ABSTRACT
Inborn errors of immunity (IEI) are a heterogeneous group of hereditary disorders that affect in number and/or function different components of the immune system, resulting in an increased risk and severity of infections, autoimmune diseases, allergic manifestations, autoinflammation and malignancy. Inactivated vaccines are generally safe in these patients, but may be ineffective in some cases, due to difference in immunogenicity. However, live viral and bacterial vaccines may lead to disease, with high morbidity and mortality, so it is essential a previous immunological work-out. In this document, the Pediatric Immunology Work Group of the Sociedad Argentina de Pediatría summarizes recommendations about immunizations in patients with IEI, their household contacts, as well as in patients under immunosuppressive treatment and hematopoietic stem cell transplant recipients.
Los errores innatos de la inmunidad (EII) constituyen un grupo heterogéneo de enfermedades hereditarias que afectan el número y/o la función de los distintos componentes del sistema inmune, lo que predispone a un incremento de la tasa y gravedad de infecciones, enfermedades autoinmunes, manifestaciones alérgicas, autoinflamación y malignidad. En estos pacientes, la inmunización con vacunas inactivadas es generalmente segura, pero puede no ser efectiva en determinados grupos de EII, sin generar el efecto protector deseado. La aplicación de vacunas vivas atenuadas (virales y bacterianas) puede llevar al desarrollo de enfermedad asociada a la inmunización, con elevada morbimortalidad, por lo que amerita previamente consultar al especialista. El presente informe resume las conclusiones del Grupo de Trabajo de Inmunología de la Sociedad Argentina de Pediatría respecto a la vacunación en pacientes con EII y sus convivientes, en pacientes bajo inmunosupresión farmacológica y en receptores de trasplante de células precursoras hematopoyéticas.
ABSTRACT
The complement system, a vital component of innate immunity, consists of various proteins and pathways crucial for the recognition and elimination of pathogens. In addition, it plays a major role in the initiation of adaptive response through the opsonization of antigens, contributing to B-cell activation and memory maintenance. Deficiencies in complement proteins, particularly C3, can lead to severe and recurrent infections as well as immune complex disorders. Here, we present a case report of two siblings with total C3 deficiency resulting from compound heterozygous mutations in C3 (NM_000064.4): c.305dup; [p.Asn103GlnfsTer66] and c.1269 + 5G>T, previously unreported in C3-related diseases. Both, the index case and her sister, presented a history of recurrent infections since early childhood and one of them developed hemolytic uremic syndrome (HUS). Immunological evaluation revealed absent plasma C3 levels, decreased memory B cells, hypogammaglobulinemia, and impaired response to polysaccharide antigens. The siblings showed partial responses to antimicrobial prophylaxis and vaccination, requiring intravenous immunoglobulin replacement therapy, resulting in clinical improvement. Genetic analysis identified additional risk polymorphisms associated with atypical HUS. This case highlights the importance of comprehensive genetic and immunological evaluations in complement deficiencies, along with the potential role of immunoglobulin replacement therapy in managing associated antibody defects.
ABSTRACT
Common variable immunodeficiency is a heterogeneous symptomatic group of inborn errors of immunity that mainly affects antibodies production and/or function, predisposing patients to recurrent and severe infections. More than half of them usually develop autoimmunity, lymphoproliferation, enteropathy, and malignancies. Among these conditions, chronic lung disease such as granulomatous-lymphocytic interstitial lung disease is one of the leading causes of death in these patients. Recently, many genes that play a key role in B and T cells' development, maintenance, and/or cytokines signaling pathways have been implicated in the pathogenesis of the disease. Here, we describe the first Argentinian patient presenting with common variable immunodeficiency and granulomatous-lymphocytic interstitial lung disease, harboring two in cis heterozygous variants in the SOCS1 gene.
ABSTRACT
Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.
Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert.
Subject(s)
Humans , Child , Chemoprevention , Immune System Diseases/congenitalABSTRACT
Inborn errors of immunity, previously named primary immunodeficiency are a heterogeneous group of genetic defects of different components of the immune system. Patients present high susceptibility to an only or several microorganisms, developing recurrent infections; the severity is related to the specific genetic type of immunity defect. The main strategy on the management of these illness is the prevention of infections. These consensus guidelines made by the Pediatric Immunology Work Group of Sociedad Argentina de Pediatría, givese main approaches of infection prevention in order to provide a useful tool for all practitioners who are involved in the management of these patients, based on scientific evidence and broad consensus of a specialized panel expert..
