Human Inborn Errors of Immunity: 2019 Update on the Classification from the International Union of Immunological Societies Expert Committee

Abstract

We report the updated classification of Inborn Errors of Immunity/Primary Immunodeficiencies, compiled by the International Union of Immunological Societies Expert Committee. This report documents the key clinical and laboratory features of 430 inborn errors of immunity, including 64 gene defects that have either been discovered in the past 2 years since the previous update (published January 2018) or were characterized earlier but have since been confirmed or expanded upon in subsequent studies. The application of next-generation sequencing continues to expedite the rapid identification of novel gene defects, rare or common; broaden the immunological and clinical phenotypes of conditions arising from known gene defects and even known variants; and implement gene-specific therapies. These advances are contributing to greater understanding of the molecular, cellular, and immunological mechanisms of disease, thereby enhancing immunological knowledge while improving the management of patients and their families. This report serves as a valuable resource for the molecular diagnosis of individuals with heritable immunological disorders and also for the scientific dissection of cellular and molecular mechanisms underlying inborn errors of immunity and related human diseases.

The clinical, immunological and genetic features of 12 Chinese patients with STAT3 mutations

“…A molecular study found that HIES is caused by variations in STAT3, Dedicator of cytokinesis 8 (DOCK8) [28], phosphoglucomutase 3 gene (PGM3) [9] and ZNF341 [29]. Simultaneously, STAT3-de ciency disease is categorized into two types: STAT3 LOF mutation disease comprises immunode ciencies with syndromic features, while STAT3 GOF mutation disease involves immune dysregulation, especially regulatory T cell defects, according to the International Union of Immunological Societies in 2019 [30]. Our patients overwhelmingly had STAT3 LOF mutations.…”

Newborn Screening for Presymptomatic Diagnosis of Complement and Phagocyte Deficiencies

“…Accurate and early diagnosis is vital as complement deficiencies and phagocytic disorders are associated with numerous immunological complications. Complement deficiencies cause recurrent and persistent infections in the upper respiratory tract, recurrent pneumococcal and meningococcal infections, hereditary angioedema (HAE), autoimmune complications, and renal failure due to atypical hemolytic uremic syndrome (aHUS) and glomerulonephritis (GN) (8). Severe congenital neutropenia (SCN) and chronic granulomatous disease (CGD) are characterized by low granulocyte counts or defects in the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase pathway, leading to conditions such as delayed wound healing, deep organ infections, and abscess formation.…”

“…Considering the disease mechanisms of complement and phagocytic defects that involve the absence, or expression/structural alteration of a functional protein, protein profiling of blood samples could provide a fundamental diagnostic tool (10). Here, we developed a newborn screening assay based on suspension bead array technology for parallel profiling of the main reported disease-associated proteins in the complement cascade, phagocytosis and respiratory burst function (8). The method uses a fraction of DBS corresponding to a sub-microliter volume of blood, and is applicable for population-scale performance (Figure 1).…”

Primary immunodeficiencies in cytosolic pattern‐recognition receptor pathways: Toward host‐directed treatment strategies

“…Primary immunodeficiencies (PIDs) refer to a heterogeneous group of inherited disorders, predominantly caused by single‐gene defects 1 . The American Colonel Bruton is generally considered to have serendipitously discovered the first PID case in 1952, describing agammaglobulinemia as the cause of recurrent pneumonia in an 8‐year old boy 2 .…”