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1.
Rinsho Ketsueki ; 60(9): 1358-1365, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597864

RESUMO

The former definition of gene therapy was the infusion of genes or cells transduced with genes into humans for the treatment or prevention of a disease, i.e., gene therapy adds a functional gene into the patients' genome, whereas the mutated gene remains as it is. Because most of the immune immunodeficiency disorders (PID) are caused by single gene mutations, this therapeutic option may provide a clinical effect. However, the treatment has a severe problem of leukemogenesis caused by insertional mutagenesis; therefore, it is not applicable for diseases caused by the gain-of-function of mutated genes. To address this, gene therapy using gene correction techniques will come to the forefront of the mainstream research. Herein, I have focused on the present outline of gene therapy by gene addition and described the future prospects of gene therapy by gene correction for PID.


Assuntos
Terapia Genética , Síndromes de Imunodeficiência/terapia , Humanos
2.
Rev Prat ; 69(6): 659-665, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-31626429

RESUMO

Primary immune deficiencies (PIDs) include rare and heterogeneous syndromes due to genetic abnormalities involving the immune system. In the registry of the French National Reference Center for Primary Immune Deficiencies (CEREDIH), the median age of clinical onset is 2 years, but 25% of patients develop the first symptoms after 15 years. A diagnosis of PID should be considered in the presence of an unusual association of infections, autoimmune pathologies, granulomatous disease, polyclonal lymphoproliferation or atypical lymphoma. PID management currently benefits from new antibiotic prophylaxis, the improvement of allogeneic hematopoietic stem cell transplantation procedure and the development of gene therapy. In addition, the understanding of the pathophysi ological mechanisms led to new treatments targeting the pathways implicated by the genetic defects. In this review, we briefly recall the classification of PID. We illustrate the problem of PID in adults with clinical cases and then summarize the main principles of management in adults PID patients.


Assuntos
Síndromes de Imunodeficiência , Adulto , Criança , Pré-Escolar , Terapia Genética , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Sistema de Registros
3.
Immunity ; 50(4): 832-850, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30995502

RESUMO

The common cytokine receptor γ chain, γc, is a component of the receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21. Mutation of the gene encoding γc results in X-linked severe combined immunodeficiency in humans, and γc family cytokines collectively regulate development, proliferation, survival, and differentiation of immune cells. Here, we review the basic biology of these cytokines, highlighting mechanisms of signaling and gene regulation that have provided insights for immunodeficiency, autoimmunity, allergic diseases, and cancer. Moreover, we discuss how studies of this family stimulated the development of JAK3 inhibitors and present an overview of current strategies targeting these pathways in the clinic, including novel antibodies, antagonists, and partial agonists. The diverse roles of these cytokines on a range of immune cells have important therapeutic implications.


Assuntos
Citocinas/classificação , Subunidade gama Comum de Receptores de Interleucina/genética , Família Multigênica/imunologia , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/genética , Citocinas/imunologia , Evolução Molecular , Regulação da Expressão Gênica , Terapia Genética , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Janus Quinase 3/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Janus Quinases/fisiologia , Subpopulações de Linfócitos/imunologia , Camundongos , Terapia de Alvo Molecular , Família Multigênica/genética , Neoplasias/genética , Neoplasias/imunologia , Subunidades Proteicas , Fatores de Transcrição STAT/fisiologia , Transdução de Sinais , Pesquisa Médica Translacional , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/genética , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/imunologia , Doenças por Imunodeficiência Combinada Ligada ao Cromossomo X/terapia
4.
Indian J Pathol Microbiol ; 62(2): 279-282, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30971555

