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1.
Int J Mol Sci ; 25(5)2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38474223

RESUMO

The Janus kinase (JAK) family is a small group of protein tyrosine kinases that represent a central component of intracellular signaling downstream from a myriad of cytokine receptors. The JAK3 family member performs a particularly important role in facilitating signal transduction for a key set of cytokine receptors that are essential for immune cell development and function. Mutations that impact JAK3 activity have been identified in a number of human diseases, including somatic gain-of-function (GOF) mutations associated with immune cell malignancies and germline loss-of-function (LOF) mutations associated with immunodeficiency. The structure, function and impacts of both GOF and LOF mutations of JAK3 are highly conserved, making animal models highly informative. This review details the biology of JAK3 and the impact of its perturbation in immune cell-related diseases, including relevant animal studies.


Assuntos
Síndromes de Imunodeficiência , Neoplasias , Animais , Humanos , Janus Quinase 3/metabolismo , Transdução de Sinais , Janus Quinases/metabolismo , Receptores de Citocinas/metabolismo , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo
2.
Iran J Allergy Asthma Immunol ; 23(1): 122-126, 2024 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-38485907

RESUMO

Actinrelated protein 2/3 complex subunit 1B (ARPC1B) deficiency is an inborn error of immunity (IEI) characterized by a combination of immunodeficiency and immune dysregulation and classified as an IEI with allergic manifestations. Here, we describe two patients with pathogenic variants in the ARPC1B gene. The first patient presented with eczema and bronchospasm at six months of age. The second patient presented with eczema and milk protein allergy at five months of age. The c.899_944 (p.Glu300Glyfs*7) pathogenic variant was previously described, whereas the c.863del (p.Pro288Leufs*9) variant was novel. ARPC1B deficiency should be considered because of the severe allergic manifestations at an early age.


Assuntos
Eczema , Hipersensibilidade Alimentar , Síndromes de Imunodeficiência , Hipersensibilidade a Leite , Animais , Humanos , Lactente , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Alérgenos , Eczema/genética , Síndromes de Imunodeficiência/genética , Leite , Hipersensibilidade a Leite/diagnóstico , Hipersensibilidade a Leite/genética
3.
Life Sci Alliance ; 7(6)2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38519141

RESUMO

Chemokine receptors are members of the G protein-coupled receptor superfamily. The C-X-C chemokine receptor type 4 (CXCR4), one of the most studied chemokine receptors, is widely expressed in hematopoietic and immune cell populations. It is involved in leukocyte trafficking in lymphoid organs and inflammatory sites through its interaction with its natural ligand CXCL12. CXCR4 assumes a pivotal role in B-cell development, ranging from early progenitors to the differentiation of antibody-secreting cells. This review emphasizes the significance of CXCR4 across the various stages of B-cell development, including central tolerance, and delves into the association between CXCR4 and B cell-mediated disorders, from immunodeficiencies such as WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome to autoimmune diseases such as systemic lupus erythematosus. The potential of CXCR4 as a therapeutic target is discussed, especially through the identification of novel molecules capable of modulating specific pockets of the CXCR4 molecule. These insights provide a basis for innovative therapeutic approaches in the field.


Assuntos
Agamaglobulinemia , Síndromes de Imunodeficiência , Verrugas , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Verrugas/terapia , Linfócitos B , Receptores CXCR4
5.
N Engl J Med ; 390(12): 1105-1117, 2024 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-38507753

