Abstract
Primary antibody deficiencies (PADs) are the most common types of inherited primary immunodeficiency diseases (PIDs) presenting at any age, with a broad spectrum of clinical manifestations including susceptibility to infections, autoimmunity and cancer. Antibodies are produced by B cells, and consequently, genetic defects affecting B cell development, activation, differentiation or antibody secretion can all lead to PADs. Whole exome and whole genome sequencing approaches have helped identify genetic defects that are involved in the pathogenesis of PADs. Here, we summarize the clinical manifestations, causal genes, disease mechanisms and clinical treatments of different types of PADs.
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References
Abolhassani H, Edwards ES, Ikinciogullari A, Jing H, Borte S, Buggert M et al (2017) Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J Exp Med 214(1):91–106. https://doi.org/10.1084/jem.20160849
Accetta D, Syverson G, Bonacci B, Reddy S, Bengtson C, Surfus J et al (2011) Human phagocyte defect caused by a Rac2 mutation detected by means of neonatal screening for T-cell lymphopenia. J Allergy Clin Immunol 127(2), 535–538.e1–2. https://doi.org/10.1016/j.jaci.2010.10.013
Alkhairy OK, Perez-Becker R, Driessen GJ, Abolhassani H, van Montfrans J, Borte S et al (2015a) Novel mutations in TNFRSF7/CD27: clinical, immunologic, and genetic characterization of human CD27 deficiency. J Allergy Clin Immunol 136(3):703–712 e10. https://doi.org/10.1016/j.jaci.2015.02.022
Alkhairy OK, Rezaei N, Graham RR, Abolhassani H, Borte S, Hultenby K et al (2015b) RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J Allergy Clin Immunol 135(5):1380–134 e1-5. https://doi.org/10.1016/j.jaci.2014.10.039
Ambruso DR, Knall C, Abell AN, Panepinto J, Kurkchubasche A, Thurman G et al (2000) Human neutrophil immunodeficiency syndrome is associated with an inhibitory Rac2 mutation. Proc Natl Acad Sci U S A 97(9):4654–4659. https://doi.org/10.1073/pnas.080074897
Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR et al (2013) Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 342(6160):866–871. https://doi.org/10.1126/science.1243292
Arandi N, Mirshafiey A, Jeddi-Tehrani M, Abolhassani H, Sadeghi B, Mirminachi B et al (2013) Evaluation of CD4+ CD25+ FOXP3+ regulatory T cells function in patients with common variable immunodeficiency. Cell Immunol 281(2):129–133. https://doi.org/10.1016/j.cellimm.2013.03.003
Avery DT, Deenick EK, Ma CS, Suryani S, Simpson N, Chew GY et al (2010) B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans. J Exp Med 207(1):155–171. https://doi.org/10.1084/jem.20091706
Aydin SE, Kilic SS, Aytekin C, Kumar A, Porras O, Kainulainen L et al (2015) DOCK8 deficiency: clinical and immunological phenotype and treatment options—a review of 136 patients. J Clin Immunol 35(2):189–198. https://doi.org/10.1007/s10875-014-0126-0
Azizi G, Ahmadi M, Abolhassani H, Yazdani R, Mohammadi H, Mirshafiey A et al (2016) Autoimmunity in primary antibody deficiencies. Int Arch Allergy Immunol 171(3–4):180–193. https://doi.org/10.1159/000453263
Bain G, Maandag EC, Izon DJ, Amsen D, Kruisbeek AM, Weintraub BC et al (1994) E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell 79(5):885–892. https://doi.org/10.1016/0092-8674(94)90077-9
Ballow M, Akdis CA, Casale TB, Wardlaw AJ, Wenzel SE, Ballas Z et al (2012) Immune response modifiers in the treatment of asthma: a PRACTALL document of the American Academy of Allergy, Asthma & Immunology and the European Academy of Allergy and Clinical Immunology. J Allergy Clin Immunol 130(2):311–324. https://doi.org/10.1016/j.jaci.2012.04.046
Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI et al (2013) Protein kinase cdelta deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum 65(8):2161–2171. https://doi.org/10.1002/art.38008
Ben-Ali M, Yang J, Chan KW, Ben-Mustapha I, Mekki N, Benabdesselem C et al (2017) Homozygous transcription factor 3 gene (TCF3) mutation is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia. J Allergy Clin Immunol 140(4):1191–1194.e4. https://doi.org/10.1016/j.jaci.2017.04.037
Bernier GM, Gunderman JR, Ruymann FB (1972) Kappa-chain deficiency. Blood 40(6):795–805
Beziat V, Li J, Lin JX, Ma CS, Li P, Bousfiha A et al (2018) A recessive form of hyper-IgE syndrome by disruption of ZNF341-dependent STAT3 transcription and activity. Sci Immunol 3(24). https://doi.org/10.1126/sciimmunol.aat4956
