The immunology of rheumatoid arthritis

Abstract

The immunopathogenesis of rheumatoid arthritis (RA) spans decades, beginning with the production of autoantibodies against post-translationally modified proteins (checkpoint 1). After years of asymptomatic autoimmunity and progressive immune system remodeling, tissue tolerance erodes and joint inflammation ensues as tissue-invasive effector T cells emerge and protective joint-resident macrophages fail (checkpoint 2). The transition of synovial stromal cells into autoaggressive effector cells converts synovitis from acute to chronic destructive (checkpoint 3). The loss of T cell tolerance derives from defective DNA repair, causing abnormal cell cycle dynamics, telomere fragility and instability of mitochondrial DNA. Mitochondrial and lysosomal anomalies culminate in the generation of short-lived tissue-invasive effector T cells. This differentiation defect builds on a metabolic platform that shunts glucose away from energy generation toward the cell building and motility programs. The next frontier in RA is the development of curative interventions, for example, reprogramming T cell defects during the period of asymptomatic autoimmunity.

Figure 1.. Evolution of Rheumatoid Arthritis over Lifetime.

The disease process of RA begins with transition of an at-risk host to a host with overt autoimmunity. Recognition of modified protein antigens and emergence of autoantibodies mark the loss of self-tolerance (Checkpoint 1). Timing and space of this tolerance defect are not precisely identified, but autoantibodies appear years to decades prior to frank joint disease. The host with overt autoimmunity is clinically asymptomatic. A cell-intrinsic shift in metabolic networks and DNA instability drive T cell mal-differentiation towards tissue-invasive short-lived effector T cells. Failure of tissue tolerance manifests as early synovitis during the sixth decade of life (Checkpoint 2) and transitions relatively fast into chronic synovitis (Checkpoint 3). Auto-aggressive de-differentiated synoviocytes, loss of tissue-protective macrophage populations and T cell pyroptosis drive joint damage. The loss of tissue tolerance is irreversible in the majority of cases.

Figure 2.. DNA Repair Deficits in Rheumatoid Arthritis.

In patients with RA, molecular defects have been localized to the machinery that senses and repairs DNA double strand breaks. Insufficient DNA repair occurs in hematopoietic stem cells, neutrophils and naïve and memory CD4+ T cells. Age-inappropriate decline of the repair molecules ATM and MRE11A leads to accumulation of damaged DNA in the nucleus, at the telomeric ends and in the mitochondria. Downstream consequences include deviations in cell cycle passage, premature telomeric loss and cytoplasmic leakage of mitochondrial DNA triggering inflammasome activation. Ultimately, insufficient DNA repair gives rise to a T cell differentiation defect favoring the induction of short-lived effector T cells at the expense of long-lived memory precursor cells. Also, unrepaired DNA damage promotes T cell pyroptosis, immune exhaustion and premature immune aging. Breakage of mitochondrial DNA affects the electron transport chain, impairs production of ATP and metabolic intermediates, and reprograms the cell’s energy production and biosynthetic program.

Figure 3.. Metabolic reprogramming and pro-inflammatory effector functions in RA T cells.

Several molecular defects have been identified which shift the metabolic and bioenergetic conditions in RA T cells, ultimately deviating the cell’s differentiation program and shortening survival. Transcriptional repression of the glycolytic enzyme phosphofructokinase (PFKFB3) impairs pyruvate production and thus mitochondrial function, favoring induction of short-lived effector T cells (SLEC) over long-lived memory T cells. Increased activity of glucose-6-phosphate dehydrogenase (G6DH) shunts glucose into the pentose phosphate pathway, supporting biosynthetic activity and daughter cell generation. Oversupply of NADPH supports the lipogenic program and formation of tissue-invasive membrane structures. Damage of mitochondrial DNA weakens mitochondrial fitness and energy production and triggers inflammasome activation and ultimately immunogenic T cell death. Misrouting of the energy sensor AMPK away from the lysosomal surface, caused by deficiency of N-myristoyltransferase 1, enables unopposed mTORC1 activation and SLEC generation.