Publications by authors named "Bodo Grimbacher"

210 Publications

TACI deficiency - a complex system out of balance.

Curr Opin Immunol 2021 Jul 8;71:81-88. Epub 2021 Jul 8.

Institute for Immunodeficiency, Center for Chronic Immunodeficiencies, Medical Center - University Hospital Freiburg, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany.

TACI promotes T-cell independent antibody responses and plasma cell differentiation and counteracts BAFF driven B-cell activation. Mutations in TNFRSF13B (encoding TACI) are associated with common variable immunodeficiency (CVID) but are also found in 1-2% of the general population. Although not diseases causing, certain TNFRSF13B mutations predispose CVID patients to autoimmunity and lymphoproliferation. Recently, studies of TACI-deficient humans and murine models revealed novel aspects of TACI, especially its crosstalk with the TLR pathways, differential expression of TACI isoforms, and its role in the generation of autoreactive B-cells. Vice versa, these studies are instrumental for a better understanding of TACI deficiency in humans and suggest that gene dosage, mutation type, and additional clinical or laboratory abnormalities influence the relevance of TNFRSF13B variants in individual CVID patients. TACI is embedded in a complex and well-balanced system, which is vulnerable to genetic and possibly also environmental hits.
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http://dx.doi.org/10.1016/j.coi.2021.06.004DOI Listing
July 2021

Pembrolizumab for treatment of progressive multifocal leukoencephalopathy in primary immunodeficiency and/or hematologic malignancy: a case series of five patients.

J Neurol 2021 Jul 1. Epub 2021 Jul 1.

Department of Neurology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacherstr. 64, 79106, Freiburg, Germany.

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor.
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http://dx.doi.org/10.1007/s00415-021-10682-8DOI Listing
July 2021

There is no gene for CVID - novel monogenetic causes for primary antibody deficiency.

Curr Opin Immunol 2021 Jun 18;72:176-185. Epub 2021 Jun 18.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany. Electronic address:

'There is no gene for fate' (citation from the movie 'GATTACA') - and there is no gene for CVID. Common Variable ImmunoDeficiency (CVID) is the most prevalent primary immunodeficiency in humans. CVID is characterized by an increased susceptibility to infections, hypogammaglobulinemia, reduced switched memory B cell numbers in peripheral blood and a defective response to vaccination, often complicated by autoimmune and autoinflammatory conditions. However, as soon as a genetic diagnosis has been made in a patient with CVID, the diagnosis must be changed to the respective genetic cause (www.esid.org). Therefore, there are genetic causes for primary antibody deficiencies, but not for CVID. Primary antibody deficiencies (PADs) are a heterogeneous group of disorders. Several attempts have been made to gain further insights into the pathogenesis of PAD, using unbiased approaches such as whole exome or genome sequencing. Today, in just about 35% of cases with PAD, monogenic mutations (including those in the gene TNFRSF13B) can be identified in a set of 68 genes [1]. These mutations occur either sporadically or are inherited and do explain an often complex phenotype. In our review, we not only discuss gene defects identified in PAD patients previously diagnosed with CVID and/or CVID-like disorders such as IKZF1, CTNNBL1, TNFSF13 and BACH2, but also genetic defects which were initially described in non-CVID patients but have later also been observed in patients with PAD such as PLCG2, PIK3CG, PMS2, RNF31, KMT2D, STAT3. We also included interesting genetic defects in which the pathophysiology suggests a close relation to other known defects of the adaptive immune response, such as DEF6, SAMD9 and SAMD9L, and hence a CVID-like phenotype may be observed in the future. However, alternative mechanisms most likely add to the development of an antibody-deficient phenotype, such as polygenic origins, epigenetic changes, and/or environmental factors.
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http://dx.doi.org/10.1016/j.coi.2021.05.010DOI Listing
June 2021

Therapeutic options for CTLA-4 insufficiency.

J Allergy Clin Immunol 2021 Jun 7. Epub 2021 Jun 7.

The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania.

Background: Heterozygous germline mutations in cytotoxic T lymphocyte-associated antigen-4 (CTLA4) impair the immunomodulatory function of regulatory T cells. Affected individuals are prone to life-threatening autoimmune and lymphoproliferative complications. A number of therapeutic options are currently being used with variable effectiveness.

Objective: Our aim was to characterize the responsiveness of patients with CTLA-4 insufficiency to specific therapies and provide recommendations for the diagnostic workup and therapy at an organ-specific level.