Los errores innatos de la inmunidad (EII), antes llamados inmunodeficiencias primarias (IDP), son un grupo heterogéneo de trastornos genéticos con defectos en uno o más componentes del sistema inmune. Los pacientes afectados por EII presentan aumentada susceptibilidad a microorganismos únicos o múltiples que se manifestará con infecciones recurrentes de diferente tipo y gravedad dependiendo del tipo de la localización del defecto. La prevención de infecciones es uno de los pilares fundamentales en el abordaje integral de los pacientes con EII. En este trabajo se resumen las conclusiones consensuadas en el Grupo de Trabajo de Inmunología Pediátrica de la Sociedad Argentina de Pediatría, sobre la base de la revisión de la evidencia disponible, respecto a los principios esenciales para el cuidado, la prevención de infecciones y la quimioprofilaxis en los errores innatos de la inmunidad para la orientación del pediatra y especialista dedicados al seguimiento de estas enfermedades.
Subject(s)
Chemoprevention , Child , Humans , ArgentinaABSTRACT
CD40 ligand (CD40L) deficiency is a rare inborn error of immunity presenting with heterogeneous clinical manifestations. While a detailed characterization of patients affected by CD40L deficiency is essential to an accurate diagnosis and management, information about this disorder in Latin American patients is limited. We retrospectively analyzed data from 50 patients collected by the Latin American Society for Immunodeficiencies registry or provided by affiliated physicians to characterize the clinical, laboratory, and molecular features of Latin American patients with CD40L deficiency. The median age at disease onset and diagnosis was 7 months and 17 months, respectively, with a median diagnosis delay of 1 year. Forty-seven patients were genetically characterized revealing 6 novel mutations in the CD40LG gene. Pneumonia was the most common first symptom reported (66%). Initial immunoglobulin levels were variable among patients. Pneumonia (86%), upper respiratory tract infections (70%), neutropenia (70%), and gastrointestinal manifestations (60%) were the most prevalent clinical symptoms throughout life. Thirty-five infectious agents were reported, five of which were not previously described in CD40L deficient patients, representing the largest number of pathogens reported to date in a cohort of CD40L deficient patients. The characterization of the largest cohort of Latin American patients with CD40L deficiency adds novel insights to the recognition of this disorder, helping to fulfill unmet needs and gaps in the diagnosis and management of patients with CD40L deficiency.
Subject(s)
CD40 Ligand , Immunologic Deficiency Syndromes , CD40 Ligand/genetics , Cohort Studies , Humans , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/therapy , Latin America/epidemiology , Retrospective StudiesABSTRACT
Germinal heterozygous activating STAT3 mutations represent a novel monogenic defect associated with multi-organ autoimmune disease and, in some cases, severe growth retardation. By using whole-exome sequencing, we identified two novel STAT3 mutations, p.E616del and p.C426R, in two unrelated pediatric patients with IGF-I deficiency and immune dysregulation. The functional analyses showed that both variants were gain-of-function (GOF), although they were not constitutively phosphorylated. They presented differences in their dephosphorylation kinetics and transcriptional activities under interleukin-6 stimulation. Both variants increased their transcriptional activities in response to growth hormone (GH) treatment. Nonetheless, STAT5b transcriptional activity was diminished in the presence of STAT3 GOF variants, suggesting a disruptive role of STAT3 GOF variants in the GH signaling pathway. This study highlights the broad clinical spectrum of patients presenting activating STAT3 mutations and explores the underlying molecular pathway responsible for this condition, suggesting that different mutations may drive increased activity by slightly different mechanisms.
