Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis
Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cell...
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doaj-86d72c2e66b644d88963f2078026ac442021-04-02T04:20:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-04-011210.3389/fimmu.2021.652771652771Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid ArthritisJingtao Qiu0Bowen Wu1Stuart B. Goodman2Gerald J. Berry3Jorg J. Goronzy4Cornelia M. Weyand5Department of Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Orthopedic Surgery, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Pathology, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, United StatesDepartment of Medicine, Stanford University School of Medicine, Stanford, CA, United StatesLike other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease.https://www.frontiersin.org/articles/10.3389/fimmu.2021.652771/fullT cellmetabolismautoimmunityrheumatoid arthritismitochondriaglycolysis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Jingtao Qiu Bowen Wu Stuart B. Goodman Gerald J. Berry Jorg J. Goronzy Cornelia M. Weyand |
spellingShingle |
Jingtao Qiu Bowen Wu Stuart B. Goodman Gerald J. Berry Jorg J. Goronzy Cornelia M. Weyand Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis Frontiers in Immunology T cell metabolism autoimmunity rheumatoid arthritis mitochondria glycolysis |
author_facet |
Jingtao Qiu Bowen Wu Stuart B. Goodman Gerald J. Berry Jorg J. Goronzy Cornelia M. Weyand |
author_sort |
Jingtao Qiu |
title |
Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis |
title_short |
Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis |
title_full |
Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis |
title_fullStr |
Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis |
title_full_unstemmed |
Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis |
title_sort |
metabolic control of autoimmunity and tissue inflammation in rheumatoid arthritis |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-04-01 |
description |
Like other autoimmune diseases, rheumatoid arthritis (RA) develops in distinct stages, with each phase of disease linked to immune cell dysfunction. HLA class II genes confer the strongest genetic risk to develop RA. They encode for molecules essential in the activation and differentiation of T cells, placing T cells upstream in the immunopathology. In Phase 1 of the RA disease process, T cells lose a fundamental function, their ability to be self-tolerant, and provide help for autoantibody-producing B cells. Phase 2 begins many years later, when mis-differentiated T cells gain tissue-invasive effector functions, enter the joint, promote non-resolving inflammation, and give rise to clinically relevant arthritis. In Phase 3 of the RA disease process, abnormal innate immune functions are added to adaptive autoimmunity, converting synovial inflammation into a tissue-destructive process that erodes cartilage and bone. Emerging data have implicated metabolic mis-regulation as a fundamental pathogenic pathway in all phases of RA. Early in their life cycle, RA T cells fail to repair mitochondrial DNA, resulting in a malfunctioning metabolic machinery. Mitochondrial insufficiency is aggravated by the mis-trafficking of the energy sensor AMPK away from the lysosomal surface. The metabolic signature of RA T cells is characterized by the shunting of glucose toward the pentose phosphate pathway and toward biosynthetic activity. During the intermediate and terminal phase of RA-imposed tissue inflammation, tissue-residing macrophages, T cells, B cells and stromal cells are chronically activated and under high metabolic stress, creating a microenvironment poor in oxygen and glucose, but rich in metabolic intermediates, such as lactate. By sensing tissue lactate, synovial T cells lose their mobility and are trapped in the tissue niche. The linkage of defective DNA repair, misbalanced metabolic pathways, autoimmunity, and tissue inflammation in RA encourages metabolic interference as a novel treatment strategy during both the early stages of tolerance breakdown and the late stages of tissue inflammation. Defining and targeting metabolic abnormalities provides a new paradigm to treat, or even prevent, the cellular defects underlying autoimmune disease. |
topic |
T cell metabolism autoimmunity rheumatoid arthritis mitochondria glycolysis |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.652771/full |
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