RESUMO

Griscelli syndrome is a rare autosomal recessive inherited disorder characterized by hypopigmentation, silver colored hair, and associated immunological deficiency, which proves fatal in the absence of timely intervention. Our patients diagnosed with Griscelli syndrome-2 presented with fever, hepatosplenomegaly, and deranged hematological and biochemical parameters. Both cases underwent detailed investigations comprising of hair mount microscopic examination, degranulation assay, and mutational studies. Our cases showed defective degranulation activity by NK cells and gene mutation analysis revealed RAB27A mutation that causes defect of cytotoxic granule exocytosis from natural killer (NK) and T-cells, manifesting clinically as hemophagocytic lymphohistiocytosis (HLH). Hematopoietic stem cell transplantation in one of the patients resulted in stable chimerism; however, the second case relapsed within a month after SCT. Stem cell transplantation is the only curative therapeutic option for GS2; thus, improvement in posttransplantation management may reduce mortality and posttransplant complications. Hence, any child who presents with partial albinism and clinical features suggestive of HLH, a peripheral blood, hair shaft mount examination along with basic immunological NK and T-cell cytotoxicity assay by flow cytometry will help clinch the diagnosis early. It can subsequently be confirmed by molecular study. Timely therapeutic intervention can prevent relapses and severe infection and improve outcome in these cases.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Linfo-Histiocitose Hemofagocítica/genética , Linfo-Histiocitose Hemofagocítica/terapia , Piebaldismo/genética , Piebaldismo/terapia , Pré-Escolar , Feminino , Cabelo , Humanos , Síndromes de Imunodeficiência/patologia , Células Matadoras Naturais/patologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/patologia , Masculino , Mutação , Piebaldismo/patologia , Resultado do Tratamento , Proteínas rab27 de Ligação ao GTP/genética
5.
Vox Sang ; 114(3): 237-246, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30883804

RESUMO

BACKGROUND AND OBJECTIVE: Immunoglobulin replacement therapy (IRT) is often used to support patients with primary immunodeficiency disease (PID) and secondary immunodeficiency disease (SID). Home-based subcutaneous immunoglobulin (SCIg) is reported to be a cheaper and more efficient option compared to hospital-based intravenous immunoglobulin (IVIg) for PID. In contrast, there is little information on the cost-effectiveness of IRT in SID. However, patients who develop hypogammaglobulinaemia secondary to other conditions (SID) have different clinical aetiology compared to PID. This study assesses whether SCIg provides a good value-for-money treatment option in patients with secondary immunodeficiency disease (SID). METHODS: A Markov cohort simulation model with six health states was used to compare cost-effectiveness of IVIg with SCIg from a healthcare system perspective. The costs of treatment, infection and quality-adjusted life years (QALYs) for IVIg and SCIg treatment options were modelled with a time horizon of 10 years and weekly cycles. Deterministic and probabilistic sensitivity analyses were performed around key parameters. RESULTS: The cumulative cost for IVIg was A$151 511 and for SCIg A$144 296. The QALYs with IVIg were 3·07 and with SCIg 3·51. Based on the means, SCIg is the dominant strategy with better outcomes and at lower cost. The probabilistic sensitivity analysis shows that 88·3% of the 50 000 iterations fall below the nominated willingness to pay threshold of A$50 000 per QALY. Therefore, SCIg is a cost-effective treatment option. CONCLUSION: For SID patients in Queensland (Australia), the home-based SCIg treatment option provides better health outcomes and cost savings.


Assuntos
Análise Custo-Benefício , Imunização Passiva/economia , Imunoglobulinas Intravenosas/economia , Austrália , Feminino , Custos Hospitalares , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/terapia , Masculino
6.
Soins ; 64(833): 13-18, 2019 Mar.
Artigo em Francês | MEDLINE | ID: mdl-30879622

RESUMO

Immunoglobulin preparations are medicines derived from blood used as a replacement therapy for immunodeficiencies or as an immunomodulator. While they are generally well-tolerated, side effects, rarely severe, can nevertheless occur when administered intravenously. They are usually related to an excessive perfusion rate. The recent arrival of safer products administered subcutaneously represents progress in the treatment of patients.


