Review Article | Published:

Immunological and genetic bases of new primary immunodeficiencies

Nature Reviews Immunology volume 7, pages 851861 (2007) | Download Citation


Since 1952, when congenital agammaglobulinaemia was described by Bruton, the characterization of genetically defined immunodeficiencies in humans has been crucial for a better understanding of the biology of the innate and adaptive immune responses. This Review focuses on the characterization of new primary immunodeficiencies and disease-related genes. A series of primary defects of innate immunity have recently been discovered and are discussed here. Moreover, new defects in pre-B-cell and B-cell differentiation and antibody maturation are summarized and recently discovered monogenic immunodeficiencies that disturb the homeostasis of both the innate and the adaptive immune systems are discussed.

Key points

  • This Review reports on a series of recent discoveries that have added to the characterization of the molecular and cellular basis of primary immunodeficiencies (PIDs) in humans. A total of more than 200 PIDs that are caused by mutations in over 100 distinct genes are now known.

  • The spectrum of mutations in genes that are associated with innate immunity that predispose the individual to selected pathogenic infections is expanding. The discovery that mutations in Toll-like receptor 3 (TLR3) and in UNC93B (an adaptor protein involved in TLR signalling) cause increased susceptibility to herpes simplex virus (HSV) encephalitis indicates that TLR3-mediate signalling has a non-redundant role in the control of HSV infection.

  • Defects in the JAK–STAT (Janus kinase–signal transducer and activator of transcription) pathway have been recognized to be responsible for hyper-IgE syndrome (HIES). In particular, mutations in TYK2 (tyrosine kinase 2) have been identified in one patient with autosomal recessive HIES, whereas the more common autosomal dominant variant is caused by dominant negative mutations in STAT3. These mutations impair cytokine-mediated signalling, T-helper-1-cell differentiation, and probably affect interleukin-17 (IL-17) and IL-22 production.

  • Mutations in HAX1 and MAPBPIP have been identified to cause chronic neutropaenia by interfering with apoptosis and with the trafficking of intracellular proteins and granules, respectively. In addition, activating mutations in WASP (Wiskott–Aldrich syndrome protein) have been found to cause neutropaenia by interfering with cytokinesis, mitosis and genomic stability.

  • The molecular basis of leukocyte adhesion deficiency type III has been identified. Mutations in RASGRP2 cause impaired inside-out integrin signalling.

  • Novel forms of genetically determined humoral immunodeficiency include mutations in B29 (the gene encoding Igβ) and CD19. In addition, there is growing evidence that defects in DNA repair might be involved in immunodeficiencies that are associated with impaired class-switch recombination and possibly also in common variable immunodeficiency.

  • The molecular spectrum of well-defined combined immunodeficiencies now also includes mutations in ORAI1, a component of calcium-regulated activated calcium (CRAC) channels that is essential to operate calcium influx.

  • Finally, mutations in immune genes can result in defects in immune regulation, with autoimmunity and lymphoproliferation. New examples are represented by mutations in XIAP (resulting in X-linked lymphoproliferative disease type 2), CD95 ligand and NRAS (resulting in two forms of autoimmune lymphoproliferative syndrome), in CD25 (resulting in an immunodysregulation, polyendocrinopathy and enteropathy, X-linked (IPEX)-like syndrome) and in SP110 (resulting in combined immunodeficiency and hepatic veno-occlusive disease).

  • This remarkable series of advances, produced within one year, indicates the value of continuing to study human subjects affected with rare diseases. Characterization of these unique patients is of great importance to better define the mechanisms that govern immune-system development and function, and might offer the basis for new and targeted immune interventions.

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Supported by the Hungarian Research Fund (OTKA 49,174) (L.M.) and by European Union EURO-POLICY-PID and CARIPLO-NOBEL grants (L.D.N.). We thank M. Erdõs for input on the figures.

Author information


  1. Department of Infectious and Pediatric Immunology, University of Debrecen Medical and Health Science Center, H-4,012 Debrecen, Hungary.

    • László Maródi
  2. Division of Immunology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Luigi D. Notarangelo


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Corresponding authors

Correspondence to László Maródi or Luigi D. Notarangelo.


