Monique M. van Ostaijen-ten Dam

Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects

Immunodeficiency with centromeric instability and facial anomalies (ICF) syndrome is a primary immunodeficiency, predominantly characterized by agammaglobulinemia or hypoimmunoglobulinemia, centromere instability and facial anomalies. Mutations in two genes have been discovered to cause ICF syndrome: DNMT3B and ZBTB24. To characterize the clinical features of this syndrome, as well as genotype–phenotype correlations, we compared clinical and genetic data of 44 ICF patients. Of them, 23 had mutations in DNMT3B (ICF1), 13 patients had mutations in ZBTB24 (ICF2), whereas for 8 patients, the gene defect has not yet been identified (ICFX). While at first sight these patients share the same immunological, morphological and epigenetic hallmarks of the disease, systematic evaluation of all reported informative cases shows that: (1) the humoral immunodeficiency is generally more pronounced in ICF1 patients, (2) B- and T-cell compartments are both involved in ICF1 and ICF2, (3) ICF2 patients have a significantly higher incidence of intellectual disability and (4) congenital malformations can be observed in some ICF1 and ICF2 cases. It is expected that these observations on prevalence and clinical presentation will facilitate mutation-screening strategies and help in diagnostic counseling.

Mutations in DNMT3B Modify Epigenetic Repression of the D4Z4 Repeat and the Penetrance of Facioscapulohumeral Dystrophy

Facioscapulohumeral dystrophy (FSHD) is associated with somatic chromatin relaxation of the D4Z4 repeat array and derepression of the D4Z4-encoded DUX4 retrogene coding for a germline transcription factor. Somatic DUX4 derepression is caused either by a 1-10 unit repeat-array contraction (FSHD1) or by mutations in SMCHD1, which encodes a chromatin repressor that binds to D4Z4 (FSHD2). Here, we show that heterozygous mutations in DNA methyltransferase 3B (DNMT3B) are a likely cause of D4Z4 derepression associated with low levels of DUX4 expression from the D4Z4 repeat and increased penetrance of FSHD. Recessive mutations in DNMT3B were previously shown to cause immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome. This study suggests that transcription of DUX4 in somatic cells is modified by variations in its epigenetic state and provides a basis for understanding the reduced penetrance of FSHD within families.

Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome.

The life-threatening Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) syndrome is a genetically heterogeneous autosomal recessive disorder. Twenty percent of patients cannot be explained by mutations in the known ICF genes DNA methyltransferase 3B or zinc-finger and BTB domain containing 24. Here we report mutations in the cell division cycle associated 7 and the helicase, lymphoid-specific genes in 10 unexplained ICF cases. Our data highlight the genetic heterogeneity of ICF syndrome; however, they provide evidence that all genes act in common or converging pathways leading to the ICF phenotype.

Early cytomegalovirus reactivation leaves a specific and dynamic imprint on the reconstituting T cell compartment long-term after hematopoietic stem cell transplantation.

Human cytomegalovirus (CMV) reactivation frequently occurs during the early phase of immune recovery after allogeneic hematopoietic stem cell transplantation (HSCT). Whereas the recovery of virus-specific immunity in the early phase after HSCT is extensively studied, the impact of CMV on the reconstitution and composition of the T cell compartment long-term after HSCT is unknown. We analyzed T cell reconstitution 1 to 2 years after HSCT in 131 pediatric patients. One year after HSCT, patients with early CMV reactivation (n = 46) had 3-fold higher CD8(+) T cell numbers (median, 1323 versus 424 cells/μL; P < .0001) compared with patients without CMV reactivation (n = 85). This effect, caused by a major expansion of CD8(+) effector memory (EM) and end-stage effector (EMRA) T cells, was independent of pretransplantation donor and recipient CMV serostatus and not seen after Epstein-Barr virus or adenovirus reactivations. At 1 and 2 years after HSCT, the absolute numbers of CD8(+) naive and central memory T cells, as well as CD4(+) naive, CM, EM, and EMRA T cells, did not differ between patients with or without CMV reactivation. In the second year after HSCT, a significant contraction of the initially expanded CD8(+) EM and EMRA T cell compartments was observed in patients with early CMV reactivation. In conclusion, CMV reactivation early after pediatric HSCT leaves a specific and dynamic imprint on the size and composition of the CD8(+) T cell compartment without compromising the reconstitution of CD8(+) and CD4(+) naive and central memory T cells pivotal in the response to neo and recall antigens.

Reduced thymic expression of ErbB receptors without auto-antibodies against synaptic ErbB in myasthenia gravis

In myasthenia gravis (MG), the neuromuscular transmission is impaired mainly by auto-antibodies against the acetylcholine receptor (AChR) or MuSK. In about 5% of the MG patients, however, the auto-antigen is still unknown. We investigated whether these idiopathic MG patients (iMG) have auto-antibodies against ErbB proteins, which influence the AChR density at the NMJ. Our results show reduced mRNA expression levels of ErbB4 in thymus tissue of iMG patients compared to AChR-MG and non-MG patients, but we could not detect anti-ErbB antibodies in sera of iMG patients. Therefore, our results do not support a role for ErbB receptors as auto-antigens in iMG patients.

CD56(dim)CD16⁻ NK cell phenotype can be induced by cryopreservation.