Assuntos
Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/terapia , Humanos , Imunoglobulinas/efeitos adversos , Imunoglobulinas Intravenosas/efeitos adversos , Infusões Subcutâneas , Resultado do Tratamento
7.
Autoimmun Rev ; 18(5): 535-541, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30844552

RESUMO

BACKGROUND: Consensus guidelines are not available for the use of immunoglobulin replacement therapy (IGRT) in patients developing iatrogenic secondary antibody deficiency following B-cell targeted therapy (BCTT) in autoimmune rheumatic disease. OBJECTIVES: To evaluate the role of IGRT to manage hypogammaglobulinemia following BCTT in autoimmune rheumatic disease (AIRD). METHODS: Using an agreed search string we performed a systematic literature search on Medline with Pubmed as vendor. We limited the search to English language papers with abstracts published over the last 10 years. Abstracts were screened for original data regarding hypogammaglobulinemia following BCTT and the use of IGRT for hypogammaglobulinemia following BCTT. We also searched current recommendations from national/international organisations including British Society for Rheumatology, UK Department of Health, American College of Rheumatology, and American Academy of Asthma, Allergy and Immunology. RESULTS: 222 abstracts were identified. Eight papers had original relevant data that met our search criteria. These studies were largely retrospective cohort studies with small patient numbers receiving IGRT. The literature highlights the induction of a sustained antibody deficiency, risk factors for hypogammaglobulinemia after BCTT including low baseline serum IgG levels, how to monitor patients for the development of hypogammaglobulinemia and the limited evidence available on intervention thresholds for commencing IGRT. CONCLUSION: The benefit of BCTT needs to be balanced against the risk of inducing a sustained secondary antibody deficiency. Consensus guidelines would be useful to enable appropriate assessment prior to and following BCTT in preventing and diagnosing hypogammaglobulinemia. Definitions for symptomatic hypogammaglobulinemia, intervention thresholds and treatment targets for IGRT, and its cost-effectiveness are required.


Assuntos
Antirreumáticos/efeitos adversos , Linfócitos B/imunologia , Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/induzido quimicamente , Síndromes de Imunodeficiência/terapia , Doenças Reumáticas/tratamento farmacológico , Agamaglobulinemia/induzido quimicamente , Agamaglobulinemia/terapia , Doenças Autoimunes/tratamento farmacológico , Humanos , Imunização Passiva/métodos , Estudos Retrospectivos , Rituximab/efeitos adversos
8.
Vnitr Lek ; 65(2): 126-130, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30909702

RESUMO

The basis of treatment of patients with hypogammaglobulinemia, primary or secondary, is immunoglobulin replacement. Current immunoglobulin derivates contain highly purified IgG from healthy human donors. Intravenous or subcutaneous route are almost exclusively used at present. The treatment must be individualized. Adequate doses of immunoglobulin derivates must be administered to avoid frequent and severe infections of the respiratory tract. Antibiotic prophylaxis may be alternative and complementary treatment to immunoglobulin substitution.


Assuntos
Agamaglobulinemia , Síndromes de Imunodeficiência , Administração Intravenosa , Agamaglobulinemia/terapia , Anticorpos , Humanos , Imunoglobulina G , Imunoglobulinas Intravenosas , Síndromes de Imunodeficiência/terapia , Infusões Subcutâneas
9.
Eur J Haematol ; 102(6): 447-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30801785

RESUMO

OBJECTIVE: Despite long-standing safe and effective use of immunoglobulin replacement therapy (IgRT) in primary immunodeficiency, clinical data on IgRT in patients with secondary immunodeficiency (SID) due to B-cell lymphoproliferative diseases are limited. Here, we examine the correlation between approved IgRT indications, treatment recommendations, and clinical practice in SID. METHODS: An international online survey of 230 physicians responsible for the diagnosis of SID and the prescription of IgRT in patients with hematological malignancies was conducted. RESULTS: Serum immunoglobulin was measured in 83% of patients with multiple myeloma, 76% with chronic lymphocytic leukemia, and 69% with non-Hodgkin lymphoma. Most physicians (85%) prescribed IgRT after ≥2 severe infections. In Italy, Germany, Spain, and the United States, immunoglobulin use was above average in patients with hypogammaglobulinemia, while in the UK considerably fewer patients received IgRT. The use of subcutaneous immunoglobulin was highest in France (34%) and lowest in Spain (19%). Immunologists measured specific antibody responses, performed test immunization, implemented IgRT, and used subcutaneous immunoglobulin more frequently than physicians overall. CONCLUSIONS: The management of SID in hematological malignancies varied regionally. Clinical practice did not reflect treatment guidelines, highlighting the need for robust clinical studies on IgRT in this population and harmonization between countries and disciplines.