Methods: Clinical features, laboratory findings, and response to treatment were reviewed retrospectively in an international cohort of 173 carriers of CTLA4 mutation. Patients were followed between 2014 and 2020 for a total of 2624 months from diagnosis. Clinical manifestations were grouped on the basis of organ-specific involvement. Medication use and response were recorded and evaluated.

Results: Among the 173 CTLA4 mutation carriers, 123 (71%) had been treated for immune complications. Abatacept, rituximab, sirolimus, and corticosteroids ameliorated disease severity, especially in cases of cytopenias and lymphocytic organ infiltration of the gut, lungs, and central nervous system. Immunoglobulin replacement was effective in prevention of infection. Only 4 of 16 patients (25%) with cytopenia who underwent splenectomy had a sustained clinical response. Cure was achieved with stem cell transplantation in 13 of 18 patients (72%). As a result of the aforementioned methods, organ-specific treatment pathways were developed.

Conclusion: Systemic immunosuppressants and abatacept may provide partial control but require ongoing administration. Allogeneic hematopoietic stem cell transplantation offers a possible cure for patients with CTLA-4 insufficiency.
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http://dx.doi.org/10.1016/j.jaci.2021.04.039DOI Listing
June 2021

Dysregulated immunity in PID patients with low GARP expression on Tregs due to mutations in LRRC32.

Cell Mol Immunol 2021 Jul 31;18(7):1677-1691. Epub 2021 May 31.

Division of Rheumatology and Clinical Immunology, Department of Internal Medicine IV, Ludwig-Maximilians-University of Munich, Munich, Germany.

Immune dysregulation diseases are characterized by heterogeneous clinical manifestations and may have severe disease courses. The identification of the genetic causes of these diseases therefore has critical clinical implications. We performed whole-exome sequencing of patients with immune dysregulation disorders and identified two patients with previously undescribed mutations in LRRC32, which encodes glycoprotein A repetitions predominant (GARP). These patients were characterized by markedly reduced numbers and frequencies of regulatory T cells (Tregs). Tregs with mutated LRRC32 exhibited strongly diminished cell-surface GARP expression and reduced suppressor function. In a model of conditional Garp deficiency in mice, we confirmed increased susceptibility to inflammatory diseases once GARP expression on Tregs was decreased. Garp deficiency led to an unstable Treg phenotype due to diminished Foxp3 protein acetylation and stability. Our study reinforces the understanding of the immunological mechanisms of immune dysregulation and expands the knowledge on the immunological function of GARP as an important regulator of Treg stability.
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http://dx.doi.org/10.1038/s41423-021-00701-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245512PMC
July 2021

A Pathogenic Missense Variant in Causes Common Variable Immunodeficiency Due to Detrimental Protein Damage.

Front Immunol 2021 27;12:621503. Epub 2021 Apr 27.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

In common variable immunodeficiency (CVID), heterozygous damaging variants represent the most frequent monogenic cause. encodes the precursor p105, which undergoes proteasomal processing to generate the mature NF-κB transcription factor subunit p50. The majority of sequence changes comprises missense variants of uncertain significance (VUS), each requiring functional evaluation to assess causality, particularly in families with multiple affected members presenting with different phenotypes. In four affected members of a German family, all diagnosed with CVID, we identified a previously uncharacterized heterozygous missense variant (c.1049A>G; p.Tyr350Cys). The clinical phenotypes varied markedly regarding onset, frequency and severity of infections. Consistent immunologic findings were hypogammaglobulinemia with normal specific antibody response to protein- and polysaccharide-based vaccinations, reduced switched memory B cells and decreased lymphocyte proliferation upon stimulation with the B cell mitogen SAC. To assess the pathogenicity of the missense variant, we employed immunophenotyping and functional analyses in a routine cell culture model. Following site-directed mutagenesis to introduce the variant into overexpression vectors encoding EGFP-fused p105 or p50, we analyzed transiently transfected HEK293T cells by confocal imaging and Western blotting. The cytoplasmic p105-Tyr350Cys precursor gained only weak expression levels indicating accelerated decay. The missense change disabled processing of the precursor to prevent the generation of mutant p50. Unlike the wildtype p50, the overexpressed mutant p50-Tyr350Cys was also not sustainable and showed a conspicuous subnuclear mislocalization with accumulation in dense aggregates instead of a homogenous distribution. Electrophoretic mobility shift assays, fluorescence-based reporter gene analyses and co-transfection experiments however demonstrated, that the DNA-binding activity of p50-Tyr350Cys and the interaction with RelA(p65), IκBα and wildtype p50 were preserved. Mutation carriers had reduced p105 and p50 levels, indicating insufficient protein amounts as the most likely primary defect. In conclusion, the missense variant c.1049A>G caused a detrimental defect, preventing the persistent expression of both, the p105-Tyr350Cys precursor and the mature p50-Tyr350Cys. The variable clinical phenotypes among affected family members sharing an identical pathogenic variant support a disease mechanism provoked by a p105/p50 (haplo)insufficient condition.
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http://dx.doi.org/10.3389/fimmu.2021.621503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115018PMC
June 2021

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction.

