Background: Limited clinical tools exist for characterizing primary immune regulatory disorders (PIRD), which are often diagnoses of exclusion. 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: To develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity.
Methods: We recruited 71 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 featuring 1616 full-length, conformationally intact protein antigens. The 97.5th percentile in the controls serves as the upper limit of normal for percentages of cTfh cells, 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% 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: 0.5852 - 0.8158) and 85% specificity (95% CI: 0.6396 - 0.9476) for patients with PIRD compared to controls.
Conclusion: By integrating CD4+ T cell phenotyping and total burden of autoantibodies, this approach provides additional tools for the diagnosis of PIRD lacking clinical diagnostic criteria.
Keywords: T follicular helper cells; autoantibodies; autoimmunity; primary immune regulatory disorders.