Predominantly antibody deficiency: Difference between revisions

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==IKAROS Deficiency==
==IKAROS Deficiency==
*IKAROS gene encodes for a family of hemopoietic-specific zinc finger proteins which are essential for lymphocyte development.<ref name="pmid9143685">{{cite journal |vauthors=Georgopoulos K, Winandy S, Avitahl N |title=The role of the Ikaros gene in lymphocyte development and homeostasis |journal=Annu. Rev. Immunol. |volume=15 |issue= |pages=155–76 |date=1997 |pmid=9143685 |doi=10.1146/annurev.immunol.15.1.155 |url=}}</ref>
*Individuals show varied severity of clinical disease, despite most patients having low B cell and antibody count.
*Deficiency leads to hypogammaglobulinemia, decreased response to vaccines, recurrent bacterial infections and malignancies.
*Treatment is via replacement of immunoglobulins and  treatment of infections with antibiotics.<ref name="pmid26981933">{{cite journal |vauthors=Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, Maffucci P, Pierce KR, Abbott JK, Voelkerding KV, South ST, Augustine NH, Bush JS, Dolen WK, Wray BB, Itan Y, Cobat A, Sorte HS, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova JL, Fleisher TA, Hill HR, Kumánovics A, Conley ME, Rosenzweig SD |title=Loss of B Cells in Patients with Heterozygous Mutations in IKAROS |journal=N. Engl. J. Med. |volume=374 |issue=11 |pages=1032–1043 |date=March 2016 |pmid=26981933 |pmc=4836293 |doi=10.1056/NEJMoa1512234 |url=}}</ref>


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}

Revision as of 20:35, 6 December 2018

Immunodeficiency Main Page

Home

Overview

Classification

Immunodeficiency Affecting Cellular and Humoral Immunity

Combined Immunodeficiency

Predominantly Antibody Deficiency

Diseases of Immune Dysregulation

Congenital Defects of Phagocytes

Defects in Intrinsic and Innate Immunity

Auto-inflammatory Disorders

Complement Deficiencies

Phenocopies of Primary Immunodeficiency

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ali Akram, M.B.B.S.[2], Anmol Pitliya, M.B.B.S. M.D.[3]

Overview

Classification

 
 
Predominantly antibody deficiencies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hypogammaglobulinemia
 
Other antibody deficiencies


Hypogammaglobulinemia


 
 
 
 
Predominantly antibody deficiencies
(A): Hypogammaglobulinemia
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum immunoglobulin assays : IgG, IgA, IgM, IgE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IgG, IgA, and/or IgM ↓↓
→ B Lymphocyte (CD19+) enumeration (CMF)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
B absent
 
 
 
B >1%
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-Linked Agammaglobulinemia
 
Common Variable Immunodeficiency Phenotype
 
 
 
CD19 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
µ heavy chain Def
 
 
 
CVID with no gene defect specified
 
 
CD20 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Igα def
 
 
 
PIK3CD mutation(GOF),PIK3R1 deficiency(LOF)
 
 
CD21 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Igβ def
 
 
 
PTEN deficiency(LOF)
 
 
TRNT1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BLNK def
 
 
 
CD81 deficiency
 
 
NFKB1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
λ5 def
 
 
 
TACI deficiency
 
 
NFKB2 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI3KR1 def
 
 
 
BAFF receptor deficiency
 
 
IKAROS deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
E47 transcription factor def
 
 
 
TWEAK deficiency
 
 
ATP6AP1 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mannosyl-oligosaccharide glucosidase deficiency (MOGS)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TTC37 deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRF2BP2 deficiency
 
 
 
 
 
 

Other Antibody deficiencies

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Predominantly antibody deficiencies
(B): Other antibody deficiencies
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Immunolobulin Assays: IgG, IgA, IgM, IgE
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Severe Reduction in Serum IgG and IgA with NI/elevated IgM and Normal Numbers of B cells: Hyper IgM Syndromes
 
 
 
 
Isotype, Light Chain, or Functional Deficiencies with Generally NI Numbers of B cells
 
 
 
High B cell numbers due to constitutive NF-kB activation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AID deficiency
 
 
 
 
 
Selective IgA deficiency
 
 
 
 
CARD11 Gain of Function
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
UNG deficiency
 