Bogaert DJ, Dullaers M, Lambrecht BN, Vermaelen KY, De Baere E, Haerynck F (2016) Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J Med Genet 53(9):575–590. https://doi.org/10.1136/jmedgenet-2015-103690
Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T et al (2013) A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J Clin Invest 123(11):4781–4785. https://doi.org/10.1172/jci71927
Bonilla FA, Barlan I, Chapel H, Costa-Carvalho BT, Cunningham-Rundles C, de la Morena MT et al (2016) International Consensus Document (ICON): common variable immunodeficiency disorders. J Allergy Clin Immunol Pract 4(1):38–59. https://doi.org/10.1016/j.jaip.2015.07.025
Bourgeois P, Esteve C, Chaix C, Beroud C, Levy N, consortium Tc et al (2018) Tricho-Hepato-Enteric Syndrome mutation update: mutations spectrum of TTC37 and SKIV2L, clinical analysis and future prospects. Hum Mutat 39(6):774–789. https://doi.org/10.1002/humu.23418
Boutboul D, Kuehn HS, Van de Wyngaert Z, Niemela JE, Callebaut I, Stoddard J et al (2018) Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency. J Clin Invest 128(7):3071–3087. https://doi.org/10.1172/jci98164
Boyle RJ, Le C, Balloch A, Tang ML (2006) The clinical syndrome of specific antibody deficiency in children. Clin Exp Immunol 146(3):486–492. https://doi.org/10.1111/j.1365-2249.2006.03242.x
Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D et al (2016) NF-kappaB1 haploinsufficiency causing immunodeficiency and EBV-driven lymphoproliferation. J Clin Immunol 36(6):533–540. https://doi.org/10.1007/s10875-016-0306-1
Bravo Garcia-Morato M, Garcia-Minaur S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, Lopez-Granados E et al (2017) Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol 179:77–80. https://doi.org/10.1016/j.clim.2017.03.004
Browning MJ, Chandra A, Carbonaro V, Okkenhaug K, Barwell J (2015) Cowden’s syndrome with immunodeficiency. J Med Genet 52(12):856–859. https://doi.org/10.1136/jmedgenet-2015-103266
Buck D, Malivert L, de Chasseval R, Barraud A, Fondaneche MC, Sanal O et al (2006) Cernunnos, a novel nonhomologous end-joining factor, is mutated in human immunodeficiency with microcephaly. Cell 124(2):287–299. https://doi.org/10.1016/j.cell.2005.12.030
Cagdas D, Gur Cetinkaya P, Karaatmaca B, Esenboga S, Tan C, Yilmaz T et al (2018) ADA deficiency: evaluation of the clinical and laboratory features and the outcome. J Clin Immunol 38(4):484–493. https://doi.org/10.1007/s10875-018-0496-9
Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T, Durie D et al (2014) Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood 124(18):2867–2871. https://doi.org/10.1182/blood-2014-08-591370
Charbit-Henrion F, Jeverica AK, Begue B, Markelj G, Parlato M, Avcin SL et al (2017) Deficiency in mucosa-associated lymphoid tissue lymphoma translocation 1: a novel cause of IPEX-like syndrome. J Pediatr Gastroenterol Nutr 64(3):378–384. https://doi.org/10.1097/mpg.0000000000001262
Chavanas S, Bodemer C, Rochat A, Hamel-Teillac D, Ali M, Irvine AD et al (2000) Mutations in SPINK5, encoding a serine protease inhibitor, cause Netherton syndrome. Nat Genet 25(2):141–142. https://doi.org/10.1038/75977
Chen HH, Handel N, Ngeow J, Muller J, Huhn M, Yang HT et al (2017) Immune dysregulation in patients with PTEN hamartoma tumor syndrome: analysis of FOXP3 regulatory T cells. J Allergy Clin Immunol 139(2):607–620.e15. https://doi.org/10.1016/j.jaci.2016.03.059
Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL et al (2013) Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet 93(5):812–824. https://doi.org/10.1016/j.ajhg.2013.09.009
Cifaldi C, Scarselli A, Petricone D, Di Cesare S, Chiriaco M, Claps A et al (2016) Agammaglobulinemia associated to nasal polyposis due to a hypomorphic RAG1 mutation in a 12 years old boy. Clin Immunol 173:121–123. https://doi.org/10.1016/j.clim.2016.09.013
Compeer EB, Janssen W, van Royen-Kerkhof A, van Gijn M, van Montfrans JM, Boes M (2015) Dysfunctional BLK in common variable immunodeficiency perturbs B-cell proliferation and ability to elicit antigen-specific CD4+ T-cell help. Oncotarget 6(13):10759–10771. https://doi.org/10.18632/oncotarget.3577
Conley ME, Dobbs AK, Farmer DM, Kilic S, Paris K, Grigoriadou S et al (2009) Primary B cell immunodeficiencies: comparisons and contrasts. Annu Rev Immunol 27:199–227. https://doi.org/10.1146/annurev.immunol.021908.132649
Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E et al (2012) Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J Exp Med 209(3):463–470. https://doi.org/10.1084/jem.20112533
D’Elios MM, Rizzi M (2019) Humoral primary immunodeficiencies. Springer. https://doi.org/10.1007/978-3-319-91785-6
Dadi H, Jones TA, Merico D, Sharfe N, Ovadia A, Schejter Y et al (2018) Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11). J Allergy Clin Immunol 141(5):1818–1830.e2. https://doi.org/10.1016/j.jaci.2017.06.047
Davis SD, Schaller J, Wedgwood RJ (1966) Job’s syndrome. recurrent, “cold”, staphylococcal abscesses. Lancet 1(7445):1013–1015. https://doi.org/10.1016/s0140-6736(66)90119-x
de la Morena MT (2016) Clinical phenotypes of hyper-IgM syndromes. J Allergy Clin Immunol Pract 4(6):1023–1036. https://doi.org/10.1016/j.jaip.2016.09.013
Driessen GJ, IJspeert H, Wentink M, Yntema HG, van Hagen PM, van Strien A et al (2016) Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. J Allergy Clin Immunol 138(6):1744–1747.e5. https://www.doi.org/10.1016/j.jaci.2016.07.010
Durandy A, Kracker S, Fischer A (2013) Primary antibody deficiencies. Nat Rev Immunol 13(7):519–533. https://doi.org/10.1038/nri3466
Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hulsdunker J, Eskandarian Z et al (2016) Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol 183(2):221–229. https://doi.org/10.1111/cei.12706
Ferrari S, Giliani S, Insalaco A, Al-Ghonaium A, Soresina AR, Loubser M et al (2001) Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc Natl Acad Sci U S A 98(22):12614–12619. https://doi.org/10.1073/pnas.221456898
Ferrari S, Lougaris V, Caraffi S, Zuntini R, Yang J, Soresina A et al (2007) Mutations of the Igbeta gene cause agammaglobulinemia in man. J Exp Med 204(9):2047–2051. https://doi.org/10.1084/jem.20070264
Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K et al (2015) Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet 97(3):389–403. https://doi.org/10.1016/j.ajhg.2015.07.008
Frans G, Moens L, Schaballie H, Wuyts G, Liston A, Poesen K et al (2017) Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood. J Allergy Clin Immunol 139(1):360–363 e6. https://doi.org/10.1016/j.jaci.2016.06.050
Freeman AF, Holland SM (2010) Clinical manifestations of hyper IgE syndromes. Dis Markers 29(3–4):123–30. https://doi.org/10.3233/DMA-2010-0734
Frey-Jakobs S, Hartberger JM, Fliegauf M, Bossen C, Wehmeyer ML, Neubauer JC et al (2018) ZNF341 controls STAT3 expression and thereby immunocompetence. Sci Immunol 3(24). https://doi.org/10.1126/sciimmunol.aat4941
Fried AJ, Bonilla FA (2009) Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections. Clin Microbiol Rev 22(3):396–414. https://doi.org/10.1128/CMR.00001-09
Gardes P, Forveille M, Alyanakian MA, Aucouturier P, Ilencikova D, Leroux D et al (2012) Human MSH6 deficiency is associated with impaired antibody maturation. J Immunol 188(4):2023–2029. https://doi.org/10.4049/jimmunol.1102984
Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ (1972) Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet 2(7786):1067–1069. https://doi.org/10.1016/s0140-6736(72)92345-8
Greil J, Rausch T, Giese T, Bandapalli OR, Daniel V, Bekeredjian-Ding I et al (2013) Whole-exome sequencing links caspase recruitment domain 11 (CARD11) inactivation to severe combined immunodeficiency. J Allergy Clin Immunol 131(5):1376–83.e3. https://doi.org/10.1016/j.jaci.2013.02.012
Hammarstrom L, Vorechovsky I, Webster D (2000) Selective IgA deficiency (SIgAD) and common variable immunodeficiency (CVID). Clin Exp Immunol 120(2):225–231. https://doi.org/10.1046/j.1365-2249.2000.01131.x
Hannula-Jouppi K, Laasanen SL, Ilander M, Furio L, Tuomiranta M, Marttila R et al (2016) Intrafamily and interfamilial phenotype variation and immature immunity in patients with Netherton syndrome and Finnish SPINK5 founder mutation. JAMA Dermatol 152(4):435–442. https://doi.org/10.1001/jamadermatol.2015.5827
Hartley JL, Zachos NC, Dawood B, Donowitz M, Forman J, Pollitt RJ et al (2010) Mutations in TTC37 cause trichohepatoenteric syndrome (phenotypic diarrhea of infancy). Gastroenterology 138(7):2388–2398, 2398.e1–2. https://doi.org/10.1053/j.gastro.2010.02.010
Hedayat M, Massaad MJ, Lee YN, Conley ME, Orange JS, Ohsumi TK et al (2014) Lessons in gene hunting: a RAG1 mutation presenting with agammaglobulinemia and absence of B cells. J Allergy Clin Immunol 134(4):983–985.e1. https://doi.org/10.1016/j.jaci.2014.04.037
