Metabolic Control of Autoimmunity and Tissue Inflammation in Rheumatoid Arthritis

Abstract

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.

Macrophages: The Good, the Bad, and the Gluttony

“…One method would be to reprogram macrophages in situ to switch their functional phenotype. We now have a greater understanding of how metabolism in macrophages influences their pro or anti-inflammatory properties, as well as how the RA environment directs this programming (117). RA patients have an increased M1 macrophage profile compared to other arthritides (118) and inflammatory models demonstrate a complex relationship between M1 and M2 subsets depending on the stage of the disease and tissues studied (119,120).…”

Thousands of CpGs Show DNA Methylation Differences in ACPA-Positive Individuals

“…Glutamate was found to participate in adhesion, migration, proliferation, survival and activation of T cells [ 18 ]. Molecular biological analyses discussed the role of glutamate in synovial fibroblasts and possible involvement of glutamatergic signaling in the pathophysiology of RA [ 19 , 20 ]. A complete list of identified DMRs in the regions of RA GWAS genes can be extracted from Supplementary Tables S1 and S5 .…”

Impacto en la calidad de vida con manejo biorregulador en un paciente con artritis reumatoide. Reporte de casos clínico

“…Se conoce bien que por el proceso fisiopatológico de la enfermedad, la artritis reumatoide se caracteriza por tener un ambiente acidificado, principalmente dado por la alteración del metabolismo de la glucosa el cual está desplazada hacia la glucólisis, lo que baja la eficiencia de generación de energía y favorece la producción de lactato deshidrogenasa, el cual se acumula en la matriz y la acidifica, generando un inapropiado funcionamiento de las células inmunitarias y perpetúa el estado inflamatorio. (24). El Lymphomyosot, el Berberis Homaccord, y el Ubichinon compositum por sus efectos antioxidantes participan en la actividad de catalizadores enzimáticos a nivel hepático.…”