RESUMO

BACKGROUND: Autoantibodies against interleukin-12 (anti-interleukin-12) are often identified in patients with thymoma, but opportunistic infections develop in only some of these patients. Interleukin-12 (with subunits p40 and p35) shares a common subunit with interleukin-23 (subunits p40 and p19). In a patient with disseminated Burkholderia gladioli infection, the identification of both anti-interleukin-23 and anti-interleukin-12 prompted further investigation. METHODS: Among the patients (most of whom had thymoma) who were known to have anti-interleukin-12, we screened for autoantibodies against interleukin-23 (anti-interleukin-23). To validate the potential role of anti-interleukin-23 with respect to opportunistic infection, we tested a second cohort of patients with thymoma as well as patients without either thymoma or known anti-interleukin-12 who had unusual infections. RESULTS: Among 30 patients with anti-interleukin-12 who had severe mycobacterial, bacterial, or fungal infections, 15 (50%) also had autoantibodies that neutralized interleukin-23. The potency of such neutralization was correlated with the severity of these infections. The neutralizing activity of anti-interleukin-12 alone was not associated with infection. In the validation cohort of 91 patients with thymoma, the presence of anti-interleukin-23 was associated with infection status in 74 patients (81%). Overall, neutralizing anti-interleukin-23 was detected in 30 of 116 patients (26%) with thymoma and in 30 of 36 patients (83%) with disseminated, cerebral, or pulmonary infections. Anti-interleukin-23 was present in 6 of 32 patients (19%) with severe intracellular infections and in 2 of 16 patients (12%) with unusual intracranial infections, including Cladophialophora bantiana and Mycobacterium avium complex. CONCLUSIONS: Among patients with a variety of mycobacterial, bacterial, or fungal infections, the presence of neutralizing anti-interleukin-23 was associated with severe, persistent opportunistic infections. (Funded by the National Institute of Allergy and Infectious Diseases and others.).


Assuntos
Autoanticorpos , Síndromes de Imunodeficiência , Interleucina-23 , Infecções Oportunistas , Adulto , Humanos , Autoanticorpos/imunologia , Síndromes de Imunodeficiência/imunologia , Interleucina-12/antagonistas & inibidores , Interleucina-12/imunologia , Interleucina-23/antagonistas & inibidores , Interleucina-23/imunologia , Micoses/imunologia , Infecções Oportunistas/imunologia , Timoma/imunologia , Neoplasias do Timo/imunologia , Anticorpos Neutralizantes/imunologia , Infecções Bacterianas/imunologia
6.
BMJ Case Rep ; 17(3)2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38499350

RESUMO

Zeta-chain associated protein kinase 70 kDa (ZAP-70) deficiency is one of the rare immunodeficiency disorders due to autosomal recessive homozygous or compound heterozygous loss-of-function mutations in the ZAP-70 GENE In the literature, patients with ZAP-70 deficiency have been reported with a broad spectrum of clinical manifestations including recurrent respiratory infections (81.8%), cutaneous involvement (57.9%), lymphoproliferation (32.4%), autoimmunity (19.4%), enteropathy (18.4%) and increased risk of malignancies (8.1%). The most common immunological phenotype in those patients was low CD8+ T cell counts (97.9%) and normal non-functioning CD4+ T cell. Haematopoietic stem cell transplantation was applied as a curative treatment for this disorder.


Assuntos
Anemia Hemolítica Autoimune , Síndromes de Imunodeficiência , Humanos , Anemia Hemolítica Autoimune/complicações , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/genética , Mutação , Fenótipo , Linfócitos T CD4-Positivos/metabolismo
7.
J Clin Immunol ; 44(3): 79, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38457046

RESUMO

Congenital athymia is a rare T-lymphocytopaenic condition, which requires early corrective treatment with thymus transplantation (TT). Athymic patients are increasingly identified through newborn screening (NBS) for severe combined immunodeficiency (SCID). Lack of relatable information resources contributes to challenging patient and family journeys during the diagnostic period following abnormal NBS results. Patient and Public Involvement and Engagement (PPIE) activities, including parental involvement in paediatrics, are valuable initiatives to improve clinical communication and parental information strategies. Parents of infants with suspected athymia were therefore invited to discuss the information they received during the diagnostic period following NBS with the aim to identify parental information needs and targeted strategies to address these adequately. Parents reported that athymia was not considered with them as a possible differential diagnosis until weeks after initial NBS results. Whilst appropriate clinical information about athymia and TT was available upon referral to specialist immunology services, improved access to easy-to-understand information from reliable sources, including from clinical nurse specialists and peer support systems, remained desirable. A roadmap concept, with written or digital information, addressing parental needs in real time during a potentially complex diagnostic journey, was proposed and is transferrable to other inborn errors of immunity (IEI) and rare diseases. This PPIE activity provides insight into the information needs of parents of infants with suspected athymia who are identified through SCID NBS, and highlights the role for PPIE in promoting patient- and family-centred strategies to improve IEI care.


