PMID- 35818684
OWN - NLM
STAT- MEDLINE
DCOM- 20221229
LR  - 20230415
IS  - 2326-5205 (Electronic)
IS  - 2326-5191 (Print)
IS  - 2326-5191 (Linking)
VI  - 75
IP  - 1
DP  - 2023 Jan
TI  - Phosphatidylinositol 3-Kinase delta Deficiency Protects From Antimyeloperoxidase 
      Vasculitis.
PG  - 64-70
LID - 10.1002/art.42298 [doi]
AB  - OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is a 
      systemic autoimmune disease in which glomerulonephritis is an important 
      manifestation. Antibodies against myeloperoxidase (MPO) or proteinase 3 are 
      thought to be important in pathogenesis. Phosphoinositide 3-kinase delta (PI3Kdelta) 
      mediates a number of effects in lymphocytes, but its role in myeloid cell 
      responses is less clear. Therefore, this study was undertaken to assess this in a 
      preclinical model of glomerulonephritis induced by the transfer of antibodies to 
      MPO. METHODS: D910A mice with inactive PI3Kdelta were compared with wild-type 
      controls. Disease protocols allowed for a comparison of experimental groups in 
      the setting of both mild and more severe disease. Adoptive transfer experiments 
      were performed, with flow cytometric analysis of digested kidneys taken at the 
      end of the experiment. RESULTS: With mild disease, D910A mice had fewer 
      glomerular macrophages, fewer glomerular neutrophils, and reduced albuminuria 
      compared with wild-type controls. With more severe disease, they also had fewer 
      glomerular crescents and lower serum creatinine levels, indicating protection 
      from acute kidney injury. Adoptive transfer experiments showed a defect in the 
      recruitment of D910A monocytes to the diseased kidney. CONCLUSION: Mice with 
      inactive PI3Kdelta were protected from anti-MPO vasculitis. This is due to cell 
      intrinsic defect in the recruitment of monocytes to the kidney. These findings 
      suggest that PI3Kdelta is a potential therapeutic target in AAV.
CI  - (c) 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC 
      on behalf of American College of Rheumatology.
FAU - Florez-Barros, Fernanda
AU  - Florez-Barros F
AD  - School of Immunology and Microbial Sciences, King's College London, Guy's 
      Hospital, London, UK.
FAU - Freeley, Simon
AU  - Freeley S
AD  - School of Immunology and Microbial Sciences, King's College London, Guy's 
      Hospital, London, UK.
FAU - Tham, El Li
AU  - Tham EL
AD  - School of Immunology and Microbial Sciences, King's College London, Guy's 
      Hospital, London, UK.
FAU - Robson, Michael G
AU  - Robson MG
AUID- ORCID: 0000-0002-1192-1353
AD  - School of Immunology and Microbial Sciences, King's College London, Guy's 
      Hospital, London, UK.
LA  - eng
GR  - MR/R004870/1/Medical Research Council/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20221118
PL  - United States
TA  - Arthritis Rheumatol
JT  - Arthritis & rheumatology (Hoboken, N.J.)
JID - 101623795
RN  - 0 (Antibodies, Antineutrophil Cytoplasmic)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 1.11.1.7 (Peroxidase)
SB  - IM
MH  - Mice
MH  - Animals
MH  - Antibodies, Antineutrophil Cytoplasmic
MH  - Phosphatidylinositol 3-Kinase
MH  - Phosphatidylinositol 3-Kinases/therapeutic use
MH  - *Glomerulonephritis
MH  - *Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy
MH  - Peroxidase
PMC - PMC10099887
EDAT- 2022/07/13 06:00
MHDA- 2022/12/30 06:00
PMCR- 2023/04/13
CRDT- 2022/07/12 02:33
PHST- 2022/05/27 00:00 [revised]
PHST- 2021/12/23 00:00 [received]
PHST- 2022/07/07 00:00 [accepted]
PHST- 2022/07/13 06:00 [pubmed]
PHST- 2022/12/30 06:00 [medline]
PHST- 2022/07/12 02:33 [entrez]
PHST- 2023/04/13 00:00 [pmc-release]
AID - ART42298 [pii]
AID - 10.1002/art.42298 [doi]
PST - ppublish
SO  - Arthritis Rheumatol. 2023 Jan;75(1):64-70. doi: 10.1002/art.42298. Epub 2022 Nov 
      18.