A Critical Review on the Standardization and Quality Assessment of Nonfunctional Laboratory Tests Frequently Used to Identify Inborn Errors of Immunity

Abstract

Inborn errors of immunity (IEI), which were previously termed primary immunodeficiency diseases, represent a large and growing heterogeneous group of diseases that are mostly monogenic. In addition to increased susceptibility to infections, other clinical phenotypes have recently been associated with IEI, such as autoimmune disorders, severe allergies, autoinflammatory disorders, benign lymphoproliferative diseases, and malignant manifestations. The IUIS 2019 classification comprises 430 distinct defects that, although rare individually, represent a group affecting a significant number of patients, with an overall prevalence of 1:1,200-2,000 in the general population. Early IEI diagnosis is critical for appropriate therapy and genetic counseling, however, this process is deeply dependent on accurate laboratory tests. Despite the striking importance of laboratory data for clinical immunologists, several IEI-relevant immunoassays still lack standardization, including standardized protocols, reference materials, and external quality assessment programs. Moreover, well-established reference values mostly remain to be determined, especially for early ages, when the most severe conditions manifest and diagnosis is critical for patient survival. In this article, we intend to approach the issue of standardization and quality control of the nonfunctional diagnostic tests used for IEI, focusing on those frequently utilized in clinical practice. Herein, we will focus on discussing the issues of nonfunctional immunoassays (flow cytometry, enzyme-linked immunosorbent assays, and turbidimetry/nephelometry, among others), as defined by the pure quantification of proteins or cell subsets without cell activation or cell culture-based methods.

Case Report: A novel IRF2BP2 mutation in an IEI patient with recurrent infections and autoimmune disorders

“…Immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis (with flow cytometry analysis), and measurement of serum immunoglobulins (using turbidimetry/nephelometry and enzyme-linked immunosorbent assay) ( 17 , 18 ). In addition, due to recurrent fever of the patient, mNGS of blood, cerebrospinal fluid and biopsy from small intestine were used to detect unbiased thousands of pathogens.…”

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

“…Characteristic clinical findings include benign, chronic lymphadenopathy and splenomegaly, autoimmune cytopenias, and a high risk for the development of lymphoma. The classical laboratory hallmark of ALPS is the presence of circulating mature double-negative T cells (α/β receptor-carrying T cells that do not express CD4 or CD8 (57). Prenatal manifestations have been described in a few fetuses with genomic homozygous deletion of FAS/TNFRSF6 (11,58,59).…”