Clinical Scoring of Immune Deficiency and Dysregulation Correlated with Immune Biomarkers in Mennonite Patients with Hypomorphic RAG1 Variant Clinical Scoring of Immune Deficiency in Hypomorphic RAG

Introduction Monogenetic inborn errors of immunity disorders are often characterized by both immune dysregulation and infections. One such disorder is caused by hypomorphic mutations in the recombinase-activating genes 1 and 2 (RAG1/RAG2) known as partial Rag deficiency (pRD). Patients with pRD present with variable clinical phenotypes ranging from clinically well to severe infections and/or immune dysregulation and need of a combination of immunoglobulin replacement, immune modulation, and hematopoietic stem cell transplant. This clinical variability in pRD is well represented by the tight-knit U.S. Mennonite community with an inherited founder variant RAG1 p.C176F (25.6% recombinase activity). Methods In the current study, we applied assessment of clinical features of immune dysregulation and immune markers to understand disease progression and timing for intervention in this unique cohort. Specifically, we applied the Immune Deficiency and Dysregulation Activity (IDDA2.1 “Kaleidoscope”) clinical scoring system to our Mennonite pRD cohort of 10 patients with 32 separate timepoints. We correlated IDDA2.1 scoring of these timepoints with plasma cytokine levels and immune subsets representing dysregulation (CD21loCD11c++ B cells, follicular helper T cells) throughout their clinical journey. Results IDDA2.1 point scoring at the most severe clinical stage timepoint segregated these monogenic patients into three distinct groups of mild (0-12 points), moderate (12-36), and severe (36-180). Of note, all severe patients required hematopoietic stem cell transplant, as well as the most highly scored moderate patient. When IDDA2.1 score severity was correlated with several immune subsets, expansion of circulating T follicular helper cells (cTfh) positively correlated with IDDA2.1 disease score (R squared = 0.53, p = 0.017). Cd21loCD11c+ B cells also held a positive correlation with IDDA2.1 scores for mild and moderate patient groups only. Conclusions The combined method of using a clinical scoring system longitudinally and relating it to characteristic immune biomarkers within pRD may be important for the decision to proceed with definitive treatment, particularly if early biomarkers prove to be predictive of clinical state.