Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Primary antibody deficiencies

Nature Reviews Immunology volume 13, pages 519–533 (2013)Cite this article

Subjects

Key Points

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Pre-BCR and BCR signalling defects in PADs.
Figure 2: B cell migration defects in PADs.
Figure 3: B cell survival defects in PADs.
Figure 4: B cell activation defects and CSR defects in PADs.

Similar content being viewed by others

References

  1. Conley, M. E. et al. Primary B cell immunodeficiencies: comparisons and contrasts. Annu. Rev. Immunol. 27, 199–227 (2009).

    CAS  PubMed  Google Scholar 

  2. Berkowska, M. A., van der Burg, M., van Dongen, J. J. & van Zelm, M. C. Checkpoints of B cell differentiation: visualizing Ig-centric processes. Ann. NY Acad. Sci. 1246, 11–25 (2011).

    CAS  PubMed  Google Scholar 

  3. Tangye, S. G., Deenick, E. K., Palendira, U. & Ma, C. S. T cell-B cell interactions in primary immunodeficiencies. Ann. NY Acad. Sci. 1250, 1–13 (2012).

    CAS  PubMed  Google Scholar 

  4. Durandy, A., Revy, P. & Fischer, A. Human models of inherited immunoglobulin class switch recombination and somatic hypermutation defects (hyper-IgM syndromes). Adv. Immunol. 82, 295–330 (2004).

    CAS  PubMed  Google Scholar 

  5. Meffre, E. The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann. NY Acad. Sci. 1246, 1–10 (2011).

    CAS  PubMed  Google Scholar 

  6. Salzer, U. et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113, 1967–1976 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Conley, M. E. et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K. J. Exp. Med. 209, 463–470 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Vetrie, D. et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361, 226–233 (1993). This paper provided the first description of a gene defect causative of an inherited immune deficiency.

    CAS  PubMed  Google Scholar 

  9. Fruman, D. A. Phosphoinositide 3-kinase and its targets in B-cell and T-cell signaling. Curr. Opin. Immunol. 16, 314–320 (2004).

    CAS  PubMed  Google Scholar 

  10. Lopez-Granados, E., Perez de Diego, R., Ferreira Cerdan, A., Fontan Casariego, G. & Garcia Rodriguez, M. C. A genotype-phenotype correlation study in a group of 54 patients with X-linked agammaglobulinemia. J. Allergy Clin. Immunol. 116, 690–697 (2005).

    CAS  PubMed  Google Scholar 

  11. Bykowsky, M. J. et al. Discordant phenotype in siblings with X-linked agammaglobulinemia. Am. J. Hum. Genet. 58, 477–483 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Wood, P. M. et al. A mutation in Bruton's tyrosine kinase as a cause of selective anti-polysaccharide antibody deficiency. J. Pediatr. 139, 148–151 (2001).

    CAS  PubMed  Google Scholar 

  13. Hernandez, P. A. et al. Mutations in the chemokine receptor gene CXCR4 are associated with WHIM syndrome, a combined immunodeficiency disease. Nature Genet. 34, 70–74 (2003).

    CAS  PubMed  Google Scholar 

  14. Derry, J. M., Ochs, H. D. & Francke, U. Isolation of a novel gene mutated in Wiskott-Aldrich syndrome. Cell 78, 635–644 (1994).

    CAS  PubMed  Google Scholar 

  15. Westerberg, L. et al. Wiskott-Aldrich syndrome protein deficiency leads to reduced B-cell adhesion, migration, and homing, and a delayed humoral immune response. Blood 105, 1144–1152 (2005).

    CAS  PubMed  Google Scholar 

  16. Westerberg, L. S. et al. Wiskott-Aldrich syndrome protein (WASP) and N-WASP are critical for peripheral B-cell development and function. Blood 119, 3966–3974 (2012). This study precisely characterizes the role of WASP in B cell development and function.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Becker-Herman, S. et al. WASp-deficient B cells play a critical, cell-intrinsic role in triggering autoimmunity. J. Exp. Med. 208, 2033–2042 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Lanzi, G. et al. A novel primary human immunodeficiency due to deficiency in the WASP-interacting protein WIP. J. Exp. Med. 209, 29–34 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhang, Q. et al. Combined immunodeficiency associated with DOCK8 mutations. N. Engl. J. Med. 361, 2046–2055 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Randall, K. L. et al. Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production. Nature Immunol. 10, 1283–1291 (2009). References 19 and 20 simultaneously provided the first description of the role of DOCK8 in B cells and T cell immunity.