Nucleic Acids Res 2021 05;49(9):5057-5073

Epigenetics and Immune Disease Group, Josep Carreras Research Institute (IJC), 08916 Badalona, Barcelona, Spain.

Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.
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http://dx.doi.org/10.1093/nar/gkab322DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136777PMC
May 2021

Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations.

J Allergy Clin Immunol 2021 Apr 23. Epub 2021 Apr 23.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany. Electronic address:

Background: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.

Objective: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.

Methods: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.

Results: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.

Conclusions: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.
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http://dx.doi.org/10.1016/j.jaci.2021.04.015DOI Listing
April 2021

Altered Spectrum of Lymphoid Neoplasms in a Single-Center Cohort of Common Variable Immunodeficiency with Immune Dysregulation.

J Clin Immunol 2021 Aug 19;41(6):1250-1265. Epub 2021 Apr 19.

University of Freiburg, Freiburg, Germany.

Purpose: Common variable immune deficiency (CVID) confers an increased risk of lymphoid neoplasms, but reports describing the precise WHO specification of the lymphoma subtypes and their immunological environment are lacking. We therefore classified lymphomas-occurring in a cohort of 21 adult CVID patients during a 17-year period at our center-according to the 2016 WHO classification and characterized the local and systemic immunological context RESULTS: The median time between the onset of CVID and lymphoma was 14 years. Patients showed a high prevalence of preceding immune dysregulation: lymphadenopathy (n = 13, 62%), splenomegaly (n = 18, 86%), autoimmune cytopenia (n = 14, 67%), and gastrointestinal involvement (n = 15, 71%). The entities comprised extranodal marginal zone lymphoma (n = 6), diffuse large B cell lymphoma (n = 7), plasmablastic lymphoma (n = 1), classic Hodgkin lymphoma (n = 4, including three cases with germline CTLA4 mutations), T cell large granular lymphocytic leukemia (n = 2), and peripheral T cell lymphoma, not otherwise specified (n = 1), but no follicular lymphoma. An Epstein-Barr virus association was documented in eight of 16 investigated lymphomas. High expression of PDL1 by tumor cells in five and of PDL1 and PD1 by tumor-infiltrating macrophages and T cells in 12 of 12 investigated lymphomas suggested a tolerogenic immunological tumor environment.

Conclusion: In summary, a diverse combination of specific factors like genetic background, chronic immune activation, viral trigger, and impaired immune surveillance contributes to the observed spectrum of lymphomas in CVID. In the future, targeted therapies, e.g., PD1/PDL1 inhibitors in CVID associated lymphomas with a tolerogenic environment may improve therapy outcome.
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http://dx.doi.org/10.1007/s10875-021-01016-4DOI Listing
August 2021

Gain-of-function variants in SYK cause immune dysregulation and systemic inflammation in humans and mice.

Nat Genet 2021 04 29;53(4):500-510. Epub 2021 Mar 29.

Department of Biochemistry, University of Toronto, Toronto, Ontario, Canada.

Spleen tyrosine kinase (SYK) is a critical immune signaling molecule and therapeutic target. We identified damaging monoallelic SYK variants in six patients with immune deficiency, multi-organ inflammatory disease such as colitis, arthritis and dermatitis, and diffuse large B cell lymphomas. The SYK variants increased phosphorylation and enhanced downstream signaling, indicating gain of function. A knock-in (SYK-Ser544Tyr) mouse model of a patient variant (p.Ser550Tyr) recapitulated aspects of the human disease that could be partially treated with a SYK inhibitor or transplantation of bone marrow from wild-type mice. Our studies demonstrate that SYK gain-of-function variants result in a potentially treatable form of inflammatory disease.
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http://dx.doi.org/10.1038/s41588-021-00803-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245161PMC
April 2021

What can clinical immunology learn from inborn errors of epigenetic regulators?

