Rheumatoid arthritis: a role for immunosenescence?

Abstract

Aging is accompanied by a progressive decline in the integrity of the immune system, a process known as immunosenescence. Pathological features typical of immune dysfunction in older adults, encompassing dysregulation of innate and adaptive immune responses, characterize rheumatoid arthritis (RA), an autoimmune disease whose incidence increases with age. Recent evidence suggests that certain features of immunosenescence, such as the decrease in T-cell generation and diversity, may contribute to the development of RA. Thus, physiological immunosenescence may render older adults susceptible to RA, and premature immunosenescence may contribute to the development of RA in young adults. In addition, other features of immunosenescence may result from the chronic immune stimulation that occurs in RA and lead to worsening of the disease. This article reviews the immunopathological features common to aging and RA and discusses the mechanisms by which immunosenescence may contribute to the development or progression of RA.

Figure 1

Induction of a primary adaptive immune response. Antigen-presenting cells such as dendritic cells (DCs) take up pathogens and present the pathogen antigens to naïve T cells. Those T cells that bear a T-cell receptor (TCR) specific for the antigen presented undergo clonal expansion and differentiate into CD8⁺ and CD4⁺ effector T cells. For this to occur, the T cell must receive two signals from the DC. Signal 1 is delivered by the interaction of the TCR with the antigen/ major histocompatibility complex (MHC) on the DC. Signal 2 is delivered upon binding of the B7 molecule on the DC to the CD28 receptor on the T cell. Cytotoxic CD8⁺ T cells recognize the antigen/MHC complex on the surface of cells, and are activated to destroy the infected cells. Naïve B cells bearing immunoglobulin receptors specific for the antigen internalize the antigen and present it to antigen-specific CD4⁺ T cells, which in turn induce the B cells to clonally expand and differentiate into antibody-producing plasma cells. The antibodies produced target extracellular pathogens and their toxic products via the processes of neutralization, opsonization, or complement activation. A small proportion of activated T and B cells form long-lived memory cells, which are responsible for mounting a stronger, secondary immune response upon subsequent encounters with their cognate antigen.

Figure 2

Breakdown of peripheral tolerance in aging. Normally, two signals are required for the full activation of T cells. (A) When a dendritic cell (DC) presents a pathogenic antigen to a T cell, signal 1 is delivered by the T-cell receptor (TCR) when it binds to the antigen/self-MHC complex, while signal 2 is delivered via the CD28 receptor on the T-cell surface when it binds to the B7 molecule on the DC surface. Further co-stimulatory signals are provided by secretion of cytokines from the DC. (B) In the absence of infection, DCs express no or very little B7. A T cell that interacts strongly with self-peptide (rather than with a pathogenic antigen) in the periphery will receive signal 1 but not signal 2. This either kills the T cell or renders it refractory to activation, a state known as anergy. Although originally thought to be restricted to naïve T-cell activation, CD28 co-stimulation requirement has more recently been shown to extend to memory T-cell activation. (C) In the aged immune system, the T-cell repertoire is skewed toward recognition of self-peptide, likely as a result of multiple mechanisms acting on naïve and memory T cells. The aged T-cell repertoire is also characterized by a predominance of memory cells. A subset of memory T cells have lost expression of CD28 and acquired expression of stimulatory killer immunoglobulin-like receptors (KIR), NKG2D receptors, and lymphocyte function-associated antigen 1 (LFA-1). De novo expression of these stimulatory receptors on memory CD28⁻ T cells changes the way in which these T cells interact with their cellular environment, lowering the threshold for antigen-specific activation and even enabling activation independent of the appropriate antigen. Together with de novo expression of stimulatory receptors, development of cytotoxic granules endows CD28⁻ T cells with certain natural killer cell functions, including cytotoxic killing. Furthermore, DCs secrete greater amounts of cytokines, and are able to induce T-cell proliferation, in response to self-peptides. These aberrations promote autoimmunity. MHC, major histocompatibility complex.

Figure 3

Accelerated decline in T-cell generation leads to premature emergence of senescent T cells in RA. In healthy individuals, the generation of new T cells progressively declines. This decline is compensated for by the homeostatic proliferation of mature T cells in the periphery. With age, progressively fewer new T cells enter the T-cell compartment and mature T cells must increasingly proliferate to fill the void. Eventually, the continually replicating mature T cells become exhausted and take on a senescent phenotype characterized by blunted replicative potential, contracted T-cell repertoire, T_H17 polarization, loss of CD28 expression, and de novo expression of stimulatory receptors such as killer-like immunoglobulin receptors (KIR). In RA patients, T-cell generation is age-inappropriately decreased, matching that of healthy individuals 20–30 years older; consequently, homeostatic T-cell proliferation is increased, resulting in premature senescence of T cells. In (normal) aging, the progressive decline in T-cell generation hinges on involution of the thymus, but may also involve senescence of haematopoietic stem cells (HSC). In RA, the age-inappropriate decline in T-cell generation, and hence T-cell senescence, has been ascribed to premature thymic involution or premature HSC senescence. Premature T-cell senescence has also been attributed to deficiency in telomerase activity in mature T cells. The line graphs are adapted from Figure 1 in Weyand and Goronzy 2002.

Figure 4

Aging of the immune system increases susceptibility to disease. The arrow indicates the progressive decline in integrity of the immune system with age. Such aging of the immune system, or immunosenescence, involves a decrease in T-cell generation and diversity, and an increase in levels of proinflammatory cytokines and autoantibodies. Loss of peripheral T-cell tolerance, owing to dysregulation of dendritic cells (DCs) and T cells, may also be involved. The decline in immune function is paralleled by an increase in incidence of several diseases, including infectious disease, cancer, and rheumatoid arthritis (RA). The line graph of RA incidence is a schematic approximation of the general trend in incidence with age. That RA incidence is generally higher in women, increases progressively with age, and decreases in the oldest age groups is a finding consistent across multiple studies; the late decrease is observed earlier among women than among men.–