Measuring the T-cell down-regulation of TCR-zeta, ZAP-70 and CD28 in arthritis patients: An old tool for new biomarkers

Low T-cell receptor (TCR)/CD28 signaling lymphocytes are expanded in arthritis. We asked whether the down-expression of TCR-related molecules correlates with specific arthritis characteristics and if it has clinical implications. TCR-ZETA, ZAP-70 and CD28 expression was measured by flow cytometry in synovial fluid (SF) and peripheral blood (PB)-derived T cells. In PB, ZETA-downregulation in CD4(+)CD28(+) and consequent CD4(+)CD28lowZETAlow cell expansion correlate with CRP elevation, leukocyte recruitment into SF and, primarily, disease activity (DAS). In some patients, ZETA-downregulation extends to CD8(+)CD28null and/or CD8(+)CD28(+) cells, and this correlates with enhanced leukocyte recruitment, multiple joint involvement, and disability index (HAQ). ZETA-downregulation in CD4(+)CD28(+) may also lead to CD4(+)CD28(+)ZETAnull cell expansion, which strongly correlates with HAQ. In SF, ZETA-downregulation in CD8(+)CD28null and consequent CD8(+)CD28nullZETAlow/null cell expansion correlate with CRP elevation and neutrophilic influx into SF, whereas ZAP-downregulation in CD8(+)CD28(+) and consequent CD8(+)CD28lowZAPlow cell expansion strongly correlate with HAQ and DAS. ZETA-downregulation is preponderant in SF of seronegative arthritides, with seronegative rheumatoid arthritis showing significant down-regulation in CD8(+)CD28null, and non-rheumatoid arthritides showing significant down-regulation in CD4(+)CD28(+). Altogether, we identified new molecular and cellular biomarkers of arthritis-related T-cell inflammation, useful for assessing arthritis activity, predicting polyarticular progression and functional impairment, characterizing seronegative arthritides, and possibly tailoring immunotherapies.