Key Points
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More than 120 primary immunodeficiency diseases have been described, and the genetic basis of many of these has now been determined. Antibody deficiencies constitute the largest group within the primary immunodeficiencies.
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Severe combined immunodeficiency (SCID) is characterized by lack of an adaptive immune response and is fatal if untreated. The early diagnosis of SCID through a newborn-screening programme would allow life-saving haematopoietic stem-cell transplantation to occur in the neonatal period.
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T-cell immunodysregulation involved in self-recognition is seen in three conditions: IPEX (immunodysregulation, polyendocrinopathy and enteropathy, X-linked syndrome), APECED (autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy syndrome) and ALPS (autoimmune lymphoproliferative syndrome).
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Seven defects that are known to be involved in the hyper-IgM syndromes (HIGMs) have been characterized: defects in the CD40 ligand gene, classified as HIGM type 1 (HIGM1; also known as X-linked HIGM); defects in the activation-induced cytidine deaminase (AID) gene, classified as HIGM2; defects in CD40, classified as HIGM3; defective class-switch recombination with preserved somatic hypermutation, classified as HIGM4; defects in the uracil-DNA glycosylase (UNG) gene; defects in IKKG (IκB (inhibitor of nuclear factor-κB, NF-κB) kinase-γ); and defects in NFKBIA (which encodes IκBα).
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There is an emerging understanding of the importance of components of the innate immune system in the aetiology of primary immunodeficiency, including mutations in NFKBIA, IRAK4 (interleukin-1-receptor-associated kinase 4) and the caspase-12 gene. The innate and adaptive immune systems, which were historically thought of as segregated, do not function as distinct entities; instead, they are interdependent and function together to coordinate the host immune response.
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Common variable immunodeficiency (CVID) is characterized by a defect in antibody production. The mutated genes that produce the CVID phenotype are known only for a minority of patients, and they are diverse in their influence on immune function and include ICOS (inducible T-cell co-stimulator), SH2D1A — which encodes SAP (signalling lymphocytic activation molecule (SLAM)-associated protein) and is involved in X-linked lymphoproliferative syndrome — and three genes that have recently been described to be involved: CD19, BAFFR (B-cell-activating-factor receptor) and TACI (transmembrane activator and calcium-modulating cyclophilin-ligand interactor).
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Haematopoietic stem-cell transplantation has been attempted for the treatment of patients with several types of primary immunodeficiency, most successfully for individuals with SCID.
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Clinical trials have been carried out using gene therapy for the treatment of patients with X-linked, recessive SCID (which is caused by common cytokine-receptor γ-chain deficiency) and patients with adenosine-deaminase deficiency. Insertional mutagenesis proved to be a serious adverse event in some patients, and further insight is needed for the design and delivery of retroviral vectors before this life-saving therapy can be provided in the future.
Abstract
More than 120 inherited primary immunodeficiency diseases have been discovered in the past five decades, and the precise genetic defect in many of these diseases has now been identified. Increasing understanding of these molecular defects has considerably influenced both basic and translational research, and this has extended to many branches of medicine. Recent advances in both diagnosis and therapeutic modalities have allowed these defects to be identified earlier and to be more precisely defined, and they have also resulted in more promising long-term outcomes. The prospect of gene therapy continues to be included in the armamentarium of treatment considerations, because these conditions could be among the first to benefit from gene-therapy trials in humans.
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Glossary
- T-CELL-RECEPTOR EXCISION CIRCLES
-
(TRECs). DNA episomes that are normally produced during the thymic maturation of T cells, specifically during recombination of the T-cell-receptor genes.
- X-LINKED LYMPHOPROLIFERATIVE SYNDROME
-
(XLP). A rare, often fatal, primary immunodeficiency disease that is characterized by an inability to mount an effective immune response to Epstein–Barr virus. This can lead to lymphoma or hypogammaglobulinaemia.
- CD4+CD25hi REGULATORY T CELLS
-
A thymus-derived subpopulation of T cells that expresses the transcription factor forkhead box P3 (FOXP3) and is involved in the suppression of immune responses, either by cell–cell contact or cytokine release.
- CYCLOSPORIN A AND TACROLIMUS
-
Calcineurin inhibitors that are used to prevent transplant rejection and that function by inhibiting nuclear factor of activated T cells (NFAT).
- CLASS-SWITCH RECOMBINATION
-
(CSR). A switch in the DNA that encodes the constant region of the immunoglobulin heavy chain, from Cμ (which encodes the constant region of IgM) to DNA that is further downstream and encodes the constant region of another immunoglobulin class: that is, to Cγ, Cα or Cε, which encode the constant region of IgG, IgA and IgE, respectively. This is accomplished through an intrachromosomal deletional rearrangement.
- SOMATIC HYPERMUTATION
-
(SHM). The introduction of point mutations at a high frequency in the variable regions of immunoglobulin genes.
- HYPOMORPHIC MUTATION
-
A type of mutation that results in either diminished quantity of a normal gene product or diminished function of a gene product.
- HYPODONTIA
-
The partial congenital absence of one or more teeth.
- TOLL-LIKE RECEPTORS
-
(TLRs). A family of evolutionarily conserved pattern-recognition receptors. These molecules are located intracellularly and at the cell surface of macrophages, dendritic cells, B cells and intestinal epithelial cells. Their natural ligands are conserved molecular patterns, known as pathogen-associated molecular patterns, that are found in bacteria, viruses and fungi.
- BRONCHIECTASIS
-
A permanent dilation of the bronchi, owing to chronic inflammation, that increases susceptibility to recurrent infections.
- TERMINAL DEOXY-NUCLEOTIDYLTRANSFERASE
-
(TdT). An enzyme that inserts nucleotides into the variable regions of T-cell receptor and immunoglobulin genes, thereby creating junctional diversity.
- INDUCIBLE T-CELL COSTIMULATOR
-
(ICOS). A homodimeric transmembrane protein that is selectively expressed at the surface of activated T cells. It specifically interacts with ICOS ligand (also known as B7-H2), which is expressed by many cell types, including professional antigen-presenting cells, fibroblasts, epithelial cells and endothelial cells.
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Cunningham-Rundles, C., Ponda, P. Molecular defects in T- and B-cell primary immunodeficiency diseases. Nat Rev Immunol 5, 880–892 (2005). https://doi.org/10.1038/nri1713
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DOI: https://doi.org/10.1038/nri1713
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