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2.
J Autoimmun ; 101: 145-152, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31054942

RESUMO

BACKGROUND: Cytotoxic T lymphocyte antigen-4 (CTLA-4) limits T-cell activation and is expressed on T-regulatory cells. Human CTLA-4 deficiency results in severe immune dysregulation. Abatacept (CTLA-4 Ig) is approved for the treatment of rheumatoid arthritis (RA) and its mechanism of action is attributed to effects on T-cells. It is known that CTLA-4 modulates the expression of its ligands CD80 and CD86 on antigen presenting cells (APC) by transendocytosis. As B-cells express CD80/CD86 and function as APC, we hypothesize that B-cells are a direct target of abatacept. OBJECTIVES: To investigate direct effects of abatacept on human B-lymphocytes in vitro and in RA patients. METHODS: The effect of abatacept on healthy donor B-cells' phenotype, activation and CD80/CD86 expression was studied in vitro. Nine abatacept-treated RA patients were studied. Seven of these were followed up to 24 months, and two up to 12 months only and treatment response, immunoglobulins, ACPA, RF concentrations, B-cell phenotype and ACPA-specific switched memory B-cell frequency were assessed. RESULTS: B-cell development was unaffected by abatacept. Abatacept treatment resulted in a dose-dependent decrease of CD80/CD86 expression on B-cells in vitro, which was due to dynamin-dependent internalization. RA patients treated with abatacept showed a progressive decrease in plasmablasts and serum IgG. While ACPA-titers only moderately declined, the frequency of ACPA-specific switched memory B-cells significantly decreased. CONCLUSIONS: Abatacept directly targets B-cells by reducing CD80/CD86 expression. Impairment of antigen presentation and T-cell activation may result in altered B-cell selection, providing a new therapeutic mechanism and a base for abatacept use in B-cell mediated autoimmunity.

3.
Front Immunol ; 10: 514, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941143

RESUMO

Objective: Rheumatic diseases with involvement of the central nervous system (RDwCNS) may mimic multiple sclerosis (MS). Inversely, up to 60% of MS-patients have antinuclear autoantibodies (ANAs) and may be misdiagnosed as RDwCNS. The detection of antibodies against extractable nuclear antigens (ENA) and oligoclonal bands (OCB) are established valuable diagnostic tools in the differential diagnosis of RDwCNS and MS. The MRZ-reaction (MRZR) is defined by three antibody indices (AIs) against neurotropic viruses and is frequently positive in MS. To investigate the added value of MRZR combined with testing for antibodies against ENAs and OCB detection to distinguish RDwCNS from ANA positive MS. Methods: MRZR was evaluated in RDwCNS (n = 40) and 68 ANA positive MS-patients. Two stringency levels, MRZR-1 and MRZR-2 (at least one respectively two of three AIs positive) were applied. Autoantibody testing included ANA plus ENA and anti-dsDNA antibodies, antiphospholipid antibodies, and anti-neutrophil cytoplasmic antibodies. Results: Most of the RDwCNS patients (n = 32; 80%) suffered from systemic lupus erythematosus. Within the RDwCNS group 20% had a positive MRZR-1 and 8.5% a positive MRZR-2 compared to 80.9 and 60%, respectively within the MS-group (p < 0.0001 for both comparisons). Oligoclonal bands were found in 28.6% of the RDwCNS patients and 94.3% of the MS-patients (p < 0.0001). Conversely, autoantibodies to specific nuclear antigens or phospholipids were found more frequently in RDwCNS. A positive MRZR in conjunction with the absence of ENA autoantibodies distinguished MS from RDwCNS with high specificity (97.5%). Conclusions: We suggest combining MRZR, OCBs, and specific autoantibody diagnostics to differentiate RDwCNS from MS.