J Allergy Clin Immunol 2021 May 17;147(5):1602-1618. Epub 2021 Feb 17.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany; RESIST- Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany. Electronic address:

The epigenome is at the interface between environmental factors and the genome, regulating gene transcription, DNA repair, and replication. Epigenetic modifications play a crucial role in establishing and maintaining cell identity and are especially crucial for neurology, musculoskeletal integrity, and the function of the immune system. Mutations in genes encoding for the components of the epigenetic machinery lead to the development of distinct disorders, especially involving the central nervous system and host defense. In this review, we focus on the role of epigenetic modifications for the function of the immune system. By studying the immune phenotype of patients with monogenic mutations in components of the epigenetic machinery (inborn errors of epigenetic regulators), we demonstrate the importance of DNA methylation, histone modifications, chromatin remodeling, noncoding RNAs, and mRNA processing for immunity. Moreover, we give a short overview on therapeutic strategies targeting the epigenome.
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http://dx.doi.org/10.1016/j.jaci.2021.01.035DOI Listing
May 2021

Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome.

J Clin Immunol 2021 Jul 1;41(5):934-943. Epub 2021 Feb 1.

Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor T17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.
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http://dx.doi.org/10.1007/s10875-021-00971-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8249289PMC
July 2021

A distinct CD38+CD45RA+ population of CD4+, CD8+, and double-negative T cells is controlled by FAS.

J Exp Med 2021 Feb;218(2)

Department of General Paediatrics, Clinic Oldenburg, Oldenburg, Germany.

The identification and characterization of rare immune cell populations in humans can be facilitated by their growth advantage in the context of specific genetic diseases. Here, we use autoimmune lymphoproliferative syndrome to identify a population of FAS-controlled TCRαβ+ T cells. They include CD4+, CD8+, and double-negative T cells and can be defined by a CD38+CD45RA+T-BET- expression pattern. These unconventional T cells are present in healthy individuals, are generated before birth, are enriched in lymphoid tissue, and do not expand during acute viral infection. They are characterized by a unique molecular signature that is unambiguously different from other known T cell differentiation subsets and independent of CD4 or CD8 expression. Functionally, FAS-controlled T cells represent highly proliferative, noncytotoxic T cells with an IL-10 cytokine bias. Mechanistically, regulation of this physiological population is mediated by FAS and CTLA4 signaling, and its survival is enhanced by mTOR and STAT3 signals. Genetic alterations in these pathways result in expansion of FAS-controlled T cells, which can cause significant lymphoproliferative disease.
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http://dx.doi.org/10.1084/jem.20192191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658692PMC
February 2021

Enabling External Inquiries to an Existing Patient Registry by Using the Open Source Registry System for Rare Diseases: Demonstration of the System Using the European Society for Immunodeficiencies Registry.

JMIR Med Inform 2020 Oct 7;8(10):e17420. Epub 2020 Oct 7.

Medical Informatics Group, University Hospital Frankfurt, Frankfurt am Main, Germany.

Background: The German Network on Primary Immunodeficiency Diseases (PID-NET) utilizes the European Society for Immunodeficiencies (ESID) registry as a platform for collecting data. In the context of PID-NET data, we show how registries based on custom software can be made interoperable for better collaborative access to precollected data. The Open Source Registry System for Rare Diseases (Open-Source-Registersystem für Seltene Erkrankungen [OSSE], in German) provides patient organizations, physicians, scientists, and other parties with open source software for the creation of patient registries. In addition, the necessary interoperability between different registries based on the OSSE, as well as existing registries, is supported, which allows those registries to be confederated at both the national and international levels.

Objective: Data from the PID-NET registry should be made available in an interoperable manner without losing data sovereignty by extending the existing custom software of the registry using the OSSE registry framework.

Methods: This paper describes the following: (1) the installation and configuration of the OSSE bridgehead, (2) an approach using a free toolchain to set up the required interfaces to connect a registry with the OSSE bridgehead, and (3) the decentralized search, which allows the formulation of inquiries that are sent to a selected set of registries of interest.

Results: PID-NET uses the established and highly customized ESID registry software. By setting up a so-called OSSE bridgehead, PID-NET data are made interoperable according to a federated approach, and centrally formulated inquiries for data can be received. As the first registry to use the OSSE bridgehead, the authors introduce an approach using a free toolchain to efficiently implement and maintain the required interfaces. Finally, to test and demonstrate the system, two inquiries are realized using the graphical query builder. By establishing and interconnecting an OSSE bridgehead with the underlying ESID registry, confederated queries for data can be received and, if desired, the inquirer can be contacted to further discuss any requirements for cooperation.

Conclusions: The OSSE offers an infrastructure that provides the possibility of more collaborative and transparent research. The decentralized search functionality includes registries into one search application while still maintaining data sovereignty. The OSSE bridgehead enables any registry software to be integrated into the OSSE network. The proposed toolchain to set up the required interfaces consists of freely available software components that are well documented. The use of the decentralized search is uncomplicated to use and offers a well-structured, yet still improvable, graphical user interface to formulate queries.
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http://dx.doi.org/10.2196/17420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7578818PMC
October 2020

Altered Microbiota, Impaired Quality of Life, Malabsorption, Infection, and Inflammation in CVID Patients With Diarrhoea.

