IgM Augments Complement Bactericidal Activity with Serum from a Patient with a Novel CD79a Mutation

Antibody replacement therapy for patients with antibody deficiencies contains only IgG. As a result, concurrent IgM and IgA deficiency present in a large proportion of antibody deficient patients persists. Especially patients with IgM deficiency remain at risk for recurrent infections of the gastrointestinal and respiratory tract. The lack of IgM in the current IgG replacement therapy is likely to contribute to the persistence of these mucosal infections because this antibody class is especially important for complement activation on the mucosal surface. We evaluated whether supplementation with IgM increased serum bactericidal capacity in vitro. Serum was collected from a patient with agammaglobulinemia and supplemented with purified serum IgM to normal levels. Antibody and complement deposition on the bacterial surface was determined by multi-color flow cytometry. Bacterial survival in serum was determined by colony-forming unit counts. We present a patient previously diagnosed with agammaglobulinemia due to CD79A (Igα) deficiency revealing a novel pathogenic insertion variant in the CD79a gene (NM_001783.3:c.353_354insT). Despite IgG replacement therapy and antibiotic prophylaxis, this patient developed a Campylobacter jejuni spondylodiscitis of lumbar vertebrae L4–L5. We found that serum IgM significantly contributes to complement activation on the bacterial surface of C. jejuni. Furthermore, supplementation of serum IgM augmented serum bactericidal activity significantly. In conclusion, supplementation of intravenous IgG replacement therapy with IgM may potentially offer greater protection against bacterial infections, also in the context of increasing antibiotic resistance

Immunodeficiency in Bloom’s Syndrome

Bloom’s syndrome (BS) is an autosomal recessive disease, caused by mutations in the BLM gene. This gene codes for BLM protein, which is a helicase involved in DNA repair. DNA repair is especially important for the development and maturation of the T and B cells. Since BLM is involved in DNA repair, we aimed to study if BLM deficiency affects T and B cell development and especially somatic hypermutation (SHM) and class switch recombination (CSR) processes. Clinical data of six BS patients was collected, and immunoglobulin serum levels were measured at different time points. In addition, we performed immune phenotyping of the B and T cells and analyzed the SHM and CSR in detail by analyzing IGHA and IGHG transcripts using next-generation sequencing. The serum immunoglobulin levels were relatively low, and patients had an increased number of infections. The absolute number of T, B, and NK cells were low but still in the normal range. Remarkably, all BS patients studied had a high percentage (20–80%) of CD4+ and CD8+ effector memory T cells. The process of SHM seems normal; however, the Ig subclass distribution was not normal, since the BS patients had more IGHG1 and IGHG3 transcripts. In conclusion, BS patients have low number of lymphocytes, but the immunodeficiency seems relatively mild since they have no severe or opportunistic infections. Most changes in the B cell development were seen in the CSR process; however, further studies are necessary to elucidate the exact role of BLM in CSR

Failure To Detect Circulating Aspergillus Markers in a Patient with Chronic Granulomatous Disease and Invasive Aspergillosis

We report a patient with chronic granulomatous disease who developed invasive pulmonary aspergillosis and a subphrenic abscess. During treatment, high levels of Aspergillus antigen were detected in the abscess, but circulating antigen and Aspergillus DNA were undetectable in the serum

The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome

DNA methylation is an important regulator of genetic information in species ranging from bacteria to humans. DNA methylation appears to be critical for mammalian development because mice nullizygous for a targeted disruption of the DNMT1 DNA methyltransferase die at an early embryonic stage. No DNA methyltransferase mutations have been reported in humans until now. We describe here the first example of naturally occurring mutations in a mammalian DNA methyltransferase gene. These mutations occur in patients with a rare autosomal recessive disorder, which is termed the ICF syndrome, for immunodeficiency, centromeric instability, and facial anomalies. Centromeric instability of chromosomes 1, 9, and 16 is associated with abnormal hypomethylation of CpG sites in their pericentromeric satellite regions. We are able to complement this hypomethylation defect by somatic cell fusion to Chinese hamster ovary cells, suggesting that the ICF gene is conserved in the hamster and promotes de novo methylation. ICF has been localized to a 9-centimorgan region of chromosome 20 by homozygosity mapping. By searching for homologies to known DNA methyltransferases, we identified a genomic sequence in the ICF region that contains the homologue of the mouse Dnmt3b methyltransferase gene. Using the human sequence to screen ICF kindreds, we discovered mutations in four patients from three families. Mutations include two missense substitutions and a 3-aa insertion resulting from the creation of a novel 3′ splice acceptor. None of the mutations were found in over 200 normal chromosomes. We conclude that mutations in the DNMT3B are responsible for the ICF syndrome

Recurrent and opportunistic infections in children with primary intestinal lymphangiectasia.

Contains fulltext : 53477.pdf (publisher's version ) (Closed access

Dilemma of Reporting Incidental Findings in Newborn Screening Programs for SCID: Parents' Perspective on Ataxia Telangiectasia.

Background: Ataxia Telangiectasia (A-T) is a severe DNA repair disorder that leads to a broad range of symptoms including neurodegeneration and a variable immunodeficiency. A-T is one of the incidental findings that accompanies newborn screening (NBS) for severe combined immunodeficiency (SCID), leading to an early diagnosis of A-T at birth in a pre-symptomatic stage. While some countries embrace all incidental findings, the current policy in the Netherlands on reporting untreatable incidental findings is more conservative. We present parents' perspectives and considerations on the various advantages vs. disadvantages of early and late diagnosis of A-T. Methods: A questionnaire was developed and sent to 4,000 parents of healthy newborns who participated in the Dutch SONNET-study (implementation pilot for newborn screening for SCID). The questionnaire consisted of open-ended and scale questions on advantages and disadvantages of early and late diagnosis of A-T. To address potential bias, demographic characteristics of the study sample were compared to a reference population. Results: A total of 664 of 4,000 parents sent back the questionnaire (response rate 16.6%). The vast majority of parents (81.9%) favored early diagnosis of A-T over late diagnosis. Main arguments were to avoid a long period of uncertainty prior to diagnosis and to ensure the most optimal clinical care and guidance from the onset of symptoms. Parents who favored late diagnosis of A-T stated that early diagnosis would not lead to improved quality of life and preferred to enjoy the asymptomatic "golden years" with their child. The majority of parents (81.1%) stated that they would participate in newborn screening for A-T if a test was available. Conclusions: Reporting untreatable incidental findings remains a disputed topic worldwide. Although the current policy in the Netherlands is not to report untreatable incidental findings, unless the health advantage is clear, the majority of parents of healthy newborns are in favor of an early A-T diagnosis in the pre-symptomatic phase of the disorder. Our results as well as other studies that showed support for the screening of untreatable disorders may serve as valuable tools to inform policymakers in their considerations about NBS for untreatable disorders

Gastrointestinal zygomycosis due to Rhizopus microsporus var. rhizopodiformis as a manifestation of chronic granulomatous disease.

Contains fulltext : 70218.pdf (publisher's version ) (Closed access)A case of gastrointestinal zygomycosis in a 10-month-old boy with chronic granulomatous disease (CGD) is presented. Zygomycetes are an uncommon cause of fungal disease in CGD patients and gastrointestinal zygomycosis has not been previously described in individuals with CGD. To improve outcome, a timely and correct diagnosis is of utmost importance