Immunodeficiency With Hyper-Igm, Type 2

A number sign (#) is used with this entry because autosomal recessive immunodeficiency with hyper-IgM type 2 (HIGM2) is caused by homozygous or compound heterozygous mutation in the gene encoding activation-induced cytidine deaminase (AICDA; 605257) on chromosome 12p13.

Description

Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections.

For a discussion of genetic heterogeneity of immunodeficiency with hyper-IgM, see HIGM1 (308230).

Clinical Features

Revy et al. (2000) described 18 patients from 12 unrelated families who were diagnosed with hyper-IgM syndrome defined by markedly diminished serum levels of IgG and IgA with normal or increased serum level of IgM. All patients presented in childhood with recurrent bacterial sino-respiratory and gastrointestinal tract infections. In addition, 13 of the patients demonstrated lymphoid hyperplasia. None of the patients had a history of opportunistic infection. This feature is in contrast to patients with HIGM1 or HIGM3 (606843), who often present with opportunistic infections. Revy et al. (2000) showed that 3 major abnormalities characterize HIGM2: the absence of immunoglobulin class switch recombination (CSR), the lack of immunoglobulin somatic hypermutations, and lymph node hyperplasia caused by the presence of giant germinal centers.

Inheritance

HIGM2 follows autosomal recessive inheritance (Callard et al., 1994; Conley et al., 1994).

Pathogenesis

In HIGM2 patients, the CD40 and CD40LG gene sequences and membrane molecule expressions are normal (Durandy et al., 1997). In contrast to B cells from CD40LG-deficient patients with HIGM1 (308230), B cells from HIGM2 patients do not undergo Ig class switch recombination in vitro in the presence of CD40 agonists. Activation by CD40 agonists of monocytes and dendritic cells from HIGM2 patients is consistently detectable (Revy et al., 1998), strongly suggesting that the intrinsic defect originates in B cells, either in a B cell-specific CD40-triggered event or in the CSR mechanism itself. Opportunistic infections do not occur because cell-mediated immunity is intact. Revy et al. (2000) suggested that lymphoid hyperplasia in HIGM2, which is absent in HIGM1 and HIGM3, is a result of continuous proliferation of B cells by antigen in the absence of successful Ig somatic mutation.

Molecular Genetics

To identify the genetic basis of HIGM2, Revy et al. (2000) performed a genomewide search for susceptibility loci using polymorphic microsatellite markers in affected consanguineous families, and demonstrated strong linkage to 12p13. Because AICDA also maps to 12p13, the authors investigated whether AICDA gene defects cause HIGM2. Revy et al. (2000) identified 10 independent mutations in the AICDA gene (see, e.g., 605257.0001-605257.0009) in homozygous or compound heterozygous state in 18 patients with HIGM2 from 12 families.

Animal Model

Dahlberg et al. (2014) identified a mouse line incapable of inducing Ig class switching in vitro and in vivo. The mice inherited abolished IgG serum titers in a recessive manner resulting from a spontaneous G-to-A transition in the Aicda gene, leading to an arg112-to-his (R112H) substitution. Expression of wildtype Aicda restored class switching in these mutant mice. Mice homozygous for the mutation had peripheral B-cell hyperplasia and large germinal centers in the absence of antigen challenge. Immunization with sheep red blood cells resulted in failure to produce IgG1 in mutant, but not wildtype, mice. Dahlberg et al. (2014) noted that the phenotype in R112H mutant mice recapitulated human HIGM2 resulting from point mutations in AICDA. They proposed that the R112H mouse model of HIGM2 may be a more precise and powerful tool than gene deletion strategies.