Assuntos
Síndromes de Imunodeficiência , Imunodeficiência Combinada Severa , Timo/anormalidades , Lactente , Recém-Nascido , Humanos , Criança , Triagem Neonatal , Pais , Imunodeficiência Combinada Severa/diagnóstico , Imunodeficiência Combinada Severa/terapia
9.
Int J Mol Sci ; 25(4)2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38396937

RESUMO

This study investigated the association between autoimmunity and immunodeficiency in pediatric patients, focusing on the case of a 15-year-old female diagnosed with juvenile idiopathic arthritis (JIA) and secondary Sjögren's syndrome. The patient presented with a variety of symptoms, including joint pain, bronchial asthma, leukopenia, and skin lesions. Genetic testing revealed a de novo mutation in the DOCK8 gene, associated with DOCK8 deficiency, a condition usually associated with immunodeficiencies. The clinical course, diagnostic pathway, and treatment history are detailed, highlighting the importance of molecular diagnostics in understanding the genetic basis of rheumatic diseases. This case highlights the need to consider innate immune errors in patients with multiple diseases or atypical symptoms of rheumatic diseases. Furthermore, the study highlights the importance of targeted treatment, including genetic counseling, to improve patient outcomes. The observed association between autoimmunity and immune deficiency reinforces the importance of molecular testing in elucidating the causes of previously idiopathic rheumatic diseases, contributing to improved patient care and quality of life.


Assuntos
Artrite Juvenil , Síndromes de Imunodeficiência , Síndrome de Sjogren , Adolescente , Criança , Feminino , Humanos , Artrite Juvenil/complicações , Artrite Juvenil/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Mutação , Qualidade de Vida , Síndrome de Sjogren/complicações , Síndrome de Sjogren/genética
10.
BMC Immunol ; 25(1): 18, 2024 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-38378441

RESUMO

BACKGROUND: Here, the perspective of patients with primary and secondary immunodeficiency receiving subcutaneous immunoglobulin (SCIg) via introductory smaller size pre-filled syringes (PFS) or vials were compared. METHODS: An online survey was conducted in Canada by the Association des Patients Immunodéficients du Québec (APIQ) (10/2020-03/2021). Survey questions included: reasons for choosing SCIg packaging and administration methods, training experiences, infusion characteristics, and switching methods. The survey captured structured patient-reported outcomes: treatment satisfaction and its sub-domains, symptom state, general health perception, and physical and mental function. Respondents using PFS were compared with vial users, overall and stratified by their administration method (pump or manual push). RESULTS: Of the 132 total respondents, 66 respondents used vials, with 38 using a pump and 28 using manual push. PFS (5 and 10 mL sizes) were being used by 120 respondents, with 38 using a pump and 82 using manual push. PFS users were associated with a 17% lower median (interquartile range) SCIg dose (10 [8, 12] vs. 12 [9, 16] g/week, respectively), a significantly shorter infusion preparation time (15 [10, 20] vs. 15 [10, 30] mins, respectively), and a trend for shorter length of infusion (60 [35, 90] vs. 70 [48, 90] mins, respectively) compared with those on vials. Patient-reported treatment satisfaction scores were overall similar between vial and PFS users (including on the domains of effectiveness and convenience), except for a higher score for vials over PFS on the domain of global satisfaction (p=0.02). CONCLUSIONS: Consistent with prescribing that reflects a recognition of less wastage, PFS users were associated with a significantly lower SCIg dose compared with vial users. PFS users were also associated with shorter pre-infusion times, reflecting simpler administration mechanics compared with vial users. Higher global satisfaction with treatment among vial users compared with PFS users was consistent with users being limited to smaller PFS size options in Canada during the study period. Patient experience on PFS is expected to improve with the introduction of larger PFS sizes. Overall, treatment satisfaction for SCIg remains consistently high with the introduction of PFS packaging compared with vials.