Assuntos
Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Síndromes de Imunodeficiência/epidemiologia , Síndromes de Imunodeficiência/etiologia , Gerenciamento Clínico , Saúde Global , Humanos , Imunoglobulinas/sangue , Imunoglobulinas/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/terapia , Infecção/etiologia , Controle de Infecções , Vigilância em Saúde Pública , Resultado do Tratamento
10.
Exp Hematol ; 71: 43-50, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30664903

RESUMO

Primary immunodeficiency diseases (PIDs) are a heterogeneous group of rare immune disorders with genetic causes. Effective treatments using hematopoietic stem cells or pharmaceutical agents have been around for decades. However, for many patients, these treatment options are ineffective, partly because the rarity of these PIDs complicates the diagnosis and therapy. Induced pluripotent stem cells (iPSCs) offer a potential solution to these problems. The proliferative capacity of iPSCs allows for the preparation of a large, stable supply of hematopoietic cells with the same genome as the patient, allowing for new human cell models that can trace cellular abnormalities during the pathogenesis and lead to new drug discovery. PID models using patient iPSCs have been instrumental in identifying deviations in the development or function of several types of immune cells, revealing new molecular targets for experimental therapies. These models are only in their early stages and for the most part have recapitulated results from existing models using animals or primary cells. However, iPSC-based models are being used to study complex diseases of other organs, including those with multigenic causes, suggesting that advances in differentiation processes will expand iPSC-based models to complex PIDs as well.


Assuntos
Síndromes de Imunodeficiência/etiologia , Síndromes de Imunodeficiência/terapia , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Transplante de Células-Tronco , Animais , Biomarcadores , Diferenciação Celular , Humanos , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Modelos Biológicos , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/patologia , Transplante de Células-Tronco/métodos
11.
Nat Chem Biol ; 15(3): 304-313, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30692685

RESUMO

MALT1 paracaspase is central for lymphocyte antigen-dependent responses including NF-κB activation. We discovered nanomolar, selective allosteric inhibitors of MALT1 that bind by displacing the side chain of Trp580, locking the protease in an inactive conformation. Interestingly, we had previously identified a patient homozygous for a MALT1 Trp580-to-serine mutation who suffered from combined immunodeficiency. We show that the loss of tryptophan weakened interactions between the paracaspase and C-terminal immunoglobulin MALT1 domains resulting in protein instability, reduced protein levels and functions. Upon binding of allosteric inhibitors of increasing potency, we found proportionate increased stabilization of MALT1-W580S to reach that of wild-type MALT1. With restored levels of stable MALT1 protein, the most potent of the allosteric inhibitors rescued NF-κB and JNK signaling in patient lymphocytes. Following compound washout, MALT1 substrate cleavage was partly recovered. Thus, a molecular corrector rescues an enzyme deficiency by substituting for the mutated residue, inspiring new potential precision therapies to increase mutant enzyme activity in other deficiencies.


Assuntos
Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/antagonistas & inibidores , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , Regulação da Expressão Gênica , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Linfócitos/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Sistema de Sinalização das MAP Quinases/fisiologia , Masculino , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/genética , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/ultraestrutura , NF-kappa B/metabolismo , Proteínas de Neoplasias , Transdução de Sinais
12.
Pediatr Blood Cancer ; 66(4): e27602, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30609294

RESUMO

Allogeneic hematopoietic stem cell transplantation is curative for primary immunodeficiencies. Bone marrow from an unaffected human leukocyte antigen (HLA)-identical sibling donor is the ideal graft source. For minor donors, meaningful consent or assent may not be feasible, and permission from parents or legal guardians is considered acceptable. Adverse events, albeit extremely small, can be associated with bone marrow harvest in pediatric donors. Donor safety concerns potentially increase with multiple bone marrow harvests. Very little is known about multiple bone marrow harvests from pediatric donors. We describe the ethical considerations and clinical decision-making in an unusual clinical situation where three patients with the same primary immunodeficiency were HLA identical to one another and their younger sibling, who underwent bone marrow harvests three times between 1.3 and 4 years of age, resulting in successful transplantation for all three patients. We hope that this experience will provide guidance to providers and families in a similar situation.


