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Front Immunol. 2018 Jul 2;9:1506. doi: 10.3389/fimmu.2018.01506. eCollection 2018.

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

Author information

1
Research Unit Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University Graz, Graz, Austria.
2
Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands.
3
Hereditary Cancer Laboratory, University Hospital Doce de Octubre, i+12 Research Institute, Madrid, Spain.
4
Department of Pediatric Hematology and Oncology, Virgen de la Salud Hospital, Toledo, Spain.
5
i+12 Research Institute, University Hospital Doce de Octubre, Madrid, Spain.
6
Department of Immunology, University Hospital Doce de Octubre, i+12 Research Institute, Madrid, Spain.
7
Genetics Department, Curie Institute, Paris, France.
8
Department of Pediatrics, Sana Kliniken Duisburg, Duisburg, Germany.
9
Department of Pediatrics, Comenius University Bratislava, Bratislava, Slovakia.
10
The Genetics Institute, Rambam Health Care Campus, The Ruth and Bruce Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
11
Pediatric Hematology and Oncology, Klinikum Kassel, Kassel, Germany.
12
Pediatric Oncology Center, Department of Pediatrics, Technische Universität München, Munich, Germany.
13
Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands.
14
Department of Pediatric Oncology, Hematology and Transplantation, Poznań University of Medical Sciences, Poznań, Poland.
15
Pediatrics Department, Hematology-Oncology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt.
16
Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
17
Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
18
Department of Applied Tumor Biology, Institute of Pathology, Medical University Heidelberg, Heidelberg, Germany.
19
Department of Hematology, Oncology, and Immunology, Olgahospital Stuttgart, Stuttgart, Germany.
20
Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Villejuif, France.

Abstract

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.

KEYWORDS:

DNA repair defect; IgA deficiency; IgG subclass deficiency; class-switch recombination; hyper-IgM syndrome; mismatch repair; primary immunodeficiency; somatic hypermutation

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