ABSTRACT
The fifth edition of the World Health Organization (WHO) classification of lymphohematopoietic system tumors updated the terminology, types of lesions, diagnostic criteria, nomenclature, and other aspects of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation. The important updates and main changes in this section were briefly introduced, in order to guide the precise classification of lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation, and standardize pathological reports.
Subject(s)
Lymphoma , World Health Organization , Humans , Lymphoma/pathology , Lymphoma/classification , Lymphoproliferative Disorders/pathology , Lymphoproliferative Disorders/classification , Immunologic Deficiency Syndromes/classification , Immunologic Deficiency Syndromes/pathology , Terminology as Topic , Hematologic Neoplasms/pathology , Hematologic Neoplasms/classificationABSTRACT
Inborn errors of immunity (IEI) are a genetically heterogeneous group of disorders with a broad clinical spectrum. Identification of molecular and functional bases of these disorders is important for diagnosis, treatment, and an understanding of the human immune response. We identified 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immune defects, and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8, encoding the endosomal Toll-like receptor 8 (TLR8). Interestingly, 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism responsible for the clinical phenotype. Mosaicism was also detected in skin-derived fibroblasts in 3 patients, demonstrating that mutations were not limited to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants conferred gain of function to TLR8 protein, and immune phenotyping demonstrated a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B-cell maturation. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells demonstrated increased responsiveness to TLR8. Together, these findings demonstrate that gain-of-function variants in TLR8 lead to a novel childhood-onset IEI with lymphoproliferation, neutropenia, infectious susceptibility, B- and T-cell defects, and in some cases, bone marrow failure. Somatic mosaicism is a prominent molecular mechanism of this new disease.
Subject(s)
Bone Marrow Failure Disorders/pathology , Gain of Function Mutation , Immunologic Deficiency Syndromes/pathology , Inflammation/pathology , Mosaicism , Pancytopenia/pathology , Toll-Like Receptor 8/genetics , Adolescent , Adult , B-Lymphocytes/pathology , Bone Marrow Failure Disorders/etiology , Bone Marrow Failure Disorders/metabolism , Cell Differentiation , Child , Child, Preschool , Cytokines/metabolism , Female , Follow-Up Studies , Humans , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/metabolism , Infant , Inflammation/etiology , Inflammation/metabolism , Lymphocyte Activation , Male , Pancytopenia/etiology , Pancytopenia/metabolism , Pedigree , Prognosis , T-Lymphocytes/immunology , Young AdultABSTRACT
BACKGROUND: Patients with some types of immunodeficiency can experience chronic or relapsing infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This leads to morbidity and mortality, infection control challenges, and the risk of evolution of novel viral variants. The optimal treatment for chronic coronavirus disease 2019 (COVID-19) is unknown. OBJECTIVE: Our aim was to characterize a cohort of patients with chronic or relapsing COVID-19 disease and record treatment response. METHODS: We conducted a UK physician survey to collect data on underlying diagnosis and demographics, clinical features, and treatment response of immunodeficient patients with chronic (lasting ≥21 days) or relapsing (≥2 episodes) of COVID-19. RESULTS: We identified 31 patients (median age 49 years). Their underlying immunodeficiency was most commonly characterized by antibody deficiency with absent or profoundly reduced peripheral B-cell levels; prior anti-CD20 therapy, and X-linked agammaglobulinemia. Their clinical features of COVID-19 were similar to those of the general population, but their median duration of symptomatic disease was 64 days (maximum 300 days) and individual patients experienced up to 5 episodes of illness. Remdesivir monotherapy (including when given for prolonged courses of ≤20 days) was associated with sustained viral clearance in 7 of 23 clinical episodes (30.4%), whereas the combination of remdesivir with convalescent plasma or anti-SARS-CoV-2 mAbs resulted in viral clearance in 13 of 14 episodes (92.8%). Patients receiving no therapy did not clear SARS-CoV-2. CONCLUSIONS: COVID-19 can present as a chronic or relapsing disease in patients with antibody deficiency. Remdesivir monotherapy is frequently associated with treatment failure, but the combination of remdesivir with antibody-based therapeutics holds promise.
Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/therapy , Immunologic Deficiency Syndromes/therapy , SARS-CoV-2/drug effects , Adenosine Monophosphate/therapeutic use , Adult , Aged , Aged, 80 and over , Alanine/therapeutic use , B-Lymphocytes/immunology , B-Lymphocytes/pathology , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Chronic Disease , Female , Humans , Immunization, Passive , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Immunologic Deficiency Syndromes/virology , Lymphocyte Count , Male , Middle Aged , Recombinant Fusion Proteins/administration & dosage , Recurrence , SARS-CoV-2/pathogenicity , Treatment Failure , COVID-19 SerotherapyABSTRACT
Warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome is a rare primary immunodeficiency predominantly caused by heterozygous gain-of-function mutations in CXCR4 C-terminus. We assessed genotype-phenotype correlations for known pathogenic CXCR4 variants and in vitro response of each variant to mavorixafor, an investigational CXCR4 antagonist. We used cell-based assays to analyze CXCL12-induced receptor trafficking and downstream signaling of 14 pathogenic CXCR4 variants previously identified in patients with WHIM syndrome. All CXCR4 variants displayed impaired receptor trafficking, hyperactive downstream signaling, and enhanced chemotaxis in response to CXCL12. Mavorixafor inhibited CXCL12-dependent signaling and hyperactivation in cells harboring CXCR4WHIM mutations. A strong correlation was found between CXCR4 internalization defect and severity of blood leukocytopenias and infection susceptibility, and between AKT activation and immunoglobulin A level and CD4+ T-cell counts. This study is the first to show WHIM syndrome clinical phenotype variability as a function of both CXCR4WHIM genotype diversity and associated functional dysregulation. Our findings suggest that CXCR4 internalization may be used to assess the pathogenicity of CXCR4 variants in vitro and also as a potential WHIM-related disease biomarker. The investigational CXCR4 antagonist mavorixafor inhibited CXCL12-dependent signaling in all tested CXCR4-variant cell lines at clinically relevant concentrations.
Subject(s)
Agammaglobulinemia , Immunologic Deficiency Syndromes , Neutropenia , Warts , Agammaglobulinemia/genetics , Aminoquinolines , Benzimidazoles , Biomarkers , Butylamines , Genetic Association Studies , Humans , Immunoglobulin A/genetics , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Neutropenia/genetics , Neutropenia/metabolism , Primary Immunodeficiency Diseases , Proto-Oncogene Proteins c-akt/genetics , Receptors, CXCR4/genetics , Receptors, CXCR4/metabolism , Warts/genetics , Warts/metabolism , Warts/pathologyABSTRACT
WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis), a primary immunodeficiency disorder involving panleukopenia, is caused by autosomal dominant gain-of-function mutations in CXC chemokine receptor 4 (CXCR4). Myelokathexis is neutropenia caused by neutrophil retention in bone marrow. Patients with WHIM syndrome are often treated with granulocyte colony-stimulating factor (G-CSF), which can increase neutrophil counts but does not affect cytopenias other than neutropenia. In this investigator-initiated, open-label study, three severely affected patients with WHIM syndrome who could not receive G-CSF were treated with low-dose plerixafor, a CXCR4 antagonist, for 19 to 52 months. Myelofibrosis, panleukopenia, anemia, and thrombocytopenia were ameliorated, the wart burden and frequency of infection declined, human papillomavirus-associated oropharyngeal squamous-cell carcinoma stabilized, and quality of life improved markedly. Adverse events were mainly infections attributable to the underlying immunodeficiency. One patient died from complications of elective reconstructive surgery. (Funded by the National Institutes of Health.).
Subject(s)
Bone Marrow/pathology , Heterocyclic Compounds/therapeutic use , Immunologic Deficiency Syndromes/drug therapy , Receptors, CXCR4/antagonists & inhibitors , Warts/drug therapy , Benzylamines , Bone Marrow Examination , Cyclams , Fatal Outcome , Humans , Immunologic Deficiency Syndromes/pathology , Male , Middle Aged , Neoplasms, Squamous Cell/drug therapy , Neoplasms, Squamous Cell/genetics , Phenotype , Primary Immunodeficiency Diseases , Primary Myelofibrosis/drug therapy , Primary Myelofibrosis/pathology , Receptors, CXCR4/genetics , Warts/pathologyABSTRACT
To assess how B cell phenotype analysis correlates with antigen responses in patients with class switch recombination defects (CSRD) we quantified memory B cells by flow-cytometry and immunized CSRD patients with the neoantigen bacteriophage phiX174 (phage). CSRD patients showed uniformly absent or markedly reduced switched memory B cells (IgM-IgD-CD27+). CD40L patients had reduced CD27+ memory B cells (both non-switched and switched). In NEMO patients, results varied depending on the IKKγ gene variant. Three of four AID patients had normal percentages of CD27+ memory B cells while CD27+IgM-IgD- switched memory B cells were markedly reduced in all AID patients. Antibody response to phage was remarkably decreased with lack of memory amplification and class-switching in immunized CD40L, UNG deficient, and NEMO patients. Distinct B-cell phenotype pattern correlated with abnormal antibody responses to a T-cell dependent neoantigen, representing a powerful tool to identify CSRD patients.
