KEGG DISEASE: Common variable immunodeficiency

DISEASE: Common variable immunodeficiency

Entry

H00088                      Disease

Name

Common variable immunodeficiency

Supergrp

Disorders of adaptive immunity [DS:H02526]
Primary immunodeficiency disease [DS:H01725]

Description

There are three major categories of antibody deficiencies: (a) defects in early B cell development, (b) hyper-IgM syndromes (also called class switch recombination defects), and (c) common variable immunodeficiency (CVID). Category (c) CVID, also called acquired hypogammaglobulinemia, adult-onset hypogammaglobulinemia, or dysgammaglobulinemia, is a heterogeneous group of disorders involving both B-cell and T-cell immune function, the predominant manifestation of which is hypogammaglobulinemia. CVID is characterized by recurrent bacterial infections, decreased serum Ig levels, and abnormal antibody responses. The mutated genes that produce the CVID phenotype are known only for a minority of patients, and they are diverse in their influence on immune function. Homozygous mutations in ICOS are clearly the cause of disease. Heterozygous mutations in the TNF receptor family member TACI (transmembrane activator and calcium-modulating cyclophilin ligand interactor) can be found in up to 10% of patients with CVID.

Category

Immune system disease

Brite

Human diseases in ICD-11 classification [BR:br08403]
04 Diseases of the immune system
  Primary immunodeficiencies
   4A01  Primary immunodeficiencies due to disorders of adaptive immunity
    H00088  Common variable immunodeficiency
Pathway-based classification of diseases [BR:br08402]
Signal transduction
  nt06516  TNF signaling
   H00088  Common variable immunodeficiency
Immune system
  nt06537  TCR/BCR signaling
   H00088  Common variable immunodeficiency

Pathway

hsa04151 PI3K-Akt signaling pathway

hsa04662 B cell receptor signaling pathway

hsa04660 T cell receptor signaling pathway

Network

nt06516 TNF signaling
nt06537 TCR/BCR signaling

Gene

(CVID1) ICOS [HSA:29851] [KO:K06713]
(CVID2) TNFRSF13B [HSA:23495] [KO:K05150]
(CVID3) CD19 [HSA:930] [KO:K06465]
(CVID4) TNFRSF13C [HSA:115650] [KO:K05151]
(CVID5) MS4A1 [HSA:931] [KO:K06466]
(CVID6) CD81 [HSA:975] [KO:K06508]
(CVID7) CR2 [HSA:1380] [KO:K04012]
(CVID8) LRBA [HSA:987] [KO:K24181]
(CVID10) NFKB2 [HSA:4791] [KO:K04469]
(CVID11) IL21 [HSA:59067] [KO:K05434]
(CVID12) NFKB1 [HSA:4790] [KO:K02580]
(CVID13) IKZF1 [HSA:10320] [KO:K09220]
(CVID14) IRF2BP2 [HSA:359948] [KO:K27448]
(CVID15) SEC61A1 [HSA:29927] [KO:K10956]

Other DBs

ICD-11:

4A01.0Z

ICD-10:

D80

MeSH:

D017074

OMIM:

607594 240500 613493 613494 613495 613496 614699 614700 615577 615767 616576 616873 617765 620670

Reference

PMID:18424339

Authors

Morra M, Geigenmuller U, Curran J, Rainville IR, Brennan T, Curtis J, Reichert V, Hovhannisyan H, Majzoub J, Miller DT.

Title

Genetic diagnosis of primary immune deficiencies.

Journal

Immunol Allergy Clin North Am 28:387-412, x (2008)
DOI:10.1016/j.iac.2008.01.004

Reference

PMID:17952897

Authors

Geha RS, Notarangelo LD, Casanova JL, Chapel H, Conley ME, Fischer A, Hammarstrom L, Nonoyama S, Ochs HD, Puck JM, Roifman C, Seger R, Wedgwood J.

Title

Primary immunodeficiency diseases: an update from the International Union of Immunological Societies Primary Immunodeficiency Diseases Classification Committee.

Journal

J Allergy Clin Immunol 120:776-94 (2007)
DOI:10.1016/j.jaci.2007.08.053

Reference

PMID:22236429

Authors

Park JH, Resnick ES, Cunningham-Rundles C

Title

Perspectives on common variable immune deficiency.

Journal

Ann N Y Acad Sci 1246:41-9 (2011)
DOI:10.1111/j.1749-6632.2011.06338.x

Reference

PMID:12577056 (CVID1)

Authors

Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Drager R, Eibel H, Fischer B, Schaffer AA, Mages HW, Kroczek RA, Peter HH

Title

Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency.

Journal

Nat Immunol 4:261-8 (2003)
DOI:10.1038/ni902

Reference

PMID:16007086 (CVID2)

Authors

Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS

Title

TACI is mutant in common variable immunodeficiency and IgA deficiency.

Journal

Nat Genet 37:829-34 (2005)
DOI:10.1038/ng1601

Reference

PMID:16672701 (CVID3)

Authors

van Zelm MC, Reisli I, van der Burg M, Castano D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patino PJ, van Dongen JJ, Franco JL

Title

An antibody-deficiency syndrome due to mutations in the CD19 gene.

