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1.
Front Immunol ; 10: 2618, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803180

RESUMO

Adult-onset primary immunodeficiency is characterized by recurrent infections, hypogammaglobulinemia, and poor antibody response to vaccines. In this study, we have analyzed targeted gene panel sequencing results of 270 patients diagnosed with antibody deficiency and identified five disease-associated variants in NFKB1 in five unrelated families. We detected two single base pair deletions and two single base pair insertions, causing severe protein truncations, and one missense mutation. Immunoblotting, lymphocyte stimulation, immunophenotyping, and ectopic expression assays demonstrated the functional relevance of NFKB1 mutations. Besides antibody deficiency, clinical manifestations included infections, autoimmune features, lymphoproliferation, lymphoma, Addison's disease, type 2 diabetes and asthma. Although partial clinical penetrance was observed in almost all pedigrees, all carriers presented a deficiency in certain serum immunoglobulins and the majority showed a lack of memory B cells (CD19+CD27+). Among all tested genes, NFKB1 alterations were the most common monoallelic cause of antibody deficiency in our cohort.

2.
Clin Immunol ; 210: 108269, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31683054

RESUMO

Genetic studies have led to identification of an increasing number of monogenic primary immunodeficiency disorders. Monoallelic pathogenic gain-of-function (GOF) variants in NFKBIA, the gene encoding IκBα, result in an immunodeficiency disorder, typically accompanied by anhidrotic ectodermal dysplasia (EDA). So far, 14 patients with immunodeficiency due to NFKBIA GOF mutations have been reported. In this study we report three patients from the same family with immunodeficiency, presenting with recurrent respiratory tract infections, bronchiectasis and viral skin conditions due to a novel pathogenic NFKBIA variant (c.106 T > G, p.Ser36Ala), which results in reduced IκBα degradation. Immunological investigations revealed inadequate antibody responses against vaccine antigens, despite hypergammaglobulinemia. Interestingly, none of the studied patients displayed features of EDA. Therefore, missense NFKBIA variants substituting serine 36 of IκBα, differ from the rest of pathogenic GOF NFKBIA variants in that they cause combined immunodeficiency, even in the absence of EDA.

3.
Sci Rep ; 9(1): 14552, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31601947

RESUMO

Although several risk factors exist for acute coronary syndrome (ACS) no biomarkers for survival or risk of re-infarction have been validated. Previously, reduced serum concentrations of anti-ß1AR Ab have been implicated in poorer ACS outcomes. This study further evaluates the prognostic implications of anti-ß1AR-Ab levels at the time of ACS onset. Serum anti-ß1AR Ab concentrations were measured in randomly selected patients from within the PLATO cohort. Stratification was performed according to ACS event: ST-elevation myocardial infarct (STEMI) vs. non-ST elevation myocardial infarct (NSTEMI). Antibody concentrations at ACS presentation were compared to 12-month all-cause and cardiovascular mortality, as well as 12-month re-infarction. Sub-analysis, stratifying for age and the correlation between antibody concentration and conventional cardiac risk-factors was subsequently performed. Serum anti-ß1AR Ab concentrations were measured in 400/799 (50%) STEMI patients and 399 NSTEMI patients. Increasing anti-ß1AR Ab concentrations were associated with STEMI (p = 0.001). Across all ACS patients, no associations between anti-ß1AR Ab concentration and either all-cause cardiovascular death or myocardial re-infarction (p = 0.14) were evident. However among STEMI patients ≤60 years with anti-ß1AR Ab concentration median (14/198 (7.1%) vs. 2/190 (1.1%)); p = 0.01). Similarly, the same sub-group demonstrated greater risk of cardiovascular death in year 1, including re-infarction and stroke (22/198 (11.1%) vs. 10/190 (5.3%); p = 0.017). ACS Patients ≤60 years, exhibiting lower concentrations of ß1AR Ab carry a greater risk for early re-infarction and cardiovascular death. Large, prospective studies quantitatively assessing the prognostic relevance of Anti-ß1AR Ab levels should be considered.

