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1.
Clin Lab Med ; 39(4): 609-623, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31668273

RESUMO

Laboratory assays of immune cell function are essential for understanding the type and function of immune defects. These assessments should be performed in conjunction with a detailed history and physical examination, which should guide the evaluation of patients with a suspected immune deficiency. Laboratory assays of immune cell function are critical for assessing and demonstrating the functional impact of genetic mutations. Advances in diagnostic techniques continue to expand the ability of clinicians and researchers to understand the complex immune pathophysiology that underlies these disorders.

3.
Sci Signal ; 12(604)2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31641080

RESUMO

Transitional B cells must actively undergo selection for self-tolerance before maturing into their resting follicular B cell successors. We found that metabolic quiescence was acquired at the follicular B cell stage in both humans and mice. In follicular B cells, the expression of genes involved in ribosome biogenesis, aerobic respiration, and mammalian target of rapamycin complex 1 (mTORC1) signaling was reduced when compared to that in transitional B cells. Functional metabolism studies, profiling of whole-cell metabolites, and analysis of cell surface proteins in human B cells suggested that this transition was also associated with increased extracellular adenosine salvage. Follicular B cells increased the abundance of the cell surface ectonucleotidase CD73, which coincided with adenosine 5'-monophosphate-activated protein kinase (AMPK) activation. Differentiation to the follicular B cell stage in vitro correlated with surface acquisition of CD73 on human transitional B cells and was augmented with the AMPK agonist, AICAR. Last, individuals with gain-of-function PIK3CD (PI3Kδ) mutations and increased pS6 activation exhibited a near absence of circulating follicular B cells. Together, our data suggest that mTORC1 attenuation may be necessary for human follicular B cell development. These data identify a distinct metabolic switch during human B cell development at the transitional to follicular stages, which is characterized by an induction of extracellular adenosine salvage, AMPK activation, and the acquisition of metabolic quiescence.

5.
JCI Insight ; 4(14)2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31341110

RESUMO

Advances in genomic medicine have elucidated an increasing number of genetic etiologies for patients with common variable immunodeficiency (CVID). However, there is heterogeneity in clinical and immunophenotypic presentations and a limited understanding of the underlying pathophysiology of many cases. The primary defects in CVID may extend beyond the adaptive immune system, and the combined defect in both the myeloid and lymphoid compartments suggests the mechanism may involve bone marrow output and earlier progenitors. Using the methylation profile of the human androgen receptor (AR) gene as a surrogate epigenetic marker for bone marrow clonality, we examined the hematopoietic compartments of patients with CVID. Our data show that clonal hematopoiesis is common among patients with adult-onset CVID who do not have associated noninfectious complications. Nonblood tissues did not show a skewed AR methylation status, supporting a model of an acquired clonal hematopoietic event. Attenuation of memory B cell differentiation into long-lived plasma cells (CD20-CD27+CD38+CD138+) was associated with marked changes in the postdifferentiation methylation profile, demonstrating the functional consequence of clonal hematopoiesis on humoral immunity in these patients. This study sheds light on a potential etiology of a subset of patients with CVID, and the findings suggest that it is a stage of an acquired lymphocyte maturation disorder.

6.
Allergy Asthma Proc ; 40(1): 7-13, 2019 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-30582490

RESUMO

Hereditary angioedema (HAE) is a rare, autosomal dominant, genetic disorder associated with a deficiency in C1 inhibitor protein. HAE is characterized by recurrent and unpredictable episodes of swelling of the extremities, abdomen, face, and upper airway. There are several newly approved drugs as well as investigational products that are currently under study for the management of patients with HAE, with the potential to optimize care and improve quality of life for patients with HAE. We reviewed the evolution of HAE treatment options in the United States and discussed mechanisms of action, routes of administration, and efficacy of these therapies.