    CAS  Google Scholar 

  21. Jabara, H. H. et al. DOCK8 functions as an adaptor that links TLR-MyD88 signaling to B cell activation. Nature Immunol. 13, 612–620 (2012).

    CAS  Google Scholar 

  22. Pan, D. The hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Nehme, N. T. et al. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival. Blood 119, 3458–3468 (2012).

    CAS  PubMed  Google Scholar 

  24. Abdollahpour, H. et al. The phenotype of human STK4 deficiency. Blood 119, 3450–3457 (2012). References 23 and 24 simultaneously provided the first description of the role of MST1 in B cell and T cell immunity.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Warnatz, K. et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl Acad. Sci. USA 106, 13945–13950 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang, H. Y. et al. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc. Natl Acad. Sci. USA 110, 5127–5132 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. van Zelm, M. C. et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354, 1901–1912 (2006). This paper provides the first description of an inherited hypogammaglobulinaemia caused by defective BCR co-stimulatory molecules.

    CAS  PubMed  Google Scholar 

  28. van Zelm, M. C. et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J. Clin. Invest. 120, 1265–1274 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Thiel, J. et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J. Allergy Clin. Immunol. 129, 801–810.e6 (2012).

    CAS  PubMed  Google Scholar 

  30. Kuijpers, T. W. et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J. Clin. Invest. 120, 214–222 (2010).

    CAS  PubMed  Google Scholar 

  31. Xu, G. L. et al. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature 402, 187–191 (1999).

    CAS  PubMed  Google Scholar 

  32. de Greef, J. C. et al. Mutations in ZBTB24 are associated with immunodeficiency, centromeric instability, and facial anomalies syndrome type 2. Am. J. Hum. Genet. 88, 796–804 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Blanco-Betancourt, C. E. et al. Defective B-cell-negative selection and terminal differentiation in the ICF syndrome. Blood 103, 2683–2690 (2004).

    CAS  PubMed  Google Scholar 

  34. Picard, C. et al. STIM1 mutation associated with a syndrome of immunodeficiency and autoimmunity. N. Engl. J. Med. 360, 1971–1980 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Feske, S. et al. A mutation in Orai1 causes immune deficiency by abrogating CRAC channel function. Nature 441, 179–185 (2006).

    CAS  PubMed  Google Scholar 

  36. Stepensky, P. et al. Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J. Allergy Clin. Immunol. 131, 477–485.e1 (2013).

    CAS  PubMed  Google Scholar 

  37. Snow, A. L. et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J. Exp. Med. 209, 2247–2261 (2012). References 36 and 37 report that deficiency in CARD11, a key protein in the canonical NF-κB pathway, leads to a PAD owing to both intrinsic and extrinsic B cell defects.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Zonana, J. et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-γ (NEMO). Am. J. Hum. Genet. 67, 6 (2000).

    Google Scholar 

  39. Hanson, E. P. et al. Hypomorphic nuclear factor-κB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J. Allergy Clin. Immunol. 122, 1169–1177.e16 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Pachlopnik Schmid, J. et al. Polymerase epsilon1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ('FILS syndrome'). J. Exp. Med. 209, 2323–2330 (2012).

    PubMed  PubMed Central  Google Scholar 

  41. Courtois, G. et al. A hypermorphic IκBα mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J. Clin. Invest. 112, 1108–1115 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ohnishi, H. et al. A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome. J. Allergy Clin. Immunol. 129, 578–580 (2012).

    PubMed  Google Scholar 

  43. Victoratos, P. et al. FDC-specific functions of p55TNFR and IKK2 in the development of FDC networks and of antibody responses. Immunity 24, 65–77 (2006).

    CAS  PubMed  Google Scholar 

  44. Boisson, B. et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nature Immunol. 13, 1178–1186 (2012).

    CAS  Google Scholar 

  45. Alangari, A. et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J. Allergy Clin. Immunol. 130, 481–488.e2 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Lopez-Herrera, G. et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am. J. Hum. Genet. 90, 986–1001 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ferrari, S. et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc. Natl Acad. Sci. USA 98, 12614–12619 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000). This study provides a description of AID as a key molecule in class-switch recombination and somatic hypermutation in humans.

    CAS  PubMed  Google Scholar 

  49. Imai, K. et al. Analysis of class switch recombination and somatic hypermutation in patients affected with autosomal dominant hyper-IgM syndrome type 2. Clin. Immunol. 115, 277–285 (2005).