4.
Front Immunol ; 10: 1272, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379802

RESUMO

Introduction: The German PID-NET registry was founded in 2009, serving as the first national registry of patients with primary immunodeficiencies (PID) in Germany. It is part of the European Society for Immunodeficiencies (ESID) registry. The primary purpose of the registry is to gather data on the epidemiology, diagnostic delay, diagnosis, and treatment of PIDs. Methods: Clinical and laboratory data was collected from 2,453 patients from 36 German PID centres in an online registry. Data was analysed with the software Stata® and Excel. Results: The minimum prevalence of PID in Germany is 2.72 per 100,000 inhabitants. Among patients aged 1-25, there was a clear predominance of males. The median age of living patients ranged between 7 and 40 years, depending on the respective PID. Predominantly antibody disorders were the most prevalent group with 57% of all 2,453 PID patients (including 728 CVID patients). A gene defect was identified in 36% of patients. Familial cases were observed in 21% of patients. The age of onset for presenting symptoms ranged from birth to late adulthood (range 0-88 years). Presenting symptoms comprised infections (74%) and immune dysregulation (22%). Ninety-three patients were diagnosed without prior clinical symptoms. Regarding the general and clinical diagnostic delay, no PID had undergone a slight decrease within the last decade. However, both, SCID and hyper IgE- syndrome showed a substantial improvement in shortening the time between onset of symptoms and genetic diagnosis. Regarding treatment, 49% of all patients received immunoglobulin G (IgG) substitution (70%-subcutaneous; 29%-intravenous; 1%-unknown). Three-hundred patients underwent at least one hematopoietic stem cell transplantation (HSCT). Five patients had gene therapy. Conclusion: The German PID-NET registry is a precious tool for physicians, researchers, the pharmaceutical industry, politicians, and ultimately the patients, for whom the outcomes will eventually lead to a more timely diagnosis and better treatment.

5.
Clin Exp Rheumatol ; 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31140396

RESUMO

OBJECTIVES: Spondyloarthritis (SpA) is a chronic inflammatory disease of unknown aetiology. Previously, we identified autoantibodies against CD74 in sera of SpA patients. The aim of this study was to evaluate CD74 as a T cell antigen in SpA. METHODS: Recombinant CD74 protein and a panel of selected peptides representing its amino acid residues were examined for their capability to stimulate peripheral blood mononuclear cells from patients with SpA. In particular, cytokine production by CD4+ T cells was evaluated with flow cytometric detection of intracellular TNF-α, IFNγ, TGFß and IL-17A. Patients' sera were tested for antibodies against CD74 using ELISA. Samples from patients with rheumatoid arthritis and healthy blood donors were similarly tested as controls. RESULTS: Significantly more CD4+ T cells from SpA patients produced TNF-α, IFNγ and IL-17A in response to recombinant CD74 than patients with rheumatoid arthritis or healthy blood donors. Among evaluated epitopes, the most promiscuous one lies within the peptide of the amino acid residues 142-185, which appeared more immunogenic. Further, the proportion of cytokine producing CD4+ T cells was significantly higher among SpA patients with autoantibodies against CD74. CONCLUSIONS: CD74 is a T cell antigen in SpA, eliciting Th1 and Th17 responses, which may be relevant in disease pathogenesis. Recognition of the highly immunogenic amino acid residues of CD74 may contribute to our understanding of autoimmune responses of T helper cells in SpA.

7.
Diseases ; 7(2)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987377

RESUMO

Immunodeficiency, centromeric instability and facial anomalies syndrome 2 (ICF2) is a rare autosomal recessive primary immunodeficiency disorder. So far, 27 patients have been reported. Here, we present three siblings with ICF2 due to a homozygous ZBTB24 gene mutation (c.1222 T>G, p. (Cys408Gly)). Immune deficiency in these patients ranged from late-onset combined immunodeficiency (CID) with severe respiratory tract infections and recurrent shingles to asymptomatic selective antibody deficiency. Evident clinical heterogeneity manifested despite a common genetic background, suggesting the pathogenic relevance of epigenetic modification. Immunological follow-up reveals a previously unidentified gradual depletion of B and CD4⁺ T cells in all three presented patients with transition of a common variable immunodeficiency (CVID)-like disease to late-onset-CID in one of them. Considering all previously published cases with ICF2, we identify inadequate antibody responses to vaccines and reduction in CD27⁺ memory B cells as prevalent immunological traits. High mortality among ICF2 patients (20%) together with the progressive course of immunodeficiency suggest that hematopoietic stem cell transplantation (HSCT) should be considered as a treatment option in due time.