Subject(s)
B-Lymphocytes/cytology , Bacteriophage phi X 174/immunology , Immunoglobulin Class Switching/genetics , Immunoglobulin Class Switching/immunology , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Adolescent , Adult , Antibody Formation/genetics , Antibody Formation/immunology , CD40 Ligand/deficiency , Child , Child, Preschool , Female , Flow Cytometry , Humans , I-kappa B Proteins/genetics , Immunization , Immunoglobulin D/immunology , Immunoglobulin M/immunology , Immunologic Deficiency Syndromes/pathology , Immunologic Memory/genetics , Immunologic Memory/immunology , Infant , Male , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunologyABSTRACT
AMPK (adenosine monophosphate-activated protein kinase) is phosphorylated (AMPK-P) in response to low energy through allosteric activation by Adenosine mono- or diphosphate (AMP/ADP). Folliculin (FLCN) and the FLCN-interacting proteins 1 and 2 (FNIP1, 2) modulate AMPK. FNIP1 deficiency patients have a AMPK-P gain of function phenotype with hypertrophic cardiomyopathy, Wolff-Parkinson-White pre-excitation syndrome, myopathy of skeletal muscles and combined immunodeficiency.
Subject(s)
Cardiomyopathies , Carrier Proteins , Genes, Recessive , Immunologic Deficiency Syndromes , Mutation , Pre-Excitation Syndromes , Cardiomyopathies/genetics , Cardiomyopathies/immunology , Cardiomyopathies/pathology , Carrier Proteins/genetics , Carrier Proteins/immunology , Female , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Male , Pre-Excitation Syndromes/genetics , Pre-Excitation Syndromes/immunology , Pre-Excitation Syndromes/pathologyABSTRACT
Lymphadenopathies can be part of the clinical spectrum of several primary immunodeficiencies, including diseases with immune dysregulation and autoinflammatory disorders, as the clinical expression of benign polyclonal lymphoproliferation, granulomatous disease or lymphoid malignancy. Lymphadenopathy poses a significant diagnostic dilemma when it represents the first sign of a disorder of the immune system, leading to a consequently delayed diagnosis. Additionally, the finding of lymphadenopathy in a patient with diagnosed immunodeficiency raises the question of the differential diagnosis between benign lymphoproliferation and malignancies. Lymphadenopathies are evidenced in 15-20% of the patients with common variable immunodeficiency, while in other antibody deficiencies the prevalence is lower. They are also evidenced in different combined immunodeficiency disorders, including Omenn syndrome, which presents in the first months of life. Interestingly, in the activated phosphoinositide 3-kinase delta syndrome, autoimmune lymphoproliferative syndrome, Epstein-Barr virus (EBV)-related lymphoproliferative disorders and regulatory T cell disorders, lymphadenopathy is one of the leading signs of the entire clinical picture. Among autoinflammatory diseases, the highest prevalence of lymphadenopathies is observed in patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) and hyper-immunoglobulin (Ig)D syndrome. The mechanisms underlying lymphoproliferation in the different disorders of the immune system are multiple and not completely elucidated. The advances in genetic techniques provide the opportunity of identifying new monogenic disorders, allowing genotype-phenotype correlations to be made and to provide adequate follow-up and treatment in the single diseases. In this work, we provide an overview of the most relevant immune disorders associated with lymphadenopathy, focusing on their diagnostic and prognostic implications.
