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1.
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
2.
Rheumatology (Oxford) ; 58(5): 889-896, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590695

RESUMO

OBJECTIVES: The association of B cell targeted therapies with development of hypogammaglobulinaemia and infection is increasingly recognized. Our aim was to develop consensus recommendations for immunoglobulin replacement therapy for management of hypogammaglobulinaemia following B cell targeted therapies in autoimmune rheumatic diseases. METHODS: A modified Delphi exercise involved a 17-member Taskforce committee, consisting of immunologists, rheumatologists, nephrologists, haematologists, a gastroenterologist, an immunology specialist nurse and a patient representative. The first round identified the most pertinent topics to address in the recommendations. A search string was agreed upon for the identification of publications in PubMed focusing on these areas, for a systematic literature review. Original data was presented from this review to the Taskforce committee. Recommendations from the British Society for Rheumatology, the UK Department of Health, EULAR, the ACR, and the American Academy of Allergy, Asthma, and Immunology were also reviewed. The evidence was discussed in a face-to-face meeting to formulate recommendation statements. The levels of evidence and statements were graded according to Scottish Intercollegiate Guidelines Network methodology. RESULTS: Three overarching principles, eight recommendation statements and a research agenda were formulated. The Taskforce committee voted on these statements, achieving 82-100% agreement for each recommendation. The strength of the recommendations was restricted by the low quality of the available evidence, with no randomized controlled trial data. The recommendations cover risk factors, monitoring, referral for hypogammaglobulinaemia; indications, dosage and discontinuation of immunoglobulin replacement therapy. CONCLUSION: These are the first recommendations specifically formulated for B cell targeted therapies related to hypogammaglobulinaemia in autoimmune rheumatic diseases. The recommendations are to aid health-care professionals with clinical decision making for patients with hypogammaglobulinaemia.

3.
J Immunol Methods ; 459: 1-10, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29800575

RESUMO

Response to polysaccharide vaccination can be an invaluable tool for assessing functionality of the adaptive immune system. Measurement of antibodies raised in response to Pneumovax®23 is the current gold standard test, but there are significant challenges and constraints in both the measurement and interpretation of the response. An alternative polysaccharide vaccine approach (Salmonella typhi Vi capsule (ViCPS)) has been suggested. In the present article, we review current evidence for the measurement of ViCPS antibodies in the diagnosis of primary and secondary antibody deficiencies. In particular, we review emerging data suggesting their interpretation in combination with the response to Pneumovax®23 and comment upon the utility of these vaccines to assess humoral immune responses while receiving immunoglobulin replacement therapy (IGRT).

4.
J Allergy Clin Immunol ; 142(4): 1285-1296, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29477724

RESUMO

BACKGROUND: The genetic cause of primary immunodeficiency disease (PID) carries prognostic information. OBJECTIVE: We conducted a whole-genome sequencing study assessing a large proportion of the NIHR BioResource-Rare Diseases cohort. METHODS: In the predominantly European study population of principally sporadic unrelated PID cases (n = 846), a novel Bayesian method identified nuclear factor κB subunit 1 (NFKB1) as one of the genes most strongly associated with PID, and the association was explained by 16 novel heterozygous truncating, missense, and gene deletion variants. This accounted for 4% of common variable immunodeficiency (CVID) cases (n = 390) in the cohort. Amino acid substitutions predicted to be pathogenic were assessed by means of analysis of structural protein data. Immunophenotyping, immunoblotting, and ex vivo stimulation of lymphocytes determined the functional effects of these variants. Detailed clinical and pedigree information was collected for genotype-phenotype cosegregation analyses. RESULTS: Both sporadic and familial cases demonstrated evidence of the noninfective complications of CVID, including massive lymphadenopathy (24%), unexplained splenomegaly (48%), and autoimmune disease (48%), features prior studies correlated with worse clinical prognosis. Although partial penetrance of clinical symptoms was noted in certain pedigrees, all carriers have a deficiency in B-lymphocyte differentiation. Detailed assessment of B-lymphocyte numbers, phenotype, and function identifies the presence of an increased CD21low B-cell population. Combined with identification of the disease-causing variant, this distinguishes between healthy subjects, asymptomatic carriers, and clinically affected cases. CONCLUSION: We show that heterozygous loss-of-function variants in NFKB1 are the most common known monogenic cause of CVID, which results in a temporally progressive defect in the formation of immunoglobulin-producing B cells.