8.
Infect Dis Ther ; 7(4): 485-494, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30377976

RESUMO

INTRODUCTION: The way syphilis affects the immunologic and virologic parameters of a human immunodeficiency virus (HIV) infection remains controversial. The aim of this study was to investigate the impact of syphilis infection on lymphocyte and lymphocyte subset counts as well as viral load in HIV-infected patients. METHODS: All HIV-infected patients attending the outpatient clinic for infectious diseases of Hannover Medical University Hospital diagnosed with syphilis between 2009 and 2016 were retrospectively evaluated for changes in total lymphocyte, B cell, CD3+ T cell, CD4+ and CD8+ T cell counts as well as in HIV viral load. These parameters were assessed at three different time points, i.e., 3-6 months before, at diagnosis and 3-6 months after treatment of syphilis. RESULTS: Eighty-four HIV-infected patients, all with early syphilis, were identified. The vast majority were men who have sex with men (MSM), and 80% were receiving antiretroviral therapy (ART). Syphilis was associated with a significant reduction in the total lymphocyte count and counts of all studied lymphocyte subsets, including CD4+ T cells, whose percentage among lymphocytes did not change. No significant changes in HIV viral load were observed at any of the studied time points. Further, antibiotic treatment of syphilis restored lymphocyte counts back to pretreatment levels. CONCLUSION: Syphilis induces a relative non-CD4+ T cell-specific lymphopenia in HIV-infected patients. Our data suggest that serologic testing for syphilis should be considered in HIV-infected MSM in case of an otherwise unexplained drop in total lymphocyte count.

9.
J Med Case Rep ; 12(1): 332, 2018 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-30400821

RESUMO

BACKGROUND: Osteoarticular tuberculosis is rare in Germany. In particular, trochanteric bursitis is an extremely rare manifestation of osteoarticular tuberculosis. We describe a case of tuberculous coxitis with trochanteric bursitis, successfully treated with a fourfold tuberculostatic therapy. CASE PRESENTATION: We report the case of a 43-year-old human immunodeficiency virus-negative Sudanese man with osteoarticular tuberculosis, who was originally admitted with the suspected diagnosis of ankylosing spondylitis. Low grade fever together with the positive result of an interferon-gamma release assay test as well as findings from magnetic resonance imaging provided clues to the diagnosis. A definitive diagnosis could be set after a computed tomography-guided biopsy. CONCLUSIONS: Apart from a rare involvement pattern of osteoarticular tuberculosis, including trochanteric bursitis, this case highlights the increasing importance of osteoarticular tuberculosis as a differential diagnosis of rheumatic disorders. With the growing migration flows from tuberculosis-endemic African countries, clinicians in central and northern Europe may be more frequently confronted with atypical involvement patterns of osteoarticular tuberculosis.


Assuntos
Antituberculosos/uso terapêutico , Bursite/tratamento farmacológico , Bursite/fisiopatologia , Emigrantes e Imigrantes , Fêmur/fisiopatologia , Tuberculose Osteoarticular/diagnóstico , Tuberculose Osteoarticular/tratamento farmacológico , Adulto , Alemanha , Humanos , Masculino , Sudão , Resultado do Tratamento
10.
Artigo em Inglês | MEDLINE | ID: mdl-30275412

RESUMO

During the current period of immigration to Western Europe, national healthcare systems are confronted with high numbers of asylum seekers with largely unknown health status. To improve care taking strategies, we assessed healthcare utilization in a large, representative cohort of newly arriving migrants consisting of n = 1533 residents of a reception center in Northern Germany in 2015. Most asylum seekers were young, male adults, and the majority came from the Eastern Mediterranean region. Overall, we observed a frequency of 0.03 visits to the onsite primary healthcare ward per asylum seeker and day of camp residence (IQR 0.0⁻0.07, median duration of residence 38.0 days, IQR 30.0⁻54.25). Female asylum seekers showed higher healthcare utilization rates than their male counterparts, and healthcare utilization was particularly low in asylum seekers in their second decade of life. Furthermore, a significant correlation between time after camp entrance and healthcare utilization behavior occurred: During the first week of camp residence, 37.1 visits/100 asylum seekers were observed, opposed to only 9.5 visits/100 asylum seekers during the sixth week of camp residence. This first data on healthcare utilization in a large, representative asylum seeker cohort entering Western Europe during the current crisis shows that primary care is most needed in the first period directly after arrival. Our dataset may help to raise awareness for refugee and migrant healthcare needs and to adapt care taking strategies accordingly.