 
 
 
 
Transient hypogammaglobuliemia of infancy
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
INO80
 
 
 
 
 
IgG subclass deficiency with IgA deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MSH6
 
 
 
 
 
Isolated IgG subclass deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Specific antibody deficiency with normal Ig levels and normal B cells
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ig heavy chain muations and deletions
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kappa chain deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Selective IgM deficiency
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

X-linked Agammaglobulinemia

  • It is an X linked disease, first described by Bruton in 1952.
  • It is caused by the mutation of BTK gene (present on the long arm of X chromosome) which encodes for the protein Bruton tyrosine kinase,which is associated with the maturation and differentiation of the pre B cell.[1]
  • The disruption of this protein can lead to significant decrease in all antibody isotypes, due to failure of Ig heavy chain rearrangement.[2]
  • Affected individuals generally present between 3 months to 3 years of age, with almost 90% becoming symptomatic by 5 years of age.[3]
  • Presence of maternal immunoglobulins provide transient protection, concealing symptoms of the disease and preventing early detection.
  • Physical examination typically shows absence of lymph nodes.
  • Patients are susceptible to recurrent infections with encapsulated organisms and enteroviruses, primarily effecting respiratory and gastrointestinal tracts.
  • Laboratory findings show defect in humoral immunity with absence or negligible amount of IgM, IgG, and IgA, as well as <2% of B cells lymphocytes. Neutropenia can also be seen.[4][1][5]
  • Treatment is mainly via hematopoietic stem cell therapy and through replacement of immunoglobulins either by intravenous or subcutaneous routes. Recurrent infections are prevented and treated by antibiotics.[6]

For more information on X-linked agammaglobulinemia, click here.

µ Heavy Chain Deficiency

Igα Deficiency

Igβ Deficiency

BLNK Deficiency

λ5 Deficiency

PI3KR1 Deficiency

  • PIK3R1 gene encodes for the p85α subunit of class IA phosphoinositide 3-kinases (PI3Ks).[15]
  • Patients present with history of recurrent bacterial infections and positive family history, similar to clinical features seen in X-linked agammaglobulinemia.[16]
  • Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.[10]

E47 transcription factor Deficiency

  • Mutation of E47 transcription factor.
  • This mutation leads to improper differentiation of B cell from lymphoid precursors.[17]
  • Patients present with few B cells characterized increased expression of CD19, but without B cell receptor (BCR).[18]
  • Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.[10]

CVID With No Gene Specified

  1. Hypogammaglobulinaemia with IgG levels two standard deviations below the mean.
  2. Impaired vaccine responses or absent isohemagglutinins.
  3. Exclusion of other causes of hypogammaglobulinaemia.
  • Patients are susceptible to recurrent infections, autoimmunity and malignancy.
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins.[20]

PIK3CD mutation,PIK3R1 deficiency

  • Also known as Activated phosphoinositide 3-kinase δ syndrome (APDS).
  • Autosomal dominant gain of function (GOF) mutation of PIK3CD gene, which encodes for P110δ subunit of phosphoinositide 3-kinase (PI3K) and loss of function (LOF) mutation of PIK3R1 gene, which encodes the p85α subunit of PI3K.
  • Mutations in PIK3CD gene leads to clinical features similar to mutation in PIK3R1 gene.[21]
  • Patients with mutations of gene for PIK3R1 show characteristics similar to that of patients carrying gain-of-function mutations of PIK3CD gene.
  • Mutations lead to hyperactive PI3K/AKT/mTOR signaling.[15][22]
  • Disease is characterized by low numbers of naive T cells, but a larger number of senescent effector T cells.
  • Patients present with upper and lower respiratory tract infections, lymphadenopathy, nodular lymphoid hyperplasia, early-onset autoimmunity, malignancies and recurrent viral infections with cytomegalovirus (CMV) and Epstein Barr virus (EBV).[23]
  • Treatment is via sirolimus and selective PI3Kδ inhibitors, intavenous and subcutaneous immunoglobulin replacement, prophylactic antibiotic, and hematopoietic stem cell transplant.[24]