Assuntos
Imunoglobulina G , Síndromes de Imunodeficiência , Humanos , Embalagem de Medicamentos , Infusões Subcutâneas , Síndromes de Imunodeficiência/tratamento farmacológico , Medidas de Resultados Relatados pelo Paciente , Imunoglobulinas Intravenosas/uso terapêutico
11.
J Immunol ; 212(6): 962-973, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38315012

RESUMO

NK cell deficiency (NKD) occurs when an individual's major clinical immunodeficiency derives from abnormal NK cells and is associated with several genetic etiologies. Three categories of ß-actin-related diseases with over 60 ACTB (ß-actin) variants have previously been identified, none with a distinct NK cell phenotype. An individual with mild developmental delay, macrothrombocytopenia, and susceptibility to infections, molluscum contagiosum virus, and EBV-associated lymphoma had functional NKD for over a decade. A de novo ACTB variant encoding G342D ß-actin was identified and was consistent with the individual's developmental and platelet phenotype. This novel variant also was found to have direct impact in NK cells because its expression in the human NK cell line YTS (YTS-NKD) caused increased cell spreading in lytic immune synapses created on activating surfaces. YTS-NKD cells were able to degranulate and perform cytotoxicity, but they demonstrated defective serial killing because of prolonged conjugation to the killed target cell and thus were effectively unable to terminate lytic synapses. G342D ß-actin results in a novel, to our knowledge, mechanism of functional NKD via increased synaptic spreading and defective lytic synapse termination with resulting impaired serial killing, leading to overall reductions in NK cell cytotoxicity.


Assuntos
Actinas , Síndromes de Imunodeficiência , Humanos , Actinas/metabolismo , Células Matadoras Naturais , Linhagem Celular , Plaquetas/metabolismo , Síndromes de Imunodeficiência/metabolismo
13.
Front Cell Infect Microbiol ; 14: 1341236, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38410723

RESUMO

Bacille Calmette-Guérin (BCG) is a live strain of Mycobacterium bovis (M.bovis) for use as an attenuated vaccine to prevent tuberculosis (TB) infection, while it could also lead to an infection in immunodeficient patients. M.bovis could infect patients with immunodeficiency via BCG vaccination. Disseminated BCG disease (BCGosis) is extremely rare and has a high mortality rate. This article presents a case of a 3-month-old patient with disseminated BCG infection who was initially diagnosed with hemophagocytic syndrome (HPS) and eventually found to have X-linked severe combined immunodeficiency (X-SCID). M.bovis and its drug resistance genes were identified by metagenomics next-generation sequencing (mNGS) combined with targeted next-generation sequencing (tNGS) in blood and cerebrospinal fluid. Whole exome sequencing (WES) revealed a pathogenic variant in the common γ-chain gene (IL2RG), confirming X-SCID. Finally, antituberculosis therapy and umbilical cord blood transplantation were given to the patient. He was successfully cured of BCGosis, and his immune function was restored. The mNGS combined with the tNGS provided effective methods for diagnosing rare BCG infections in children. Their combined application significantly improved the sensitivity and specificity of the detection of M.bovis.


Assuntos
Síndromes de Imunodeficiência , Tuberculose Latente , Mycobacterium bovis , Tuberculose , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X , Masculino , Lactente , Criança , Humanos , Mycobacterium bovis/genética , Vacina BCG/efeitos adversos , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/diagnóstico , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/complicações , Tuberculose/microbiologia , Síndromes de Imunodeficiência/complicações , Sequenciamento de Nucleotídeos em Larga Escala
14.
Clin Exp Med ; 24(1): 17, 2024 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-38280023