Subject(s)
Common Variable Immunodeficiency/immunology , Immunologic Deficiency Syndromes/immunology , Lymphadenopathy/immunology , Lymphoproliferative Disorders/immunology , Common Variable Immunodeficiency/diagnosis , Common Variable Immunodeficiency/genetics , Common Variable Immunodeficiency/pathology , Epstein-Barr Virus Infections/immunology , Genetic Predisposition to Disease/genetics , Herpesvirus 4, Human/immunology , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/pathology , Infant , Infant, Newborn , Lymphadenopathy/diagnosis , Lymphadenopathy/pathology , Lymphoproliferative Disorders/diagnosis , Lymphoproliferative Disorders/genetics , Lymphoproliferative Disorders/pathologyABSTRACT
Spondyloepimetaphyseal dysplasia (SEMD) is a group of genetic skeletal disorders characterized by disproportionate short stature, and varying degrees of vertebral, epiphyseal, and metaphyseal involvement of the skeleton. According to the Nosology and classification of genetic skeletal disorders 2019 revision, more than 20 types of SEMD have been identified, and SEMD with immune deficiency, EXTL3 type is one of the newcomers. Affected individuals display variable skeletal abnormalities and neurodevelopmental findings. Liver and kidney cysts have also been reported frequently. Patients may exhibit varying degrees of immune deficiency as well. To date, only 14 patients from 9 unrelated families with SEMD with immune deficiency, EXTL3 type have been reported in the literature. We report a new patient who is currently 15 years old in whom cystic liver lesions were detected in the prenatal period. Disproportionate short stature, mild developmental delay and a T- NK+ B+ immunological profile were detected in the postnatal follow-up. Exome sequence analysis revealed a previously reported homozygous missense variant in exon 3 c.953C > T; p.(Pro318Leu) in EXTL3.
Subject(s)
Autoimmune Diseases/genetics , Genetic Predisposition to Disease , Immunologic Deficiency Syndromes/genetics , N-Acetylglucosaminyltransferases/genetics , Osteochondrodysplasias/genetics , Adolescent , Autoimmune Diseases/immunology , Autoimmune Diseases/pathology , Child , Child, Preschool , Dwarfism/genetics , Dwarfism/pathology , Female , Genetic Testing , Homozygote , Humans , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Infant , Male , Mutation, Missense/genetics , N-Acetylglucosaminyltransferases/deficiency , Osteochondrodysplasias/immunology , Osteochondrodysplasias/pathology , Pedigree , Spine/pathology , Young AdultABSTRACT
The mammalian Na+/H+ exchanger isoform one (NHE1) is a plasma membrane protein that is ubiquitously present in human cells. It functions to regulate intracellular pH removing an intracellular proton in exchange for one extracellular sodium and is involved in heart disease and in promoting metastasis in cancer. It is made of a 500 amino acid membrane domain plus a 315 amino acid, regulatory cytosolic tail. The membrane domain is thought to have 12 transmembrane segments and a large membrane-associated extracellular loop. Early studies demonstrated that in mice, disruption of the NHE1 gene results in locomotor ataxia and a phenotype of slow-wave epilepsy. Defects included a progressive neuronal degeneration. Growth and reproductive ability were also reduced. Recent studies have identified human autosomal homozygous recessive mutations in the NHE1 gene (SLC9A1) that result in impaired development, ataxia and other severe defects, and explain the cause of the human disease Lichtenstein-Knorr syndrome. Other human mutations have been identified that are stop codon polymorphisms. These cause short non-functional NHE1 proteins, while other genetic polymorphisms in the NHE1 gene cause impaired expression of the NHE1 protein, reduced activity, enhanced protein degradation or altered kinetic activation of the protein. Since NHE1 plays a key role in many human physiological functions and in human disease, genetic polymorphisms of the protein that significantly alter its function and are likely play significant roles in varying human phenotypes and be involved in disease.
Subject(s)
Fibrous Dysplasia of Bone/pathology , Immunologic Deficiency Syndromes/pathology , Mutation , Neurodegenerative Diseases/pathology , Neutropenia/pathology , Sodium-Hydrogen Exchanger 1/genetics , Amino Acid Sequence , Animals , Facies , Fibrous Dysplasia of Bone/genetics , Fibrous Dysplasia of Bone/metabolism , Humans , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Neutropenia/genetics , Neutropenia/metabolism , Protein Transport , Proteolysis , Sodium-Hydrogen Exchanger 1/metabolismABSTRACT
BACKGROUND: Immunoglobulin replacement therapy is recommended in case of severe hypogammaglobulinemia after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the supposed increased risk of infection in case of hypogammaglobulinemia has not been confirmed in allo-HSCT. In this study, we assessed the relationship between the gamma globulin level and the risk of infection during the 100 days following the allo-HSCT. METHODS: We gathered the weekly laboratory tests from day 7 to day 100 of 76 allograft patients, giving a total of 1 044 tests. 130 infections were documented clinically, by imaging, or microbiologically. RESULTS: Average gamma globulin levels between D-7 and D100 did not differ between patients with or without infection (642 ± 232 and 671 ± 246 mg/dL, respectively, P = .65). Gamma globulin level <400 mg/dl was not associated with the occurrence of infection between the test studied and the next one (aOR 1.33 [0.84-2.15], P = .24). The gamma globulin level was not predictive of bacterial or fungal infections (AUC 0.54 [95%CI: 0.47-0.61]) nor of viral reactivations (AUC 0.51 [95%CI: 0.43-0.60]). CONCLUSIONS: This confirmed that the humoral deficiency is a minor part of the immune deficiency in the 100 days post-transplant. This questions the relevance of the indications of immunoglobulin substitution during this period.
Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Immunoglobulins, Intravenous/therapeutic use , Immunologic Deficiency Syndromes/therapy , Leukemia/therapy , Lymphoma/therapy , Myelodysplastic Syndromes/therapy , Opportunistic Infections/diagnosis , Aged , Bacterial Infections/diagnosis , Bacterial Infections/immunology , Bacterial Infections/microbiology , Cyclosporine/administration & dosage , Cyclosporine/adverse effects , Female , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Graft vs Host Disease/prevention & control , Humans , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/pathology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Leukemia/immunology , Leukemia/pathology , Lymphoma/immunology , Lymphoma/pathology , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , Mycoses/diagnosis , Mycoses/immunology , Mycoses/microbiology , Myeloablative Agonists/therapeutic use , Myelodysplastic Syndromes/immunology , Myelodysplastic Syndromes/pathology , Opportunistic Infections/immunology , Opportunistic Infections/microbiology , Opportunistic Infections/virology , Prognosis , ROC Curve , Transplantation Conditioning/methods , Transplantation, Homologous , Virus Activation/drug effects , gamma-Globulins/metabolismABSTRACT
BACKGROUND: Type 1 diabetes (T1D) may coexist with primary immunodeficiencies, indicating a shared genetic background. OBJECTIVE: To evaluate the prevalence and clinical characteristics of immunoglobulin deficiency (IgD) among children with T1D. METHODS: Serum samples and medical history questionnaires were obtained during routine visits from T1D patients aged 4-18 years. IgG, IgA, IgM, and IgE were measured by nephelometry and enzyme-linked immunosorbent assay (ELISA). IgG and IgM deficiency (IgGD, IgMD) were defined as IgG/IgM >2 standard deviations (SD) below age-adjusted mean. IgE deficiency was defined as IgE <2 kIU/L. IgA deficiency (IgAD) was defined as IgA >2 SD below age-adjusted mean irrespective of other immunoglobulin classes (absolute if <0.07 g/L, partial otherwise) and as selective IgAD when IgA >2 SD below age-adjusted mean with normal IgG and IgM (absolute if <0.07 g/L, partial otherwise). RESULTS: Among 395 patients (53.4% boys) with the median age of 11.2 (8.4-13.7) and diabetes duration 3.6 (1.1-6.0) years, 90 (22.8%) were found to have hypogammaglobulinemia. The IgGD and IgAD were the most common each in 40/395 (10.1%). Complex IgD was found in seven patients. Increased odds of infection-related hospitalization (compared to children without any IgD) was related to having any kind of IgD and IgAD; OR (95%CI) = 2.1 (1.2-3.7) and 3.7 (1.8-7.5), respectively. Furthermore, IgAD was associated with having a first-degree relative with T1D OR (95%CI) = 3.3 (1.4-7.6) and suffering from non-autoimmune comorbidities 3.3 (1.4-7.6), especially neurological disorders 3.5 (1.2-10.5). CONCLUSIONS: IgDs frequently coexist with T1D and may be associated with several autoimmune and nonimmune related disorders suggesting their common genetic background.
