Clinical, immunologic and genetic analysis of 29 patients with autosomal recessive hyper-IgM syndrome due to Activation-Induced Cytidine Deaminase deficiency
Introduction
Hyper-IgM (HIGM) syndrome is a primary immunodeficiency characterized by normal or elevated serum IgM levels together with an absence of IgG, IgA and IgE indicating a defective class switch recombination (CSR) process [1]. The X-linked form of the disease called HIGM1 is caused by mutations in the gene encoding CD40-Ligand (CD40-L, CD154) [2], [3], [4], [5]. CD40-L is expressed on activated helper T cells and its interaction with CD40, which is constitutively expressed on B cells, is required for full B-cell terminal differentiation in germinal centers of secondary lymphoid organs [6], [7]. CD40 is also expressed on monocytes, dendritic cells and myeloid progenitor cells [8], [9]. HIGM1 patients are thus not only prone to bacterial and enteroviral infections, in a similar way to other patients with severe B-cell deficiencies, but also to opportunistic infections mainly due to Pneumocystis carinii and Cryptosporidium as observed in patients with T-cell defects [10], [11], [12], [13] and to neutropenic complications. Another form of X-linked HIGM syndrome associated with anhydrotic ectodermal dysplasia has been described secondary to missense mutations in the gene encoding nuclear factor kappa B (NF-κB) essential modulator (NEMO or IKKγ) which is required for CD40-induced activation of the transcription factor NF-κB [14], [15], [16].
Besides the defined HIGM syndromes with X-linked inheritance, other causes of HIGM have been described [17], [18], [19], [20]. In most of the patients, the HIGM syndrome is clearly transmitted with an autosomal recessive inheritance pattern. Four patients in three consanguineous families have been reported as suffering from defective expression of CD40 molecules due to homozygous mutations in the CD40 gene, resulting in an immunodeficiency comparable to that observed in HIGM1 patients [21], [22]. Recently, a more frequent entity characterized by a selective CSR deficiency has been described as HIGM4 syndrome [23] and mutations of the uracyl-DNA-glycosylase UNG gene have been found in humans with autosomal recessive HIGM syndrome [24]. A more frequent form of autosomal recessive HIGM syndrome (HIGM2) has been related to mutations in the gene coding for the Activation-Induced Cytidine Deaminase (AID), a recently described molecule selectively expressed in vivo and in vitro CSR-induced B cells [25]. These patients present not only a CSR defect characterized by a lack of IgG, IgA and IgE production but also defective generation of somatic hypermutations (SHM) in the immunoglobulin variable region genes resulting in impaired antibody affinity maturation [26]. This observation, in keeping with the identical phenotype of AID-deficient mice [27], provides strong evidence for the essential role of AID in the major events of B-cell terminal differentiation occurring in germinal centers, that is, CSR and SHM generation. In an effort to better characterize the clinical and immunologic phenotype of HIGM2 patients and to analyze whether genotype–phenotype correlations could be found, we retrospectively analyzed a cohort of 29 patients with a diagnosis of AID deficiency.
Section snippets
Patient selection and data collection
Between December 1999 and June 2002, 56 patients with HIGM syndrome, as defined by markedly diminished serum levels of IgG and IgA with normal or increased serum levels of IgM, normal CD40L cell surface expression and no CD40L gene mutation were tested for AID gene mutations. Thirty-one patients from twenty-three distinct families were diagnosed as carrying AID gene mutations. Detailed clinical data of 29 patients from 22 distinct families were available. Clinical and immunologic data had been
Patient baseline characteristics
Patients were either of Caucasian (n = 28) or Asiatic (n = 1) ethnic origin. Out of 29 patients, 18 were from consanguineous families. In the other patients, the pedigrees were consistent with an autosomal recessive pattern of inheritance. In two cases, older brothers died from infections, including bacterial meningitis in the elder brother of Patient 14. Sex ratio was 22M/7F, likely due to a bias in patients' recruitment.
The median age at first clinical manifestation was 2.0 years (range: 0.3
Discussion
We have described clinical, immunologic and genetic characteristics of 29 patients with autosomal recessive hyper-IgM syndrome caused by AID gene mutations (HIGM2 syndrome). The spectrum of clinical manifestations associated with AID deficiency was found wider in this series than it has previously been reported [20]. While infections and lymphoid hyperplasia were common complications, as previously reported, diverse chronic autoimmune and inflammatory manifestations developed in 21% of
Acknowledgements
We thank Drs. A. Huissoon, Necil Kütükçüler and Nuran Salman for their participation to this study. We thank Dr. Daniel Turnberg for critical reading and corrections. We acknowledge Mrs. M. Forveille for excellent technical assistance.
This work was supported by INSERM (N. Catalan, A. Fischer, A. Durandy), CEE contract no. QLG1-CT-2001-01536- IMPAD (S. Plebani, A. Durandy), l'Association de la Recherche contre le Cancer, la Ligue contre le cancer and the Louis Jeantet Fondation.
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These authors equally contributed to this work.