PTEN deficiency

CD 81 Deficiency

  • CD81 is a B cell surface protein (part of CD19 complex) which helps in antigen recognition.
  • Deficiency is characterized by decreased in number of B cell, hypogammaglobulinemia , impaired antibody responses, and absence of CD19 expression on B cells.
  • Patients present with recurrent infections of upper and lower respiratory tract.
  • Treatment is mainly through replacement of immunoglobulins by intravenous or subcutaneous routes, hematopoietic stem cell therapy and use of prophylactic and curative antibiotics.[27]

TACI Deficiency

  • Transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) is a part of tumor necrosis factor family and involved in B cell class switching.
  • Missense mutation of one allele of TNFRSF13B gene encoding for TACI leads to CVID like immunodeficiency.[28]
  • Patients present with increased suseptability to encapsulated organisms, autoimmunity, and hypogammaglobulinemia.[29][30]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins.[20]

BAFF Receptor Deficiency

  • Mutation of B-cell activating factor receptor (BAFF-R) prevents maturation of transitional B cell, leading to a CVID type adult onset immunodeficiency.
  • Incomplete maturation leads to hypogammaglobulinemia, but can in a few cases not manifest to clinical disease, with recurrent infections.
  • Patients show varying degrees immunodeficiency but normal IgA levels.[31][32]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

TWEAK Deficiency

  • CVID like phenotype caused by, an autosomal dominant transmitted, deficiency in TNF-like weak inducer of apoptosis (TWEAK).
  • Mutation in TWEAK is associated with regulation of BAFF associated B cell development leading to impared B cell survival and isotype class switching.
  • Disease is characterized by recurrent infection and impaired response to vaccination.[33]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

MOGS Deficiency

  • Mannosyl-oligosaccharide glucosidase (MOGS) deficiency causes a congenital disorder of glycosylation type IIb (CDG-IIb), also known as MOGS-CDG.
  • MOGS deficiency leads to improper processing of immunoglobulins, which shortens their half-life in circulation.
  • Few studies show that unlike most antibody deficiencies MOGS deficiency does not lead to clinical features of hypogammaglobulinemia like recurrent infections.
  • This is because cells with MOGS deficiency have altered glycosylation which prevents productive infection of multiple enveloped viruses.[34][35]

TTC37 Deficiency

  • Tetratricopeptide Repeat Domain 37 (TTC37) deficency is an autosomal recessive disease causing syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) which has a similar immune phenotype to CVID.
  • TTC37 is involved in aberrant mRNAs decay.
  • Patient presents in infancy with low IgG and poor antigen-stimulation to vaccine.
  • Clinical features show infantile onset refractory diarrhea, hair and facial anomalies.[36][37]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

IRF2BP2 Deficiency

  • Interferon Regulatory Factor 2 Binding Protein 2 (IRF2BP2) mutation leads to impaired differentiation of B cells.
  • Few studies show that most patients with this mutation are diagnosed with CVID in childhood.
  • Disease is characterized by recurrent infections,low levels of IgG, IgA and IgM , and decreased number of memory B cells. There is no T cell dysfunction.[38]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

CD19 Deficiency

  • CD19 surface expression can be absent in cases of homozygous CD19 deficiency or CD81 deficiency.
  • Deficiency leads to impaired formation of CD19 complex and B cell development and antibody response.[39]
  • Patients show increased susceptibility to infection, hypogammaglobulinemia and impaired response to vaccines.[40]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

CD20 Deficiency

  • CD20 is essential for T cell independent antibody response.
  • Deficiency of CD20 therefore leads to reduced ability to mount an antibody response.
  • Patients have increased risk of infections by encapsulated bacteria, hypogammaglobulinemia, due to decrease somatic hypermutation, and normal B cell numbers; but a decrease in number of circulating memory B cells.[41]
  • Treatment is by intravenous or subcutaneous replacement of immunoglobulins and by curative antibiotics.[20]

CD21 Deficiency

  • CD21 is a receptor for complement C3d which helps in antigen specific response.
  • Patients present with increased susceptibility to infections, decreased immunoglobulin class switching, chronic diarrhea and hypogammaglobulinemia.
  • Unlike patients with CD19 and CD20 deficiency patients with CD 21 have less sever clinical phenotype, and are able to mount specific antibody response to vaccines but not very well with polysaccharide vaccines.[42]
  • Treatment is by curative antibiotics to treat recurrent infections.[20]