Assuntos
Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Refugiados/estatística & dados numéricos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Assistência à Saúde , Feminino , Alemanha , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Atenção Primária à Saúde , Migrantes/estatística & dados numéricos , Adulto Jovem
12.
Artigo em Inglês | MEDLINE | ID: mdl-29904012

RESUMO

BACKGROUND: In 2015, a high number of refugees with largely unknown health statuses immigrated to Western Europe. To improve caretaking strategies, we assessed the prevalence of latent tuberculosis infection (LTBI) in a refugee cohort. METHODS: Interferon-Gamma release assays (IGRA, Quantiferon) were performed in n = 232 inhabitants of four German refugee centers in the summer of 2015. RESULTS: Most refugees were young, male adults. Overall, IGRA testing was positive in 17.9% (95% CI = 13.2⁻23.5%) of subjects. Positivity rates increased with age (0% <18 years versus 46.2% >50 years). Age was the only factor significantly associated with a positive IGRA in multiple regression analysis including gender, C reactive protein, hemoglobin, leukocyte, and thrombocyte count and lymphocyte, monocyte, neutrophil, basophil, and eosinophil fraction. For one year change in age, the odds are expected to be 1.06 times larger, holding all other variables constant (p = 0.015). CONCLUSION: Observed LTBI frequencies are lower than previously reported in similar refugee cohorts. However, as elderly people are at higher risk for developing active tuberculosis, the observed high rate of LTBI in senior refugees emphasizes the need for new policies on the detection and treatment regimens in this group.


Assuntos
Tuberculose Latente/diagnóstico , Tuberculose Latente/epidemiologia , Refugiados/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Criança , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Testes de Liberação de Interferon-gama , Masculino , Pessoa de Meia-Idade , Prevalência , Fatores Sexuais , Teste Tuberculínico , Adulto Jovem
13.
J Immigr Minor Health ; 20(6): 1332-1338, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29582203

RESUMO

Currently, vast numbers of migrants with largely unknown health statuses have been entering Europe. To improve care taking strategies, prevalence, severity and types of anemia in a large refugee cohort were assessed. Blood counts were performed in n = 787 inhabitants from six German refugee centers. Most included migrants were young, male adults. Anemia was present in 22.5% of subjects with an age-dependent prevalence increase (7.9% > 18 years vs. 30.8% > 50 years). More females than males were anemic (27.1% vs. 20.4%). The majority of affected migrants had mild anemia (86.2%) of either normocytic/normochromic (55.9%) or microcytic/hypochromic (20.9%) type. Observed anemia frequencies are in accordance with global anemia prevalence recently estimated by the WHO. However, the observed high rates of anemia particularly in female and older refugees emphasize the need for adapted care taking strategies in refugee medicine. Further evaluation of causes of anemia in the migrating population is needed.


Assuntos
Anemia/etnologia , Refugiados/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Idoso , Anemia/classificação , Criança , Feminino , Alemanha/epidemiologia , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Índice de Gravidade de Doença , Fatores Sexuais , Adulto Jovem
15.
Eur J Immunol ; 48(4): 696-704, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29277896

RESUMO

IgG Fc receptors (FcγRs) and the C5a anaphylatoxin receptor (C5aR) were identified as key regulators of type II autoimmune injury in mice. However, and with respect to C5aR, the relative importance of C5a for IgG autoantibody-induced cellular destruction remained unclear. Using an experimental model of autoimmune hemolytic anemia (AIHA), we here report marked differences in the development of AIHA between mice lacking C5aR and C5-deficient (Hc0 ) strain, indicating a limited role of C5 in this type of C5aR-regulated disease. Ex-vivo-analyses of liver homogenates from anemic Hc0 mice demonstrate C5a-independent C5aR activation, upregulation of FcγR expression and amplification of erythrophagocytosis by macrophages. As assessed by pharmacological inhibition studies, targeting of C5aR, but not of C5, is effective in treating experimental AIHA. Collectively, these results define a previously unrecognized disease mechanism of C5aR activation in AIHA that does not necessarily involve C5 and C5a.