Heimall J, Freeman A, Holland SM (2010) Pathogenesis of hyper IgE syndrome. Clin Rev Allergy Immunol 38(1):32–38. https://doi.org/10.1007/s12016-009-8134-1
Holland SM, DeLeo FR, Elloumi HZ, Hsu AP, Uzel G, Brodsky N et al (2007) STAT3 mutations in the hyper-IgE syndrome. N Engl J Med 357(16):1608–1619. https://doi.org/10.1056/NEJMoa073687
Hoshino A, Okada S, Yoshida K, Nishida N, Okuno Y, Ueno H et al (2017) Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. J Allergy Clin Immunol 140(1):223–231. https://doi.org/10.1016/j.jaci.2016.09.029
Hsu AP, Donko A, Arrington ME, Swamydas M, Fink D, Das A et al (2019) Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects. Blood 133(18):1977–1988. https://doi.org/10.1182/blood-2018-11-886028
Hubbard N, Hagin D, Sommer K, Song Y, Khan I, Clough C et al (2016) Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome. Blood 127(21):2513–2522. https://doi.org/10.1182/blood-2015-11-683235
Imai K, Slupphaug G, Lee WI, Revy P, Nonoyama S, Catalan N et al (2003) Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat Immunol 4(10):1023–1028. https://doi.org/10.1038/ni974
Izawa K, Martin E, Soudais C, Bruneau J, Boutboul D, Rodriguez R et al (2017) Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J Exp Med 214(1):73–89. https://doi.org/10.1084/jem.20160784
Jabara HH, Ohsumi T, Chou J, Massaad MJ, Benson H, Megarbane A et al (2013) A homozygous mucosa-associated lymphoid tissue 1 (MALT1) mutation in a family with combined immunodeficiency. J Allergy Clin Immunol 132(1):151–158. https://doi.org/10.1016/j.jaci.2013.04.047
Jansen EJ, Timal S, Ryan M, Ashikov A, van Scherpenzeel M, Graham LA et al (2016) ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat Commun 7:11600. https://doi.org/10.1038/ncomms11600
Jiang SH, Athanasopoulos V, Ellyard JI, Chuah A, Cappello J, Cook A et al (2019) Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nat Commun 10(1):2201. https://doi.org/10.1038/s41467-019-10242-9
Kaustio M, Haapaniemi E, Goos H, Hautala T, Park G, Syrjanen J et al (2017) Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J Allergy Clin Immunol 140(3):782–796. https://doi.org/10.1016/j.jaci.2016.10.054
Keller B, Cseresnyes Z, Stumpf I, Wehr C, Fliegauf M, Bulashevska A et al (2017) Disturbed canonical nuclear factor of kappa light chain signaling in B cells of patients with common variable immunodeficiency. J Allergy Clin Immunol 139(1):220–231.e8. https://doi.org/10.1016/j.jaci.2016.04.043
Keller MD, Pandey R, Li D, Glessner J, Tian L, Henrickson SE et al (2016) Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J Allergy Clin Immunol 138(2):544–550 e4. https://doi.org/10.1016/j.jaci.2016.01.018
Kerns HM, Ryu BY, Stirling BV, Sather BD, Astrakhan A, Humblet-Baron S et al (2010) B cell-specific lentiviral gene therapy leads to sustained B-cell functional recovery in a murine model of X-linked agammaglobulinemia. Blood 115(11):2146–2155. https://doi.org/10.1182/blood-2009-09-241869
Kiykim A, Ogulur I, Baris S, Salzer E, Karakoc-Aydiner E, Ozen AO et al (2015) Potentially beneficial effect of hydroxychloroquine in a patient with a novel mutation in protein kinase cdelta deficiency. J Clin Immunol 35(6):523–526. https://doi.org/10.1007/s10875-015-0178-9
Korthauer U, Graf D, Mages HW, Briere F, Padayachee M, Malcolm S et al (1993) Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 361(6412):539–541. https://doi.org/10.1038/361539a0
Kotlarz D, Zietara N, Milner JD, Klein C (2014) Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency. Curr Opin Pediatr 26(6):704–712. https://doi.org/10.1097/mop.0000000000000160
Kotlarz D, Zietara N, Uzel G, Weidemann T, Braun CJ, Diestelhorst J et al (2013) Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J Exp Med 210(3):433–443. https://doi.org/10.1084/jem.20111229
Kracker S, Di Virgilio M, Schwartzentruber J, Cuenin C, Forveille M, Deau MC et al (2015) An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex. J Allergy Clin Immunol 135(4):998–1007 e6. https://doi.org/10.1016/j.jaci.2014.08.030
Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW et al (2016) Loss of B cells in patients with heterozygous mutations in IKAROS. N Engl J Med 374(11):1032–1043. https://doi.org/10.1056/NEJMoa1512234
Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL et al (2013) Loss-of-function of the protein kinase C delta (PKCdelta) causes a B-cell lymphoproliferative syndrome in humans. Blood 121(16):3117–3125. https://doi.org/10.1182/blood-2012-12-469544