TRNT1 Deficiency

NFKB1 Deficiency

NFKB2 Deficiency

  • Nuclear factor kappa-B subunit 2 (NFKB2) is a part of noncolonical NF-κB pathway and is involved in B cell maturation and antibody development.[48]
  • Mutations leading to deficiency cause CVID with early onset central adrenal insufficiency and at times ectodermal dysplasia.
  • Patients presents with ACTH deficiency, recurrent infections, hypogammaglobulinemia, decreased response to vaccines and autoimmunity effecting the skin, hair, and nails
  • Treatment is via immunoglobulin replacement therapy and gucucorticoid replacement.[49]

IKAROS Deficiency

  • IKAROS gene encodes for a family of hemopoietic-specific zinc finger proteins which are essential for lymphocyte development.[50]
  • Individuals show varied severity of clinical disease, despite most patients having low B cell and antibody count.
  • Deficiency leads to hypogammaglobulinemia, decreased response to vaccines, recurrent bacterial infections and malignancies.
  • Treatment is via replacement of immunoglobulins and treatment of infections with antibiotics.[51]

References

  1. 1.0 1.1 Hernandez-Trujillo VP, Scalchunes C, Cunningham-Rundles C, Ochs HD, Bonilla FA, Paris K, Yel L, Sullivan KE (August 2014). "Autoimmunity and inflammation in X-linked agammaglobulinemia". J. Clin. Immunol. 34 (6): 627–32. doi:10.1007/s10875-014-0056-x. PMC 4157090. PMID 24909997.
  2. Rawlings DJ, Witte ON (April 1994). "Bruton's tyrosine kinase is a key regulator in B-cell development". Immunol. Rev. 138: 105–19. PMID 8070812.
  3. Winkelstein JA, Marino MC, Lederman HM, Jones SM, Sullivan K, Burks AW, Conley ME, Cunningham-Rundles C, Ochs HD (July 2006). "X-linked agammaglobulinemia: report on a United States registry of 201 patients". Medicine (Baltimore). 85 (4): 193–202. doi:10.1097/01.md.0000229482.27398.ad. PMID 16862044.
  4. Fried AJ, Bonilla FA (July 2009). "Pathogenesis, diagnosis, and management of primary antibody deficiencies and infections". Clin. Microbiol. Rev. 22 (3): 396–414. doi:10.1128/CMR.00001-09. PMC 2708392. PMID 19597006.
  5. Berglöf A, Turunen JJ, Gissberg O, Bestas B, Blomberg KE, Smith CI (December 2013). "Agammaglobulinemia: causative mutations and their implications for novel therapies". Expert Rev Clin Immunol. 9 (12): 1205–21. doi:10.1586/1744666X.2013.850030. PMID 24215410.
  6. 6.0 6.1 Cunningham-Rundles C (June 2011). "Key aspects for successful immunoglobulin therapy of primary immunodeficiencies". Clin. Exp. Immunol. 164 Suppl 2: 16–9. doi:10.1111/j.1365-2249.2011.04390.x. PMC 3087906. PMID 21466548.
  7. Yel L, Minegishi Y, Coustan-Smith E, Buckley RH, Trübel H, Pachman LM, Kitchingman GR, Campana D, Rohrer J, Conley ME (November 1996). "Mutations in the mu heavy-chain gene in patients with agammaglobulinemia". N. Engl. J. Med. 335 (20): 1486–93. doi:10.1056/NEJM199611143352003. PMID 8890099.
  8. Abolhassani H, Vitali M, Lougaris V, Giliani S, Parvaneh N, Parvaneh L, Mirminachi B, Cheraghi T, Khazaei H, Mahdaviani SA, Kiaei F, Tavakolinia N, Mohammadi J, Negahdari B, Rezaei N, Hammarstrom L, Plebani A, Aghamohammadi A (2016). "Cohort of Iranian Patients with Congenital Agammaglobulinemia: Mutation Analysis and Novel Gene Defects". Expert Rev Clin Immunol. 12 (4): 479–86. doi:10.1586/1744666X.2016.1139451. PMID 26910880.
  9. Wang Y, Kanegane H, Sanal O, Tezcan I, Ersoy F, Futatani T, Miyawaki T (April 2002). "Novel Igalpha (CD79a) gene mutation in a Turkish patient with B cell-deficient agammaglobulinemia". Am. J. Med. Genet. 108 (4): 333–6. PMID 11920841.