RESUMO

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a rare genetic disorder that presents clinically as a primary immunodeficiency. Clinical presentation of APDS includes severe, recurrent infections, lymphoproliferation, lymphoma, and other cancers, autoimmunity and enteropathy. Autosomal dominant variants in two independent genes have been demonstrated to cause APDS. Pathogenic variants in PIK3CD and PIK3R1, both of which encode components of the PI3-kinase, have been identified in subjects with APDS. APDS1 is caused by gain of function variants in the PIK3CD gene, while loss of function variants in PIK3R1 have been reported to cause APDS2. We conducted a review of the medical literature and identified 256 individuals who had a molecular diagnosis for APDS as well as age at last report; 193 individuals with APDS1 and 63 with APDS2. Despite available treatments, survival for individuals with APDS appears to be shortened from the average lifespan. A Kaplan-Meier survival analysis for APDS showed the conditional survival rate at the age of 20 years was 87%, age of 30 years was 74%, and ages of 40 and 50 years were 68%. Review of causes of death showed that the most common cause of death was lymphoma, followed by complications from HSCT. The overall mortality rate for HSCT in APDS1 and APDS2 cases was 15.6%, while the mortality rate for lymphoma was 47.6%. This survival and mortality data illustrate that new treatments are needed to mitigate the risk of death from lymphoma and other cancers as well as infection. These analyses based on real-world evidence gathered from the medical literature comprise the largest study of survival and mortality for APDS to date.


Assuntos
Síndromes de Imunodeficiência , Linfoma , Neoplasias , Doenças da Imunodeficiência Primária , Adulto , Humanos , Adulto Jovem , Classe I de Fosfatidilinositol 3-Quinases/genética , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Mutação , Neoplasias/genética , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinases , Taxa de Sobrevida , Pessoa de Meia-Idade
15.
Int Immunopharmacol ; 128: 111447, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38185032

RESUMO

Immunoglobulin G (IgG) replacement therapy is the standard of care for patients with primary immunodeficiencies with antibody deficiencies. Intravenous (IVIG), subcutaneous (SCIG), and hyaluronidase-facilitated subcutaneous immunoglobulin (fSCIG) therapies differ in their pharmacokinetic (PK) profiles, administration routes, and dosing regimens. Information on use of subcutaneous therapy in IgG treatment-naive patients is limited. This study used population pharmacokinetic (popPK) model-based simulations to characterize IgG PKs in IgG-naive patients with varying disease severity across several IVIG, SCIG, and fSCIG dosing regimens. An integrated popPK model, developed and validated using data from eight clinical trials, was utilized to simulate scenarios that varied by therapy, loading regimen, maintenance dose (equivalent to 400, 600, or 800 mg/kg every 4 weeks [Q4W]), and baseline endogenous total IgG concentration (1.5 or 4.0 g/L). Simulations were performed for age groups of 2-<6, 6-<12, 12-<18, and ≥18 years. Steady-state serum trough IgG concentrations (Cmin,ss), proportion of patients achieving Cmin,ss ≥ 7 g/L, and days taken to reach this threshold were summarized. SCIG provided greater mean Cmin,ss values than IVIG and fSCIG for any scenario. Across all therapies, Cmin,ss tended to increase with age, dose, and endogenous concentration. Although the findings are model-based and not a summarization of real-world observations, doses ≥ 800 mg/kg Q4W with corresponding loading regimens are likely to be clinically appropriate for achieving target IgG concentrations in treatment-naive patients in a timely manner, especially at low endogenous starting concentrations. Therapy-specific dose adjustment based on baseline endogenous IgG concentration, clinical status, and patient characteristics may be warranted.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Humanos , Adolescente , Imunoglobulina G/uso terapêutico , Imunoglobulinas Intravenosas/uso terapêutico , Hialuronoglucosaminidase , Síndromes de Imunodeficiência/tratamento farmacológico , Doenças da Imunodeficiência Primária/tratamento farmacológico , Infusões Subcutâneas
16.
Indian Pediatr ; 61(2): 149-153, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38217268

RESUMO

OBJECTIVE: To evaluate the incidence and types of primary immunodeficiency diseases (PIDs) in hospitalized children with infection. METHODS: This prospective study was conducted in five tertiary-care facilities in Kolkata over two consecutive years between November 1, 2018 and October 31, 2020. We included all children aged upto 12years who were hospitalized and screened them for PID. Children were screened for suspected IPD using Jeffrey Modell Foundation (JMF) Criteria; any child who satisfied at least 2 out of 10 warning signs was further evaluated for PIDs. RESULTS: Out of 33,204 hospital admissions, 50 children satisfied JMF criteria. Out of 50 children screened during the study period, 27 were finally diagnosed with an underlying PID, with a prevalence of 1 in 1000 hospitalized children. Majority (37.03%) of them had antibody deficiency followed by phagocytic defect (33.3%). Chronic granulomatous disease was the commonest PID followed by common variable immunodeficiency. Around 62.97% children presented with respiratory infections and overall Acinetobacter baumannii was the commonest isolated organism. CONCLUSION: Our study presents the first cohort of PID from eastern India. A methodical step-wise clinical and diagnostic approach can facilitate early diagnosis and timely therapeutic interventions.