Assuntos
Temas Bioéticos , Transplante de Medula Óssea/ética , Transplante de Células-Tronco Hematopoéticas/etnologia , Síndromes de Imunodeficiência/terapia , Irmãos , Doadores de Tecidos , Pré-Escolar , Feminino , Humanos , Lactente , Masculino
13.
Immunol Rev ; 287(1): 62-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565235

RESUMO

Human adenosine deaminase 1 deficiency was described in the 1970s to cause severe combined immunodeficiency. The residual adenosine deaminase activity in these patients was attributed to adenosine deaminase 2. Human adenosine deaminase type 2 deficiency (DADA2), due to biallelic deleterious mutations in the ADA2 gene, is the first described monogenic type of small- and medium-size vessel vasculitis. The phenotype of DADA2 also includes lymphoproliferation, cytopenia, and variable degrees of immunodeficiency. The physiological role of ADA2 is still enigmatic hence the pathophysiology of the condition is unclear. Preliminary data showed that in the absence of ADA2, macrophage differentiation is skewed to a pro-inflammatory M1 subset, which is detrimental for endothelial integrity. The inflammatory phenotype responds well to anti-TNF therapy with etanercept and that is the first-line treatment for prevention of severe vascular events including strokes. The classic immunosuppressive drugs are not successful in controlling the disease activity. However, hematopoietic stem cell transplantation (HSCT) has been shown to be a definitive cure in DADA2 patients who present with a severe cytopenia. HSCT can also cure the vascular phenotype and is the treatment modality for patients' refractory to anti-cytokine therapies. In this review, we describe what is currently known about the molecular mechanisms of DADA2. Further research on the pathophysiology of this multifaceted condition is needed to fine-tune and steer future therapeutic strategies.


Assuntos
Adenosina Desaminase/genética , Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Macrófagos/imunologia , Animais , Diferenciação Celular , Humanos , Síndromes de Imunodeficiência/imunologia , Síndromes de Imunodeficiência/terapia , Poliarterite Nodosa , Acidente Vascular Cerebral Lacunar
14.
Immunol Rev ; 287(1): 91-102, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565238

RESUMO

WHIM syndrome is a rare, autosomal dominant immunodeficiency which is named for the four key manifestations: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. It results from heterozygous gain-of-function mutations in the chemokine receptor CXCR4 which is widely expressed on leukocytes and has profound influences on immune system homeostasis and organogenesis. New treatments for the disease using drugs to reduce CXCR4 function are excellent examples of precision medicine. Since CXCR4 and its ligand CXCL12 play an important role in a variety of infectious, inflammatory, autoimmune, and malignant diseases, the study of WHIM syndrome provides important insights into both the physiologic and disease roles of these molecules.


Assuntos
Síndromes de Imunodeficiência/imunologia , Papillomaviridae/fisiologia , Infecções por Papillomavirus/imunologia , Receptores CXCR4/genética , Verrugas/imunologia , Agamaglobulinemia , Animais , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Infecção , Leucopenia , Terapia de Alvo Molecular , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/terapia , Medicina de Precisão , Verrugas/genética , Verrugas/terapia
15.
Immunol Rev ; 287(1): 73-90, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565244

RESUMO

Mutations of the recombinase activating genes (RAG) in humans underlie a broad spectrum of clinical and immunological phenotypes that reflect different degrees of impairment of T- and B-cell development and alterations of mechanisms of central and peripheral tolerance. Recent studies have shown that this phenotypic heterogeneity correlates, albeit imperfectly, with different levels of recombination activity of the mutant RAG proteins. Furthermore, studies in patients and in newly developed animal models carrying hypomorphic RAG mutations have disclosed various mechanisms underlying immune dysregulation in this condition. Careful annotation of clinical outcome and immune reconstitution in RAG-deficient patients who have received hematopoietic stem cell transplantation has shown that progress has been made in the treatment of this disease, but new approaches remain to be tested to improve stem cell engraftment and durable immune reconstitution. Finally, initial attempts have been made to treat RAG deficiency with gene therapy.