Front Immunol 2020 31;11:1654. Epub 2020 Jul 31.

Institute of Immunity and Transplantation, Royal Free Hospital, University College London, London, United Kingdom.

Diarrhoea is the commonest gastrointestinal symptom in patients with common variable immunodeficiency (CVID). The aim of this study was to describe the prevalence and clinical presentation of chronic and recurrent diarrhoea in the Royal-Free-Hospital (RFH) London CVID cohort, including symptoms, infections, level of inflammation, and microbial diversity. A cross-sectional study of adult CVID patients (139 out of 172 diagnosed with CVID completed the screening questionnaire). Those with diarrhoea ≥6 days/month had stool and blood samples analysed and completed the short Inflammatory Bowel Disease Questionnaire (sIBDQ). BMI, spleen-size, lymphocytes and gut-microbial diversity were compared. Due to logistical and clinical restraints, not all patients could be analysed on all measures. 46/139 (33.1%) patients had current significant diarrhoea. In patients with past or present diarrhoea, BMI was lower (median 23.7 vs. 26, = 0.005), malabsorption more common (57.97 vs. 35.71%, = 0.011). CD4+ lymphocytes were higher in patients with diarrhoea ( = 0.028; = 138), but CD4+ naïve lymphocytes were significantly higher in non-diarrhoea patients ( = 0.009, = 28). Nine patients had confirmed or probable current gastrointestinal infections. Calprotectin was >60 μg/g in 13/29 with significant diarrhoea including 9 without infection. SIBDQ revealed a low median score of 4.74. Microbial alpha diversity was significantly lower in CVID patients compared to healthy household controls. There was no significant difference in alpha diversity in relation to antibiotic intake during the 6 weeks prior to providing samples. Patients with CVID and significant diarrhoea had infections, raised calprotectin, malabsorption, a lower BMI, an impaired quality of life (comparable to active IBD), and they differed from non-diarrhoea patients in their lymphocyte phenotyping. Furthermore, microbial diversity was altered. These findings strongly imply that there may be an inflammatory nature and a systemic predisposition to diarrhoea in CVID, which necessitates further investigation.
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http://dx.doi.org/10.3389/fimmu.2020.01654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412961PMC
April 2021

Bile acids regulate intestinal antigen presentation and reduce graft-versus-host disease without impairing the graft-versus-leukemia effect.

Haematologica 2020 Jul 16. Epub 2020 Jul 16.

Department of Medicine I, Medical Center - University of Freiburg, Germany;

Acute graft-versus-host disease causes significant mortality in patients undergoing allogeneic hematopoietic cell transplantation. Immunosuppressive treatment for graft-versus-host disease can impair the beneficial graft-versus-leukemia effect and facilitate malignancy relapse. Therefore, novel approaches that protect and regenerate injured tissues without impeding the donor immune system are needed. Bile acids regulate multiple cellular processes and are in close contact with the intestinal epithelium, a major target of acute graft-versus-host disease. Here, we found that the bile acid pool is reduced following graft-versus-host disease induction in a preclinical model. We evaluated the efficacy of bile acids to protect the intestinal epithelium without reducing anti-tumor immunity. We observed that application of bile acids decreased cytokine-induced cell death in intestinal organoids and cell lines. Systemic prophylactic administration of tauroursodeoxycholic acid, the most potent compound in our in vitro studies, reduced graft-versus-host disease severity in three different murine transplantation models. This effect was mediated by decreased activity of the antigen presentation machinery and subsequent prevention of apoptosis of the intestinal epithelium. Moreover, bile acid administration did not alter the bacterial composition in the intestine suggesting that its effects are cell-specific and independent of the microbiome. Treatment of human and murine leukemic cell lines with tauroursodeoxycholic acid did not interfere with the expression of antigen presentation-related molecules. Systemic T cell expansion and especially their cytotoxic capacity against leukemic cells remained intact. This study establishes a role for bile acids in the prevention of acute graft-versus-host disease without impairing the graft-versus-leukemia effect. In particular, we provide a scientific rationale for the systematic use of tauroursodeoxycholic acid in patients undergoing allogeneic hematopoietic cell transplantation.
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http://dx.doi.org/10.3324/haematol.2019.242990DOI Listing
July 2020

Dynamics in protein translation sustaining T cell preparedness.

Nat Immunol 2020 08 6;21(8):927-937. Epub 2020 Jul 6.

Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland.

In response to pathogenic threats, naive T cells rapidly transition from a quiescent to an activated state, yet the underlying mechanisms are incompletely understood. Using a pulsed SILAC approach, we investigated the dynamics of mRNA translation kinetics and protein turnover in human naive and activated T cells. Our datasets uncovered that transcription factors maintaining T cell quiescence had constitutively high turnover, which facilitated their depletion following activation. Furthermore, naive T cells maintained a surprisingly large number of idling ribosomes as well as 242 repressed mRNA species and a reservoir of glycolytic enzymes. These components were rapidly engaged following stimulation, promoting an immediate translational and glycolytic switch to ramp up the T cell activation program. Our data elucidate new insights into how T cells maintain a prepared state to mount a rapid immune response, and provide a resource of protein turnover, absolute translation kinetics and protein synthesis rates in T cells ( https://www.immunomics.ch ).
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http://dx.doi.org/10.1038/s41590-020-0714-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610365PMC
August 2020

Safety and efficacy of abatacept in patients with treatment-resistant SARCoidosis (ABASARC) - protocol for a multi-center, single-arm phase IIa trial.

Contemp Clin Trials Commun 2020 Sep 29;19:100575. Epub 2020 May 29.

Department of Pneumology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.

Introduction: Sarcoidosis is a granulomatous systemic disease that becomes chronic in approximately one third of affected patients resulting in quality of life and functional impairment. Immunosuppressive drugs other than steroids represent alternative therapeutic options, but side effects like liver and bone marrow toxicity or increased susceptibility to infections limit their use. Pathophysiological studies in sarcoidosis patients demonstrate altered regulatory T-cell functions with a reduced expression of CTLA-4 (CD152) and prolonged inflammation. Therefore, interfering with CTLA-4 using abatacept might be a therapeutic option in sarcoidosis similar to rheumatoid arthritis therapy.

Methods/design: This is a multicenter prospective open-labeled single arm phase II study addressing the safety of abatacept in sarcoidosis patients. 30 patients with chronic sarcoidosis requiring immunosuppressive therapy beyond 5 mg prednisolone equivalent will be treated with abatacept in combination with corticosteroids for one year in two centers.The primary endpoint is the number and characterization of severe infectious complications under treatment with abatacept.Secondary endpoints are the rate of all infections, patient-related outcomes (assessed by questionnaires), lung function and immunological parameters including alveolar inflammation assessed by bronchoaveolar lavage.

Discussion: This is the first trial of abatacept in patients with sarcoidosis. It is hypothesized that administration of abatacept is safe in patients with chronic sarcoidosis and can limit ongoing inflammation. Patients' wellbeing is assessed by established questionnaires. Immunological work-up will highlight the effect of abatacept on inflammatory pathways in sarcoidosis.

Trial Registration: The trial has been registered at the German Clinical Trial Registry () with the identity number DRKS00011660.
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http://dx.doi.org/10.1016/j.conctc.2020.100575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292904PMC
September 2020

Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans.

Blood 2020 09;136(12):1442-1455

Department of Medicine I, Faculty of Medicine, Medical Center University of Freiburg (MCUF).

Acute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2-based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.
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http://dx.doi.org/10.1182/blood.2020005957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498363PMC
September 2020

Clinical Phenotypes and Immunological Characteristics of 18 Egyptian LRBA Deficiency Patients.

J Clin Immunol 2020 08 6;40(6):820-832. Epub 2020 Jun 6.

Pediatrics Department, Faculty of Medicine, Cairo University, Giza, Egypt.

LPS-responsive beige-like anchor (LRBA) deficiency is an autosomal recessive primary immunodeficiency disorder, OMIM (#614700). LRBA deficiency patients suffer from variable manifestations including recurrent infections, immune dysregulation, autoimmunity, cytopenias, and enteropathy. This study describes different clinical phenotypes and immunological characteristics of 18 LRBA deficiency patients diagnosed from Egypt. T and B lymphocyte subpopulations, LRBA, and cytotoxic T lymphocyte-associated protein 4 (CTLA4) expression were evaluated in resting and stimulated T cells using flow cytometry. Next-generation sequencing was used to identify mutations in the LRBA gene. LRBA deficiency patients had significantly lower B cells and increased percentage of memory T cells. CTLA4 levels were lower in LRBA-deficient T regulatory cells in comparison to healthy donors at resting conditions and significantly increased upon stimulation of T cells. We identified 11 novel mutations in LRBA gene ranging from large deletions to point mutations. Finally, we were able to differentiate LRBA-deficient patients from healthy control and common variable immunodeficiency patients using a simple flow cytometry test performed on whole blood and without need to prior stimulation. LRBA deficiency has heterogeneous phenotypes with poor phenotype-genotype correlation since the same mutation may manifest differently even within the same family. Low LRBA expression, low numbers of B cells, increased numbers of memory T cells, and defective CTLA4 expression (which increase to normal level upon T cell stimulation) are useful laboratory tests to establish the diagnosis of LRBA deficiency. Screening of the siblings of affected patients is very important as patients may be asymptomatic at the beginning of the disease course.
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http://dx.doi.org/10.1007/s10875-020-00799-2DOI Listing
August 2020