Assuntos
Anemia Hemolítica Autoimune/imunologia , Autoimunidade/imunologia , Complemento C5a/deficiência , Macrófagos do Fígado/imunologia , Receptor da Anafilatoxina C5a/metabolismo , Receptores de IgG/imunologia , Animais , Eritrócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fagocitose/imunologia , Receptor da Anafilatoxina C5a/antagonistas & inibidores , Receptor da Anafilatoxina C5a/genética , Receptores de IgG/biossíntese
16.
Inflammation ; 41(1): 42-49, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28852968

RESUMO

Store-operated calcium entry (SOCE) is the most common mode of calcium influx in non-excitable cells, including immune cells. The two STIM isoforms mediate SOCE as well as Fc receptor (FcR)-downstream activation of macrophages and mast cells-which appears to be relevant in vivo, in models of antibody-dependent tissue injury and allergy. Hence, the pathway of SOCE may be a therapeutic target for treatment of immune complex (IC)-mediated autoimmunity and allergic asthma. The pyrazole derivative, BTP2 is an efficient inhibitor of SOCE, which has already been shown to attenuate allergic inflammation. However, its effect on Fc gamma receptor (FcγR) signaling and IC-induced tissue injury had not yet been studied. Here, we show that BTP2 is a potent inhibitor of SOCE in primary macrophages, blocking FcγR-mediated responses. To investigate the effect of inhibition of SOCE in IC-mediated tissue injury, we induced reverse passive Arthus reaction to IgG immune complexes in the skin and lungs of BTP2- or control-treated mice. Treatment with BTP2 resulted in markedly attenuated inflammation in both the skin and the lungs. Our findings indicate the involvement of SOCE in FcγR-mediated responses in vitro and in vivo and suggest that BTP2-mediated inhibition of SOCE may have a therapeutic potential on IC-mediated autoimmunity.


Assuntos
Anilidas/farmacologia , Anti-Inflamatórios/farmacologia , Complexo Antígeno-Anticorpo/imunologia , Reação de Arthus/prevenção & controle , Imunoglobulina G/imunologia , Macrófagos Peritoneais/efeitos dos fármacos , Pneumonia/prevenção & controle , Tiadiazóis/farmacologia , Animais , Complexo Antígeno-Anticorpo/metabolismo , Reação de Arthus/imunologia , Reação de Arthus/metabolismo , Autoimunidade/efeitos dos fármacos , Sinalização do Cálcio/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Imunoglobulina G/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/metabolismo , Camundongos Endogâmicos C57BL , Fagocitose/efeitos dos fármacos , Pneumonia/imunologia , Pneumonia/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismo , Molécula 1 de Interação Estromal/metabolismo , Fatores de Tempo
17.
Front Cardiovasc Med ; 5: 170, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30619882

RESUMO

Background: Anti-beta-1-adrenergic receptor antibodies (anti-ß1AR Ab) are associated with ischemic cardiomyopathies (ICM). Evidence continues to emerge supporting an autoimmune component to various cardiac diseases. This study compares anti-ß1AR Ab concentrations in patients with different entities of acute coronary syndromes (ACS) to asymptomatic non-ACS patients with positron-emission computed tomography (PET/CT)-proven atherosclerosis, and healthy controls. Methods: Serum anti-ß1AR Ab IgG concentrations were measured in 212 ACS patients, 100 atherosclerosis patients, and 62 controls using ELISA. All ACS patients underwent coronary angiography. All 374 patients participating completed a structured questionnaire regarding traditional cardiovascular risk factors. ACS patients were followed up for 6 months. Results: Patients with ACS exhibited lower anti-ß1AR Ab levels compared to patients with atherosclerosis or healthy controls (both p < 0.001). No differences in the ab levels were evident between healthy controls and patients with atherosclerosis. In the ACS groups, lower concentrations were found in patients with ST-elevation myocardial infarction (STEMI) (0.67 µg/ml) compared to patients with angina pectoris (AP) and non-ST elevation myocardial infarction (NSTEMI) (both 0.76 µg/ml, p = 0.008). Anti-ß1AR Ab levels ≤ 0.772 µg/ml were predictive for death and reinfarction (AUC 0.77, p = 0.006). No significant correlations between anti-ß1AR Ab levels and atherosclerotic burden or traditional cardiovascular risk factors were identified. Conclusions: Lower anti-ß1AR Ab concentrations appear to characterize ACS phenotypes and could serve as diagnostic and prognostic markers independent from traditional risk factors for atheroscle. The prognostic predictive value of anti-ß1AR Ab in ACS remains to be confirmed in larger studies.