4.
Transfusion ; 59(2): 454-457, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30727042

RESUMO

BACKGROUND: Few and inconsistent data exist describing the effect of storage duration on glycated hemoglobin (HbA1c) concentrations of red blood cells (RBCs), impeding interpretation of HbA1c values in transfused diabetic patients. Hence the aim of this study was to evaluate to what extent HbA1c concentrations of RBCs change during the maximum allowed storage period of 42 days. STUDY DESIGN AND METHODS: Blood was drawn from 16 volunteers, leukofiltered, and stored under standard blood banking conditions. HbA1c concentrations of RBCs were measured on Days 1 and 42 of storage using three different validated devices (ion-exchange high-performance liquid chromatography Method A1 and A2, turbidimetric immunoassay Method B). RESULTS: Mean HbA1c concentrations of RBCs on Day 1 were 5.3 ± 0.3% (Method A1), 5.4 ± 0.4% (Method A2), and 5.1 ± 0.4% (Method B). HbA1c concentrations increased to 5.6 ± 0.3% (A1, p < 0.0001), 5.7 ± 0.3% (A2, p = 0.004), and 5.5 ± 0.4% (B, p < 0.0001) on Day 42, respectively, corresponding to a 1.06-fold increase across all methods. Glucose concentrations in the storage solution of RBCs decreased from 495 ± 27 to 225 ± 55 mg/dL (p < 0.0001), confirming that stored RBCs were metabolically active. CONCLUSION: These results suggest a significant, albeit minor, and most likely clinically insignificant increase in HbA1c concentrations during storage of RBCs for 42 days.


Assuntos
Bancos de Sangue , Preservação de Sangue , Eritrócitos/metabolismo , Hemoglobina A Glicada/metabolismo , Adulto , Eritrócitos/citologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Tempo
6.
Artigo em Inglês | MEDLINE | ID: mdl-29729943

RESUMO

BACKGROUND: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is a negative immune regulator. Heterozygous CTLA4 germline mutations can cause a complex immune dysregulation syndrome in human subjects. OBJECTIVE: We sought to characterize the penetrance, clinical features, and best treatment options in 133 CTLA4 mutation carriers. METHODS: Genetics, clinical features, laboratory values, and outcomes of treatment options were assessed in a worldwide cohort of CTLA4 mutation carriers. RESULTS: We identified 133 subjects from 54 unrelated families carrying 45 different heterozygous CTLA4 mutations, including 28 previously undescribed mutations. Ninety mutation carriers were considered affected, suggesting a clinical penetrance of at least 67%; median age of onset was 11 years, and the mortality rate within affected mutation carriers was 16% (n = 15). Main clinical manifestations included hypogammaglobulinemia (84%), lymphoproliferation (73%), autoimmune cytopenia (62%), and respiratory (68%), gastrointestinal (59%), or neurological features (29%). Eight affected mutation carriers had lymphoma, and 3 had gastric cancer. An EBV association was found in 6 patients with malignancies. CTLA4 mutations were associated with lymphopenia and decreased T-, B-, and natural killer (NK) cell counts. Successful targeted therapies included application of CTLA-4 fusion proteins, mechanistic target of rapamycin inhibitors, and hematopoietic stem cell transplantation. EBV reactivation occurred in 2 affected mutation carriers after immunosuppression. CONCLUSIONS: Affected mutation carriers with CTLA-4 insufficiency can present in any medical specialty. Family members should be counseled because disease manifestation can occur as late as 50 years of age. EBV- and cytomegalovirus-associated complications must be closely monitored. Treatment interventions should be coordinated in clinical trials.

7.
BMC Neurol ; 18(1): 14, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-29386006

RESUMO

BACKGROUND: Some rheumatologic disorders may initially manifest with central nervous system (CNS) affection, mimicking the clinical, magnetic resonance imaging, and cerebrospinal fluid findings of multiple sclerosis (MS). The MRZ reaction (MRZR), composed of the three respective antibody indices (AIs) against measles, rubella, and varicella zoster virus, has been found positive frequently in MS patients. However, it is unclear whether the MRZR is helpful to distinguish rheumatologic disorders with CNS involvement (RDwCNS) from MS. METHODS: The MRZR was evaluated in patients with RDwCNS (n = 23), MS (n = 46; age and sex matched to patients with RDwCNS), and other inflammatory autoimmune neurological diseases affecting the CNS (OIND; n = 48). Both the stringency levels that have been used in previous MRZR studies, MRZR-1 (≥ 1 of 3 AIs positive) and MRZR-2 (≥ 2 of 3 AIs positive), were applied. RESULTS: There was no statistically significant difference in the prevalence of positive MRZR between patients with RDwCNS (MRZR-1: 13.0% and MRZR-2: 8.7%, respectively) and OIND (MRZR-1: 22.9% and MRZR-2: 8.3%, respectively). Compared to these two study cohorts, the MS group exhibited significantly higher prevalences of positive MRZR (MRZR-1: 82.6%, MRZR-2: 63.0%; p < 0.005 each). CONCLUSIONS: Considering the high specificity of MRZR-2 for MS found in this study, MRZR-2 can be a useful diagnostic tool for distinguishing MS from RDwCNS or OIND.