Subject(s)
Germ Cells/metabolism , Growth Disorders/genetics , Hearing Loss, Sensorineural/genetics , Immune System Diseases/genetics , Insulin-Like Growth Factor I/deficiency , Mutation/genetics , STAT3 Transcription Factor/genetics , Amino Acid Sequence , Child, Preschool , Female , HEK293 Cells , Human Growth Hormone/pharmacology , Humans , Infant , Infant, Newborn , Insulin-Like Growth Factor I/genetics , Interleukin-5/metabolism , Luciferases/metabolism , Male , Models, Molecular , Phosphorylation/drug effects , Protein Multimerization , RNA, Messenger/genetics , RNA, Messenger/metabolism , STAT3 Transcription Factor/chemistry , STAT3 Transcription Factor/metabolism , STAT5 Transcription Factor/metabolism , Suppressor of Cytokine Signaling 3 Protein/genetics , Suppressor of Cytokine Signaling 3 Protein/metabolism , Transcription, Genetic/drug effects , Exome SequencingABSTRACT
BACKGROUND: Autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency (AD EDA-ID) is caused by heterozygous point mutations at or close to serine 32 and serine 36 or N-terminal truncations in IκBα that impair its phosphorylation and degradation and thus activation of the canonical nuclear factor κ light chain enhancer of activated B cells (NF-κB) pathway. The outcome of hematopoietic stem cell transplantation is poor in patients with AD EDA-ID despite achievement of chimerism. Mice heterozygous for the serine 32I mutation in IκBα have impaired noncanonical NF-κB activity and defective lymphorganogenesis. OBJECTIVE: We sought to establish genotype-phenotype correlation in patients with AD EDA-ID. METHODS: A disease severity scoring system was devised. Stability of IκBα mutants was examined in transfected cells. Immunologic, biochemical, and gene expression analyses were performed to evaluate canonical and noncanonical NF-κB signaling in skin-derived fibroblasts. RESULTS: Disease severity was greater in patients with IκBα point mutations than in those with truncation mutations. IκBα point mutants were expressed at significantly higher levels in transfectants compared with truncation mutants. Canonical NF-κB-dependent IL-6 secretion and upregulation of the NF-κB subunit 2/p100 and RELB proto-oncogene, NF-κB subunit (RelB) components of the noncanonical NF-κB pathway were diminished significantly more in patients with point mutations compared with those with truncations. Noncanonical NF-κB-driven generation of the transcriptionally active p100 cleavage product p52 and upregulation of CCL20, intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1), which are important for lymphorganogenesis, were diminished significantly more in LPS plus α-lymphotoxin ß receptor-stimulated fibroblasts from patients with point mutations compared with those with truncations. CONCLUSIONS: IκBα point mutants accumulate at higher levels compared with truncation mutants and are associated with more severe disease and greater impairment of canonical and noncanonical NF-κB activity in patients with AD EDA-ID.
Subject(s)
Ectodermal Dysplasia/genetics , Ectodermal Dysplasia/immunology , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/immunology , Genotype , Immunologic Deficiency Syndromes/genetics , Immunologic Deficiency Syndromes/immunology , Signal Transduction , Carrier Proteins/genetics , Carrier Proteins/immunology , Chemokine CCL20/genetics , Chemokine CCL20/immunology , Ectodermal Dysplasia/pathology , Genetic Diseases, X-Linked/pathology , HEK293 Cells , Humans , Immunologic Deficiency Syndromes/pathology , Intercellular Adhesion Molecule-1/genetics , Intercellular Adhesion Molecule-1/immunology , Interleukin-6/genetics , Interleukin-6/immunology , NF-KappaB Inhibitor alpha/genetics , NF-KappaB Inhibitor alpha/immunology , NF-kappa B p52 Subunit/genetics , NF-kappa B p52 Subunit/immunology , Point Mutation , Primary Immunodeficiency Diseases , Proto-Oncogene Mas , Signal Transduction/genetics , Signal Transduction/immunologyABSTRACT
Antecedentes: Arthrographis kalrae es un hongo hialino de crecimiento lento que, en su desarrollo, forma artroconidios. Es un patógeno oportunista que causa infecciones en personas inmunocomprometidas e inmunocompetentes, y ha sido aislado muy raramente en muestras clínicas de seres humanos. Caso clínico: Se describe el caso de un paciente con inmunodeficiencia primaria y afectación pulmonar con evolución tórpida. Presentó compromiso de ambos pulmones a pesar del tratamiento antibiótico y antifúngico instaurado. Durante su seguimiento, se realizaron múltiples biopsias pulmonares y se aisló A. kalrae en el cultivo de tejido pulmonar. Recibió tratamiento con posaconazol, con buena respuesta y remisión de las lesiones. Conclusión: Este es el primer caso reportado de infección pulmonar por A. kalrae en un paciente pediátrico con enfermedad granulomatosa crónica en Argentina.
Background: Arthrographis kalrae is a hyaline fungus that grows forming arthroconidia. It is an opportunistic pathogen that causes infections in immunocompromised as in immunocompetent people and has been rarely isolated from human clinical samples. Case report: We describe the case of a male child with primary immunodeficiency who initially presented unilateral pneumonia and progressed to bilateral involvement despite antibiotic, antifungal treatment. A. kalrae was diagnosed by pulmonary biopsy. He received posaconazole with resolution of disease. Conclusions: This is the first case of A. kalrae pulmonary infection in a pediatric patient with chronic granulomatous disease in Argentina.
