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, 97 (16), 9203-8

T Cell Homeostasis in Patients With Rheumatoid Arthritis

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T Cell Homeostasis in Patients With Rheumatoid Arthritis

K Koetz et al. Proc Natl Acad Sci U S A.

Abstract

The immune system is equipped with an extremely large spectrum of structurally diverse receptors to recognize all potential antigens. This fundamental principle of receptor diversity is no longer upheld in patients with rheumatoid arthritis (RA), who have a marked contraction of the T cell receptor repertoire. In this study, the ability of RA patients to produce T cells and to maintain T cell homeostasis was examined. CD4 T cells containing T cell receptor rearrangement excision circles (TREC) were substantially reduced in RA patients; TREC levels in young adult patients matched those of controls 20 years older. Increased self-replication of T cells in RA was indicated by age-inappropriate erosion of telomeres in circulating T cells with almost complete attrition of telomeric reserves in patients 20-30 yr of age. The degree of telomere loss was not related to disease duration or the use of disease-modifying medication and was most pronounced in CD4(+)CD45RO(null) (naive) T cells. The loss of TREC-positive T cells could be a consequence of a primary defect in peripheral T cell homeostasis. Alternatively, RA patients may have impaired thymic function with the increased turnover of peripheral T cells being a secondary compensatory event.

Figures

Figure 1
Figure 1
Decreased number of TREC-expressing CD4 T cells in RA patients. Signal joint TREC in peripheral CD4 T cells of control donors (circles) and RA patients (triangles) were quantified by competitive PCR as a marker of recent thymic emigrants. RA patients had a significantly lower number of TREC, suggesting reduced thymic activity. Regression lines of normals (dashed line) and patients (solid line) differed significantly (P = 0.0001). This difference was already apparent during early adulthood.
Figure 2
Figure 2
Premature telomere erosion in CD4 cells of patients with RA. TRF length analysis was performed by using purified peripheral CD4 T cells of 42 control donors (Upper) and 51 RA patients (Lower). In control donors, TRF progressively shortened with age (r2 = 0.56, P = 0.0001), with an accelerated loss between the ages of 40 and 65 yr. In RA patients, TRF length did not correlate with age (r2 = 0.09, P = 0.5). Patients <40 yr already had nearly reached the plateau of aged control individuals (>65 yr). Regression lines for normals and patients differed significantly (P = 0.005).
Figure 3
Figure 3
Premature telomere shortening in RA patients affects CD4 and CD8 T cells. CD4 and CD8 T cells were purified from 16 RA patients and 14 control donors, all between the ages of 25 and 40 yr, and the TRF lengths were determined. Results are shown as box plots displaying medians, 25th and 75th percentiles as boxes, and 10th and 90th percentiles as whiskers. RA patients had significantly shorter telomeres in CD4 (P = 0.015) and CD8 T cells (P = 0.022).
Figure 4
Figure 4
Shortened telomeres in naive T cells from RA patients. CD4 T cells were separated into naive and memory T cells. Results from six RA patients and six age-matched controls are shown as box plots. Patients and control individuals differed in naive T cells (P = 0.01) but not in memory cells (P = 0.2).
Figure 5
Figure 5
Clinical correlative of telomere shortening. Results of telomere length analysis were evaluated by mutivariate regression analysis to determine the influence of clinical variables, including RF status and previous or current treatment. RF positivity showed a positive association that was independent of disease duration and age (P = 0.02). There was a trend for patients on methotrexate to have shorter telomeres (P = 0.06); however, this trend was lost after correction for RF-positivity. Data are expressed as the difference from the age-expected TRF and are shown as box plots.
Figure 6
Figure 6
Telomere erosion and disease duration. TRF lengths in CD4 T cells from RA patients are expressed as the distance in kilobases from the age-appropriate point on the regression line for the normal population (Fig. 2). There was no correlation between the duration of RA and telomere loss. The results were unchanged when patients older than 50 yr were excluded from the analysis (data not shown).
Figure 7
Figure 7
Reduced replicative capacity in naive T cells from RA patients. Naive (Upper) and memory (Lower) T cells were purified from RA patients (shaded bars) and age-matched control donors (open bars) and stimulated in vitro. Cell recovery from parallel cultures was assessed every third day, and mean population doublings were calculated. Results are shown as box plots displaying medians, 25th and 75th percentiles as boxes, and 10th and 90th percentiles as whiskers. Growth rates and maximal clonal expansion were reduced in naive T cells from RA patients (P = 0.001).

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