Incidence of SCID in Germany from 2014 to 2015 an ESPED* Survey on Behalf of the API*** Erhebungseinheit für Seltene Pädiatrische Erkrankungen in Deutschland (German Paediatric Surveillance Unit) ** Arbeitsgemeinschaft Pädiatrische Immunologie.

J Clin Immunol 2020 07 26;40(5):708-717. Epub 2020 May 26.

Institute of Social Paediatrics and Adolescent Medicine, University of Munich, Munich, Germany.

Purpose: Severe combined immunodeficiencies (SCID) are a heterogeneous group of fatal genetic disorders, in which the immune response is severely impaired. SCID can be cured if diagnosed early. We aim to determine the incidence of clinically defined SCID cases, acquire data of reported cases and evaluate their possible prediction by newborn screening, before introduction of a general screening program in Germany.

Methods: The German Surveillance Unit for rare Paediatric Diseases (ESPED) prospectively queried the number of incident SCID cases in all German paediatric hospitals in 2014 and 2015. Inclusion criteria were (1) opportunistic or severe infections or clinical features associated with SCID (failure to thrive, lacking thymus or lymphatic tissue, dysregulation of the immune system, graft versus host reaction caused by maternal T cells), (2) dysfunctional T cell immunity or proof of maternal T cells and (3) exclusion of a secondary immunodeficiency such as human immunodeficiency virus (HIV) infection. In a capture-recapture analysis, cases were matched with cases reported to the European Society for Immunodeficiencies (ESID).

Results: Fifty-eight patients were initially reported to ESPED, 24 reports could be confirmed as SCID, 21 patients were less than 1 year old at time of diagnosis. One SCID case was reported to ESID only. The estimated incidence of SCID in Germany is 1.6/100,000 (1:62,500) per year in children less than 1 year of age. Most patients reported were symptomatic and mortality in regard to reported outcome was high (29% (6/22)). The majority of incident SCID cases were considered to be probably detectable by newborn screening.

Conclusions: SCID is a rare disease with significant mortality. Newborn screening may give the opportunity to improve the prognosis in a significant number of children with SCID.
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http://dx.doi.org/10.1007/s10875-020-00782-xDOI Listing
July 2020

Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations.

J Allergy Clin Immunol 2020 10 9;146(4):901-911. Epub 2020 Apr 9.

Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal.

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (NF-κB) signaling.

Results: We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88.9%), reduced switched memory B cells (60.3%), and respiratory (83%) and gastrointestinal (28.6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57.4%), lymphoproliferation (52.4%), noninfectious enteropathy (23.1%), opportunistic infections (15.7%), autoinflammation (29.6%), and malignancy (16.8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
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http://dx.doi.org/10.1016/j.jaci.2019.11.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246418PMC
October 2020

Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome.

J Exp Med 2020 06;217(6)

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.

Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients' heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.
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http://dx.doi.org/10.1084/jem.20191804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971136PMC
June 2020

Nonpermissive bone marrow environment impairs early B-cell development in common variable immunodeficiency.

Blood 2020 04;135(17):1452-1457

Department of Rheumatology and Clinical Immunology.

Common variable immunodeficiency (CVID) is a disease characterized by increased susceptibility to infections, hypogammaglobulinemia, and immune dysregulation. Although CVID is thought to be a disorder of the peripheral B-cell compartment, in 25% of patients, early B-cell development in the bone marrow is impaired. Because poor B-cell reconstitution after hematopoietic stem cell transplantation has been observed, we hypothesized that in some patients the bone marrow environment is not permissive to B-cell development. Studying the differentiation dynamics of bone marrow-derived CD34+ cells into immature B cells in vitro allowed us to distinguish patients with B-cell intrinsic defects and patients with a nonpermissive bone marrow environment. In the former, immature B cells did not develop and in the latter CD34+ cells differentiated into immature cells in vitro, but less efficiently in vivo. In a further group of patients, the uncommitted precursors were unable to support the constant development of B cells in vitro, indicating a possible low frequency or exhaustion of the precursor population. Hematopoietic stem cell transplantation would result in normal B-cell repopulation in case of intrinsic B-cell defect, but in defective B-cell repopulation in a nonpermissive environment. Our study points to the importance of the bone marrow niche in the pathogenesis of CVID.
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http://dx.doi.org/10.1182/blood.2019003855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195542PMC
April 2020

Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.