    CAS  PubMed  Google Scholar 

  50. Ta, V. T. et al. AID mutant analyses indicate requirement for class-switch-specific cofactors. Nature Immunol. 4, 843–848 (2003).

    CAS  Google Scholar 

  51. Imai, K. et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nature Immunol. 4, 1023–1028 (2003). The description of a new immunodeficiency in this paper provides strong evidence for a DNA-editing activity of AID in humans.

    CAS  Google Scholar 

  52. Du, L. et al. Cernunnos influences human immunoglobulin class switch recombination and may be associated with B cell lymphomagenesis. J. Exp. Med. 209, 291–305 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Stewart, G. S. et al. The RIDDLE syndrome protein mediates a ubiquitin-dependent signaling cascade at sites of DNA damage. Cell 136, 420–434 (2009).

    CAS  PubMed  Google Scholar 

  54. Peron, S. et al. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J. Exp. Med. 205, 2465–2472 (2008). This paper provided the first description in humans that mismatch repair enzymes are involved in class-switch recombination.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gardes, P. et al. Human MSH6 deficiency is associated with impaired antibody maturation. J. Immunol. 188, 2023–2029 (2012).

    CAS  PubMed  Google Scholar 

  56. Avery, D. T. et al. B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J. Exp. Med. 207, 155–171 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kotlarz, D. et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J. Exp. Med. 210, 433–443 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Minegishi, Y. et al. Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature 448, 1058–1062 (2007).

    CAS  PubMed  Google Scholar 

  59. Ozaki, K. et al. A critical role for IL-21 in regulating immunoglobulin production. Science 298, 1630–1634 (2002). This paper provides a description of IL-21 as a key cytokine in antibody production.

    CAS  PubMed  Google Scholar 

  60. Recher, M. et al. IL-21 is the primary common gamma chain-binding cytokine required for human B-cell differentiation in vivo. Blood 118, 6824–6835 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Hacein-Bey-Abina, S. et al. Efficacy of gene therapy for X-linked severe combined immunodeficiency. N. Engl. J. Med. 363, 355–364 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Puel, A., Ziegler, S. F., Buckley, R. H. & Leonard, W. J. Defective IL7R expression in T−B+NK+ severe combined immunodeficiency. Nature Genet. 20, 394–397 (1998).

    CAS  PubMed  Google Scholar 

  63. Dadi, H. K., Simon, A. J. & Roifman, C. M. Effect of CD3δ deficiency on maturation of α/β and γ/δ T-cell lineages in severe combined immunodeficiency. N. Engl. J. Med. 349, 1821–1828 (2003).

    CAS  PubMed  Google Scholar 

  64. de Saint Basile, G. et al. Severe combined immunodeficiency caused by deficiency in either the δ or the ε subunit of CD3. J. Clin. Invest. 114, 1512–1517 (2004).

    CAS  PubMed  Google Scholar 

  65. Rieux-Laucat, F. et al. Inherited and somatic CD3ζ mutations in a patient with T-cell deficiency. N. Engl. J. Med. 354, 1913–1921 (2006).

    CAS  PubMed  Google Scholar 

  66. Greenberg, F. et al. Familial DiGeorge syndrome and associated partial monosomy of chromosome 22. Hum. Genet. 65, 317–319 (1984).

    CAS  PubMed  Google Scholar 

  67. Elder, M. E. et al. Human severe combined immunodeficiency due to a defect in ZAP-70, a T cell tyrosine kinase. Science 264, 1596–1599 (1994).

    CAS  PubMed  Google Scholar 

  68. Huck, K. et al. Girls homozygous for an IL-2-inducible T cell kinase mutation that leads to protein deficiency develop fatal EBV-associated lymphoproliferation. J. Clin. Invest. 119, 1350–1358 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Hauck, F. et al. Primary T-cell immunodeficiency with immunodysregulation caused by autosomal recessive LCK deficiency. J. Allergy Clin. Immunol. 130, 1144–1152 e1111 (2012).

    CAS  PubMed  Google Scholar 

  70. Lisowska-Grospierre, B. et al. A defect in the regulation of major histocompatibility complex class II gene expression in human HLA-DR negative lymphocytes from patients with combined immunodeficiency syndrome. J. Clin. Invest. 76, 381–385 (1985).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Ma, C. S., Deenick, E. K., Batten, M. & Tangye, S. G. The origins, function, and regulation of T follicular helper cells. J. Exp. Med. 209, 1241–1253 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Warnatz, K. et al. Human ICOS-deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107, 3045–3052 (2005).