Subject(s)
Diabetes Mellitus, Type 1 , Immunologic Deficiency Syndromes , Adolescent , Age of Onset , Child , Cohort Studies , Diabetes Mellitus, Type 1/classification , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/pathology , Female , Humans , IgG Deficiency/complications , IgG Deficiency/epidemiology , IgG Deficiency/pathology , Immunoglobulin A/analysis , Immunoglobulin A/blood , Immunoglobulin G/analysis , Immunoglobulin G/blood , Immunologic Deficiency Syndromes/classification , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/pathology , Male , Phenotype , Poland/epidemiology , PrevalenceABSTRACT
Aspergillosis infection is a major complication of acquired immunosuppression, and is associated with poor prognosis in its invasive form. Cardiac dissemination of invasive aspergillosis is a rare and usually fatal consequence of systemic mycosis. We describe a pediatric case of myocardial aspergillosis abscess in a 12-year-old girl diagnosed with multimodality cardiac imaging approach. The patient underwent prolonged antimycotic treatment and bone marrow transplant, which improved her immunity, and, for the first time in the literature, resulted in a favorable outcome.
Subject(s)
Abscess/etiology , Aspergillosis/complications , Cardiomyopathies/etiology , Immunologic Deficiency Syndromes/complications , Myocardium/pathology , Abscess/pathology , Aspergillosis/pathology , Cardiomyopathies/pathology , Child , Female , Humans , Immunologic Deficiency Syndromes/pathologyABSTRACT
Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.
Subject(s)
Anemia, Dyserythropoietic, Congenital/genetics , Immunologic Deficiency Syndromes/genetics , Inflammation/genetics , MAP Kinase Kinase Kinases/genetics , NFATC Transcription Factors/genetics , Nuclear Proteins/genetics , Osteomyelitis/genetics , Adipose Tissue/metabolism , Adipose Tissue/pathology , Anemia, Dyserythropoietic, Congenital/metabolism , Anemia, Dyserythropoietic, Congenital/pathology , Animals , Bone Resorption/genetics , Bone Resorption/metabolism , Bone Resorption/pathology , Cell Differentiation/genetics , Humans , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Inflammation/metabolism , Inflammation/pathology , Lipopolysaccharides/genetics , Macrophages/metabolism , Macrophages/pathology , Mice , Mice, Knockout , NF-kappa B/genetics , Nuclear Proteins/deficiency , Nuclear Proteins/metabolism , Osteoclasts/metabolism , Osteogenesis/genetics , Osteomyelitis/metabolism , Osteomyelitis/pathology , RANK Ligand/genetics , Signal Transduction/genetics , Transcription Factor RelA/geneticsABSTRACT
PURPOSE OF REVIEW: By establishing mechanisms that deliver oxygen to sustain cells and tissues, fight life-threatening pathogens and harness the immune system to eradicate cancer cells, hematopoietic stem and progenitor cells (HSPCs) are vital in health and disease. The cell biological framework for HSPC generation has been rigorously developed, yet recent single-cell transcriptomic analyses have unveiled permutations of the hematopoietic hierarchy that differ considerably from the traditional roadmap. Deploying mutants that disrupt specific steps in hematopoiesis constitutes a powerful strategy for deconvoluting the complex cell biology. It is striking that a single transcription factor, GATA2, is so crucial for HSPC generation and function, and therefore it is instructive to consider mechanisms governing GATA2 expression and activity. The present review focuses on an essential GATA2 enhancer (+9.5) and how +9.5 mutants inform basic and clinical/translational science. RECENT FINDINGS: +9.5 is essential for HSPC generation and function during development and hematopoietic regeneration. Human +9.5 mutations cause immunodeficiency, myelodysplastic syndrome, and acute myeloid leukemia. Qualitatively and quantitatively distinct contributions of +9.5 cis-regulatory elements confer context-dependent enhancer activity. The discovery of +9.5 and its mutant alleles spawned fundamental insights into hematopoiesis, and given its role to suppress blood disease emergence, clinical centers test for mutations in this sequence to diagnose the cause of enigmatic cytopenias. SUMMARY: Multidisciplinary approaches to discover and understand cis-regulatory elements governing expression of key regulators of hematopoiesis unveil biological and mechanistic insights that provide the logic for innovating clinical applications.