J Allergy Clin Immunol 2020 05 27;145(5):1452-1463. Epub 2019 Dec 27.

Department of Bone Marrow Transplantation, Hadassah, Hebrew University Medical Centre, Jerusalem, Israel.

Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant.

Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant.

Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices.

Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome.

Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.
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http://dx.doi.org/10.1016/j.jaci.2019.12.896DOI Listing
May 2020

Structural Noninfectious Manifestations of the Central Nervous System in Common Variable Immunodeficiency Disorders.

J Allergy Clin Immunol Pract 2020 03 16;8(3):1047-1062.e6. Epub 2019 Dec 16.

Department of Rheumatology and Clinical Immunology, Division of Immunodeficiency, Medical Center of the University Hospital, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Electronic address:

Background: Central nervous system (CNS) disease in adult common variable immunodeficiency (CVID) is rare, and therefore diagnostic and therapeutic protocols are lacking.

Objective: To provide clinical information aiming to establish awareness and first experience-based recommendations.

Methods: We reviewed clinical manifestations, genetic and immunological characteristics, diagnostic evaluation, and treatment of patients with CVID with abnormal magnetic resonance imaging (MRI) of the CNS disease in our cohort.

Results: Seventeen patients with CNS manifestation and a previous diagnosis of CVID were identified. Presenting symptoms of the CNS disease included loss of sensory or motoric function, headache, or epilepsy. Contrast-enhancing lesions of the brain or solely the spinal cord were the most common findings on MRI. The prevalence of splenomegaly, lymphadenopathy, interstitial lung disease, and autoimmune cytopenia was significantly increased compared with control CVID patients. In 8 patients, a molecular defect was identified, including mutations in CTLA4, NFKB1, and CECR1. Patients with CVID with CNS involvement generally displayed lymphopenia, skewed CD4 T-cell subsets, and increased proportions of CD21 B cells in the peripheral blood. CNS involvement usually responded well to high-dose steroids, but regularly required maintenance therapy to prevent relapse.

Conclusion: CNS disease is a severe but rare complication in CVID disorders, particularly affecting patients with other noninfectious disease symptoms. Diagnostic evaluation needs to rule out infectious causes by all means; a genetic evaluation is recommended given the high probability of an underlying monogenic disorder. Possible treatment consists of steroids with yet to be determined optimal maintenance therapy in case of relapse.
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http://dx.doi.org/10.1016/j.jaip.2019.11.039DOI Listing
March 2020

Late-Onset Antibody Deficiency Due to Monoallelic Alterations in .

Front Immunol 2019 14;10:2618. Epub 2019 Nov 14.

Department for Clinical Immunology and Rheumatology, Hannover Medical School, Hanover, Germany.

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19CD27). Among all tested genes, alterations were the most common monoallelic cause of antibody deficiency in our cohort.
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http://dx.doi.org/10.3389/fimmu.2019.02618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6871540PMC
November 2020

Distinct molecular response patterns of activating STAT3 mutations associate with penetrance of lymphoproliferation and autoimmunity.

Clin Immunol 2020 01 23;210:108316. Epub 2019 Nov 23.

Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Pediatrics, Medical Center, University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany. Electronic address:

Germline STAT3 gain-of-function (GOF) mutations have been linked to poly-autoimmunity and lymphoproliferation with variable expressivity and incomplete penetrance. Here we studied the impact of 17 different STAT3 GOF mutations on the canonical STAT3 signaling pathway and correlated the molecular results with clinical manifestations. The mutations clustered in three groups. Group 1 mutants showed altered STAT3 phosphorylation kinetics and strong basal transcriptional activity. They were associated with the highest penetrance of lymphoproliferation and autoimmunity. Group 2 mutants showed a strongly inducible transcriptional reporter activity and were clinically less penetrant. Group 3 mutants were mostly located in the DNA binding domain and showed the strongest DNA binding affinity despite a poor transcriptional reporter response. Thus, the GOF effect of STAT3 mutations is determined by a heterogeneous response pattern at the molecular level. The correlation of response pattern and clinical penetrance indicates a significant contribution of mutation-determined effects on disease manifestations.
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http://dx.doi.org/10.1016/j.clim.2019.108316DOI Listing
January 2020
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