Assuntos
Anticorpos Antivirais/líquido cefalorraquidiano , Artrite Reumatoide/diagnóstico , Esclerose Múltipla/diagnóstico , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Herpesvirus Humano 3/imunologia , Humanos , Masculino , Vírus do Sarampo/imunologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Vírus da Rubéola/imunologia , Adulto Jovem
9.
Eur J Haematol ; 99(5): 449-458, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28886228

RESUMO

OBJECTIVE: The heavy/light chain (HLC)-immunoassay quantifies light chain types of each immunoglobulin class in patients with monoclonal gammopathies. METHODS: We assessed 147 consecutive patients with different forms and stages of plasma cell dyscrasias (PCD) who received standard tests (serum and urine protein electrophoresis [SPEP, UPEP], immunofixation [IFE], serum-free light chain [SFLC]), and HLC-immunoassay. Patients with multiple myeloma (MM, n = 102), smoldering MM (SMM, n = 5), monoclonal gammopathy of undetermined significance (MGUS, n = 28), and Waldenström's macroglobulinemia (WM, n = 12) were included. RESULTS: We verified a significant correlation between HLC- and standard monoclonal protein (mp)-parameters, and HLC-increases with higher disease stage and unfavorable remission status. In patients with difficult to quantify mp, more abnormal HLC- than SPEP-, immunoglobulin-, or SFLC-results were found. In WM, a pathological HLC κ/λ-ratio and M-component were observed in 95% and 58%, respectively. In 21/28 MGUS and 5/5 SMM patients, HLC κ/λ-ratios were abnormal. Testing different HLC cutoffs, patients with extreme HLC values showed impaired progression-free survival (PFS). CONCLUSIONS: Despite the fact that different PCD patients were included, the assessment of the HLC-immunoassay in MGUS, SMM, MM, and WM, our comparison with standard mp-assays, and relevant PFS differences may excite future applications, which should be confirmed in prospective multicenter trials.


Assuntos
Imunoensaio , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paraproteinemias/mortalidade , Paraproteínas , Sensibilidade e Especificidade , Avaliação de Sintomas
10.
J Allergy Clin Immunol Pract ; 5(6): 1556-1563, 2017 Nov - Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28916432

RESUMO

BACKGROUND: Rituximab (RTX) is approved for induction therapy of granulomatosis with polyangiitis and microscopic polyangiitis. In eosinophilic granulomatosis with polyangiitis (EGPA), organ-threatening manifestations are mainly treated with cyclophosphamide (CYC). RTX as treatment in EGPA has been described in small case series; however long-term data and the efficacy of RTX in EGPA refractory to CYC have not been reported yet. OBJECTIVES: To investigate the efficacy and safety of RTX and conventional immunosuppressive therapy with CYC in EGPA as induction therapy and during long-term follow-up. METHODS: Retrospective analysis of 28 patients with EGPA was done. Treatment response and disease activity were determined by Birmingham Vasculitis Activity Score, C-reactive protein, eosinophils, antineutrophil cytoplasmic antibody, and peripheral CD19+ B cells. RESULTS: Fourteen patients with EGPA treated with RTX were compared with 14 age- and sex-matched patients with EGPA treated with CYC for remission induction; 64% of the RTX-treated patients with EGPA had previously failed CYC treatment. Disease duration was longer and the number of previous immunosuppressants higher in RTX-treated patients. Five RTX-treated patients (36%) and 4 CYC-treated patients (29%) achieved complete remission. All other patients were in partial remission. There was no difference between both groups in respect to treatment response and partial and complete remission. In both treatment groups, eosinophils, C-reactive protein, and IgE levels dropped. Relapse-free survival within an observation period of 36 months was comparable between RTX- and CYC-treated patients. RTX was well tolerated, but resulted in a decline in serum immunoglobulin levels. CONCLUSIONS: RTX was effective in inducing remission and during long-term follow-up in patients with EGPA, even when previously refractory to standard immunosuppressive therapy including CYC. RTX-treated patients should be monitored for hypogammaglobulinemia.