  10. 10.0 10.1 10.2 10.3 10.4 Maarschalk-Ellerbroek LJ, Hoepelman IM, Ellerbroek PM (May 2011). "Immunoglobulin treatment in primary antibody deficiency". Int. J. Antimicrob. Agents. 37 (5): 396–404. doi:10.1016/j.ijantimicag.2010.11.027. PMID 21276714.
  11. Ferrari S, Lougaris V, Caraffi S, Zuntini R, Yang J, Soresina A, Meini A, Cazzola G, Rossi C, Reth M, Plebani A (September 2007). "Mutations of the Igbeta gene cause agammaglobulinemia in man". J. Exp. Med. 204 (9): 2047–51. doi:10.1084/jem.20070264. PMC 2118692. PMID 17709424.
  12. 12.0 12.1 Dobbs AK, Yang T, Farmer D, Kager L, Parolini O, Conley ME (August 2007). "Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development". J. Immunol. 179 (4): 2055–9. PMID 17675462.
  13. Minegishi Y, Rohrer J, Coustan-Smith E, Lederman HM, Pappu R, Campana D, Chan AC, Conley ME (December 1999). "An essential role for BLNK in human B cell development". Science. 286 (5446): 1954–7. PMID 10583958.
  14. Minegishi Y, Coustan-Smith E, Wang YH, Cooper MD, Campana D, Conley ME (January 1998). "Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia". J. Exp. Med. 187 (1): 71–7. PMC 2199185. PMID 9419212.
  15. 15.0 15.1 Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, Cavazzana M, Picard C, Durandy A, Fischer A, Kracker S (September 2014). "A human immunodeficiency caused by mutations in the PIK3R1 gene". J. Clin. Invest. 124 (9): 3923–8. doi:10.1172/JCI75746. PMC 4153704. PMID 25133428.
  16. de la Morena M, Haire RN, Ohta Y, Nelson RP, Litman RT, Day NK, Good RA, Litman GW (March 1995). "Predominance of sterile immunoglobulin transcripts in a female phenotypically resembling Bruton's agammaglobulinemia". Eur. J. Immunol. 25 (3): 809–15. doi:10.1002/eji.1830250327. PMID 7705412.
  17. Boisson B, Wang YD, Bosompem A, Ma CS, Lim A, Kochetkov T, Tangye SG, Casanova JL, Conley ME (November 2013). "A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells". J. Clin. Invest. 123 (11): 4781–5. doi:10.1172/JCI71927. PMC 3809807. PMID 24216514.
  18. Dobbs AK, Bosompem A, Coustan-Smith E, Tyerman G, Saulsbury FT, Conley ME (August 2011). "Agammaglobulinemia associated with BCR⁻ B cells and enhanced expression of CD19". Blood. 118 (7): 1828–37. doi:10.1182/blood-2011-01-330472. PMC 3158715. PMID 21693761.
  19. Park JH, Resnick ES, Cunningham-Rundles C (December 2011). "Perspectives on common variable immune deficiency". Ann. N. Y. Acad. Sci. 1246: 41–9. doi:10.1111/j.1749-6632.2011.06338.x. PMC 3428018. PMID 22236429.
  20. 20.0 20.1 20.2 20.3 20.4 20.5 20.6 20.7 20.8 Ameratunga R, Woon ST, Gillis D, Koopmans W, Steele R (November 2013). "New diagnostic criteria for common variable immune deficiency (CVID), which may assist with decisions to treat with intravenous or subcutaneous immunoglobulin". Clin. Exp. Immunol. 174 (2): 203–11. doi:10.1111/cei.12178. PMC 3828823. PMID 23859429.
  21. Ochs HD (December 2014). "Common variable immunodeficiency (CVID): new genetic insight and unanswered questions". Clin. Exp. Immunol. 178 Suppl 1: 5–6. doi:10.1111/cei.12491. PMC 4285471. PMID 25546742.
