KEGG   DISEASE: Combined immunodeficiencyHelp
Entry
H00093                      Disease                                

Name
Combined immunodeficiency
Description
The term combined immunodeficiency (CID) is used to distinguish patients with low, but not absent, T-cell function from those with severe CID (SCID) characterized by profound deficiencies of T- and B-cell (and sometimes NK- cell) function. Hyper-IgM syndrome (HIM) represents a group of distinct entities characterized by defective normal or elevated IgM in the presence of diminished IgG and IgA levels. The genetic anomaly in X-linked hyper-IgM syndrome has been mapped to Xq26, and resides in mutations of the CD40 ligand gene. Missense mutation in exon 7 of the common gamma chain (IL2RG) causes a moderate form of X-linked CID. This point mutation in IL2RG leads to a less severe degree of deficiency in cellular and humoral immunity than that seen in XSCID. Two related deficiencies of recombination activating genes, RAG1 and RAG2 result in a spectrum of SCID called RAG1/RAG2 deficiency and Omenn syndrome. Mutations that lead to total absence of RAG1 or RAG2 gene product (null mutations) are known to lead to SCID without mature lymphoid cells, whereas mutations that result in partial V(D)J recombinase activity due to missense mutation on at least one allele lead to Omenn syndrome. Mutations of both TAP1 and TAP2 genes result in deficient expression of class I HLA proteins on the cell surface with defects in natural killer cell cytotoxicity. Defective expression of major histocompatibility complex (MHC) class II molecules account for 5% of SCID. The genetic lesions responsible for this syndrome do not lie within the MHC-II locus itself, but reside instead in genes encoding transcription factors, RFX5, RFXAP, RFXANK(B), and CIITA, controlling MHC-II expression. ZAP-70 deficiency is inherited in an autosomal recessive manner. Recurrent and opportunistic infections occur within the first year of life. The mutations in genes responsible for CRAC channel function, ORAI1 and STIM1, cause the defect in Ca2+ influx.
Category
Primary immunodeficiency
Brite
Human diseases [BR:br08402]
 Immune system diseases
  Primary immunodeficiency
   H00093  Combined immunodeficiency
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
    H00093  Combined immunodeficiency
BRITE hierarchy
Pathway
hsa05340  Primary immunodeficiency
Gene
CD40L (TNFSF5) [HSA:959] [KO:K03161]
CD40 [HSA:958] [KO:K03160]
IL2RG [HSA:3561] [KO:K05070]
PNP [HSA:4860] [KO:K03783]
RAG1 [HSA:5896] [KO:K10628]
RAG2 [HSA:5897] [KO:K10988]
TAP1 [HSA:6890] [KO:K05653]
TAP2 [HSA:6891] [KO:K05654]
CIITA [HSA:4261] [KO:K08060]
RFX5 [HSA:5993] [KO:K08061]
RFXAP [HSA:5994] [KO:K08063]
RFXANK [HSA:8625] [KO:K08062]
Zap-70 [HSA:7535] [KO:K07360]
ORAI1 [HSA:84876] [KO:K16056]
STIM1 [HSA:6786] [KO:K16059]
LCK [HSA:3932] [KO:K05856]
CD8A [HSA:925] [KO:K06458]
CARD11 [HSA:84433] [KO:K07367]
MALT1 [HSA:10892] [KO:K07369]
IKBKB [HSA:3551] [KO:K07209]
TNFRSF4 [HSA:7293] [KO:K05142]
CD3G [HSA:917] [KO:K06452]
CTPS1 [HSA:1503] [KO:K01937]
BCL10 [HSA:8915] [KO:K07368]
DOCK2 [HSA:1794] [KO:K12367]
Other DBs
ICD-11: 4A01.1
ICD-10: D81
MeSH: D053632
OMIM: 308230 312863 613179 603554 233650 612782 612783 615206 617638 615468 618204 615592 615593 615607 615897 616098 616433
Reference
  Authors
Kumar A, Teuber SS, Gershwin ME.
  Title
Current perspectives on primary immunodeficiency diseases.
  Journal
Clin Dev Immunol 13:223-59 (2006)
DOI:10.1080/17402520600800705
Reference
PMID:9737224
  Authors
Ten RM.
  Title
Primary immunodeficiencies.
  Journal
Mayo Clin Proc 73:865-72 (1998)
DOI:10.4065/73.9.865
Reference
  Authors
Lim MS, Elenitoba-Johnson KS.
  Title
The molecular pathology of primary immunodeficiencies.
  Journal
J Mol Diagn 6:59-83 (2004)
DOI:10.1016/S1525-1578(10)60493-X
Reference
  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
  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
  Authors
Notarangelo LD, Fischer A, Geha RS, Casanova JL, Chapel H, Conley ME, Cunningham-Rundles C, Etzioni A, Hammartrom L, Nonoyama S, Ochs HD, Puck J, Roifman C, Seger R, Wedgwood J
  Title
Primary immunodeficiencies: 2009 update.
  Journal
J Allergy Clin Immunol 124:1161-78 (2009)
DOI:10.1016/j.jaci.2009.10.013
Reference
PMID:7883965
  Authors
Schmalstieg FC, Leonard WJ, Noguchi M, Berg M, Rudloff HE, Denney RM, Dave SK, Brooks EG, Goldman AS
  Title
Missense mutation in exon 7 of the common gamma chain gene causes a moderate form of X-linked combined immunodeficiency.
  Journal
J Clin Invest 95:1169-73 (1995)
DOI:10.1172/JCI117765
Reference
  Authors
Kuijpers TW, Baars PA, Aan de Kerk DJ, Jansen MH, Derks IA, Bredius RG, Sanders EA, van der Burg M, Alders M, van Lier RA
  Title
A novel mutation in CD132 causes X-CID with defective T-cell activation and impaired humoral reactivity.
  Journal
J Allergy Clin Immunol 128:1360-1363.e4 (2011)
DOI:10.1016/j.jaci.2011.07.001
Reference
  Authors
Niehues T, Perez-Becker R, Schuetz C
  Title
More than just SCID--the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2.
  Journal
Clin Immunol 135:183-92 (2010)
DOI:10.1016/j.clim.2010.01.013
Reference
  Authors
Schuetz C, Huck K, Gudowius S, Megahed M, Feyen O, Hubner B, Schneider DT, Manfras B, Pannicke U, Willemze R, Knuchel R, Gobel U, Schulz A, Borkhardt A, Friedrich W, Schwarz K, Niehues T
  Title
An immunodeficiency disease with RAG mutations and granulomas.
  Journal
N Engl J Med 358:2030-8 (2008)
DOI:10.1056/NEJMoa073966
Reference
  Authors
Feske S, Picard C, Fischer A
  Title
Immunodeficiency due to mutations in ORAI1 and STIM1.
  Journal
Clin Immunol 135:169-82 (2010)
DOI:10.1016/j.clim.2010.01.011
Reference
  Authors
Verbsky JW, Chatila TA
  Title
T-regulatory cells in primary immune deficiencies.
  Journal
Curr Opin Allergy Clin Immunol 11:539-44 (2011)
DOI:10.1097/ACI.0b013e32834cb8fa
Reference
  Authors
Picard C, Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM, Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE, Tang ML, Franco JL, Gaspar HB
  Title
Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015.
  Journal
J Clin Immunol 35:696-726 (2015)
DOI:10.1007/s10875-015-0201-1
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