Subject(s)
Enhancer Elements, Genetic , GATA2 Transcription Factor , Hematopoietic Stem Cells , Immunologic Deficiency Syndromes , Leukemia, Myeloid, Acute , Mutation , Myelodysplastic Syndromes , Animals , GATA2 Transcription Factor/biosynthesis , GATA2 Transcription Factor/genetics , Hematopoietic Stem Cells/metabolism , Hematopoietic Stem Cells/pathology , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/metabolism , Immunologic Deficiency Syndromes/pathology , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Leukemia, Myeloid, Acute/pathology , Myelodysplastic Syndromes/diagnosis , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Myelodysplastic Syndromes/pathology , Precision MedicineABSTRACT
The primary immunodeficiencies (PIDs), rare inherited diseases characterized by severe dysfunction of immunity, have been successfully treated by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in childhood. Controversy exists regarding optimal timing and use of Allo-HSCT in adults, due to lack of experience and previous poor outcomes. Twenty-nine consecutive adult patients, with a mean age at transplant of 24 years (range, 17-50 years), underwent Allo-HSCT. Reduced-intensity conditioning (RIC) included fludarabine (Flu)/melphalan/alemtuzumab (n = 20), Flu/busulfan (Bu)/alemtuzumab (n = 8), and Flu/Bu/antithymocyte globulin (n = 1). Stem cell donors were matched unrelated donors or mismatched unrelated donors (n = 18) and matched related donors (n = 11). Overall survival (OS), event-free survival, transplant-related mortality (TRM), acute and chronic graft-versus-host disease incidence and severity, time to engraftment, lineage-specific chimerism, immune reconstitution, and discontinuation of immunoglobulin replacement therapy were recorded. OS at 3 years for the whole cohort was 85.2%. The rarer PID patients without chronic granulomatous disease (CGD) achieved an OS at 3 years of 88.9% (n = 18), compared with 81.8% for CGD patients (n = 11). TRM was low with only 4 deaths observed at a median follow-up of 3.5 years. There were no cases of early or late rejection. In all surviving patients, either stable mixed chimerism or full donor chimerism were observed. At last follow-up, 87% of the surviving patients had no evidence of persistent or recurrent infections. Allo-HSCT is safe and effective in young adult patients with severe PID and should be considered the treatment of choice where an appropriate donor is available.
Subject(s)
Hematopoietic Stem Cell Transplantation/mortality , Immunologic Deficiency Syndromes/mortality , Adolescent , Adult , Cohort Studies , Female , Humans , Immunologic Deficiency Syndromes/pathology , Immunologic Deficiency Syndromes/therapy , Middle Aged , Prognosis , Survival Rate , Transplantation Conditioning , Transplantation, Homologous , Young AdultABSTRACT
ARPC1B is a key factor for the assembly and maintenance of the ARP2/3 complex that is involved in actin branching from an existing filament. Germline biallelic mutations in ARPC1B have been recently described in 6 patients with clinical features of combined immunodeficiency (CID), whose neutrophils and platelets but not T lymphocytes were studied. We hypothesized that ARPC1B deficiency may also lead to cytoskeleton and functional defects in T cells. We have identified biallelic mutations in ARPC1B in 6 unrelated patients with early onset disease characterized by severe infections, autoimmune manifestations, and thrombocytopenia. Immunological features included T-cell lymphopenia, low numbers of naïve T cells, and hyper-immunoglobulin E. Alteration in ARPC1B protein structure led to absent/low expression by flow cytometry and confocal microscopy. This molecular defect was associated with the inability of patient-derived T cells to extend an actin-rich lamellipodia upon T-cell receptor (TCR) stimulation and to assemble an immunological synapse. ARPC1B-deficient T cells additionally displayed impaired TCR-mediated proliferation and SDF1-α-directed migration. Gene transfer of ARPC1B in patients' T cells using a lentiviral vector restored both ARPC1B expression and T-cell proliferation in vitro. In 2 of the patients, in vivo somatic reversion restored ARPC1B expression in a fraction of lymphocytes and was associated with a skewed TCR repertoire. In 1 revertant patient, memory CD8+ T cells expressing normal levels of ARPC1B displayed improved T-cell migration. Inherited ARPC1B deficiency therefore alters T-cell cytoskeletal dynamics and functions, contributing to the clinical features of CID.