    PubMed  Google Scholar 

  73. Bossaller, L. et al. ICOS deficiency is associated with a severe reduction of CXCR5+CD4 germinal center Th cells. J. Immunol. 177, 4927–4932 (2006). This study provided the first description of a PAD caused by defective T FH cell generation and germinal centre reactions.

    CAS  PubMed  Google Scholar 

  74. Korthauer, U. et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361, 539–541 (1993). This paper provided the first description of the role of CD40L in antibody maturation.

    CAS  PubMed  Google Scholar 

  75. Litinskiy, M. B. et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nature Immunol. 3, 822–829 (2002).

    CAS  Google Scholar 

  76. Weller, S. et al. IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients. Blood 120, 4992–5001 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Weller, S. et al. CD40-CD40L independent Ig gene hypermutation suggests a second B cell diversification pathway in humans. Proc. Natl Acad. Sci. USA 98, 1166–1170 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Qi, H., Cannons, J. L., Klauschen, F., Schwartzberg, P. L. & Germain, R. N. SAP-controlled T-B cell interactions underlie germinal centre formation. Nature 455, 764–769 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Sayos, J. et al. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. Nature 395, 462–469 (1998).

    CAS  PubMed  Google Scholar 

  80. van Montfrans, J. M. et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J. Allergy Clin. Immunol. 129, 787–793.e6 (2012).

    CAS  PubMed  Google Scholar 

  81. Salzer, E. et al. Combined immunodeficiency with life-threatening EBV-associatedlymphoproliferative disorder in patients lacking functional CD27. Haematologica 98, 473–478 (2012).

    PubMed  Google Scholar 

  82. Ma, C. S. et al. Functional STAT3 deficiency compromises the generation of human T follicular helper cells. Blood 119, 3997–4008 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Puga, I. et al. B cell-helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen. Nature Immunol. 13, 170–180 (2011).

    Google Scholar 

  84. Moir, S. et al. Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells. Blood 120, 4850–4858 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Chapel, H. et al. Confirmation and improvement of criteria for clinical phenotyping in common variable immunodeficiency disorders in replicate cohorts. J. Allergy Clin. Immunol. 130, 1197–1198.e99 (2012).

    PubMed  Google Scholar 

  86. Resnick, E. S., Moshier, E. L., Godbold, J. H. & Cunningham-Rundles, C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 119, 1650–1657 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Orange, J. S. et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127, 1360–1367 e1366 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Brandtzaeg, P. & Johansen, F. E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol. Rev. 206, 32–63 (2005).

    CAS  PubMed  Google Scholar 

  89. Salzer, U. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nature Genet. 37, 820–828 (2005).

    CAS  PubMed  Google Scholar 

  90. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genet. 37, 829–834 (2005).

    CAS  PubMed  Google Scholar 

  91. Rioux, J. D. et al. Mapping of multiple susceptibility variants within the MHC region for 7 immune-mediated diseases. Proc. Natl Acad. Sci. USA 106, 18680–18685 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Lefranc, M. P., Lefranc, G. & Rabbitts, T. H. Inherited deletion of immunoglobulin heavy chain constant region genes in normal human individuals. Nature 300, 760–762 (1982).

    CAS  PubMed  Google Scholar 

  93. Kruetzmann, S. et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J. Exp. Med. 197, 939–945 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Micol, R. et al. Protective effect of IgM against colonization of the respiratory tract by nontypeable Haemophilus influenzae in patients with hypogammaglobulinemia. J. Allergy Clin. Immunol. 129, 770–777 (2012).

    CAS  PubMed  Google Scholar 

  95. Wardemann, H. et al. Predominant autoantibody production by early human B cell precursors. Science 301, 1374–1377 (2003).

    CAS  PubMed  Google Scholar 

  96. Yoshizaki, A. et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491, 264–268 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Shlomchik, M. J., Marshak-Rothstein, A., Wolfowicz, C. B., Rothstein, T. L. & Weigert, M. G. The role of clonal selection and somatic mutation in autoimmunity. Nature 328, 805–811 (1987).

    CAS  PubMed  Google Scholar 

  98. Durandy, A., Cantaert, T., Kracker, S. & Meffre, E. Potential roles of activation-induced cytidine deaminase in promotion or prevention of autoimmunity in humans. Autoimmunity 46, 148–156 (2012).

    Google Scholar 

  99. Hase, K. et al. Activation-induced cytidine deaminase deficiency causes organ-specific autoimmune disease. PLoS ONE 3, e3033 (2008).

