Telomere dysfunction, autoimmunity and aging

Abstract

Immune aging is associated with loss of critical immune functions, such as host protection from infection and malignancy. Unexpectedly, immunosenescence also renders the host susceptible to inflammation, which may translate into tissue-damaging disease as the senescent immune system loses its ability to maximize inflammatory protection while minimizing inflammatory injury. On the other hand, chronic inflammation associated with immune-mediated disease represents a profound stress factor for the immune system, affecting cellular turn-over, replication and exhaustion. Immune cell longevity is tightly connected to the functional integrity of telomeres which are regulated by cell multiplication, exposure to oxidative stress and DNA repair mechanisms. Lymphocytes are amongst the few cell types that can actively elongate telomeres through the action of telomerase. In patients with the autoimmune disease rheumatoid arthritis (RA), telomerase deficiency is associated with prematurity of immune aging. Patients with RA have other defects in DNA repair mechanisms, including the kinase Ataxia telangiectasia mutated (ATM), critically involved in the repair of DNA double strand breaks. ATM deficiency in RA shortens lymphocyte survival. Dynamics of telomeric length and structure are beginning to be understood and have distinct patterns in different autoimmune diseases, suggesting a multitude of molecular mechanisms defining the interface between chronic immune stimulation and progressive aging of the immune system.

Keywords: Autoimmunity; Diabetes; Lupus; Rheumatoid arthritis; Sarcoidosis; Shelterin; Telomerase; Telomere; Telomere Dysfunction.

Figure 1. Telomeres and Telomeric Protection

A) Telomere staining of a CD4 T-cell metaphase spread with telomeres stained in red (PNA probe) and DNA stained in blue (DAPI). Telomeres end in a 3′ overhang that is elongated by telomerase. B) Telomeric ends are protected by a protein complex termed shelterin. The shelterin members TRF1 and TRF2 bind to the double stranded portion of the telomere, POT1 binds to the single stranded part. The three proteins are interconnected by TPP1 and TIN2. RAP1 binds only to TRF2 and modulates its function.

Figure 2. Consequence of CD28 loss in T-cells

Upon aging or repeated antigenic stimulation, T-cells lose the co-stimulatory receptor CD28. The downregulation of CD28 is associated with multiple changes in T cell surface receptors, including the upregulation of the cytokine receptor IL12A as well as the acquisition of NK-cell receptors and mediators, including CD158B1, CD158K, CD94, CD244 and perforin and granzyme B and H.

Figure 3. Telomeric dysfunction in hematopoietic progenitor cells and CD4 naïve T-cells in RA

A) Healthy CD34 cells differentiate into CD4 naïve cells with a slight loss of telomeric length. Upon stimulation, CD4 naïve T-cells upregulate telomerase and are therefore capable of dampening the impact of massive cellular expansion associated with the priming response. B) CD34⁺ hematopoietic stem/progenitor cells from patients with RA already have shorter telomeres compared to their healthy counterparts. Thus, the hematopoietic differentiation program starts with a much diminished telomere reserve. Telomeres in RA naïve CD4 cells are shortened by 1500 kb. Upon stimulation, such CD4 naïve cells fail to fully upregulate telomerase leading to an aggravated loss of telomere repeats during clonal expansion.