Subject(s)
Humans , Male , Child, Preschool , Ascomycota , Granulomatous Disease, Chronic/complications , Lung Diseases, Fungal/microbiology , Mycoses/complications , Lung Diseases, Fungal/drug therapy , Mycoses/microbiology , Mycoses/drug therapyABSTRACT
BACKGROUND: Arthrographis kalrae is a hyaline fungus that grows forming arthroconidia. It is an opportunistic pathogen that causes infections in immunocompromised as in immunocompetent people and has been rarely isolated from human clinical samples. CASE REPORT: We describe the case of a male child with primary immunodeficiency who initially presented unilateral pneumonia and progressed to bilateral involvement despite antibiotic, antifungal treatment. A. kalrae was diagnosed by pulmonary biopsy. He received posaconazole with resolution of disease. CONCLUSIONS: This is the first case of A. kalrae pulmonary infection in a pediatric patient with chronic granulomatous disease in Argentina.
ANTECENDENTES: Arthrographis kalrae es un hongo hialino de crecimiento lento que, en su desarrollo, forma artroconidios. Es un patógeno oportunista que causa infecciones en personas inmunocomprometidas e inmunocompetentes, y ha sido aislado muy raramente en muestras clínicas de seres humanos. CASO CLÍNICO: Se describe el caso de un paciente con inmunodeficiencia primaria y afectación pulmonar con evolución tórpida. Presentó compromiso de ambos pulmones a pesar del tratamiento antibiótico y antifúngico instaurado. Durante su seguimiento, se realizaron múltiples biopsias pulmonares y se aisló A. kalrae en el cultivo de tejido pulmonar. Recibió tratamiento con posaconazol, con buena respuesta y remisión de las lesiones. CONCLUSIÓN: Este es el primer caso reportado de infección pulmonar por A. kalrae en un paciente pediátrico con enfermedad granulomatosa crónica en Argentina.
Subject(s)
Ascomycota , Granulomatous Disease, Chronic/complications , Lung Diseases, Fungal/microbiology , Mycoses/complications , Child, Preschool , Humans , Lung Diseases, Fungal/drug therapy , Male , Mycoses/drug therapy , Mycoses/microbiologyABSTRACT
BACKGROUND: Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients. OBJECTIVE: Our objective was to assess the effect of mycobacterial disease in patients with CGD. METHODS: We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria. RESULTS: Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients. CONCLUSION: Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.
Subject(s)
Granulomatous Disease, Chronic/complications , Mycobacterium Infections/diagnosis , Mycobacterium Infections/etiology , BCG Vaccine/administration & dosage , Bacterial Infections/diagnosis , Bacterial Infections/epidemiology , Bacterial Infections/etiology , Bacterial Infections/mortality , Child , Child, Preschool , Female , Granulomatous Disease, Chronic/epidemiology , Granulomatous Disease, Chronic/mortality , Granulomatous Disease, Chronic/therapy , Humans , Infant , Male , Mycobacterium Infections/epidemiology , Mycobacterium Infections/mortality , Mycoses/diagnosis , Mycoses/epidemiology , Mycoses/etiology , Mycoses/mortality , Patient Outcome Assessment , Retrospective Studies , Tuberculosis/diagnosis , Tuberculosis/etiologyABSTRACT
UNLABELLED: The signal transducer and activator of transcription (STAT) family of proteins regulate gene transcription in response to a variety of cytokines. STAT5B, in particular, plays an important role in T cells, where it is a key mediator of interleukin-2 (IL-2) induced responses. STAT5B deficiency causes a rare autosomal recessive disorder reported in only a handful of individuals. There are currently ten published cases of STAT5B deficiency, four of which are Argentinians. AIM: This is a report of more than 10 years follow up of the clinical and immunological features of three Argentinian STAT5B deficient patients. CONCLUSION: More than a decade of follow-up demonstrates that STAT5B deficiency is associated with various clinical pathologies that cause significant morbidity. Early diagnosis is critical for the prevention and improvement of clinical outcomes for STAT5B deficient patients.
