T-cell and autoantibody profiling for primary immune regulatory disorders.

BACKGROUND: Limited clinical tools exist for characterizing primary immune regulatory disorders (PIRD). Increased CD4(+)CXCR5(+)PD1(+) circulating T follicular helper (cTfh) cell percentages have been identified as a marker of active disease in some, but not all, autoimmune disorders. OBJECTIVE: We sought to develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity. METHODS: We recruited 74 controls and 101 pediatric patients with PIRD with autoimmunity. Flow cytometry was used to measure CD4(+)CXCR5(+) T cells expressing the chemokine receptors CXCR3 and/or CCR6. IgG and IgA autoantibodies were quantified in 56 patients and 20 controls using a microarray of 1616 full-length, conformationally intact protein antigens. The cTfh cell percentages exceeding 12% of CD4(+) T cells were considered increased, as previously published, and the 97.5th percentile in the controls was the upper limit of normal for CD4(+)CXCR5(+) T cells expressing CXCR3 and/or CCR6 and autoantibody intensity and number. RESULTS: We found that 27.7% of patients had increased percentages of CD4(+)CXCR5(+)PD1(+) cTfh cells, and 42.5% had increased percentages of CD4(+)CXCR5(+) cells expressing CXCR3 and/or CCR6. Patients had significantly more diverse IgG and IgA autoantibodies than controls, and 37.5% of patients had increased numbers of high-titer autoantibodies. Integrating measurements of cTfh cells, CD4(+)CXCR5(+) T cells with CXCR3 and/or CCR6, and numbers of high-titer autoantibodies had 71.4% sensitivity (95% CI 58.5%-81.6%) and 85.0% specificity (95% CI 64.0%-94.8%) for patients with PIRD compared with controls. CONCLUSIONS: Integrating CD4(+) T-cell phenotyping and total burden of autoantibodies can enhance detection of autoimmunity in PIRD.