Subject(s)
Actin-Related Protein 2-3 Complex/genetics , Germ-Line Mutation , Immunologic Deficiency Syndromes/genetics , T-Lymphocytes/pathology , Actin-Related Protein 2-3 Complex/chemistry , Female , Homozygote , Humans , Immunologic Deficiency Syndromes/pathology , Male , Models, Molecular , Pedigree , Protein Conformation , Severe Combined Immunodeficiency/genetics , Severe Combined Immunodeficiency/pathology , T-Lymphocytes/metabolismABSTRACT
Immunodeficiency-associated lymphoproliferative disorders (IA-LPDs) are pathologically and clinically heterogeneous. In many instances, similar features are shared by a spectrum of IA-LPDs in clinically diverse settings. However, the World Health Organization (WHO) classifies IA-LPDs by their immunodeficiency setting largely according to the paradigm of posttransplant lymphoproliferative disorders but with inconsistent terminology and disease definitions. The field currently lacks standardization and would greatly benefit from thinking across immunodeficiency categories by adopting a common working vocabulary to better understand these disorders and guide clinical management. We propose a 3-part unifying nomenclature that includes the name of the lesion, associated virus, and the specific immunodeficiency setting for all IA-LPDs. B-cell lymphoproliferative disorders (LPDs) are usually Epstein-Barr virus (EBV)+ and show a spectrum of lesions, including hyperplasias, polymorphic LPDs, aggressive lymphomas, and, rarely, indolent lymphomas. Human herpes virus 8-associated LPDs also include polyclonal and monoclonal proliferations. EBV- B-cell LPDs and T- and NK-cell LPDs are rare and less well characterized. Recognition of any immunodeficiency is important because it impacts the choice of treatment options. There is an urgent need for reappraisal of IA-LPDs because a common framework will facilitate meaningful biological insights and pave the way for future work in the field.
Subject(s)
Immunologic Deficiency Syndromes/complications , Lymphoproliferative Disorders/etiology , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/pathology , Herpesviridae Infections/complications , Herpesviridae Infections/pathology , Herpesvirus 4, Human/isolation & purification , Herpesvirus 8, Human/isolation & purification , Humans , Immunologic Deficiency Syndromes/classification , Immunologic Deficiency Syndromes/pathology , Killer Cells, Natural/pathology , Lymphoproliferative Disorders/classification , Lymphoproliferative Disorders/pathology , T-Lymphocytes/pathologyABSTRACT
Autosomal recessive SOPH syndrome was first described in the Yakuts population of Asia by Maksimova et al. in 2010. It arises from biallelic pathogenic variants in the NBAS gene and is characterized by severe postnatal growth retardation, senile facial appearance, small hands and feet, optic atrophy with loss of visual acuity and color vision, and normal intelligence (OMIM #614800). The presence of Pelger-Hüet anomaly in this disorder led to its name as an acronym for Short stature, Optic nerve atrophy, and Pelger-Hüet anomaly. Recent publications have further contributed to the characterization of this syndrome through additional phenotype-genotype correlations. We review the clinical features described in these publications and report on a 27-year-old woman with dwarfism with osteolysis and multiple skeletal problems, minor anomalies, immunodeficiency, diabetes mellitus, and multiple secondary medical problems. Her condition was considered an unknown autosomal recessive disorder for many years until exome sequencing provided the diagnosis by revealing a founder disease-causing variant that was compound heterozygous with a novel pathogenic variant in NBAS. Based on the major clinical features of this individual and others reported earlier, a revision of the acronym is warranted to facilitate clinical recognition.
Subject(s)
Dwarfism/genetics , Immunologic Deficiency Syndromes/genetics , Neoplasm Proteins/genetics , Pelger-Huet Anomaly/genetics , Adult , Dwarfism/complications , Dwarfism/pathology , Female , Genetic Predisposition to Disease , Humans , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/pathology , Mutation/genetics , Optic Atrophy/genetics , Optic Atrophy/pathology , Pelger-Huet Anomaly/complications , Pelger-Huet Anomaly/pathology , Exome SequencingABSTRACT
The N-terminal nuclear export sequence (NES) of inhibitor of nuclear factor kappa B (NF-κB) alpha (IκBα) promotes NF-κB export from the cell nucleus to the cytoplasm, but the physiological role of this export regulation remains unknown. Here we report the derivation and analysis of genetically targeted mice harboring a germline mutation in IκBα NES. Mature B cells in the mutant mice displayed nuclear accumulation of inactive IκBα complexes containing a NF-κB family member, cRel, causing their spatial separation from the cytoplasmic IκB kinase. This resulted in severe reductions in constitutive and canonical NF-κB activities, synthesis of p100 and RelB NF-κB members, noncanonical NF-κB activity, NF-κB target gene induction, and proliferation and survival responses in B cells. Consequently, mice displayed defective B cell maturation, antibody production, and formation of secondary lymphoid organs and tissues. Thus, IκBα nuclear export is essential to maintain constitutive, canonical, and noncanonical NF-κB activation potentials in mature B cells in vivo.