Kuehn HS, Niemela JE, Sreedhara K, Stoddard JL, Grossman J, Wysocki CA et al (2017) Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood 130(13):1553–1564. https://doi.org/10.1182/blood-2017-05-782177
Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM et al (2010) CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest 120(1):214–222. https://doi.org/10.1172/JCI40231
Kurosaki T, Shinohara H, Baba Y (2010) B cell signaling and fate decision. Annu Rev Immunol 28:21–55. https://doi.org/10.1146/annurev.immunol.021908.132541
Kutukculer N, Karaca NE, Demircioglu O, Aksu G (2007) Increases in serum immunoglobulins to age-related normal levels in children with IgA and/or IgG subclass deficiency. Pediatr Allergy Immunol 18(2):167–173. https://doi.org/10.1111/j.1399-3038.2006.00491.x
Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A et al (2009) Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet 41(1):106–111. https://doi.org/10.1038/ng.278
Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M et al (2014) Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 124(19):2964–2972. https://doi.org/10.1182/blood-2014-06-578542
Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assa’ad A (2014) Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol 34(8):910–915. https://doi.org/10.1007/s10875-014-0095-3
Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C et al (2015) Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349(6246):436–440. https://doi.org/10.1126/science.aaa1663
Lougaris V, Badolato R, Ferrari S, Plebani A (2005) Hyper immunoglobulin M syndrome due to CD40 deficiency: clinical, molecular, and immunological features. Immunol Rev 203:48–66. https://doi.org/10.1111/j.0105-2896.2005.00229.x
Lougaris V, Baronio M, Moratto D, Cardinale F, Plebani A (2016) Monoallelic BAFFR P21R/H159Y mutations and familiar primary antibody deficiencies. J Clin Immunol 36(1):1–3. https://doi.org/10.1007/s10875-015-0217-6
Lougaris V, Moratto D, Baronio M, Tampella G, van der Meer JWM, Badolato R et al (2017) Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1-mutated common variable immunodeficiency disease. J Allergy Clin Immunol 139(1):349–352.e1. https://doi.org/10.1016/j.jaci.2016.05.045
Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K (2016) PI3Kdelta and primary immunodeficiencies. Nat Rev Immunol 16(11):702–714. https://doi.org/10.1038/nri.2016.93
Ma CA, Stinson JR, Zhang Y, Abbott JK, Weinreich MA, Hauk PJ et al (2017) Corrigendum: germline hypomorphic CARD11 mutations in severe atopic disease. Nat Genet 49(11):1661. https://doi.org/10.1038/ng1117-1661b
Maffucci P, Filion CA, Boisson B, Itan Y, Shang L, Casanova JL et al (2016) Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front Immunol 7:220. https://doi.org/10.3389/fimmu.2016.00220
Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z et al (1998) Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet 7(3):507–515. https://doi.org/10.1093/hmg/7.3.507
McGeady SJ (2019) B cell activation in specific polysaccharide antibody deficiency. J Allergy Clin Immunol 143(2):AB78. https://doi.org/10.1016/j.jaci.2018.12.244
McKinnon ML, Rozmus J, Fung SY, Hirschfeld AF, Del Bel KL, Thomas L et al (2014) Combined immunodeficiency associated with homozygous MALT1 mutations. J Allergy Clin Immunol 133(5):1458–1462, 1462.e1–7. https://doi.org/10.1016/j.jaci.2013.10.045
Meffre E (2011) The establishment of early B cell tolerance in humans: lessons from primary immunodeficiency diseases. Ann N Y Acad Sci 1246:1–10. https://doi.org/10.1111/j.1749-6632.2011.06347.x
Minegishi Y, Coustan-Smith E, Rapalus L, Ersoy F, Campana D, Conley ME (1999) Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J Clin Invest 104(8):1115–1121. https://doi.org/10.1172/jci7696
Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME (1998) Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J Exp Med 187(1):71–77. https://doi.org/10.1084/jem.187.1.71
Mitsuiki N, Yang X, Bartol SJ, Grosserichter-Wagener C, Kosaka Y, Takada H et al (2015) Mutations in Bruton’s tyrosine kinase impair IgA responses. Int J Hematol 101(3):305–313. https://doi.org/10.1007/s12185-015-1732-1