Journal

N Engl J Med 354:1901-12 (2006)
DOI:10.1056/NEJMoa051568

Reference

PMID:19666484 (CVID4)

Authors

Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Bohm J, Kienzler AK, Pan-Hammarstrom Q, Hammarstrom L, Rakhmanov M, Schlesier M, Grimbacher B, Peter HH, Eibel H

Title

B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans.

Journal

Proc Natl Acad Sci U S A 106:13945-50 (2009)
DOI:10.1073/pnas.0903543106

Reference

PMID:20038800 (CVID5)

Authors

Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, Beaumont T, Tedder TF, van Noesel CJ, Eldering E, van Lier RA

Title

CD20 deficiency in humans results in impaired T cell-independent antibody responses.

Journal

J Clin Invest 120:214-22 (2010)
DOI:10.1172/JCI40231

Reference

PMID:20237408 (CVID6)

Authors

van Zelm MC, Smet J, Adams B, Mascart F, Schandene L, Janssen F, Ferster A, Kuo CC, Levy S, van Dongen JJ, van der Burg M

Title

CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency.

Journal

J Clin Invest 120:1265-74 (2010)
DOI:10.1172/JCI39748

Reference

PMID:22035880 (CVID7)

Authors

Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, Draeger R, Voelxen N, Bergbreiter A, Jennings S, Gutenberger S, Aichem A, Illges H, Hannan JP, Kienzler AK, Rizzi M, Eibel H, Peter HH, Warnatz K, Grimbacher B, Rump JA, Schlesier M

Title

Genetic CD21 deficiency is associated with hypogammaglobulinemia.

Journal

J Allergy Clin Immunol 129:801-810.e6 (2012)
DOI:10.1016/j.jaci.2011.09.027

Reference

PMID:25468195 (CVID8)

Authors

Charbonnier LM, Janssen E, Chou J, Ohsumi TK, Keles S, Hsu JT, Massaad MJ, Garcia-Lloret M, Hanna-Wakim R, Dbaibo G, Alangari AA, Alsultan A, Al-Zahrani D, Geha RS, Chatila TA

Title

Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA.

Journal

J Allergy Clin Immunol 135:217-27 (2015)
DOI:10.1016/j.jaci.2014.10.019

Reference

PMID:24140114 (CVID10)

Authors

Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL, Wu W, Heikal NM, Augustine NH, Ridge PG, Hill HR, Jorde LB, Weyrich AS, Zimmerman GA, Gundlapalli AV, Bohnsack JF, Voelkerding KV

Title

Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency.

Journal

Am J Hum Genet 93:812-24 (2013)
DOI:10.1016/j.ajhg.2013.09.009

Reference

PMID:24746753 (CVID11)

Authors

Salzer E, Kansu A, Sic H, Majek P, Ikinciogullari A, Dogu FE, Prengemann NK, Santos-Valente E, Pickl WF, Bilic I, Ban SA, Kuloglu Z, Demir AM, Ensari A, Colinge J, Rizzi M, Eibel H, Boztug K

Title

Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency.

Journal

J Allergy Clin Immunol 133:1651-9.e12 (2014)
DOI:10.1016/j.jaci.2014.02.034

Reference

PMID:26279205 (CVID12)

Authors

Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, Winzer S, Bulashevska A, Scerri T, Leung E, Jordan A, Keller B, de Vries E, Cao H, Yang F, Schaffer AA, Warnatz K, Browett P, Douglass J, Ameratunga RV, van der Meer JW, Grimbacher B

Title

Haploinsufficiency of the NF-kappaB1 Subunit p50 in Common Variable Immunodeficiency.

Journal

Am J Hum Genet 97:389-403 (2015)
DOI:10.1016/j.ajhg.2015.07.008

Reference

PMID:21548011 (CVID13)

Authors

Goldman FD, Gurel Z, Al-Zubeidi D, Fried AJ, Icardi M, Song C, Dovat S

Title

Congenital pancytopenia and absence of B lymphocytes in a neonate with a mutation in the Ikaros gene.

Journal

Pediatr Blood Cancer 58:591-7 (2012)
DOI:10.1002/pbc.23160

Reference

PMID:27016798 (CVID14)

Authors

Keller MD, Pandey R, Li D, Glessner J, Tian L, Henrickson SE, Chinn IK, Monaco-Shawver L, Heimall J, Hou C, Otieno FG, Jyonouchi S, Calabrese L, van Montfrans J, Orange JS, Hakonarson H

Title

Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder.

Journal

J Allergy Clin Immunol 138:544-550.e4 (2016)
DOI:10.1016/j.jaci.2016.01.018

Reference

PMID:28782633 (CVID15)

Authors

Schubert D, Klein MC, Hassdenteufel S, Caballero-Oteyza A, Yang L, Proietti M, Bulashevska A, Kemming J, Kuhn J, Winzer S, Rusch S, Fliegauf M, Schaffer AA, Pfeffer S, Geiger R, Cavalie A, Cao H, Yang F, Li Y, Rizzi M, Eibel H, Kobbe R, Marks AL, Peppers BP, Hostoffer RW, Puck JM, Zimmermann R, Grimbacher B

Title

Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1).

Journal

J Allergy Clin Immunol 141:1427-1438 (2018)
DOI:10.1016/j.jaci.2017.06.042

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