Subject(s)
Immunologic Deficiency Syndromes/immunology , STAT5 Transcription Factor/deficiency , Adult , Argentina , Autoantibodies/blood , B-Lymphocytes/immunology , Female , Humans , Immunoglobulins/blood , Immunologic Deficiency Syndromes/blood , Immunologic Deficiency Syndromes/genetics , Lymphocyte Count , Mutation , STAT5 Transcription Factor/genetics , T-Lymphocytes/immunology , Young AdultABSTRACT
Hyper-IgM (HIGM) syndrome is a heterogeneous group of disorders characterized by normal or elevated serum IgM levels associated with absent or decreased IgG, IgA and IgE. Here we summarize data from the HIGM syndrome Registry of the Latin American Society for Immunodeficiencies (LASID). Of the 58 patients from 51 families reported to the registry with the clinical phenotype of HIGM syndrome, molecular defects were identified in 37 patients thus far. We retrospectively analyzed the clinical, immunological and molecular data from these 37 patients. CD40 ligand (CD40L) deficiency was found in 35 patients from 25 families and activation-induced cytidine deaminase (AID) deficiency in 2 unrelated patients. Five previously unreported mutations were identified in the CD40L gene (CD40LG). Respiratory tract infections, mainly pneumonia, were the most frequent clinical manifestation. Previously undescribed fungal and opportunistic infections were observed in CD40L-deficient patients but not in the two patients with AID deficiency. These include the first cases of pneumonia caused by Mycoplasma pneumoniae, Serratia marcescens or Aspergillus sp. and diarrhea caused by Microsporidium sp. or Isospora belli. Except for four CD40L-deficient patients who died from complications of presumptive central nervous system infections or sepsis, all patients reported in this study are alive. Four CD40L-deficient patients underwent successful bone marrow transplantation. This report characterizes the clinical and genetic spectrum of HIGM syndrome in Latin America and expands the understanding of the genotype and phenotype of this syndrome in tropical areas.
Subject(s)
Hyper-IgM Immunodeficiency Syndrome/epidemiology , CD40 Ligand/deficiency , CD40 Ligand/genetics , Child, Preschool , Comorbidity , Cytidine Deaminase/deficiency , Cytidine Deaminase/genetics , Female , Hispanic or Latino , Humans , Hyper-IgM Immunodeficiency Syndrome/complications , Hyper-IgM Immunodeficiency Syndrome/diagnosis , Hyper-IgM Immunodeficiency Syndrome/therapy , Infant , Infant, Newborn , Infections/diagnosis , Infections/etiology , Lung/pathology , Male , Registries , Retrospective Studies , Tomography, X-Ray Computed , Treatment OutcomeABSTRACT
PURPOSE: Several studies have shown that subcutaneous immunoglobulin (SCIG) infusions demonstrate similar efficacy to intravenous Ig (IVIG) in preventing infections in patients with primary immunodeficiency diseases (PID), and are safe and well tolerated in this population. This open, prospective/retrospective, multicenter study was designed to compare the effectiveness, safety and tolerability of a 16 % liquid human IgG preparation (Beriglobina P), administered SC, with previous IVIG treatment in PID pediatric patients in Argentina. METHODS: Fifteen subjects were enrolled in the study, and a total of 13 subjects (aged 6-18 years) completed the 36-week SCIG treatment period. All children had previously received IVIG treatment. The dose of SCIG equaled the previous IVIG dose and subjects received an average weekly dose of 139 mg/kg (range 105-181) during the SCIG period. RESULTS: Significantly higher serum IgG trough levels were recorded on SCIG treatment at 16, 24, and 36 weeks, when compared with previous IgG trough levels on steady-state IVIG treatment. The annualized infection rate was 1.4 infections/subject/year during the IVIG administration period compared with 0.4 infections/subject/year during the SCIG period. All subjects who completed the study chose to continue administering SCIG at home after the study had ended. CONCLUSIONS: These data confirm that self-administered SCIG therapy is a well-tolerated and effective alternative to IVIG therapy for children with PID.