Assuntos
Angioedemas Hereditários/terapia , Fatores Etários , Angioedemas Hereditários/diagnóstico , Angioedemas Hereditários/etiologia , Angioedemas Hereditários/prevenção & controle , Terapia Combinada , Gerenciamento Clínico , Necessidades e Demandas de Serviços de Saúde , Humanos , Guias de Prática Clínica como Assunto , Serviços Preventivos de Saúde , Qualidade de Vida , Resultado do Tratamento
7.
JAMA Netw Open ; 1(7): e184169, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30646343

RESUMO

Importance: Rituximab is an anti-CD20 chimeric antibody used in a wide variety of clinical indications. There has not been widespread adoption of consistent immune monitoring before and after rituximab therapy. However, there is a subset of patients who develop prolonged, symptomatic hypogammaglobulinemia following rituximab, and monitoring before and after rituximab therapy could help to identify these patients and initiate measures to prevent excess morbidity and mortality. Objective: To determine the current levels of screening for hypogammaglobulinemia (specifically, low immunoglobulin G), infectious risks associated with hypogammaglobulinemia, and variables associated with an increased risk of mortality. Design, Setting, and Participants: A cohort study was conducted of 8633 patients receiving rituximab from January 1, 1997, to December 31, 2017, at a large, tertiary referral center (Partners HealthCare System). Exposures: Rituximab administration. Main Outcomes and Measures: The primary outcome measures were immunoglobulin measurements, infectious complications, and mortality. Cox regression analysis was used to examine the results of infectious complications on survival, adjusted for age, sex, and indication for rituximab use. Results: Of the 8633 patients who received rituximab in the large, academic, health care system, 4479 satisfied inclusion criteria, with a mean (SD) age of 59.8 (16.2) years; 2280 patients (50.9%) were women. Most patients (3824 [85.4%]) did not have immunoglobulin levels checked before rituximab therapy. Of those who had levels determined, hypogammaglobulinemia was noted in 313 (47.8%) patients before initiation of rituximab. Following rituximab administration, worsening hypogammaglobulinemia was noted. There was an increase in severe infections after rituximab use in the study cohort (from 17.2% to 21.7%; P < .001). In the survival analysis, increased mortality was associated with increasing age (hazard ratio [HR], 1.02; 95% CI, 1.01-1.02; P < .001), male sex (HR, 1.14; 95% CI, 1.02-1.28; P = .02), and severe infectious complications in the 6 months before (HR, 3.14; 95% CI, 2.77-3.55; P < .001) and after (HR, 4.97; 95% CI, 4.41-5.60; P < .001) the first rituximab infusion. A total of 201 patients (4.5%) received immunoglobulin replacement following rituximab, and among these patients, higher cumulative immunoglobulin replacement dose was associated with a reduced risk of serious infectious complications (HR, 0.98; 95% CI, 0.96-0.99; P = .002). Conclusions and Relevance: Many patients are not being screened or properly identified as having hypogammaglobulinemia both before and after rituximab administration. Monitoring of immunoglobulin levels both before and after rituximab therapy may allow for earlier identification of risk for developing significant infection and identify patients who may benefit from immunoglobulin replacement, which may in turn help to avoid excess morbidity and mortality.


Assuntos
Agamaglobulinemia/complicações , Causas de Morte , Imunoglobulina G/sangue , Programas de Rastreamento , Rituximab/efeitos adversos , Adulto , Agamaglobulinemia/diagnóstico , Agamaglobulinemia/mortalidade , Idoso , Animais , Estudos de Coortes , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prevalência , Modelos de Riscos Proporcionais , Fatores de Risco , Índice de Gravidade de Doença
8.
J Autoimmun ; 80: 1-9, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28400082

RESUMO

Immune dysregulation is a prominent feature of primary immunodeficiency disorders, which commonly manifested as autoimmunity, cytopenias and inflammatory bowel disease. In partial T-cell immunodeficiency disorders, it has been proposed that the imbalance between effector and regulatory T-cells drives the breakdown of peripheral tolerance. While there is no robust test for immune dysregulation, the T-cell receptor repertoire is used as a surrogate marker, and has been shown to be perturbed in a number of immunodeficiency disorders featuring immune dysregulation including Omenn's Syndrome, Wiskott-Aldrich Syndrome, and common variable immunodeficiency. This review discusses how recent advances in TCR next-generation sequencing and bioinformatics have led to the in-depth characterization of CDR3 sequences and an exponential growth in examinable parameters. Specifically, we highlight the use of junctional diversity as a means to differentiate intrinsic T-cell defects from secondary causes of repertoire perturbation in primary immunodeficiency disorders. However, key questions, such as the identity of antigenic targets for large, expanded T-cell clonotypes, remain unanswered despite the fact that such clones are likely to play a pathogenic role in driving immune dysregulation and autoimmunity. Finally, we discuss a number of emerging technologies such as in silico reconstruction, high-throughput pairwise αß sequencing and single-cell RNAseq that offer the potential to define the antigenic epitope and function of a given T-cell, thereby enhancing our understanding in this field.