Moshous D, Callebaut I, de Chasseval R, Corneo B, Cavazzana-Calvo M, Le Deist F et al (2001) Artemis, a novel DNA double-strand break repair/V(D)J recombination protein, is mutated in human severe combined immune deficiency. Cell 105(2):177–186. https://doi.org/10.1016/s0092-8674(01)00309-9
Nanthapisal S, Omoyinmi E, Murphy C, Standing A, Eisenhut M, Eleftheriou D et al (2017) Early-onset juvenile SLE associated with a novel mutation in protein kinase C delta. Pediatrics 139(1). https://doi.org/10.1542/peds.2016-0781
O’Driscoll M, Cerosaletti KM, Girard PM, Dai Y, Stumm M, Kysela B et al (2001) DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency. Mol Cell 8(6):1175–85. https://doi.org/10.1016/s1097-2765(01)00408-7
Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P et al (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. N Engl J Med 366(4):330–8. https://doi.org/10.1056/NEJMoa1102140
Peron S, Metin A, Gardes P, Alyanakian MA, Sheridan E, Kratz CP et al (2008) Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 205(11):2465–72. https://doi.org/10.1084/jem.20080789
Picard C, Bobby Gaspar H, Al-Herz W, Bousfiha A, Casanova JL, Chatila T et al (2018) International union of immunological societies: 2017 primary immunodeficiency diseases committee report on inborn errors of immunity. J Clin Immunol 38(1):96–128. https://doi.org/10.1007/s10875-017-0464-9
Pieper K, Grimbacher B, Eibel H (2013) B-cell biology and development. J Allergy Clin Immunol 131(4):959–71. https://doi.org/10.1016/j.jaci.2013.01.046
Rezaei N et al (2017) Primary immunodeficiency diseases. https://doi.org/10.1007/978-3-662-52909-6
Rickert RC (2013) New insights into pre-BCR and BCR signalling with relevance to B cell malignancies. Nat Rev Immunol 13(8):578–91. https://doi.org/10.1038/nri3487
Rickert RC, Jellusova J, Miletic AV (2011) Signaling by the tumor necrosis factor receptor superfamily in B-cell biology and disease. Immunol Rev 244(1):115–33. https://doi.org/10.1111/j.1600-065X.2011.01067.x
Rissone A, Weinacht KG, la Marca G, Bishop K, Giocaliere E, Jagadeesh J et al (2015) Reticular dysgenesis-associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress. J Exp Med 212(8):1185–202. https://doi.org/10.1084/jem.20141286
Rosain J, Miot C, Lambert N, Rousselet MC, Pellier I, Picard C (2017) CD21 deficiency in 2 siblings with recurrent respiratory infections and hypogammaglobulinemia. J Allergy Clin Immunol Pract 5(6):1765–1767 e3. https://doi.org/10.1016/j.jaip.2017.04.011
Ruland J, Hartjes L (2019) CARD-BCL-10-MALT1 signalling in protective and pathological immunity. Nat Rev Immunol 19(2):118–134. https://doi.org/10.1038/s41577-018-0087-2
Sadat MA, Moir S, Chun TW, Lusso P, Kaplan G, Wolfe L et al (2014) Glycosylation, hypogammaglobulinemia, and resistance to viral infections. N Engl J Med 370(17):1615–1625. https://doi.org/10.1056/NEJMoa1302846
Saffran DC, Parolini O, Fitch-Hilgenberg ME, Rawlings DJ, Afar DE, Witte ON et al (1994) Brief report: a point mutation in the SH2 domain of Bruton’s tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med 330(21):1488–91. https://doi.org/10.1056/nejm199405263302104
Salzer E, Kansu A, Sic H, Majek P, Ikinciogullari A, Dogu FE et al (2014) Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J Allergy Clin Immunol 133(6):1651–1659.e12. https://doi.org/10.1016/j.jaci.2014.02.034
Salzer E, Santos-Valente E, Keller B, Warnatz K, Boztug K (2016) Protein kinase C delta: a gatekeeper of immune homeostasis. J Clin Immunol 36(7):631–40. https://doi.org/10.1007/s10875-016-0323-0
Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK et al (2013) B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta. Blood 121(16):3112–6. https://doi.org/10.1182/blood-2012-10-460741
Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V et al (2009) Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113(9):1967–76. https://doi.org/10.1182/blood-2008-02-141937
Sarmiento E, Mora R, Rodriguez-Mahou M, Rodriguez-Molina J, Fernandez-Cruz E, Carbone J (2005) Autoimmune disease in primary antibody deficiencies. Allergol Immunopathol (Madr) 33(2):69–73. https://doi.org/10.1157/13072916
Sassi A, Lazaroski S, Wu G, Haslam SM, Fliegauf M, Mellouli F et al (2014) Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels. J Allergy Clin Immunol 133(5):1410–1419, 1419.e1–13. https://doi.org/10.1016/j.jaci.2014.02.025
Schipp C, Nabhani S, Bienemann K, Simanovsky N, Kfir-Erenfeld S, Assayag-Asherie N et al (2016) Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica 101(10):e392–e396. https://doi.org/10.3324/haematol.2016.145136
Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M et al (2018) Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J Allergy Clin Immunol 141(4):1427–1438. https://doi.org/10.1016/j.jaci.2017.06.042
Schwerd T, Twigg SRF, Aschenbrenner D, Manrique S, Miller KA, Taylor IB et al (2017) A biallelic mutation in IL6ST encoding the GP130 co-receptor causes immunodeficiency and craniosynostosis. J Exp Med 214(9):2547–2562. https://doi.org/10.1084/jem.20161810
Shi PY, Maizels N, Weiner AM (1998) CCA addition by tRNA nucleotidyltransferase: polymerization without translocation? EMBO J 17(11):3197–206. https://doi.org/10.1093/emboj/17.11.3197
Silva P, Justicia A, Regueiro A, Farina S, Couselo JM, Loidi L (2017) Autosomal recessive agammaglobulinemia due to defect in mu heavy chain caused by a novel mutation in the IGHM gene. Genes Immun 18(3):197–199. https://doi.org/10.1038/gene.2017.14
Simpfendorfer KR, Armstead BE, Shih A, Li W, Curran M, Manjarrez-Orduno N et al (2015) Autoimmune disease-associated haplotypes of BLK exhibit lowered thresholds for B cell activation and expansion of Ig class-switched B cells. Arthritis Rheumatol 67(11):2866–76. https://doi.org/10.1002/art.39301
Spencer S, Kostel Bal S, Egner W, Lango Allen H, Raza SI, Ma CA et al (2019) Loss of the interleukin-6 receptor causes immunodeficiency, atopy, and abnormal inflammatory responses. J Exp Med 216(9):1986–1998. https://doi.org/10.1084/jem.20190344
Stepensky P, Keller B, Buchta M, Kienzler AK, Elpeleg O, Somech R et al (2013) Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects. J Allergy Clin Immunol 131(2):477–85.e1. https://doi.org/10.1016/j.jaci.2012.11.050
Tang P, Upton JEM, Barton-Forbes MA, Salvadori MI, Clynick MP, Price AK et al (2018) Autosomal recessive agammaglobulinemia due to a homozygous mutation in PIK3R1. J Clin Immunol 38(1):88–95. https://doi.org/10.1007/s10875-017-0462-y
Tangye SG, Bier J, Lau A, Nguyen T, Uzel G, Deenick EK (2019) Immune dysregulation and disease pathogenesis due to activating mutations in PIK3CD-the Goldilocks’ effect. J Clin Immunol 39(2):148–158. https://doi.org/10.1007/s10875-019-00612-9
Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, et al (2012) Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol 129(3):801–810 e6. https://doi.org/10.1016/j.jaci.2011.09.027
Torres JM, Martinez-Barricarte R, Garcia-Gomez S, Mazariegos MS, Itan Y, Boisson B et al (2014) Inherited BCL10 deficiency impairs hematopoietic and nonhematopoietic immunity. J Clin Invest 124(12):5239–48. https://doi.org/10.1172/jci77493
Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I et al (1993) Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72(2):279–90. https://doi.org/10.1016/0092-8674(93)90667-f
Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E et al (2018) Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J Allergy Clin Immunol 142(4):1285–1296. https://doi.org/10.1016/j.jaci.2018.01.039
Valizadeh A, Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A (2017) A comparison of clinical and immunologic phenotypes in familial and sporadic forms of common variable immunodeficiency. Scand J Immunol 86(4):239–247. https://doi.org/10.1111/sji.12593
van der Burg M, Ijspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K et al (2009) A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest 119(1):91–8. https://doi.org/10.1172/jci37141
van Montfrans JM, Hoepelman AI, Otto S, van Gijn M, van de Corput L, de Weger RA, et al (2012) CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J Allergy Clin Immunol 129(3):787–793 e6. https://doi.org/10.1016/j.jaci.2011.11.013
Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J et al (2018) A kindred with mutant IKAROS and autoimmunity. J Allergy Clin Immunol 142(2):699–702.e12. https://doi.org/10.1016/j.jaci.2018.04.008
van Zelm MC, Bartol SJ, Driessen GJ, Mascart F, Reisli I, Franco JL et al (2014) Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J Allergy Clin Immunol 134(1):135–44. https://doi.org/10.1016/j.jaci.2013.11.015
van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ et al (2006) An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med 354(18):1901–12. https://doi.org/10.1056/NEJMoa051568
van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F et al (2010) CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest 120(4):1265–74. https://doi.org/10.1172/JCI39748
