T cell and autoantibody profiling for primary immune regulatory disorders.

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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. To develop a diagnostic approach that combines measurements of cellular and serologic autoimmunity. 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 97.5 th 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. 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. 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. Primary immune regulatory disorders (PIRD) are heterogenous and often diagnoses of exclusion if no genetic cause is identified. Current diagnostic tools do not combine cellular and serologic measures of autoimmunity. Measuring activated CD4 + T cells expressing the chemokine receptors CXCR3 and/or CCR6 and the total number of circulating autoantibodies can enhance detection of autoimmunity in PIRD beyond the capabilities of currently used tools. This study identifies new indicators of autoimmunity that can be feasibly implemented and leveraged for improving the diagnosis of PIRD.