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

Abstract

Common variable immunodeficiency (CVID) is the most prevalent antibody deficiency, characterized by remarkable genetic, immunological, and clinical heterogeneity. The diagnosis of pediatric CVID is challenging due to the immaturity of the immune response and sustained actively developing antibody affinity to antigens and immunological memory that may overlap with the inborn error of immunity. Significant progress has been recently done in the field of immunogenetics, yet a paucity of experimental and clinical studies on different systemic manifestations and immunological features of CVID in children may contribute to a delayed diagnosis and therapy. In this review, we aimed at defining the variable epidemiological, etiological, and clinical aspects of pediatric CVID with special emphasis on predominating infectious and non-infectious phenotypes in affected children.Conclusion: While pediatric CVID is a multifaceted and notorious disease, increasing the pediatricians’ awareness of this disease entity and preventing the diagnostic and therapeutic delay are needed, thereby improving the prognosis and survival of pediatric CVID patients. What is Known:• CVID is an umbrella diagnosis characterized by complex pathophysiology with an antibody deficiency as a common denominator.• It is a multifaceted disease characterized by marked genetic, immunological, and clinical heterogeneity.. What is New:• The diagnosis of pediatric CVID is challenging due to the immaturity of innate and adaptive immune response.• Increasing the pediatricians’ awareness of CVID for the early disease recognition, timely therapeutic intervention, and improving the prognosis is needed.

DNAJB9 Is a Reliable Immunohistochemical Marker of Fibrillary Glomerulonephritis: Evaluation of Diagnostic Efficacy in a Large Series of Kidney Biopsies

“…Finally, Liang et al described a DNAJB9-negative FGN case characterized by membranous-like nephropathy (LM), monotypic IgG1 and λ light chain expression (IF), and 12–20 nm fibrils (EM) [ 21 ]. In our series, we identified a DNAJB9-negative FGN case as well: this 16-year-old male presented a peculiar clinical history characterized by common variable immunodeficiency (CVID), a disease characterized by hypo-/agammaglobulinemia and requiring intravenous monomeric immunoglobulins infusion [ 24 , 25 ]. As the putative etiopathogenetic mechanism of FGN seems to involve the interaction of DNAJB9 with misfolded IgG and C3 fragments, the most accredited hypothesis for DNAJB9-negative FGN cases reported so far involved the deposition of truncated immunoglobulins in the context of a monoclonal gammopathy (so called, heavy chain FGN) [ 16 , 26 ].…”

Chromatinopathies: insight in clinical aspects and underlying epigenetic changes

“…Notably, mutations in Kabuki syndrome-related genes, i.e., KMT2D and KDM6A, lead to impaired B-lymphocyte terminal differentiation. This results in hypogammaglobulinemia and diminished memory B-cell numbers, culminating in common variable immunodeficiency (CVID) (Szczawinska-Poplonyk et al 2022 ; Boniel et al 2021b ). In the context of Cornelia de Lange syndrome, genes associated with the condition play a crucial role in maintaining immune system balance.…”

Inborn Errors of Immunity With Fetal or Perinatal Clinical Manifestations

“…This IEI category encompassed 39 diseases in the latest IUIS classification, which are the most frequently identified defects in IEI patient series worldwide (29). Antibody deficiencies have not been diagnosed during neonatal period, but from the second semester onwards when placental antibodies disappeared, or even later, as in the heterogeneous group of Common Variable Immunodeficiencies (CVID) (2,3,39). In studying 1,008 patients with well-characterized primary immunodeficiencies (PIDs) followed at our Hospital, only 17% of the cases identified under 2 years of age had "Predominantly Antibody Deficiencies, " and all of those had X-linked Agammaglobulinemia or Transient Hypogammaglobulinemia of Infancy (5).…”