Assuntos
Síndromes de Imunodeficiência/imunologia , Receptores de Antígenos de Linfócitos T/genética , Linfócitos T/imunologia , Autoantígenos/imunologia , Autoimunidade , Células Clonais , Biologia Computacional , Mapeamento de Epitopos , Sequenciamento de Nucleotídeos em Larga Escala , Homeostase , Humanos , Análise de Célula Única
9.
J Immunol ; 198(7): 2543-2555, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28228560

RESUMO

Increased expression of Th22 cytokine IL-22 is a characteristic finding in atopic dermatitis (AD). However, the specific role of IL-22 in the pathogenesis of AD in vivo has yet to be elucidated. Consistent with observations in human AD, IL-22 was significantly increased in the AD skin of mice after epicutaneous sensitization to house dust mite allergen. Utilizing a skin-specific inducible transgenic system, we show in the present study that expression of IL-22 in the skin of mice caused an AD-like phenotype characterized by chronic pruritic dermatitis associated with Th2-biased local and systemic immune responses, downregulation of epidermal differentiation complex genes, and enhanced dermatitis upon epicutaneous allergen exposure. IL-22 potently induced the expression of gastrin-releasing peptide (GRP), a neuropeptide pruritogen, in dermal immune cells and sensory afferents and in their skin-innervating sensory neurons. IL-22 also differentially upregulated the expression of GRP receptor (GRPR) on keratinocytes of AD skin. The number of GRP+ cells in the skin correlated with the AD severity and the intensity of pruritus. IL-22 directly upregulated the expression of epithelial-derived type 2 cytokines (thymic stromal lymphopoietin and IL-33) and GRP in primary keratinocytes. Furthermore, GRP not only strongly induced thymic stromal lymphopoietin but it also increased the expression of IL-33 and GRPR synergistically with IL-22. Importantly, we found that the expression of GRP was strikingly increased in the skin of patients with AD. These results indicate that IL-22 plays important pathogenic roles in the initiation and development of AD, in part through inducing keratinocyte production of type 2 cytokines and activation of the GRP/GRPR pathway.


Assuntos
Dermatite Atópica/imunologia , Peptídeo Liberador de Gastrina/imunologia , Interleucinas/imunologia , Prurido/imunologia , Animais , Western Blotting , Modelos Animais de Doenças , Humanos , Imuno-Histoquímica , Queratinócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/imunologia , Pele/imunologia
10.
J Clin Immunol ; 37(3): 287-294, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28236219

RESUMO

PURPOSE: X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. METHODS: We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. RESULTS: In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. CONCLUSIONS: Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.


Assuntos
Agamaglobulinemia/diagnóstico , Trato Gastrointestinal/patologia , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Agamaglobulinemia/complicações , Agamaglobulinemia/terapia , Idoso de 80 Anos ou mais , Biomarcadores , Gastroenteropatias/diagnóstico , Gastroenteropatias/etiologia , Estudos de Associação Genética , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Humanos , Isotipos de Imunoglobulinas/sangue , Imunofenotipagem , Lactente , Subpopulações de Linfócitos/imunologia , Subpopulações de Linfócitos/metabolismo , Masculino , Mutação , Linhagem , Fenótipo
11.
Front Immunol ; 8: 1740, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29375540