    PubMed  PubMed Central  Google Scholar 

  100. Rakhmanov, M. et al. Circulating CD21low B cells in common variable immunodeficiency resemble tissue homing, innate-like B cells. Proc. Natl Acad. Sci. USA 106, 13451–13456 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Isnardi, I. et al. Complement receptor 2/CD21- human naive B cells contain mostly autoreactive unresponsive clones. Blood 115, 5026–5036 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. De Ravin, S. S. et al. Hypomorphic Rag mutations can cause destructive midline granulomatous disease. Blood 116, 1263–1271 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Schuetz, C. et al. An immunodeficiency disease with RAG mutations and granulomas. N. Engl. J. Med. 358, 2030–2038 (2008).

    CAS  PubMed  Google Scholar 

  104. Ombrello, M. J. et al. Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N. Engl. J. Med. 366, 330–338 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Zhou, Q. et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713–720 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Feske, S., Picard, C. & Fischer, A. Immunodeficiency due to mutations in ORAI1 and STIM1. Clin. Immunol. 135, 169–182 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Moratto, D. et al. Long-term outcome and lineage-specific chimerism in 194 patients with Wiskott–Aldrich syndrome treated by hematopoietic cell transplantation in the period 1980-2009: an international collaborative study. Blood 118, 1675–1684 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Hayward, A. R. et al. Cholangiopathy and tumors of the pancreas, liver, and biliary tree in boys with X-linked immunodeficiency with hyper-IgM. J. Immunol. 158, 977–983 (1997).

    CAS  PubMed  Google Scholar 

  109. Jain, A. et al. Partial immune reconstitution of X-linked hyper IgM syndrome with recombinant CD40 ligand. Blood 118, 3811–3817 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Aiuti, A. et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N. Engl. J. Med. 360, 447–458 (2009).

    CAS  PubMed  Google Scholar 

  111. Boztug, K. et al. Stem-cell gene therapy for the Wiskott–Aldrich syndrome. N. Engl. J. Med. 363, 1918–1927 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Kerns, H. M. et al. B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood 115, 2146–2155 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Dissing, J. & Knudsen, B. Adenosine-deaminase deficiency and combined immunodeficiency syndrome. Lancet 2, 1316 (1972).

    CAS  PubMed  Google Scholar 

  114. Giblett, E. R., Anderson, J. E., Cohen, F., Pollara, B. & Meuwissen, H. J. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2, 1067–1069 (1972).

    CAS  PubMed  Google Scholar 

  115. Lagresle-Peyrou, C. et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nature Genet. 41, 106–111 (2009).

    CAS  PubMed  Google Scholar 

  116. Pannicke, U. et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nature Genet. 41, 101–105 (2009).

    CAS  PubMed  Google Scholar 

  117. Nelson, N. D. & Bertuch, A. A. Dyskeratosis congenita as a disorder of telomere maintenance. Mutat. Res. 730, 43–51 (2012).

    CAS  PubMed  Google Scholar 

  118. Dickinson, R. E. et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood 118, 2656–2658 (2011).

    CAS  PubMed  Google Scholar 

  119. Moshous, D. et al. Partial T and B lymphocyte immunodeficiency and predisposition to lymphoma in patients with hypomorphic mutations in Artemis. J. Clin. Invest. 111, 381–387 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Schwarz, K. et al. RAG mutations in human B cell-negative SCID. Science 274, 97–99 (1996).

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. National Institute of Health and Medical Research (INSERM) U768, Necker Children's Hospital, Paris, F-75015, France

    Anne Durandy, Sven Kracker & Alain Fischer

  2. Descartes-Sorbonne Paris Cité University of Paris, Imagine Institute, Paris, F-75015, France

    Anne Durandy, Sven Kracker & Alain Fischer

  3. Center for Primary Immunodeficiencies (CEDI), Assistance Publique-Hopitaux de Paris, Necker Children's Hospital, Paris, F-75015, France

    Anne Durandy

  4. Department of Immunology and Haematology, Assistance Publique-Hopitaux de Paris, Necker Children's Hospital, Paris, F-75015, France

    Anne Durandy & Alain Fischer

Authors
  1. Anne Durandy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sven Kracker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alain Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Anne Durandy.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary information S1 (table)

PADs related to B cell-intrinsic defects (PDF 125 kb)

Supplementary information S2 (table)

PADs related to B cell-extrinsic defects (PDF 116 kb)

PowerPoint slides

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Durandy, A., Kracker, S. & Fischer, A. Primary antibody deficiencies. Nat Rev Immunol 13, 519–533 (2013). https://doi.org/10.1038/nri3466

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri3466

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing