Expanded Phenotype Evaluation Of Patients With Primary Immunodeficiencies With Dysregulation

Abstract

Introduction: primary immunodeficiencies with dysregulation associate defects in the immune homeostasis leading to inappropriate immune response (lack or excess) that causes autoimmunity, allergy and/or inflammation. Impairment of different subsets of T and B compartments may be associated with these PIDs. Aim: 1) Describe T and B memory compartment of 18 PID patients (pts) with dysregulation: 1 CD25 deficiency, 3 STAT1 GOF, 1 STAT5b deficiency, 4 CTLA4 variant, 2 PI3KCD variant and 6 CVID-like (with no molecular defect) and compare them with a group of healthy donors (HD). 2) Associate cTfh profile with B cell compartment impairment. Results: 1) Pts showed a significant decrease of Naïve CD4+ T cells (CD45RA+CD27+) (52,2% vs 17,6%) (p<0.0001) with expanded central memory T cells (CD45RA-CD27+) (32.8% vs 60.8%) (p<0.0001); CD4+ T cells had higher levels of activation markers (CD4+HLA-DR+) (6,1%vs 27,4%) (p<0,0001). Pts showed a significant increase of circulating follicular T cells (cTfh) (CD45RA-CXCR5+) compared with HD (mean 30,5% vs 11,6%) (p<0,0001) with PD-1 overexpression (p<0.0001). STAT1 GOF, CTLA4, PI3KCD and CVID-like pts showed a skew towards cTfh1 (CXCR3+). Regulatory T cells (CD4+CD25++FOXP3+) were absent in CD25 and STAT5b deficiency and decreased in the other pts. Within CD8+ cells, although effector memory (CD45RA-CD27-) (p<0.002), TEMRA (CD45RA+CD27-) (p<0.009) and HLA-DR+ CD8+ (p<0.002) subsets showed a significant increase compared with HD, the behaviour was variable between different mutations. Regarding B cell compartment, pts with STAT1GOF, PI3KCD and CVID-like showed a severe impairment of switched-memory B cells (Sw-MBL) (CD27+IgD-IgM-); the STAT5b deficient patient had increased frequencies of this subset, while CTLA4 pts had a variable B defect. 2) lower Sw-MBL values were significantly associated with lower values of cTfh17 cells (p<0.007) (r=0.6975). CD21low B cells were exclusively high in CVID-like pts, and transitional B cells were increase in PI3KCD and almost all CVID-like pts. Discussion: In summary, patients with dysregulatory syndromes associate a defect of T and B homeostasis (survival, activation and differentiation). Specific mutations can differentially affect the quantity and/or the quality of cTfh. There is a strict association between the differentiation of Tfh with TH17 profile with the generation of Sw-MBL. These alterations may play a role in the pathophysiology of primary immunodeficiencies with B lymphocyte functional impairment. Immune monitoring of lymphocyte subsets of patient with dysregulation may approach to the diagnosis of specific monogenic mutations.