Data_Sheet_1_No Overt Clinical Immunodeficiency Despite Immune Biological Abnormalities in Patients With Constitutional Mismatch Repair Deficiency.docx
Victoria K. Tesch
Hanna IJspeert
Andrea Raicht
Daniel Rueda
Nerea Dominguez-Pinilla
Luis M. Allende
Chrystelle Colas
Thorsten Rosenbaum
Denisa Ilencikova
Hagit N. Baris
Michaela H. M. Nathrath
Manon Suerink
Danuta Januszkiewicz-Lewandowska
Iman Ragab
Amedeo A. Azizi
Soeren S. Wenzel
Johannes Zschocke
Wolfgang Schwinger
Matthias Kloor
Claudia Blattmann
Laurence Brugieres
Mirjam van der Burg
Katharina Wimmer
Markus G. Seidel
10.3389/fimmu.2018.01506.s001
https://frontiersin.figshare.com/articles/dataset/Data_Sheet_1_No_Overt_Clinical_Immunodeficiency_Despite_Immune_Biological_Abnormalities_in_Patients_With_Constitutional_Mismatch_Repair_Deficiency_docx/6728627
<p>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 CD38<sup>hi</sup>IgM<sup>−</sup> 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.</p>
2018-07-02 04:15:29
primary immunodeficiency
hyper-IgM syndrome
DNA repair defect
mismatch repair
somatic hypermutation
class-switch recombination
IgA deficiency
IgG subclass deficiency