  22. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, Goodlad JR, Farmer G, Steele CL, Leahy TR, Doffinger R, Baxendale H, Bernatoniene J, Edgar JD, Longhurst HJ, Ehl S, Speckmann C, Grimbacher B, Sediva A, Milota T, Faust SN, Williams AP, Hayman G, Kucuk ZY, Hague R, French P, Brooker R, Forsyth P, Herriot R, Cancrini C, Palma P, Ariganello P, Conlon N, Feighery C, Gavin PJ, Jones A, Imai K, Ibrahim MA, Markelj G, Abinun M, Rieux-Laucat F, Latour S, Pellier I, Fischer A, Touzot F, Casanova JL, Durandy A, Burns SO, Savic S, Kumararatne DS, Moshous D, Kracker S, Vanhaesebroeck B, Okkenhaug K, Picard C, Nejentsev S, Condliffe AM, Cant AJ (February 2017). "Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study". J. Allergy Clin. Immunol. 139 (2): 597–606.e4. doi:10.1016/j.jaci.2016.06.021. PMC 5292996. PMID 27555459.
  23. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G (January 2014). "Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency". Nat. Immunol. 15 (1): 88–97. doi:10.1038/ni.2771. PMC 4209962. PMID 24165795.
  24. Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, Baris S, Barzaghi F, Baxendale H, Buckland M, Burns SO, Cancrini C, Cant A, Cathébras P, Cavazzana M, Chandra A, Conti F, Coulter T, Devlin LA, Edgar J, Faust S, Fischer A, Garcia-Prat M, Hammarström L, Heeg M, Jolles S, Karakoc-Aydiner E, Kindle G, Kiykim A, Kumararatne D, Grimbacher B, Longhurst H, Mahlaoui N, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neven B, Nieters A, Olbrich P, Ozen A, Pachlopnik Schmid J, Picard C, Prader S, Rae W, Reichenbach J, Rusch S, Savic S, Scarselli A, Scheible R, Sediva A, Sharapova SO, Shcherbina A, Slatter M, Soler-Palacin P, Stanislas A, Suarez F, Tucci F, Uhlmann A, van Montfrans J, Warnatz K, Williams AP, Wood P, Kracker S, Condliffe AM, Ehl S (2018). "Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry". Front Immunol. 9: 543. doi:10.3389/fimmu.2018.00543. PMC 5863269. PMID 29599784. Vancouver style error: initials (help)
  25. Leslie NR, Longy M (April 2016). "Inherited PTEN mutations and the prediction of phenotype". Semin. Cell Dev. Biol. 52: 30–8. doi:10.1016/j.semcdb.2016.01.030. PMID 26827793.
  26. Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, Ohnishi H, Kato Z, Sekinaka Y, Zaha K, Kato T, Okano T, Takashima T, Kobayashi K, Kimura M, Kunitsu T, Maruo Y, Kanegane H, Takagi M, Yoshida K, Okuno Y, Muramatsu H, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Kojima S, Ogawa S, Ohara O, Okada S, Kobayashi M, Morio T, Nonoyama S (December 2016). "Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency". J. Allergy Clin. Immunol. 138 (6): 1672–1680.e10. doi:10.1016/j.jaci.2016.03.055. PMID 27426521.
  27. van Zelm MC, Smet J, Adams B, Mascart F, Schandené L, Janssen F, Ferster A, Kuo CC, Levy S, van Dongen JJ, van der Burg M (April 2010). "CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency". J. Clin. Invest. 120 (4): 1265–74. doi:10.1172/JCI39748. PMC 2846042. PMID 20237408.
  28. Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS (August 2005). "TACI is mutant in common variable immunodeficiency and IgA deficiency". Nat. Genet. 37 (8): 829–34. doi:10.1038/ng1601. PMID 16007086.
  29. Tsuji S, Cortesão C, Bram RJ, Platt JL, Cascalho M (November 2011). "TACI deficiency impairs sustained Blimp-1 expression in B cells decreasing long-lived plasma cells in the bone marrow". Blood. 118 (22): 5832–9. doi:10.1182/blood-2011-05-353961. PMC 3228499. PMID 21984806.
  30. Martinez-Gallo M, Radigan L, Almejún MB, Martínez-Pomar N, Matamoros N, Cunningham-Rundles C (February 2013). "TACI mutations and impaired B-cell function in subjects with CVID and healthy heterozygotes". J. Allergy Clin. Immunol. 131 (2): 468–76. doi:10.1016/j.jaci.2012.10.029. PMC 3646641. PMID 23237420.
