Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency. Issue 10 (12th May 2022) - Catak, Mehmet C.
Abstract: Background: Lipopolysaccharide‐responsive beige‐like anchor protein (LRBA) deficiency and cytotoxic T‐lymphocyte protein‐4 (CTLA‐4) insufficiency are recently described disorders that present with susceptibility to infections, autoimmunity, and lymphoproliferation. Clinical and immunological comparisons of the diseases with long‐term follow‐up have not been previously reported. We sought to compare the clinical and laboratory manifestations of both diseases and investigate the role of flow cytometry in predicting the genetic defect in patients with LRBA deficiency and CTLA‐4 insufficiency. Methods: Patients were evaluated clinically with laboratory assessments for lymphocyte subsets, T follicular helper cells (TFH ), LRBA expression, and expression of CD25, FOXP3, and CTLA4 in regulatory T cells (Tregs) at baseline and 16 h post‐stimulation. Results: LRBA‐deficient patients ( n = 29) showed significantly early age of symptom onset, higher rates of pneumonia, autoimmunity, chronic diarrhea, and failure to thrive compared to CTLA‐4 insufficiency ( n = 12). In total, 29 patients received abatacept with favorable responses and the overall survival probability was not different between transplanted versus non‐transplanted patients in LRBA deficiency. Meanwhile, higher probability of survival was observed in CTLA‐4‐insufficient patients ( p = 0.04). The T‐cell subsets showed more deviation to memory cells in CTLA‐4‐insufficiency, accompanied by low percentages of Treg and dysregulated cTFH cells response in both diseases. Cumulative numbers of autoimmunities positively correlated with cTFH frequencies. Baseline CTLA‐4 expression was significantly diminished in LRBA deficiency and CTLA‐4 insufficiency, but significant induction in CTLA‐4 was observed after short‐term T‐cell stimulation in LRBA deficiency and controls, while this elevation was less in CTLA‐4 insufficiency, allowing to differentiate this disease from LRBA deficiency with high sensitivity (87.5%) and specificity (90%). Conclusion: This cohort provided detailed clinical and laboratory comparisons for LRBA deficiency and CTLA‐4 insufficiency. The flow cytometric approach is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide rapid diagnosis and treatment for these diseases impacting the CTLA‐4 pathway. Abstract : LRBA deficiency and CTLA‐4 insufficiency are immune dysregulatory disorders presenting with infections, autoimmunity, and lymphoproliferation. LRBA deficiency shows an early‐onset, more severe clinical course than CTLA‐4 insufficiency. A stepwise diagnostic algorithm including clinical and flow cytometric assessments is useful in predicting the defective gene; thus, targeted sequencing can be conducted to provide early diagnosis for these diseases impacting the CTLA‐4 pathway.Abbreviations: CTLA‐4, cytotoxic T‐lymphocyte‐associated antigen‐4; CTLA4+/‐, CTLA‐4 insufficiency; CM, central memory; cTFH, circulating T follicular helper cells; EM, effector memory; LRBA, lipopolysaccharide‐responsive beige‐like anchor; LRBA‐/‐, LRBA deficiency; RTI, respiratory tract infection; Treg, regulatory T cells; t‐SNE, t‐distributed stochastic neighbor embedding.