Toll-like receptor

(TLR). A type of pattern-recognition receptor that recognizes unique structures derived from microorganisms. Signalling through TLRs promotes inflammatory immune responses, cytokine production and cell activation in response to microorganisms.

Hypomorphic mutation

A mutation in a gene that results in reduced expression or activity of the gene without complete loss of function.

Linkage analysis

A method for tracking the transmission of genetic information across generations to identify the map location of genetic loci on the basis of co-inheritance of genetic markers and discernable phenotypes in families.

Chediak–Higashi syndrome

An autosomal recessive disorder characterized by oculocutaneous albinism, recurrent infections, neurological abnormalities, neutrophil chemotactic defects and giant cytoplasmic granules. The lysosomal trafficking regulator (LYST) gene of as yet poorly defined function, is mutated in this syndrome.

Griscelli syndrome type 2

An autosomal recessive disorder characterized by partial albinism, silvery grey hair, variable cellular immunodeficiency, recurrent infections and an accelerated phase.

Hermansky–Pudlak syndrome type 2

An autosomal recessive disorder characterized by oculocutaneous albinism, platelet dysfunction and bleeding tendency, neutropaenia and impaired cytotoxic activity.

Inside-out signalling

The process by which intracellular signalling mechanisms result in the activation of a cell-surface receptor, such as integrins. By contrast, outside-in signalling is the process by which ligation of a cell-surface receptor activates signalling pathways inside the cell.

Class-switch recombination

(CSR). This process alters the immunoglobulin heavy chain (H) constant (C)-region gene that is expressed by B cells from Cμ to one of the other CH genes. This results in a switch of immunoglobulin isotype from IgM/IgD to IgG, IgA or IgE, without altering antigen specificity.

Somatic hypermutation

(SHM). A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, SHM leads to affinity maturation of B cells in germinal centres.


The presence of short stretches of homologous nucleotides that flank DNA double-strand breaks (DSBs). The presence of such sequences favours the alignment of DNA ends and DNA repair through microhomology-mediated end-joining (MMEJ), a mechanism that is less dependent on Ku proteins than non-homologous end-joining (NHEJ). MMEJ might function as a salvage pathway for DNA DSBs that cannot be repaired by NHEJ.

Non-homologous end-joining

(NHEJ). A pathway that rejoins DNA strand breaks without relying on significant homology. The main known pathway uses the Ku-end binding complex and is regulated by DNA protein kinase. The pathway is often used in mammalian cells to repair strand breaks caused by DNA-damaging agents, and some of the same enzymes are used during the strand-joining steps of V(D)J recombination.

Holliday junction

A point at which the strands of two double-strand DNA molecules exchange partners, which occurs as an intermediate during genetic recombination.

Intrachromosomal synapsis

The pairing of homologous chromosomes along their length. Synapsis usually occurs during prophase I of meiosis, but it can also occur in somatic cells of some organisms.

MRL–lpr mouse

A mouse strain that spontaneously develops glomerulonephritis and other symptoms of systemic lupus erythematosus (SLE). The lpr mutation causes a defect in CD95 (also known as FAS), preventing apoptosis of activated lymphocytes. The MRL strain contributes disease-associated mutations that have yet to be identified.

Immune thrombocytopaenic purpura

An acute-onset thrombocytopaenia caused by autoantibodies directed against unknown antigens on the platelet surface. Antibody-coated platelets are recognized and eliminated from the circulation by splenic macrophages. Immune thrombocytopaenic purpura usually develops 2–4 weeks after exposure to common viral pathogens, including Epstein–Barr virus and HIV.

Noonan syndrome

A developmental disorder characterized by short stature, facial dysmorphisms, congenital heart defects and skeletal anomalies.

Costello syndrome

An autosomal dominant disorder comprising growth deficiency, mental retardation, curly hair, coarse facial features, nasal papillomata, low-set ears with large lobes, cardiac anomalies, redundant skin on palms and soles with prominent creases, dark skin and propensity to certain solid tumours. HRAS mutations have been implicated in approximately 85% of the affected cases.

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