The CXCR5 T follicular helper cell compartment in children with antibody deficiencies – in search of a prognostic marker of childhood hypogammaglobulinemia

Abstract

Background: Novel immunodiagnostic markers are required in order to discriminate between mild hypogammaglobulinemia and severe humoral primary immune deficiencies in children. The efficacy of an antibody response to infections and vaccines is underpinned by T follicular helper (Tfh) cells, activating an immunoglobulin class switch recombination, somatic hyper-mutations, and affinity maturation. Objective: To determine the formation of the Tfh cells in antibody deficient children and to define their importance as prognostic markers helpful in defining the severity of hypogammaglobulinemia. Methods: We retrospectively reviewed medical records of 200 children aged from 2 months to 10 years, in whom hypogammaglobulinemia was assessed, from January to December 2019. In all the children studied, a flow cytometric analysis of the Tfh cell compartment was performed. Results: In young infants aged from 2 to 9 months, the mean relative frequency of the Tfh population was lower than in the control population. Concomitantly, the relative values of Tfh cells, corresponding with the 95th percentile, were below the reference values in all age groups. Conclusions: A deficiency of Tfh cells in young infants mirrors the immaturity of the humoral immune response, whereas in older children Tfh cells are proposed as a prognostic marker facilitating to distinguish between mild hypogammaglobulinemia and the developing common variable immunodeficiency.

Immune Dysregulation in Pediatric Common Variable Immunodeficiency: Implications for the Diagnostic Approach

“…Furthermore, a flow cytometric analysis of peripheral B and T lymph cells in children manifesting lymphoproliferative disorders has revealed developmental abnormalities of total CD19+ and switched memory B cells along with T cells subsets, such as RTE, naive Th, and Treg cells. These flow cytometric features of dysfunctional B and T lymph cell immune response were accompanied by increased numbers of follicular Th (fTh) cells, which not only may be considered as diagnostic biomarkers of costimulation to B cells and their impairment may point to CVID in children ( 40 ), but they have also been proposed to trigger autoreactive B-cell populations, thereby contributing to the development of autoimmune and lymphoproliferative complications in CVID ( 37 , 41 ). In our study group showing lymphoproliferative disorders, the clinical diagnoses included lymphadenopathy, GLILD (as shown in Figure 6 ), hepatosplenomegaly, and cutaneous granulomas.…”

The pediatric common variable immunodeficiency — from genetics to therapy: a review

“…Abnormalities of various pathways across the adaptive and innate immune responses have been revealed in pediatric CVID, and extensive attempts have been undertaken to establish correlations between the interrupted immunological homeostasis and clinical complications. The most frequently reported abnormalities within the B cell compartment were a defective generation of total memory B cell population [ 33 – 35 ], reduced number of switched memory B cells, reflecting impairment in germinal center reaction [ 34 ], deficiency in CD3 + CD4 + CD45RO + CD185 + (CXCR5 +) follicular T helper cell, and consequently, inefficient CSR, SHM, and immunoglobulin affinity maturation [ 36 ], yet defective pre-germinal center B cell maturation pathways have also been shown in CVID [ 37 ]. Among T cells, most frequently, low numbers of total CD4 + T helper cell subsets, essential for effective B cell response and antibody production [ 33 , 35 ], followed by deficiency of CD3 + CD4 + CD45RA + naïve T cells and CD3 + CD4 + CD45RA + CD31 + recent thymic emigrants were reported in pediatric CVID [ 33 ].…”