  31. Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Böhm J, Kienzler AK, Pan-Hammarström Q, Hammarström L, Rakhmanov M, Schlesier M, Grimbacher B, Peter HH, Eibel H (August 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. doi:10.1073/pnas.0903543106. PMC 2722504. PMID 19666484.
  32. Woolf N (March 1978). "The origins of atherosclerosis". Postgrad Med J. 54 (629): 156–62. PMC 2425199. PMID 349534.
  33. Wang HY, Ma CA, Zhao Y, Fan X, Zhou Q, Edmonds P, Uzel G, Oliveira JB, Orange J, Jain A (March 2013). "Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK". Proc. Natl. Acad. Sci. U.S.A. 110 (13): 5127–32. doi:10.1073/pnas.1221211110. PMC 3612633. PMID 23493554.
  34. Sadat MA, Moir S, Chun TW, Lusso P, Kaplan G, Wolfe L, Memoli MJ, He M, Vega H, Kim L, Huang Y, Hussein N, Nievas E, Mitchell R, Garofalo M, Louie A, Ireland DC, Grunes C, Cimbro R, Patel V, Holzapfel G, Salahuddin D, Bristol T, Adams D, Marciano BE, Hegde M, Li Y, Calvo KR, Stoddard J, Justement JS, Jacques J, Priel D, Murray D, Sun P, Kuhns DB, Boerkoel CF, Chiorini JA, Di Pasquale G, Verthelyi D, Rosenzweig SD (April 2014). "Glycosylation, hypogammaglobulinemia, and resistance to viral infections". N. Engl. J. Med. 370 (17): 1615–1625. doi:10.1056/NEJMoa1302846. PMC 4066413. PMID 24716661. Vancouver style error: initials (help)
  35. Chang J, Block TM, Guo JT (2015). "Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections". Antivir. Ther. (Lond.). 20 (3): 257–9. doi:10.3851/IMP2907. PMC 4446249. PMID 25318123.
  36. Rider NL, Boisson B, Jyonouchi S, Hanson EP, Rosenzweig SD, Cassanova JL, Orange JS (2015). "Novel TTC37 Mutations in a Patient with Immunodeficiency without Diarrhea: Extending the Phenotype of Trichohepatoenteric Syndrome". Front Pediatr. 3: 2. doi:10.3389/fped.2015.00002. PMC 4311608. PMID 25688341.
  37. Lee WI, Huang JL, Chen CC, Lin JL, Wu RC, Jaing TH, Ou LS (March 2016). "Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency". Medicine (Baltimore). 95 (9): e2918. doi:10.1097/MD.0000000000002918. PMC 4782876. PMID 26945392.
  38. 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 (August 2016). "Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder". J. Allergy Clin. Immunol. 138 (2): 544–550.e4. doi:10.1016/j.jaci.2016.01.018. PMC 4976039. PMID 27016798.
  39. Artac H, Reisli I, Kara R, Pico-Knijnenburg I, Adin-Çinar S, Pekcan S, Jol-van der Zijde CM, van Tol MJ, Bakker-Jonges LE, van Dongen JJ, van der Burg M, van Zelm MC (October 2010). "B-cell maturation and antibody responses in individuals carrying a mutated CD19 allele". Genes Immun. 11 (7): 523–30. doi:10.1038/gene.2010.22. PMID 20445561.
  40. van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL (May 2006). "An antibody-deficiency syndrome due to mutations in the CD19 gene". N. Engl. J. Med. 354 (18): 1901–12. doi:10.1056/NEJMoa051568. PMID 16672701.
  41. Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, Beaumont T, Tedder TF, van Noesel CJ, Eldering E, van Lier RA (January 2010). "CD20 deficiency in humans results in impaired T cell-independent antibody responses". J. Clin. Invest. 120 (1): 214–22. doi:10.1172/JCI40231. PMC 2798692. PMID 20038800.
