Study of patients with Hyper-IgM type IV phenotype who recovered spontaneously during late childhood and review of the literature

Karaca, Neslihan Edeer; Durandy, Anne; Gülez, Nesrin; Aksu, Güzide; Kütükçüler, Necil

doi:10.1007/s00431-011-1400-2

Cited by 8 publications

(5 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Child patients present also with increased levels of IgM, which is an indirect sign of CSR deficiency. IgM levels were, however, found normal in older patients, likely because IgG-and IgAproducing long-lived plasma cells compensate the CSR defect as observed in some CSR-deficient patients (38). The CSR deficiency observed in MSH6-deficient patients is reminiscent of the findings for MSH6-deficient mice (21,22), although the murine S junctions exhibited a normal pattern (21).…”

Section: Discussionmentioning

confidence: 73%

Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

Gardès

Forveille

Alyanakian

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.

show abstract

Section: Discussionmentioning

confidence: 73%

Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

Gardès

Forveille

Alyanakian

et al. 2012

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…By contrast, IgA concentrations were higher in these individuals than in younger patients (Figure 1 A, center panel). These findings are too inconsistent to support, but might be in line with, the hypothesis that long-lived IgG- and/or IgA-producing plasma cells gained relevance with age in this context ( 9 , 47 ). Furthermore, the number of patients is too little to confirm this observed trend of age-dependence or to suspect a genotype–phenotype correlation, especially since older patients in our study cohort included more individuals with PMS2 deficiency than individuals with other MMR deficiencies.…”

Section: Discussionmentioning

confidence: 67%

No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency

et al. 2018

View full text Add to dashboard Cite

Immunoglobulin class-switch recombination (CSR) and somatic hypermutations (SHMs) are prerequisites for antibody and immunoglobulin receptor maturation and adaptive immune diversity. The mismatch repair (MMR) machinery, consisting of homologs of MutSα, MutLα, and MutSβ (MSH2/MSH6, MLH1/PMS2, and MSH2/MSH3, respectively) and other proteins, is involved in CSR, primarily acting as a backup for nonhomologous end-joining repair of activation-induced cytidine deaminase-induced DNA mismatches and, furthermore, in addition to error-prone polymerases, in the repair of SHM-induced DNA breaks. A varying degree of antibody formation defect, from IgA or selective IgG subclass deficiency to common variable immunodeficiency and hyper-IgM syndrome, has been detected in a small number of patients with constitutional mismatch repair deficiency (CMMRD) due to biallelic loss-of-function mutations in one of the MMR genes (PMS2, MSH6, MLH1, or MSH2). To elucidate the clinical relevance of a presumed primary immunodeficiency (PID) in CMMRD, we systematically collected clinical history and laboratory data of a cohort of 15 consecutive, unrelated patients (10 not previously reported) with homozygous/compound heterozygous mutations in PMS2 (n = 8), MSH6 (n = 5), and MLH1 (n = 2), most of whom manifested with typical malignancies during childhood. Detailed descriptions of their genotypes, phenotypes, and family histories are provided. Importantly, none of the patients showed any clinical warning signs of PID (infections, immune dysregulation, inflammation, failure to thrive, etc.). Furthermore, we could not detect uniform or specific patterns of laboratory abnormalities. The concentration of IgM was increased in 3 out of 12, reduced in 3 out of 12, and normal in 6 out of 12 patients, while concentrations of IgG and IgG subclasses, except IgG4, and of IgA, and specific antibody formation were normal in most. Class-switched B memory cells were reduced in 5 out of 12 patients, and in 9 out of 12 also the CD38hiIgM− plasmablasts were reduced. Furthermore, results of next generation sequencing-based analyses of antigen-selected B-cell receptor rearrangements showed a significantly reduced frequency of SHM and an increased number of rearranged immunoglobulin heavy chain (IGH) transcripts that use IGHG3, IGHG1, and IGHA1 subclasses. T cell subsets and receptor repertoires were unaffected. Together, neither clinical nor routine immunological laboratory parameters were consistently suggestive of PID in these CMMRD patients, but previously shown abnormalities in SHM and rearranged heavy chain transcripts were confirmed.

show abstract

“…The high risk for hyperviscosity syndrome (hypergammaglobulinemia) justified the maintenance of optimal patient hydration and plasmapheresis option. Concerning HSCT, the authors do not consider it as an emergency due to potential spontaneous remission, [8] so for the moment, transplant option remains questionable. EBV = Epstein-Barr virus; HIGM = hyper-IgM syndrome; MSSA = Methicillin-sensitive Staphylococcus aureus; NEMO = NF-kB essential modulator; UNG = uracil-DNA glycosylase; PCR = polymerase chain reaction; PIK3CD = phosphatidyl-inositol-bisphosphate 3-kinase catalytic subunit delta; PIK3R1 = phosphoinositide-3-kinase, regulatory subunit 1 alpha; TLR = Toll like-receptors; TNF-R = tumor necrosis factor receptor.…”

Section: Discussionmentioning

confidence: 99%