42 publications

References 64 publications

ANCA-associated vasculitis

ANCA-associated vasculitis

Animal Models of ANCA Associated Vasculitis

Treg Enhancing Therapies to Treat Autoimmune Diseases

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