Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency

Quartier, Pierre; Bustamante, Jacinta; Sanal, Özden; Plebani, Alessandro; Debré, Marianne; Deville, Anne; Litzman, Jiří; Levy, Jacov; Fermand, Jean‐Paul; Lane, Peter J. L.; Horneff, Gerd; Aksu, Güzide; Yalçın, Işık; Davies, Graham; Tezcan, İlhan; Ersoy, Furgen; Catalan, Nadia; Imai, Kohsuhe; Fischer, Alain; Durandy, Anne

doi:10.1016/j.clim.2003.10.007

Cited by 230 publications

(200 citation statements)

References 33 publications

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“…43 In humans, a significant portion of patients with inactivating mutations in AID develop autoimmune syndromes by as yet unknown mechanisms. 44 Furthermore, aged AID Ϫ/Ϫ mice were recently reported to develop a fatal autoimmune gastritis linked to activation of peripheral B cells and the development of tertiary lymphoid organs. 42 We suggest that the development of autoimmune diseases in AID Ϫ/Ϫ mice may be linked to improper maintenance of the GC and potential escape of hazardous B-cell clones.…”

Section: Discussionmentioning

confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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IntroductionA fundamental hallmark of humoral immunity is the ability to produce class-switched antibodies that have enhanced affinity for antigen. This process, termed affinity maturation, allows clonally selected B cells to refine their response to theoretically target any antigen with high specificity. After activation, B cells mutate the immunoglobulin (Ig) locus in a process known as somatic hypermutation (SHM). 1 Mutated clones that have acquired increased affinity for antigen preferentially expand over their low-affinity counterparts. The selection process occurs in the germinal center (GC), a transient microenvironment that forms in secondary lymphoid tissue shortly after antigen exposure. 2 The GC provides a competitive setting for B cells whereby ineffectual clones are actively cleared from the system via apoptosis, although the processes that govern this selection still remain vague.SHM and class switch recombination (CSR) are initiated by the enzyme activation-induced cytidine deaminase (AID), 3,4 which deaminates cytidines to uridines specifically at the Ig locus. 5-10 AID-generated uridines are then engaged by various DNA repair pathways that either lead to the generation of point mutations in the antibody variable region or recombinogenic events that lead to CSR. AID Ϫ/Ϫ mice lack mutations at their Ig locus and are incapable of producing class-switched antibodies. 4 Interestingly, these mice were previously shown to harbor an abnormally high proportion of splenic GC B cells. 11 This phenotype is also recapitulated in humans with AID deficiencies. 3 Although a link between reduced gut immunity (resulting from an inability to produce mucosal IgA) and peripheral GC formation was hypothesized to account for these abnormalities, this remains to be conclusively proven, and the possibility of a B cell-intrinsic effect that could explain the profound expansion of GC B cells has not been examined.GC B cells represent a unique lymphoid compartment of actively proliferating cells where numerous apoptotic factors must synergize to induce the elimination of nonproductive clones. Factors contributing to the intrinsic pathway of apoptosis, such as Bcl-2, Bcl-x L , and Bim, 12-17 and the extrinsic pathway, such as Fas, [18][19][20][21][22] have been implicated in GC selection. The unique physiology of these cells makes them highly susceptible to disease progression, often serving as etiologic sites for autoimmune and malignant B cells. 13,[23][24][25][26] Recent evidence has implicated AID as a fundamental contributor to the genetic aberrations that lead to these disease phenotypes. 24,[27][28][29] Given the importance of apoptosis as a parameter for both GC B-cell selection and lymphomagenesis, we investigated the relationship between AID-induced DNA mutation and cell death to understand how this enzyme may impinge on survival and death within the GC niche. Here we report that many of the potentially harmful AID-induced genetic alterations may indeed lead to the death of these cells within the GC. Methods Mice...

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Section: Discussionmentioning

confidence: 99%

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Zaheen

Boulianne

Parsa

et al. 2009

Blood

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“…Both SHM and CSR require activation induced cytidine deaminase (AID), which converts deoxycytidines in the V and switch regions to uracil and initiates both processes (Muramatsu et al, 1999;Di Noia et al, 2002;Manis et al, 2002;Bransteitter et al, 2003). Patients that are genetically deficient in AID make only low affinity IgM antibodies and die of infections if they are not treated with hyperimmune immunoglobulins (Quartier et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Forced expression of AID facilitates the isolation of class switch variants from hybridoma cells

Iglesias-Ussel

Fan

et al. 2006

Journal of Immunological Methods

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Monoclonal antibodies are used in the treatment and diagnosis of diseases and to study the protective and adverse functions of antibodies in vitro and in vivo. Since the isotype determines the effector function, half-life in the serum and distribution throughout the body, it would be useful to have a battery of antibodies with the same binding site associated with different isotypes. However, since hybridomas switch isotypes at very low frequencies in tissue culture, it has been difficult and very labor intensive to isolate panels of class switch variants. We show here that stable transfection of activation-induced cytidine deaminase (AID) in hybridomas increased their frequency of switching to a level that greatly facilitated the isolation of subclones expressing monoclonal antibodies of different isotypes. Although forced expression of AID also increased the frequency of somatic hypermutation in the immunoglobulin variable regions that encode the antigen-binding site, antigen recognition was retained in the isotype switched antibodies.

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“…seven led to a premature stop codon, and one was a large deletion of all the coding sequence (Table 1). Mutations were found mostly in the homozygous state (32 families) or compound heterozygous mutations (11 families) [Quartier et al, 2004]. Some of them were recurrent and found in unrelated families.…”

Section: Aid a Dna-editing Enzyme Is Essential For Csr And Shmmentioning

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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Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency

Cited by 230 publications

References 33 publications

AID constrains germinal center size by rendering B cells susceptible to apoptosis

AID constrains germinal center size by rendering B cells susceptible to apoptosis

Forced expression of AID facilitates the isolation of class switch variants from hybridoma cells

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

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