18.
Front Immunol ; 8: 885, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28804486

RESUMO

INTRODUCTION: Interleukin 12 receptor beta 1 (IL12Rß1) deficiency is a primary immunodeficiency resulting mainly in susceptibility to opportunistic infection by non-tuberculous, environmental mycobacteria and severe infection caused by Salmonella spp. Till now, less than 300 patients with IL12Rß1 deficiency have been reported. Among them, only three have been described to develop autoimmunity. CASE PRESENTATION: We present the case of a 50-year-old male with IL12Rß1 deficiency due to compound heterozygosity [c. 1623_1624delGCinsTT (pGln542Stop) and c.1791 + 2T > C (donor splice site)], who-18 months after diagnosis of disseminated BCGitis-presented with recurrent fever and sicca syndrome. No indication of an infectious origin of these symptoms could be found at that point. The diagnosis of a Sjögren's syndrome (SS) was made on the basis of fulfilled American-European consensus classification criteria, including a positive minor salivary gland biopsy. CONCLUSION: Apart from persistent antigenic stimulation, which may drive autoimmune inflammation in primary immunodeficiency, evidence on the involvement of interleukin 12 in pathogenesis of SS suggests that the same immunological mechanism may underlie both defense against infection and the maintenance of tolerance. To our knowledge, this is the first report of a case of autoimmunity in the form of SS in a patient with a primary immunodeficiency and one of the rare cases of IL12Rß1 deficiency with manifested autoimmunity.

19.
Immun Inflamm Dis ; 3(3): 154-70, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26417434

RESUMO

Calcium (Ca(2+)) signaling in immune cells, including macrophages, controls a wide range of effector functions that are critical for host defense and contribute to inflammation and autoimmune diseases. However, receptor-mediated Ca(2+) responses consist of complex mechanisms that make it difficult to identify the pathogenesis and develop therapy. Previous studies have revealed the importance of the Ca(2+) sensor STIM1 and store-operated Ca(2+)-entry (SOCE) for Fcγ-receptor activation and IgG-induced inflammation. Here, we identify the closely related STIM2 as mediator of cell migration and cytokine production downstream of GPCR and TLR4 activation in macrophages and show that mice lacking STIM2 are partially resistant to inflammatory responses in peritonitis and LPS-induced inflammation. Interestingly, STIM2 modulates the migratory behavior of macrophages independent from STIM1 and without a strict requirement for Ca(2+) influx. While STIM2 also contributes in part to FcγR activation, the C5a-induced amplification of IgG-mediated phagocytosis is mainly dependent on STIM1. Blockade of STIM-related functions limits mortality in experimental models of AIHA and LPS-sepsis in normal mice. These results suggest benefits of Ca(2+)-inhibition for suppression of exacerbated immune reactions and illustrate the significance of alternate functions of STIM proteins in macrophage activation and in the context of innate immune inflammation.

20.
Eur J Immunol ; 45(7): 2143-53, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25912155

RESUMO

Stromal interaction molecule 1 (STIM1)-dependent store operated calcium-entry (SOCE) through Orai1-mediated calcium (Ca(2+) ) influx is considered a major pathway of Ca(2+) signaling, serving T-cell, mast cell, and platelet responses. Here, we show that Orai1 is critical for neutrophil function. Orai1-deficient neutrophils present defects in fMLP and complement C5a-induced Ca(2+) influx and migration, although they respond normally to another chemoattractant, CXCL2. Up until now, no specific contribution of Orai1 independent from STIM1 or SOCE has been recognized in immune cells. Here, we observe that Orai1-deficient neutrophils exhibit normal STIM1-dependent SOCE and STIM1-deficient neutrophils respond to fMLP and C5a efficiently. Despite substantial cytokine production, Orai1(-/-) chimeric mice show impaired neutrophil recruitment in LPS-induced peritonitis. Moreover, Orai1 deficiency results in profoundly defective C5a-triggered neutrophil lung recruitment in hypersensitivity pneumonitis. Comparative evaluation of inflammation in Stim1(-/-) chimeras reveals a distinct pathogenic contribution of STIM1, including its involvement in IgG-induced C5a production. Our data establish Orai1 as key signal mediator of C5aR activation, contributing to inflammation by a STIM1-independent pathway of Ca(2+) -influx in neutrophils.


Assuntos
Canais de Cálcio/imunologia , Complemento C5a/imunologia , Inflamação/imunologia , Infiltração de Neutrófilos/imunologia , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína ORAI1 , Receptor da Anafilatoxina C5a/imunologia
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