Assuntos
Linfócitos B/imunologia , Proteínas de Ligação a DNA/genética , Genes RAG-1/genética , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Animais , Diferenciação Celular/genética , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Mutação/genética , Fenótipo
16.
Immunol Rev ; 287(1): 9-19, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565250

RESUMO

DOCK8 immunodeficiency syndrome (DIDS) is a progressive combined immunodeficiency that can be distinguished from other combined immunodeficiencies or hyperimmunoglobulinemia E syndromes in featuring (a) profound susceptibility to virus infections of the skin, with associated skin cancers, and (b) severe food allergies. The DOCK8 locus has many repetitive sequence elements that predispose to the generation of large germline deletions as well as recombination-mediated somatic DNA repair. Residual DOCK8 protein contributes to the variable disease phenotype. The severe virus infections of the skin, and probably also VZV-associated vasculopathy, reflect an important function of DOCK8, which is normally required to maintain lymphocyte shape integrity as the cells migrate through dense tissues. Loss of DOCK8 also causes immune deficits through other mechanisms including a milder generalized cell survival defect and skewing of T helper cell subsets. Recent work has uncovered the roles for DOCK8 in dendritic cell responses that can also help explain the virus susceptibility, as well as in regulatory T cells that might help explain autoimmunity in a minority of patients. Fortunately, hematopoietic stem cell transplantation cures the eczema and infection susceptibility of DIDS, but not necessarily the other disease manifestations including food allergies.


Assuntos
Fatores de Troca do Nucleotídeo Guanina/genética , Síndromes de Imunodeficiência/imunologia , Linfócitos T/imunologia , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Suscetibilidade a Doenças , Eczema , Terapia Genética , Transplante de Células-Tronco Hematopoéticas , Humanos , Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/terapia , Neoplasias de Células Escamosas , Pneumonia , Vasculite do Sistema Nervoso Central
17.
J Pediatric Infect Dis Soc ; 7(suppl_2): S79-S82, 2018 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-30590619

RESUMO

Hematopoietic stem cell transplantation (HSCT) has been the standard of care for infants with severe combined immunodeficiency (SCID) for several decades due to the dismal prognosis early in life without immune reconstitution. In recent years, as HSCT conditioning regimens and supportive care have greatly improved, HSCT is gaining in acceptance for more non-SCID primary immunodeficiencies (PIDs) and outside the early childhood period. In addition, potential donor options for non-SCID PIDs are expanding with increasing success for haploidentical donor transplants. In this brief report of a presentation at the PIDS-St. Jude 2018 conference, PIDs for which transplants are increasingly performed outside of early childhood will be discussed.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Síndromes de Imunodeficiência/terapia , Criança , Deficiência de GATA2/terapia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Humanos , Lactente , Imunodeficiência Combinada Severa/terapia
18.
Transfusion ; 58 Suppl 3: 3056-3064, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30536429

RESUMO

Primary immunodeficiency (PID) diseases result from genetic defects of the immune system that increase a patient's susceptibility to infections. The types of infections that occur in patients with PID diseases are dictated largely by the nature of the immunodeficiency, which can be defined by dysfunction of cellular or humoral defenses. An increasing number of PID diseases, including those with both cellular and humoral defects, have antibody deficiency as a major feature, and as a result can benefit from immunoglobulin replacement therapy. In fact, the most common PID diseases worldwide are antibody deficiencies and include common variable immunodeficiency, congenital agammaglobulinemia, hyper-IgM syndrome, specific antibody deficiency, and Good syndrome. Although immunoglobulin replacement therapy is the cornerstone of treatment for the majority of these conditions, a thorough understanding of the specific infections for which these patients are at increased risk can hasten diagnosis and guide additional therapies. Moreover, the infection trends in some patients with PID disease who have profound defects of cellular immunity, such as autosomal-dominant hyper-IgE syndrome (Job/Buckley syndrome) or dedicator of cytokinesis 8 (DOCK8) deficiency, suggest that select patients might benefit from immunoglobulin replacement therapy even if their immunodeficiency is not limited to antibody defects. In this review, we provide an overview of the predisposition to infections seen in PID disease that may benefit from immunoglobulin replacement therapy.


