Mutations of<i>CD40</i>gene cause an autosomal recessive form of immunodeficiency with hyper IgM

Ferrari, Simona; Giliani, Silvia; Insalaco, Antonella; Al-Ghonaium, Abdulaziz; Soresina, Anna R.; Loubser, Michael; Avanzini, Maria Antonietta; Marconi, Massimo; Badolato, Raffaele; Ugazio, Alberto G.; Lévy, Yves; Catalan, Nadia; Durandy, Anne; Tbakhi, Abdelghani; Notarangelo, Luigi D.; Plebani, Alessandro

doi:10.1073/pnas.221456898

Cited by 348 publications

(214 citation statements)

References 32 publications

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“…Most HIGM patients also display impaired SHM generation. The first described HIGM condition was the X-linked form (MIM] 308230), related to mutations in the gene coding for a T cell activation molecule, the CD40-ligand (X67878) [Armitage et al, 1993;Aruffo et al, 1993;Korthauer et al, 1993]; more recently, mutations in its counterpart, the CD40 molecule (X60592), have been reported as responsible for a very rare autosomal recessive (AR) HIGM with a similar phenotype (MIM] 606843) [Ferrari et al, 2001]. Other HIGM are caused by an intrinsic defect likely affecting the CSR machinery in B cells.…”

Section: Dna Repairmentioning

confidence: 99%

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

et al. 2006

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For the Immunogenetics Special IssueActivation-induced cytidine deaminase (AID; gene symbol AICDA) is the key molecule required to induce immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM) of the variable regions of Ig genes. Its deficiency causes a form of hyper-IgM (HIGM) syndrome. The study of natural AID mutants associated with HIGM as well as engineered mutants led to the characterization of the active domains of the protein. AID, through its cytidine deaminase activity, induces a targeted DNA lesion as an early step required for both CSR and SHM. Besides its cytidine deaminase activity, AID plays a further essential role in CSR, likely by recruiting CSR-specific cofactors by its C-terminus. A similar binding of SHM-specific cofactors to the N-terminal part is suggested by the functional characteristics of N ter AID artificial mutants. These data require confirmation in vivo. Finally, AID acts as a homo-, di-, or multimeric complex. Together, these data strongly suggest that AID, a master molecule for antibody diversification, exerts its activity on CSR not only as a cytidine deaminase enzyme but also as a docking protein, recruiting specific cofactors to a multimeric complex.

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Section: Dna Repairmentioning

confidence: 99%

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

et al. 2006

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“…The absolute requirement for CD40 signaling in a wide range of immune responses has been demonstrated in animal models lacking either functional CD40 (1) or CD154 (2) and in humans suffering from both X-linked and CD40-associated hyper-IgM syndrome (hyper-IgM X-1 and hyper-IgM 3, respectively) (3)(4)(5)(6)(7)(8)(9). In these cases, there is clear absence of isotype switching in B cells, a lack of germinal centers, and deficient primary and secondary responses to thymus-dependent Ags.…”

Section: A Complex Containing Polypyrimidine Tract-binding Proteinmentioning

confidence: 99%

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

Kosinski

Laughlin

Singh

et al. 2003

The Journal of Immunology

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CD40 ligand (CD154) expression has been shown to be regulated, in part, at the posttranscriptional level by a pathway of “regulated instability” of mRNA decay throughout a time course of T cell activation. This pathway is modulated at late times of activation by the binding of a stability complex (termed complex I) to a CU-rich region in the 3′ untranslated region of the CD154 message. We have undertaken experiments to extend these findings and to analyze the cis-acting elements and trans-acting factors involved in this regulation. We have previously shown that the minimal binding sequence for complex I is a 63 nt CU-rich motif. However, our current study shows that when this site was deleted additional complex binding was observed upstream and downstream of the minimal binding region. Only after deletion of an extended region (termed Δ1515) was complex binding completely abolished. Analysis of complex binding using competition experiments revealed that the three adjacent regions bound related but not identical complexes. However, all three sites appeared to have a 55-kDa protein as the RNA-binding protein. Deletion of the Δ1515 region resulted in reduced transcript stability as measured by both in vitro and in vivo decay assays. Finally, using Abs against known RNA-binding proteins, we identified the polypyrimidine tract-binding protein (or heterogeneous nuclear ribonucleoprotein I) as a candidate RNA-binding component of complex I.

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“…The Xlinked hyper-IgM syndromes (HIGM1 and HIGM-3), are due to mutation of the CD40L and CD40 genes, respectively [6,7]. Mice lacking CD40 have less T reg in the spleen and transfer of their splenocytes to athymic nude mice lead to autoimmune diseases [8].…”

Section: Introductionmentioning

confidence: 99%

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

et al. 2005

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CD4 + CD25 + regulatory T cells (T reg) development and homeostasis require IL-2 and costimulation through same TNF-receptor family members. CD40KO mice have reduced number of T reg in peripheral blood, thymus and spleen. Herein we show that naive T reg express low basal level of CD40L that is upregulated upon TCR-triggered mediated activation. Treatment of wt mice with Ab blocking CD40/CD40L interaction results in a fast decrease in T reg number that rapidly recovers upon Ab withdrawal. CFSE-labeled T reg from wt mice injected into CD40KO, but not wild-type (wt) mice, showed reduced survival and proliferation in homeostatic setting. In vitro, dendritic cells from CD40KO mice but not wt mice produce diminished amount of IL-2 upon T reg encounter and are impaired in expanding T reg, a defect corrected by the addition of rIL-2. Accordingly, four daily IL-2 administrations to CD40KO mice normalize T reg number by promoting both their survival and homeostatic proliferation. Such IL-2 effect is transient since T reg number returns to the low constitutive level described in CD40KO mice within 5 days upon IL-2 withdrawal thus suggesting that IL-2 is persistently needed to assure T reg homeostasis.

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Mutations ofCD40gene cause an autosomal recessive form of immunodeficiency with hyper IgM

Cited by 348 publications

References 32 publications

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2

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Mutations ofCD40gene cause an autosomal recessive form of immunodeficiency with hyper IgM

Cited by 348 publications

References 32 publications

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

Activation-induced cytidine deaminase: structure–function relationship as based on the study of mutants

A Complex Containing Polypyrimidine Tract-Binding Protein Is Involved in Regulating the Stability of CD40 Ligand (CD154) mRNA

CD40/CD40L interaction regulates CD4+CD25+ T reg homeostasis through dendritic cell‐produced IL‐2

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CD40/CD40L interaction regulates CD4⁺CD25⁺ T reg homeostasis through dendritic cell‐produced IL‐2