Assuntos
Linfócitos B/imunologia , Síndrome de Churg-Strauss/tratamento farmacológico , Ciclofosfamida/uso terapêutico , Eosinófilos/imunologia , Granulomatose com Poliangiite/tratamento farmacológico , Imunossupressores/uso terapêutico , Rituximab/uso terapêutico , Adulto , Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Proteína C-Reativa/metabolismo , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
11.
PLoS One ; 12(6): e0178646, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28575093

RESUMO

Stomatin is an ancient, widely expressed, oligomeric, monotopic membrane protein that is associated with cholesterol-rich membranes/lipid rafts. It is part of the SPFH superfamily including stomatin-like proteins, prohibitins, flotillin/reggie proteins, bacterial HflK/C proteins and erlins. Biochemical features such as palmitoylation, oligomerization, and hydrophobic "hairpin" structure show similarity to caveolins and other integral scaffolding proteins. Recent structure analyses of the conserved PHB/SPFH domain revealed amino acid residues and subdomains that appear essential for the structure and function of stomatin. To test the significance of these residues and domains, we exchanged or deleted them, expressed respective GFP-tagged mutants, and studied their subcellular localization, molecular dynamics and biochemical properties. We show that stomatin is a cholesterol binding protein and that at least two domains are important for the association with cholesterol-rich membranes. The conserved, prominent coiled-coil domain is necessary for oligomerization, while association with cholesterol-rich membranes is also involved in oligomer formation. FRAP analyses indicate that the C-terminus is the dominant entity for lateral mobility and binding site for the cortical actin cytoskeleton.


Assuntos
Proteínas de Membrana/metabolismo , Mutação , Animais , Células COS , Linhagem Celular Tumoral , Cercopithecus aethiops , Colesterol/metabolismo , Proteínas de Fluorescência Verde/genética , Humanos , Proteínas de Membrana/química , Proteínas de Membrana/genética , Simulação de Dinâmica Molecular , Ligação Proteica , Relação Estrutura-Atividade , Frações Subcelulares/metabolismo
14.
Blood Cells Mol Dis ; 64: 15-22, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28301811

RESUMO

Recent studies on erythrocyte membrane fluctuations revealed that the erythrocyte cytoskeleton actively modulates its membrane association thereby regulating crucial membrane properties. Cationic amphiphilic drugs like chlorpromazine are known to induce a cup-like cell shape and vesicle formation into the cell interior, effectors of this process, however, are largely unknown. Using flow cytometry, this study explored conditions that influence endovesiculation induced by chlorpromazine. We found that inhibitors of membrane fluctuations, like ATP depletion, vanadate or fluoride, also inhibited endovesiculation whereas activation of PKC, known to decrease cytoskeleton association and increase membrane fluctuations, also enhanced endovesicle formation. This indicates that endovesicle formation and membrane fluctuations are modulated by the same cytoskeleton-regulated membrane properties. Further, acanthocytic erythrocytes of chorea acanthocytosis (ChAc) patients that lack the VPS13A/chorein protein - likely a crucial organizer at the erythrocyte cytoskeleton/membrane interface - showed a strong decrease in chlorpromazine-induced endovesiculation. The responses of ChAc erythrocytes to effectors of endovesiculation were similar to that of control erythrocytes, yet at drastically reduced levels. This suggests a more rigid and less dynamic interaction at the membrane-cytoskeleton interphase of ChAc erythrocytes.


