Key Points
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Primary antibody deficiencies (PADs) are the most common type of primary immunodeficiency and arise either alone or in combination with immunodeficiencies affecting other aspects of immunity against pathogens.
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PADs are not solely due to B cell-intrinsic defects; they can also result from impairments in other cell lineages (especially T cells, but also innate immune cells). These observations emphasize the fact that B cell responses are sustained by both innate and adaptive immune signals.
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Many PADs that result from B cell-intrinsic defects have now been characterized. These PADs variously involve all aspects of B cell biology, from B cell differentiation to B cell migration, survival and activation, and their characterization has helped to identify key molecules in B cell function.
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B cell-extrinsic defects that result in PADs include defects in T cells, and particularly in T follicular helper cells, thus providing evidence for the essential role of these cells in antibody production. Some recently described defects in innate immune cells highlight the role of pattern-recognition receptors and T cell-independent antibody responses.
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Depending on their underlying cause, PADs have been associated with various pathologies, including susceptibility to microbial infections, autoinflammatory and autoimmune diseases and some types of cancer.
Abstract
Primary antibody deficiencies (PADs) are the most common inherited immunodeficiencies in humans. The use of novel approaches, such as whole-exome sequencing and mouse genetic engineering, has helped to identify new genes that are involved in the pathogenesis of PADs and has enabled the characterization of the molecular pathways that are involved in B cell development and function. Here, we review the different PADs in terms of their known or putative mechanisms, which can be B cell intrinsic, B cell extrinsic or not defined so far. We also describe the clinical manifestations (including susceptibility to infections, autoimmunity and cancer) that have been associated with the various PADs.
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Acknowledgements
The authors apologize to all colleagues whose work could not be cited owing to length restrictions. The authors thank C. Picard for critical reading of the manuscript. This work was funded by grants from Institut National de la Santé et de la Recherche Médicale, the European Union's 7th RTD Framework Programme (EURO-PADnet grant number 201549 and ERC PIDIMMUNE grant number 249816), Association Contre Le Cancer and ANR Blanc 2010-CSRD. S.K. is a Centre National de la Recherche Scientifique (CNRS) researcher.
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Glossary
- Pre-B cell receptor
-
(Pre-BCR). A receptor that is formed at the surface of pre-B cells when rearranged immunoglobulin heavy chains pair with surrogate immunoglobulin light chains; the pre-BCR is associated with signalling heterodimers of Igα and Igβ. Signalling through the pre-BCR occurs in the absence of known ligands and is a crucial event in B cell development.
- Pre-B cells
-
Haematopoietic cells that appear in the bone marrow early during B cell development, downstream of the CD34+ pro-B cell precursor. At the pre-B1 stage, the cells still express CD34 but acquire the B cell-specific marker CD19. Pre-B2 cells are characterized by complete immunoglobulin heavy chain rearrangement in the absence of immunoglobulin light chain rearrangement. They express the pre-B cell receptor (which comprises a pseudo-light chain and the -heavy chain), CD19 and cytoplasmic IgM.
- V(D)J recombination
-
A site-specific recombination process (targeting recombination signal sequences) that takes place in primary lymphoid tissues and stochastically combines the different regions of the T cell and B cell receptors (variable (V), diversity (D) and joining (J) regions) in pre-T and pre-B cell precursors. The lymphoid-specific enzymes RAG1 and RAG2 and the non-lymphoid-specific non-homologous end joining DNA repair complex (which includes DNA protein kinase, Ku70–Ku80, Artemis, XRCC4, DNA ligase 4 and Cernunnos) control this process.
- Polysaccharide-specific antibodies
-
Antibodies that are secreted during T cell-independent antibody responses (especially by marginal zone B cells).
- Marginal zone
-
An anatomical site located at the interface between the red pulp and the lymphoid white pulp of the spleen, in which marginal zone B cells are rapidly recruited into early, adaptive immune responses in a T cell-independent manner. Marginal zone B cells produce IgM as the first line of defence against blood-borne antigens.
- Germinal centre
-
Within secondary lymphoid tissues, B cells exposed to migration signals (through CXCL13–CXCR5) enter the follicles and, following interaction with cognate T cells, undergo vigorous proliferation and form germinal centres. B cells undergo class-switch recombination and somatic hypermutation in these germinal centres.
- T cell-dependent antibody response
-
Antibody response to protein antigens that require T cell help. This response mostly occurs in the germinal centre in secondary lymphoid organs, via CD40L–CD40 interactions.
- T cell-independent antibody response
-
Antibody response to polymeric antigens, such as polysaccharides and lipids, that do not require T cell help.
- Class-switch recombination
-
(CSR). Region-specific DNA recombination between two different switch regions located upstream of the constant (C) regions in the immunoglobulin locus, with excision of the intervening DNA. Replacement of the Cμ region by a downstream C region from another class of immunoglobulin results in the production of antibodies of different isotypes (IgG, IgA and IgE).
- Somatic hypermutation
-
(SHM). SHM introduces mutations into the immunoglobulin variable regions and is a major component of affinity maturation, providing a basis for the selection and proliferation of B cells expressing a B cell receptor with a high affinity for the antigen.
- T follicular helper cell
-
(TFH cell). A germinal centre T helper cell that expresses the chemokine receptor CXCR5 and the co-stimulatory molecules CD40L and ICOS, but only low levels of CCR7. TFH cells are essential for class-switch recombination and somatic hypermutation in B cells. They secrete cytokines (especially interleukin-21, which acts in a paracrine and autocrine manner).
- Activation-induced cytidine deaminase
-
(AID). A key enzyme that induces somatic hypermutation and class-switch recombination by deaminating cytosine bases to uracil bases in single-stranded DNA in the variable and switch regions of the immunoglobulin locus.
- Uracil N-glycosylase
-
(UNG). A base excision repair enzyme that recognizes and removes uracils (including those induced by AID) from within DNA.
- Mismatch repair
-
(MMR). A repair pathway that recognizes and corrects mismatched base pairs (typically those that arise from errors of chromosomal DNA replication). There are two main types of MMR components: MutS homologues (MSH1–MSH6) and MutL homologues (PMS2, MLH1 and PMS1).
- B cell tolerance
-
B cell tolerance is controlled by two checkpoints: central B cell tolerance is achieved in the bone marrow, through the removal of immature B cells that express polyreactive antibodies, whereas peripheral B cell tolerance mechanisms operate at the transition between immature and mature naive B cells and counterselect self-reactive B cells that may have encountered peripheral autoantigens that are not expressed in the bone marrow. Disruption of B cell tolerance leads to autoimmunity.
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Durandy, A., Kracker, S. & Fischer, A. Primary antibody deficiencies. Nat Rev Immunol 13, 519–533 (2013). https://doi.org/10.1038/nri3466
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DOI: https://doi.org/10.1038/nri3466
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