To the editor: Natural killer (NK) cells can contribute to the control of different viruses.[1][1],[2][2] Recently, Azzi et al described the role of early differentiated NK cells in Epstein-Barr virus–driven infectious mononucleosis (IM).[3][3] Besides the conventional CD56brightCD16+/− and

A prospective, placebo controlled study on the humoral immune response to and safety of tetanus revaccination in myasthenia gravis

OBJECTIVE To investigate the humoral immune response to and safety of a tetanus revaccination in patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome. METHODS A tetanus revaccination was administered to 66 patients. Before and 4weeks after revaccination a blood sample and clinical outcome scores were obtained. Anti-tetanus IgG total, IgG1 and IgG4 titres were measured with an ELISA and disease-specific antibody titres (AChR, MuSK or VGCC) with a radio-immunoprecipitation assay. A historic healthy control group was used for comparing tetanus antibody titres with that of our patients. A placebo (saline) vaccination group was used to investigate the variability of clinical outcome scores with a 4weeks interval. RESULTS In 60 of 65 patients, a significant increase of the anti-tetanus antibody response was measured. Thymectomy did not have an impact on this responsiveness. Patients with immunosuppressive medication had a significantly lower pre and post titre compared to healthy controls, but their response was still significant. The titres of disease-specific antibodies were unchanged 4weeks after revaccination. The clinical outcome scores showed no exacerbation of symptoms of the disease. CONCLUSION A tetanus revaccination in patients with myasthenia gravis or Lambert-Eaton myasthenic syndrome is safe and induces a significant immune response, irrespectively of their immunosuppressive medication. We observed neither immunological nor clinical relevant exacerbations associated with the tetanus revaccination. CLINICAL TRIAL REGISTRY The tetanus trial is listed on clinicaltrialsregister.eu under 2014-004344-35. The placebo AChR MG group was part of another clinical trial, investigating influenza vaccination in myasthenic patients. This trial is listed on clinicaltrialsregister.eu under 2016-003138-26.

Recurrent respiratory tract infections (RRTI) in the elderly: A late onset mild immunodeficiency?

Elderly with late-onset recurrent respiratory tract infections (RRTI) often have specific anti-polysaccharide antibody deficiency (SPAD). We hypothesized that late-onset RRTI is caused by mild immunodeficiencies, such as SPAD, that remain hidden through adult life. We analyzed seventeen elderly RRTI patients and matched controls. We determined lymphocyte subsets, expression of BAFF receptors, serum immunoglobulins, complement pathways, Pneumovax-23 vaccination response and genetic variations in BAFFR and MBL2. Twelve patients (71%) and ten controls (59%) had SPAD. IgA was lower in patients than in controls, but other parameters did not differ. However, a high percentage of both patients (53%) and controls (65%) were MBL deficient, much more than in the general population. Often, MBL2 secretor genotypes did not match functional deficiency, suggesting that functional MBL deficiency can be an acquired condition. In conclusion, we found SPAD and MBL deficiency in many elderly, and conjecture that at least the latter arises with age.

Human Bone Marrow-Resident Natural Killer Cells Have a Unique Transcriptional Profile and Resemble Resident Memory CD8+ T Cells

Human lymphoid tissues harbor, in addition to CD56bright and CD56dim natural killer (NK) cells, a third NK cell population: CD69+CXCR6+ lymphoid tissue (lt)NK cells. The function and development of ltNK cells remain poorly understood. In this study, we performed RNA sequencing on the three NK cell populations derived from bone marrow (BM) and blood. In ltNK cells, 1,353 genes were differentially expressed compared to circulating NK cells. Several molecules involved in migration were downregulated in ltNK cells: S1PR1, SELPLG and CD62L. By flow cytometry we confirmed that the expression profile of adhesion molecules (CD49e−, CD29low, CD81high, CD62L−, CD11c−) and transcription factors (Eomeshigh, Tbetlow) of ltNK cells differed from their circulating counterparts. LtNK cells were characterized by enhanced expression of inhibitory receptors TIGIT and CD96 and low expression of DNAM1 and cytolytic molecules (GZMB, GZMH, GNLY). Their proliferative capacity was reduced compared to the circulating NK cells. By performing gene set enrichment analysis, we identified DUSP6 and EGR2 as potential regulators of the ltNK cell transcriptome. Remarkably, comparison of the ltNK cell transcriptome to the published human spleen-resident memory CD8+ T (Trm) cell transcriptome revealed an overlapping gene signature. Moreover, the phenotypic profile of ltNK cells resembled that of CD8+ Trm cells in BM. Together, we provide transcriptional and phenotypic data that clearly distinguish ltNK cells from both the CD56bright and CD56dim NK cells and substantiate the view that ltNK cells are tissue-resident cells, which are functionally restrained in killing and have low proliferative activity.

Expansion of cytotoxic CD56bright natural killer cells during T-cell deficiency after allogeneic hematopoietic stem cell transplantation

Please cite this article as: Lugthart G, Goedhart M, van Leeuwen MM, Melsen JE, Jol-van der Zijde CM, Vervat C, van Ostaijen-ten Dam MM, Jansen-Hoogendijk AM, van Tol MJD, Lankester AC, Schilham MW, Expansion of cytotoxic CD56bright NK cells during T cell deficiency after allogeneic hematopoietic stem cell transplantation, Journal of Allergy and Clinical Immunology (2017), doi: 10.1016/ j.jaci.2017.06.039.