  42. Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, Draeger R, Voelxen N, Völxen 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 (March 2012). J. Allergy Clin. Immunol. 129 (3): 801–810.e6. doi:10.1016/j.jaci.2011.09.027. PMID 22035880. Text "title Genetic CD21 deficiency is associated with hypogammaglobulinemia " ignored (help); Missing or empty |title= (help)
  43. Wedatilake Y, Niazi R, Fassone E, Powell CA, Pearce S, Plagnol V, Saldanha JW, Kleta R, Chong WK, Footitt E, Mills PB, Taanman JW, Minczuk M, Clayton PT, Rahman S (July 2016). "TRNT1 deficiency: clinical, biochemical and molecular genetic features". Orphanet J Rare Dis. 11 (1): 90. doi:10.1186/s13023-016-0477-0. PMC 4930608. PMID 27370603.
  44. Wiseman DH, May A, Jolles S, Connor P, Powell C, Heeney MM, Giardina PJ, Klaassen RJ, Chakraborty P, Geraghty MT, Major-Cook N, Kannengiesser C, Thuret I, Thompson AA, Marques L, Hughes S, Bonney DK, Bottomley SS, Fleming MD, Wynn RF (July 2013). "A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD)". Blood. 122 (1): 112–23. doi:10.1182/blood-2012-08-439083. PMC 3761334. PMID 23553769.
  45. Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W (March 2001). "Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia". Nat. Immunol. 2 (3): 223–8. doi:10.1038/85277. PMID 11224521.
  46. Tuijnenburg P, Lango Allen H, Burns SO, Greene D, Jansen MH, Staples E, Stephens J, Carss KJ, Biasci D, Baxendale H, Thomas M, Chandra A, Kiani-Alikhan S, Longhurst HJ, Seneviratne SL, Oksenhendler E, Simeoni I, de Bree GJ, Tool A, van Leeuwen E, Ebberink E, Meijer AB, Tuna S, Whitehorn D, Brown M, Turro E, Thrasher AJ, Smith K, Thaventhiran JE, Kuijpers TW (October 2018). "Loss-of-function nuclear factor κB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans". J. Allergy Clin. Immunol. 142 (4): 1285–1296. doi:10.1016/j.jaci.2018.01.039. PMC 6148345. PMID 29477724. Vancouver style error: initials (help)
  47. 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, Schäffer AA, Warnatz K, Browett P, Douglass J, Ameratunga RV, van der Meer JW, Grimbacher B (September 2015). "Haploinsufficiency of the NF-κB1 Subunit p50 in Common Variable Immunodeficiency". Am. J. Hum. Genet. 97 (3): 389–403. doi:10.1016/j.ajhg.2015.07.008. PMC 4564940. PMID 26279205.
  48. Chen K, Coonrod EM, Kumánovics 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 (November 2013). "Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency". Am. J. Hum. Genet. 93 (5): 812–24. doi:10.1016/j.ajhg.2013.09.009. PMC 3824125. PMID 24140114.
  49. Shi C, Wang F, Tong A, Zhang XQ, Song HM, Liu ZY, Lyu W, Liu YH, Xia WB (October 2016). "NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: A case report and review of literature". Medicine (Baltimore). 95 (40): e5081. doi:10.1097/MD.0000000000005081. PMC 5059085. PMID 27749582.
  50. Georgopoulos K, Winandy S, Avitahl N (1997). "The role of the Ikaros gene in lymphocyte development and homeostasis". Annu. Rev. Immunol. 15: 155–76. doi:10.1146/annurev.immunol.15.1.155. PMID 9143685.
  51. Kuehn HS, Boisson B, Cunningham-Rundles C, Reichenbach J, Stray-Pedersen A, Gelfand EW, Maffucci P, Pierce KR, Abbott JK, Voelkerding KV, South ST, Augustine NH, Bush JS, Dolen WK, Wray BB, Itan Y, Cobat A, Sorte HS, Ganesan S, Prader S, Martins TB, Lawrence MG, Orange JS, Calvo KR, Niemela JE, Casanova JL, Fleisher TA, Hill HR, Kumánovics A, Conley ME, Rosenzweig SD (March 2016). "Loss of B Cells in Patients with Heterozygous Mutations in IKAROS". N. Engl. J. Med. 374 (11): 1032–1043. doi:10.1056/NEJMoa1512234. PMC 4836293. PMID 26981933.