Subject(s)
Immunoglobulin G/administration & dosage , Immunoglobulins, Intravenous/administration & dosage , Immunologic Deficiency Syndromes/therapy , Immunotherapy/methods , Infections/therapy , Adolescent , Argentina , Child , Feasibility Studies , Female , Humans , Immunoglobulin G/blood , Immunologic Deficiency Syndromes/complications , Immunologic Deficiency Syndromes/epidemiology , Immunologic Deficiency Syndromes/immunology , Infections/epidemiology , Infections/immunology , Injections, Subcutaneous , Male , Prospective StudiesABSTRACT
Two populations of human natural killer (NK) cells can be identified in peripheral blood. The majority are CD3(-)CD56(dim) cells while the minority exhibits a CD3(-)CD56(bright) phenotype. In vitro evidence indicates that CD56(bright) cells are precursors of CD56(dim) cells, but in vivo evidence is lacking. Here, we studied NK cells from a patient that suffered from a melanoma and opportunistic fungal infection during childhood. The patient exhibited a stable phenotype characterized by a reduction in the frequency of peripheral blood CD3(-)CD56(dim) NK cells, accompanied by an overt increase in the frequency and absolute number of CD3(-)CD56(bright) cells. These NK cells exhibited similar expression of perforin, CD57 and CD158, the major activating receptors CD16, NKp46, NKG2D, DNAM-1, and 2B4, as well as the inhibitory receptor CD94/NKG2A, on both CD56(bright) and CD56(dim) NK cells as healthy controls. Also, both NK cell subpopulations produced IFN-γ upon stimulation with cytokines, and CD3(-)CD56(dim) NK cells degranulated in response to cytokines or K562 cells. However, upon stimulation with cytokines, a substantial fraction of CD56(dim) cells failed to up-regulate CD57 and CD158, showed a reduction in the percentage of CD16(+) cells, and CD56(bright) cells did not down-regulate CD62L, suggesting that CD56(dim) cells could not acquire a terminally differentiated phenotype and that CD56(bright) cells exhibit a maturation defect that might result in a potential altered migration pattern. These observations, support the notion that NK cells of this patient display a maturation/activation defect that precludes the generation of mature NK cells at a normal rate accompanied by CD56(dim) NK cells that cannot completely acquire a terminally differentiated phenotype. Thus, our results provide evidence that support the concept that in vivo CD56(bright) NK cells differentiate into CD56(dim) NK cells, and contribute to further understand human NK cell ontogeny.
Subject(s)
CD56 Antigen , Cell Differentiation , Cell Lineage , Killer Cells, Natural , CD56 Antigen/blood , CD56 Antigen/genetics , CD56 Antigen/immunology , Cell Differentiation/immunology , Cell Lineage/genetics , Cell Lineage/immunology , Flow Cytometry , Humans , Interferon-gamma/immunology , Interferon-gamma/metabolism , K562 Cells , Killer Cells, Natural/cytology , Killer Cells, Natural/immunology , Leukocytes, Mononuclear/cytology , Leukocytes, Mononuclear/immunologyABSTRACT
CONTEXT: Signal transducer and activator of transcription 5b (STAT5b) deficiency, first reported in a patient who carried a p.Ala630Pro missense mutation in the Src homology 2 (SH2) domain, results in a rare clinical condition of GH insensitivity (GHI), IGF-I deficiency (IGFD), and severe immune dysregulation manifesting as progressive worsening of pulmonary function. PATIENT: The new patient presented with severe cutaneous eczema, episodic infections in the first years of life, and autoimmune thyroiditis. Immunological evaluation revealed T lymphopenia, but severe pulmonary symptoms were notably absent. She concomitantly exhibited pronounced growth failure, reaching an adult height of 124.7 cm [-5.90 SD score (SDS)]. Endocrine evaluations (normal provocative GH tests; low serum IGF-I, -3.7 SDS, and IGF-binding protein-3, -4.5 SDS) were consistent with GHI and IGFD. RESULTS: Analysis of the STAT5B gene revealed a novel homozygous missense mutation, p.Phe646Ser, located within the ßD' strand of the SH2 domain. Reconstitution studies demonstrated expression of the p.Phe646Ser variant was less robust than wild type but, in contrast to the previously described STAT5B p.Ala630Pro SH2 mutation, could be phosphorylated in response to GH and interferon-γ. The phosphorylated p.Phe646Ser, however, could not drive transcription. CONCLUSION: A novel STAT5B p.Phe646Ser mutation has been identified in a patient with clinical characteristics of STAT5b deficiency. Only the second STAT5B missense mutation identified, its lack of transcriptional activities despite GH-induced phosphorylation, confirms the crucial role of STAT5b for regulating the expression of IGF1 and provides insights into the importance of the SH2 ßD' strand for full STAT5b transcriptional activities. Whether the phosphorylated p.Phe646Ser variant retained functions that prevented pulmonary distress remains unresolved.