Assuntos
Imunoglobulinas/uso terapêutico , Síndromes de Imunodeficiência/complicações , Síndromes de Imunodeficiência/terapia , Infecção/imunologia , Agamaglobulinemia/complicações , Agamaglobulinemia/imunologia , Agamaglobulinemia/terapia , Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/terapia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Síndromes de Imunodeficiência/classificação , Síndromes de Imunodeficiência/imunologia , Infecção/terapia , Fatores de Risco
19.
Int J Mol Sci ; 20(1)2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30577453

RESUMO

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.


Assuntos
Imunidade Adaptativa , Síndromes de Imunodeficiência/diagnóstico , Síndromes de Imunodeficiência/etiologia , Verrugas/diagnóstico , Verrugas/etiologia , Animais , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Quimiocina CXCL12/genética , Quimiocina CXCL12/metabolismo , Gerenciamento Clínico , Humanos , Síndromes de Imunodeficiência/metabolismo , Síndromes de Imunodeficiência/terapia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Tecido Linfoide/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Receptores CXCR4/genética , Receptores CXCR4/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Verrugas/metabolismo , Verrugas/terapia
20.
Transfusion ; 58 Suppl 3: 3065-3071, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30536437

RESUMO

BACKGROUND: To ensure that immunoglobulin (Ig) products have adequate functional antibody, the US Food and Drug Administration (FDA) requires that Ig lots contain minimum levels of measles neutralizing antibody; the current minimum is 0.48 x US Reference Ig 176. STUDY DESIGN AND METHODS: In the first part of the study, measles antibody titers were measured in donor plasma samples collected in 2007, 2011, and 2017. In the second part, trough or steady-state serum levels of measles neutralizing antibody were measured in two studies of patients with primary immunodeficiency (PID) who were treated with intravenous (Study 1; N = 46) or subcutaneous (Study 2; N = 18) Ig replacement therapy, meeting previous requirements for lot potency (≥0.6 x US Reference Ig 176). Serum measles neutralizing antibody titers were then estimated for conditions in which the potency of the Ig replacement product was 0.48 or 0.30 x US Reference Ig 176. RESULTS: Measles antibody titers in donated plasma samples declined in donors born after 1963. In the two studies of patients with PID who were treated with intravenous or subcutaneous Ig replacement therapy, all patients exhibited trough (intravenous Ig) or steady-state (subcutaneous Ig) measles neutralizing antibody titers above 0.12 IU/mL, which has been shown to protect against clinical measles in the general population. Estimates suggest that all patients except one would have continued to meet this standard if the Ig lot potency had been 0.48 or 0.30 x US Reference Ig 176. CONCLUSION: These studies provide supporting evidence that the lot release specification can be safely lowered from 0.48 to 0.30 x US Reference Ig 176, which will accommodate declining measles neutralizing antibody levels in donor plasma.


Assuntos
Anticorpos Antivirais/sangue , Doadores de Sangue , Imunoglobulinas/administração & dosagem , Síndromes de Imunodeficiência/terapia , Vacina contra Sarampo , Sarampo/prevenção & controle , Adolescente , Adulto , Idoso , Anticorpos Neutralizantes/análise , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/administração & dosagem , Anticorpos Antivirais/análise , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulinas/sangue , Imunoglobulinas Intravenosas/administração & dosagem , Imunoglobulinas Intravenosas/sangue , Síndromes de Imunodeficiência/imunologia , Estudos Longitudinais , Masculino , Sarampo/imunologia , Vacina contra Sarampo/administração & dosagem , Vacina contra Sarampo/sangue , Vacina contra Sarampo/imunologia , Pessoa de Meia-Idade , Testes Sorológicos , Titulometria , Vacinação , Potência de Vacina , Adulto Jovem
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