Assuntos
Síndromes de Imunodeficiência , Doenças da Imunodeficiência Primária , Infecções Respiratórias , Criança , Humanos , Síndromes de Imunodeficiência/diagnóstico , Criança Hospitalizada , Estudos Prospectivos , Doenças da Imunodeficiência Primária/diagnóstico , Doenças da Imunodeficiência Primária/epidemiologia , Doenças da Imunodeficiência Primária/terapia , Infecções Respiratórias/epidemiologia
17.
Pathol Res Pract ; 254: 155092, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38218042

RESUMO

Schimke immuno-osseous dysplasia (SIOD) is a rare multi-system condition caused by biallelic loss-of-function mutations in the SMARCAL1 gene. This disorder is characterized by disproportionate growth failure, T-cell deficiency, and renal dysfunction. Pathogenic variants in the SMARCAL1 gene have been reported in only approximately half of SIOD-affected individuals. Among these alterations, nonsense and frameshift mutations generally lead to a severe phenotype with early onset. In this study, we identified novel mutations in an Iranian patient with SIOD. A 4-year-old girl with developmental delay and facial dysmorphism was referred to our center for molecular diagnosis. We applied whole-exome and Sanger sequencing for co-segregation analysis. Subsequently, bioinformatic analysis was performed to assess the pathogenic effects of the variants and their post-transcriptional effects. We discovered two novel mutations (c.2281delT and c.2283delA) in exon 15 of the SMARCAL1 gene, resulting in a truncated protein with a loss of 193 amino acids (p.S761Rfs*1). Variant effect predictors indicated that these variants are pathogenic, and multi-sequence alignments revealed high conservation of this region among different species. Given that our patient exhibited severe a phenotype and passed away soon after receiving a definitive molecular diagnosis, we propose that the loss of the helicase C-terminal domain in the deleted part of SMARCAL1 may lead to the severe form of SIOD. Besides, the combination of growth retardation and bone abnormalities also plays a crucial role in the early diagnosis of the disease.


Assuntos
Arteriosclerose , Síndromes de Imunodeficiência , Síndrome Nefrótica , Osteocondrodisplasias , Doenças da Imunodeficiência Primária , Embolia Pulmonar , Feminino , Humanos , Pré-Escolar , Irã (Geográfico) , Doenças da Imunodeficiência Primária/genética , Doenças da Imunodeficiência Primária/complicações , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/metabolismo , Síndrome Nefrótica/diagnóstico , Síndrome Nefrótica/genética , Síndrome Nefrótica/complicações , DNA Helicases/genética
18.
J Pediatric Infect Dis Soc ; 13(2): 136-143, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38279954

RESUMO

BACKGROUND: Palivizumab is recommended for prevention of severe respiratory syncytial virus (RSV) disease in immunocompromised children, despite a lack of strong supporting evidence. The recent approval of substitute RSV-neutralizing monoclonal antibodies against RSV, offers an opportunity to synthesize the most current evidence supporting the palivizumab standard of care. OBJECTIVE: To evaluate the efficacy of palivizumab in preventing acute respiratory tract infection- or RSV-related hospitalization, or mortality in immunocompromised children. METHODS: We searched Ovid MEDLINE and EMBASE for published clinical studies that investigated outcomes of palivizumab use in children. We included clinical trials, cohort studies, and case-control studies. The primary outcomes were RSV-related or respiratory viral infection-related hospitalizations, or RSV-related mortality. This systematic review was registered in PROSPERO (ID CRD42021248619) and is reported in accordance with the PRISMA guidelines. RESULTS: From the 1993 records, six studies were eligible and included, for a total of 625 immunocompromised children with an heterogeneous composition of primary and acquired immunodeficiencies enrolled from palivizumab programs. There were no intervention studies. None of the studies included a control group. RSV hospitalizations were infrequent (0%-3.1% of children). Most children included received palivizumab, although one study (n = 56) did not specify how many received palivizumab. RSV mortality was neither observed, in three studies, nor reported, in three other studies. CONCLUSIONS: The evidence supporting the use of palivizumab for prevention of severe RSV disease in immunocompromised children remains extremely limited and appears insufficient to justify prioritizing this intervention as the current standard of care over alternative interventions.