8.
Transfusion ; 50(9): 1897-901, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20456696

RESUMO

BACKGROUND: A history of anaphylaxis after transfusion of immunoglobulin A (IgA)-containing blood products in selective IgA-deficient (sIgAD) patients can be a major problem, particularly in emergencies, when large quantities of blood products are required. CASE REPORT: A 19-year-old woman with end-stage Type 2 autoimmune hepatitis required liver transplantation as her only remaining treatment option. However, she also had sIgAD, anti-IgA antibodies, and episodes of anaphylaxis after receiving IgA-containing blood products. Liver transplantation would have been extremely challenging due to the difficulty of obtaining sufficient blood products from suitable IgA-deficient donors. Hence, it became imperative to devise a protocol to desensitize her to IgA-containing blood products. RESULTS: Using a continuous infusion of an IgA-enriched (6 mg/mL IgA) immunoglobulin preparation with gradual increases in concentration, she was successfully desensitized to IgA. Consequently, she was able to receive standard platelets, fresh-frozen plasma, and red blood cells with no complications. CONCLUSION: This approach could prove very useful in similar cases that may require administration of large quantities of blood products particularly in emergency lifesaving circumstances.


Assuntos
Anafilaxia/etiologia , Anafilaxia/prevenção & controle , Imunoglobulina A/imunologia , Imunoglobulina A/uso terapêutico , Reação Transfusional , Adulto , Anafilaxia/imunologia , Feminino , Humanos , Adulto Jovem
9.
Blood ; 113(26): 6619-28, 2009 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-19406987

RESUMO

Highly differentiated CD8+CD28-CD27- T cells have short telomeres, defective telomerase activity, and reduced capacity for proliferation, indicating that they are close to replicative senescence. In addition, these cells express increased levels of the senescence-associated inhibitory receptor KLRG1 and have poor capacity for IL-2 synthesis and defective Akt (ser(473)) phosphorylation after activation. It is not known whether signaling via KLRG1 contributes to any of the attenuated differentiation-related functional changes in CD8+ T cells. To address this, we blocked KLRG1 signaling during T-cell receptor activation using antibodies against its major ligand, E-cadherin. This resulted in a significant enhancement of Akt (ser(473)) phosphorylation and T-cell receptor-induced proliferative activity of CD8+CD28-CD27- T cells. Furthermore, the increase of proliferation was directly linked to the Akt-mediated induction of cyclin D and E and reduction in the cyclin inhibitor p27 expression. In contrast, the reduced telomerase activity in highly differentiated CD8+CD28(-)CD27- T cells was not altered by KLRG1 blockade, indicating the involvement of other mechanisms. This is the first demonstration of a functional role for KLRG1 in primary human CD8+ T cells and highlights that certain functional defects that arise during progressive T-cell differentiation toward replicative senescence are maintained actively by inhibitory receptor signaling.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD8-Positivos/imunologia , Lectinas Tipo C/fisiologia , Processamento de Proteína Pós-Traducional , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transativadores/fisiologia , Adulto , Idoso , Antígenos CD28/análise , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/enzimologia , Caderinas/antagonistas & inibidores , Diferenciação Celular , Senescência Celular , Ciclina D2 , Ciclina E/biossíntese , Ciclina E/genética , Inibidor de Quinase Dependente de Ciclina p27/biossíntese , Inibidor de Quinase Dependente de Ciclina p27/genética , Ciclinas/biossíntese , Ciclinas/genética , Feminino , Humanos , Lectinas Tipo C/antagonistas & inibidores , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosforilação , Fosfosserina/análise , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Telômero/ultraestrutura , Transativadores/antagonistas & inibidores , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/análise , Adulto Jovem
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