Vely F, Barlogis V, Marinier E, Coste ME, Dubern B, Dugelay E et al (2018) Combined immunodeficiency in patients with trichohepatoenteric syndrome. Front Immunol 9:1036. https://doi.org/10.3389/fimmu.2018.01036
Vetrie D, Vorechovsky I, Sideras P, Holland J, Davies A, Flinter F et al (1993) The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361(6409):226–33. https://doi.org/10.1038/361226a0
Vorechovsky I, Webster AD, Plebani A, Hammarstrom L (1999) Genetic linkage of IgA deficiency to the major histocompatibility complex: evidence for allele segregation distortion, parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition. Am J Hum Genet 64(4):1096–109. https://doi.org/10.1086/302326
Wang HY, Ma CA, Zhao Y, Fan X, Zhou Q, Edmonds P et al (2013) Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc Natl Acad Sci U S A 110(13):5127–32. https://doi.org/10.1073/pnas.1221211110
Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J et al (2009) B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci U S A 106(33):13945–50. https://doi.org/10.1073/pnas.0903543106
Wedatilake Y, Niazi R, Fassone E, Powell CA, Pearce S, Plagnol V et al (2016) TRNT1 deficiency: clinical, biochemical and molecular genetic features. Orphanet J Rare Dis 11(1):90. https://doi.org/10.1186/s13023-016-0477-0
Wentink MW, Lambeck AJ, van Zelm MC, Simons E, van Dongen JJ, IJspeert H, et al. (2015). CD21 and CD19 deficiency: Two defects in the same complex leading to different disease modalities. Clin Immunol 161(2):120–127. https://doi.org/10.1016/j.clim.2015.08.010
Wood PM (2010) Primary antibody deficiency syndromes. Curr Opin Hematol 17(4):356–61. https://doi.org/10.1097/MOH.0b013e328338f69e
Xiong E, Li Y, Min Q, Cui C, Liu J, Hong R et al (2019) MZB1 promotes the secretion of J-chain-containing dimeric IgA and is critical for the suppression of gut inflammation. Proc Natl Acad Sci U S A 116(27):13480–13489. https://doi.org/10.1073/pnas.1904204116
Yang L, Fliegauf M, Grimbacher B (2014) Hyper-IgE syndromes: reviewing PGM3 deficiency. Curr Opin Pediatr 26(6):697–703. https://doi.org/10.1097/MOP.0000000000000158
Yazdani R, Azizi G, Abolhassani H, Aghamohammadi A (2017) Selective IgA deficiency: Epidemiology, pathogenesis, clinical phenotype, diagnosis, prognosis and management. Scand J Immunol 85(1):3–12. https://doi.org/10.1111/sji.12499
Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trubel H, Pachman LM et al (1996) Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N Engl J Med 335(20):1486–93. https://doi.org/10.1056/nejm199611143352003
Zegers BJ, Maertzdorf WJ, Van Loghem E, Mul NA, Stoop JW, Van Der Laag J, et al (1976) Kappa-chain deficiency: an immunoglobulin disorder. N Engl J Med 294(19):1026–1030. https://doi.org/10.1056/nejm197605062941902
Zhang Q, Boisson B, Beziat V, Puel A, Casanova JL (2018) Human hyper-IgE syndrome: singular or plural? Mamm Genome 29(7–8):603–617. https://doi.org/10.1007/s00335-018-9767-2
Zhang Q, Davis JC, Lamborn IT, Freeman AF, Jing H, Favreau AJ et al (2009) Combined immunodeficiency associated with DOCK8 mutations. N Engl J Med 361(21):2046–55. https://doi.org/10.1056/NEJMoa0905506
Zhou Q, Lee GS, Brady J, Datta S, Katan M, Sheikh A et al (2012) A hypermorphic missense mutation in PLCG2, encoding phospholipase Cgamma2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet 91(4):713–20. https://doi.org/10.1016/j.ajhg.2012.08.006
Acknowledgements
We thank Luming Zhang for secretarial assistance, Fudan University Animal Facility for maintaining the mice and the members in Wang Lab for helpful suggestions. This work was supported by the Major Research Plan of the National Natural Science Foundation of China (91942302 to J.Y.W.), the National Key R & D Plan of the Ministry of Science and Technology (SQ2019YFE0100600 to J.Y.W.), the National Natural Science Foundation of China (81571529 and 31870898 to J.Y.W), Projects of International Cooperation and Exchanges NSFC ( to J.Y.W.) and a grant-in-aid for scientific research (C) from Japan Society for the Promotion of Science (17K08878 to J.Y.W).
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Min, Q., Meng, X., Wang, JY. (2020). Primary Antibody Deficiencies. In: Wang, JY. (eds) B Cells in Immunity and Tolerance. Advances in Experimental Medicine and Biology, vol 1254. Springer, Singapore. https://doi.org/10.1007/978-981-15-3532-1_10
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