Assuntos
Síndromes de Imunodeficiência , Infecções por Vírus Respiratório Sincicial , Criança , Humanos , Lactente , Palivizumab/uso terapêutico , Vírus Sinciciais Respiratórios , Antivirais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Infecções por Vírus Respiratório Sincicial/tratamento farmacológico , Infecções por Vírus Respiratório Sincicial/prevenção & controle , Hospitalização
19.
J Pediatr Hematol Oncol ; 46(2): e169-e173, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38277623

RESUMO

Primary immune deficiencies (PIDs) are rare genetic disorders characterized by impaired immune function, leading to frequent infections and immune dysregulation. Studies have shown that individuals with PID are at an increased risk of developing malignancies and lymphoproliferative disorders compared with the general population. In this single-center study, we aimed to analyze the occurrence of malignancies and lymphoproliferations in children diagnosed with PID. We retrospectively analyzed the medical records of 550 pediatric patients diagnosed with PIDs at our center. Among them, 17 (3,0%) patients were identified with malignancy and/or benign lymphoproliferation. Eight of the 17 patients (47.0%) had immune dysregulatory diseases, whereas ataxia-telangiectasia was the second most common PID associated with malignancy and/or benign lymphoproliferation (n = 5, 29.4%). Lymphoma was the predominant malignancy (n = 11, 64.7%), and Epstein-Barr virus was identified as the most common viral agent associated with malignancy and/or benign lymphoproliferation in patients with PID (n = 8, 47.0%). Our study highlights the association between PID and malignancies/lymphoproliferations, with immune dysregulation syndromes being the most common subclass associated with malignancies/lymphoproliferations. Early diagnosis, multidisciplinary management, and regular surveillance are crucial in improving patient outcomes and saving lives.


Assuntos
Ataxia Telangiectasia , Infecções por Vírus Epstein-Barr , Síndromes de Imunodeficiência , Neoplasias , Humanos , Criança , Infecções por Vírus Epstein-Barr/complicações , Herpesvirus Humano 4 , Estudos Retrospectivos , Neoplasias/complicações , Ataxia Telangiectasia/complicações , Síndromes de Imunodeficiência/complicações
20.
Immunol Rev ; 322(1): 178-211, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38228406

RESUMO

The thymus is the primary site of T-cell development, enabling generation, and selection of a diverse repertoire of T cells that recognize non-self, whilst remaining tolerant to self- antigens. Severe congenital disorders of thymic development (athymia) can be fatal if left untreated due to infections, and thymic tissue implantation is the only cure. While newborn screening for severe combined immune deficiency has allowed improved detection at birth of congenital athymia, thymic disorders acquired later in life are still underrecognized and assessing the quality of thymic function in such conditions remains a challenge. The thymus is sensitive to injury elicited from a variety of endogenous and exogenous factors, and its self-renewal capacity decreases with age. Secondary and age-related forms of thymic dysfunction may lead to an increased risk of infections, malignancy, and autoimmunity. Promising results have been obtained in preclinical models and clinical trials upon administration of soluble factors promoting thymic regeneration, but to date no therapy is approved for clinical use. In this review we provide a background on thymus development, function, and age-related involution. We discuss disease mechanisms, diagnostic, and therapeutic approaches for primary and secondary thymic defects.


Assuntos
Síndromes de Imunodeficiência , Linfócitos T , Timo/anormalidades , Recém-Nascido , Humanos , Diferenciação Celular
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