ICOS deficiency in patients with common variable immunodeficiency

Salzer, Ulrich; Maul-Pavicic, Andrea; Cunningham‐Rundles, Charlotte; Urschel, Simon; Belohradsky, Bernd H.; Litzman, Jiří; Holm, Are Martin; Franco, José Luis; Plebani, Alessandro; Hammarström, Lennart; Skrabl, Andrea; Schwinger, Wolfgang; Grimbacher, Bodo

doi:10.1016/j.clim.2004.07.002

Cited by 177 publications

(101 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This finding was replicated in two further CVID families but this deletion is extremely rare, explaining CVID in less than 1% of patients and it is likely that all nine CVID patients share a common founder. 23 To date, common variants in the ICOS region have not been studied in CVID or other immunodeficiencies.…”

Section: Introductionmentioning

confidence: 99%

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

et al. 2008

View full text Add to dashboard Cite

IgA deficiency (IgAD) and common variable immunodeficiency (CVID) often co-occur in families, associating with chronic inflammatory diseases such as celiac disease (CD). ICOS (inducible co-stimulator) and CTLA4 (cytotoxic T-lymphocyteassociated protein-4) may be important in both disorders, as ICOS is necessary for Ig class-switching and CTLA4 negatively regulates T-cell activation. Linkage and association of CD with CTLA4-ICOS is well documented, we thus aimed to further pinpoint CD susceptibility by haplotype-tagging analysis. We genotyped 663 CD families from Finland and Hungary, 575 additional CD patients from Finland, Hungary and Italy; 275 Swedish and Finnish IgAD individuals and 87 CVID individuals for 14-18 genetic markers in CTLA4-ICOS. Association was found between CTLA4-ICOS and both IgAD (P ¼ 0.0015) and CVID (P ¼ 0.0064). We confirmed linkage of CTLA4-ICOS with CD (LOD 2.38, P ¼ 0.0005) and found association of CTLA4-ICOS with CD (P ¼ 0.0009). Meta-analysis of the IgAD, CVID and CD materials revealed intergenic association (P ¼ 0.0005). Disease-associated markers were associated with lower ICOS and higher CTLA4 expression, indicating that the risk haplotypes contain functional variants. In summary, we identified a novel shared risk locus for IgAD, CVID and CD, the first report of association between CTLA4-ICOS and IgAD. Association between CD and CTLA4-ICOS was also confirmed in a large European data set.

show abstract

Section: Introductionmentioning

confidence: 99%

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Nine individuals have been described so far with a complete loss of ICOS on their T cells, as a result of a large homozygous deletion eliminating any protein expression, and thus leading to a "knockout" phenotype (10). The clinical phenotype is that of common variable immunodeficiency (CVID), an Ab deficiency syndrome.…”

Section: Endritic Cells (Dc)mentioning

confidence: 99%

The Role of ICOS in Directing T Cell Responses: ICOS-Dependent Induction of T Cell Anergy by Tolerogenic Dendritic Cells

Tuettenberg¹,

Hüter²,

Hubo³

et al. 2009

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Tolerogenic dendritic cells (DC) play an important role in maintaining peripheral T cell tolerance in steady-state conditions through induction of anergic, IL-10-producing T cells with suppressive properties. ICOS, an activation-induced member of the CD28 family on T cells, is involved in the induction of IL-10, which itself could contribute to induction of anergy and development of suppressive T cells. Therefore, we analyzed the functional role of ICOS in the differentiation process of human CD4+ T cells upon their interaction with tolerogenic DC. We compared the functional properties of CD4+ T cells from healthy volunteers and ICOS-deficient patients after stimulation with tolerogenic DC. We report that induction of T cell anergy and suppressive capacity is completely blocked after knockdown of ICOS expression in T cells as well as after blocking of ICOS-ICOS ligand interaction in DC/T cell cocultures. Moreover, CD4+ T cells from ICOS-deficient patients were completely resistant to anergy induction and differentiation into suppressive T cells even after supplementation of IL-10. Furthermore, ICOS/ICOS ligand interaction stabilizes IL-10R expression on T cells and thus renders them sensitive to IL-10 effects. Taken together, these results indicate a crucial role for ICOS in the induction of peripheral tolerance maintained by tolerogenic DC mediated mostly via an IL-10-independent mechanism.

show abstract

“…There has been an intensive search for genes which, when mutated, could lead to the CVID phenotype. This search has led to the discovery that mutations of the inducible costimulatory in a related kindred (15,16)-or more recently, TNF family members, B cell-activating factor receptor, or transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI)-can lead to autosomal recessive or dominant B cell defects of this phenotype or, for TACI, also IgA deficiency (17)(18)(19). However, for the great majority of patients with CVID, no molecular basis has yet been provided.…”

Section: Ommon Variable Immunodeficiency (Cvid)mentioning

confidence: 99%

TLR9 Activation Is Defective in Common Variable Immune Deficiency

Cunningham‐Rundles

Radigan

Knight

et al. 2006

The Journal of Immunology

Self Cite

107

View full text Add to dashboard Cite

Common variable immune deficiency (CVID) is a primary immune deficiency characterized by low levels of serum immune globulins, lack of Ab, and reduced numbers of CD27+ memory B cells. Although T, B, and dendritic cell defects have been described, for the great majority, genetic causes have not been identified. In these experiments, we investigated B cell and plasmacytoid dendritic cell activation induced via TLR9, an intracellular recognition receptor that detects DNA-containing CpG motifs from viruses and bacteria. CpG-DNA activates normal B cells by the constitutively expressed TLR9, resulting in cytokine secretion, IgG class switch, immune globulin production, and potentially, the preservation of long-lived memory B cells. We found that CpG-DNA did not up-regulate expression of CD86 on CVID B cells, even when costimulated by the BCR, or induce production of IL-6 or IL-10 as it does for normal B cells. TLR9, found intracytoplasmically and on the surface of oligodeoxynucleotide-activated normal B cells, was deficient in CVID B cells, as was TLR9 mRNA. TLR9 B cell defects were not related to proportions of CD27+ memory B cells. CpG-activated CVID plasmacytoid dendritic cells did not produce IFN-α in normal amounts, even though these cells contained abundant intracytoplasmic TLR9. No mutations or polymorphisms of TLR9 were found. These data show that there are broad TLR9 activation defects in CVID which would prevent CpG-DNA-initiated innate immune responses; these defects may lead to impaired responses of plasmacytoid dendritic cells and loss of B cell function.

show abstract

ICOS deficiency in patients with common variable immunodeficiency

Cited by 177 publications

References 24 publications

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

The shared CTLA4-ICOS risk locus in celiac disease, IgA deficiency and common variable immunodeficiency

The Role of ICOS in Directing T Cell Responses: ICOS-Dependent Induction of T Cell Anergy by Tolerogenic Dendritic Cells

TLR9 Activation Is Defective in Common Variable Immune Deficiency

Contact Info

Product

Resources

About