Comparing the levels of CTLA‐4‐dependent biological defects in patients with LRBA deficiency and CTLA‐4 insufficiency

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.

Deep immunophenotyping shows altered immune cell subsets in CTLA‐4 haploinsufficiency

“…Previous studies have reported variable immune cell phenotypes in patients with CTLA-4 haploinsufficiency. 7,8 While a minority of patients had reduced absolute counts of total CD3+ cells, a majority of patients had no changes in total CD3 + , CD4 + , or CD8 + T-cell frequencies compared with healthy controls. 7,8 Our data are consistent with these findings (Figure S2A).…”

“…Recently, patients with clinically symptomatic CTLA-4 haploinsufficiency were found to have increased frequencies of CXCR5 + PD1 + follicular helper T cells (Tfh) that normalized with abatacept therapy. 8,12 Our study did not include PD-1 or ICOS staining and therefore may be examining different cell populations. Further…”

“…7,8 While a minority of patients had reduced absolute counts of total CD3+ cells, a majority of patients had no changes in total CD3 + , CD4 + , or CD8 + T-cell frequencies compared with healthy controls. 7,8 Our data are consistent with these findings (Figure S2A). Additionally, we found no differences in frequencies of CD25 + CD127 − regulatory T cells or CD19 + B cells (Figure S2A).…”

Atypical Localization of Eczema Discriminates DOCK8 or STAT3 Deficiencies from Atopic Dermatitis

“…We performed a detailed clinical examination and ordered laboratory tests, including complete blood cell count, serum immunoglobulin levels, and lymphocyte immunophenotyping of whole blood (CD3 + T, CD3 + CD4 + T, CD3 + CD8 + T, CD19 + B, CD16 + CD56 + NK, and CD4 + CD45RA + CD31 + T cells (RTE -recent thymic emigrants). Peripheral B cells were classi ed into three distinct populations: naive mature B cells (CD19+CD27-IgD+), non-classswitched memory B cells (NCS B -CD19+CD27+IgD+), and class-switched memory B cells (CS B -CD19+CD27+IgD-) (24)(25)(26).…”

False Negative Next-Generation-Sequencing Analysis in a Lipopolysa ccharide-Responsive Beige-Like Anchor Defect

“…However, some patients with LRBA gene defects may have normal LRBA protein expression on flow cytometry. 1 , 5 , 6 Knowing these restrictions, we used Sanger sequencing to diagnose the patient and analyzed flow cytometric LRBA protein expression for functional confirmation.…”