RESUMO

Common variable immunodeficiency (CVID) is increasingly recognized for its association with autoimmune and inflammatory complications. Despite recent advances in immunophenotypic and genetic discovery, clinical care of CVID remains limited by our inability to accurately model risk for non-infectious disease development. Herein, we demonstrate the utility of unbiased network clustering as a novel method to analyze inter-relationships between non-infectious disease outcomes in CVID using databases at the United States Immunodeficiency Network (USIDNET), the centralized immunodeficiency registry of the United States, and Partners, a tertiary care network in Boston, MA, USA, with a shared electronic medical record amenable to natural language processing. Immunophenotypes were comparable in terms of native antibody deficiencies, low titer response to pneumococcus, and B cell maturation arrest. However, recorded non-infectious disease outcomes were more substantial in the Partners cohort across the spectrum of lymphoproliferation, cytopenias, autoimmunity, atopy, and malignancy. Using unbiased network clustering to analyze 34 non-infectious disease outcomes in the Partners cohort, we further identified unique patterns of lymphoproliferative (two clusters), autoimmune (two clusters), and atopic (one cluster) disease that were defined as CVID non-infectious endotypes according to discrete and non-overlapping immunophenotypes. Markers were both previously described {high serum IgE in the atopic cluster [odds ratio (OR) 6.5] and low class-switched memory B cells in the total lymphoproliferative cluster (OR 9.2)} and novel [low serum C3 in the total lymphoproliferative cluster (OR 5.1)]. Mortality risk in the Partners cohort was significantly associated with individual non-infectious disease outcomes as well as lymphoproliferative cluster 2, specifically (OR 5.9). In contrast, unbiased network clustering failed to associate known comorbidities in the adult USIDNET cohort. Together, these data suggest that unbiased network clustering can be used in CVID to redefine non-infectious disease inter-relationships; however, applicability may be limited to datasets well annotated through mechanisms such as natural language processing. The lymphoproliferative, autoimmune, and atopic Partners CVID endotypes herein described can be used moving forward to streamline genetic and biomarker discovery and to facilitate early screening and intervention in CVID patients at highest risk for autoimmune and inflammatory progression.

12.
BMJ Case Rep ; 20162016 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-26903364

RESUMO

We present a case of a 24-year-old woman with previously undiagnosed familial haemophagocytic lymphohistiocytosis (HLH). The patient presented with fevers and cough and was found to have pancytopaenia. She underwent an extensive work up and initially met only 3 of 8 criteria for HLH. Owing to high clinical suspicion, soluble CD25 level was sent and HLH2004 protocol initiated. The soluble CD25 level returned elevated with other laboratory work and the patient met criteria for diagnosis of HLH. Genetic studies revealed a homozygous mutation in PRF1 with absent perforin in cytotoxic cells, consistent with familial HLH. The patient expired before intrathecal chemotherapy could be initiated. This case illustrates the potential for familial HLH to present at an older age, and highlights the importance of early recognition and initiation of treatment of HLH, as patients may not initially fulfil the diagnostic criteria for HLH, and mortality is high if left untreated.


Assuntos
Encéfalo/diagnóstico por imagem , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfo-Histiocitose Hemofagocítica/diagnóstico por imagem , Perforina/genética , Evolução Fatal , Feminino , Homozigoto , Humanos , Linfo-Histiocitose Hemofagocítica/sangue , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/genética , Imagem por Ressonância Magnética , Mutação , Convulsões/etiologia , Adulto Jovem
14.
Dermatitis ; 22(1): 50-5, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21291644

RESUMO

Pruritus ani is a common distressing problem with numerous possible causes. When locally applied agents trigger irritation or allergic response, skin changes of dermatitis usually accompany the itch. Focal pruritus in the absence of dermatitis is not generally considered to be a manifestation of contact allergy. Furthermore, focal pruritus is not listed among the possible diverse presentations of the systemic delivery of a proven contact allergen. We report a case of a gentleman with a 1.5-year history of treatment-resistant pruritus ani. When patch testing revealed a positive reaction to nickel sulfate, he admitted to daily peanut butter consumption. His symptoms resolved with dietary nickel restriction. Patch testing may be useful in patients with pruritus of the anogenital region, not only to elucidate potential contact exposures contributing to the symptom but also to suggest possible dietary precipitants.


Assuntos
Dermatite de Contato/etiologia , Níquel/efeitos adversos , Prurido Anal/induzido quimicamente , Arachis/efeitos adversos , Arachis/química , Dermatite de Contato/dietoterapia , Humanos , Masculino , Pessoa de Meia-Idade , Testes do Emplastro , Prurido Anal/dietoterapia , Resultado do Tratamento
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