Assuntos
Clorpromazina/administração & dosagem , Vesículas Citoplasmáticas/metabolismo , Citoesqueleto/metabolismo , Membrana Eritrocítica/metabolismo , Neuroacantocitose/sangue , Proteínas de Transporte Vesicular/deficiência , Clorpromazina/efeitos adversos , Vesículas Citoplasmáticas/patologia , Citoesqueleto/patologia , Membrana Eritrocítica/patologia , Feminino , Citometria de Fluxo , Humanos , Masculino , Neuroacantocitose/tratamento farmacológico
15.
Cell Rep ; 18(9): 2189-2202, 2017 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-28249164

RESUMO

B cell activating factor (BAFF) provides B cells with essential survival signals. It binds to three receptors: BAFFR, TACI, and BCMA that are differentially expressed by B cell subsets. BAFFR is early expressed in circulating B cells and provides key signals for further maturation. Here, we report that highly regulated BAFFR processing events modulate BAFF responses. BAFFR processing is triggered by BAFF binding in B cells co-expressing TACI and it is executed by the metalloproteases ADAM10 and ADAM17. The degree of BAFF oligomerization, the expression of ADAM proteins in different B cell subsets, and the activation status of the cell determine the proteases involved in BAFFR processing. Inhibition of ADAM10 augments BAFF-dependent survival of primary human B cells, whereas inhibition of ADAM17 increases BAFFR expression levels on germinal center B cells. Therefore, BAFF-induced processing of BAFFR regulates BAFF-mediated B cell responses in a TACI-dependent manner.


Assuntos
Proteínas ADAM/metabolismo , Fator Ativador de Células B/metabolismo , Receptor do Fator Ativador de Células B/metabolismo , Subpopulações de Linfócitos B/metabolismo , Sobrevivência Celular/fisiologia , Peptídeo Hidrolases/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Linhagem Celular , Humanos , Ligação Proteica/fisiologia
16.
Cell Mol Life Sci ; 74(13): 2413-2438, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28243699

RESUMO

The BAR domain is the eponymous domain of the "BAR-domain protein superfamily", a large and diverse set of mostly multi-domain proteins that play eminent roles at the membrane cytoskeleton interface. BAR domain homodimers are the functional units that peripherally associate with lipid membranes and are involved in membrane sculpting activities. Differences in their intrinsic curvatures and lipid-binding properties account for a large variety in membrane modulating properties. Membrane activities of BAR domains are further modified and regulated by intramolecular or inter-subunit domains, by intermolecular protein interactions, and by posttranslational modifications. Rather than providing detailed cell biological information on single members of this superfamily, this review focuses on biochemical, biophysical, and structural aspects and on recent findings that paradigmatically promote our understanding of processes driven and modulated by BAR domains.


Assuntos
Membrana Celular/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Animais , Humanos , Fosforilação , Ligação Proteica , Domínios Proteicos , Mapeamento de Interação de Proteínas
17.
Immunol Cell Biol ; 94(9): 830-837, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27126628

RESUMO

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B-cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ-like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.


Assuntos
Linfócitos B/imunologia , Linfocitose/imunologia , Transdução de Sinais/imunologia , Adulto , Antígenos CD40/metabolismo , Pré-Escolar , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica , Humanos , Ativação Linfocitária/imunologia , Linfocitose/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Fosforilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Antígenos de Linfócitos B/metabolismo
18.
Hum Mol Genet ; 24(25): 7361-72, 2015 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-26476407

RESUMO

Null mutations in genes involved in V(D)J recombination cause a block in B- and T-cell development, clinically presenting as severe combined immunodeficiency (SCID). Hypomorphic mutations in the non-homologous end-joining gene DCLRE1C (encoding ARTEMIS) have been described to cause atypical SCID, Omenn syndrome, Hyper IgM syndrome and inflammatory bowel disease-all with severely impaired T-cell immunity. By whole-exome sequencing, we investigated the molecular defect in a consanguineous family with three children clinically diagnosed with antibody deficiency. We identified perfectly segregating homozygous variants in DCLRE1C in three index patients with recurrent respiratory tract infections, very low B-cell numbers and serum IgA levels. In patients, decreased colony survival after irradiation, impaired proliferative response and reduced counts of naïve T cells were observed in addition to a restricted T-cell receptor repertoire, increased palindromic nucleotides in the complementarity determining regions 3 and long stretches of microhomology at switch junctions. Defective V(D)J recombination was complemented by wild-type ARTEMIS protein in vitro. Subsequently, homozygous or compound heterozygous DCLRE1C mutations were identified in nine patients from the same geographic region. We demonstrate that DCLRE1C mutations can cause a phenotype presenting as only antibody deficiency. This novel association broadens the clinical spectrum associated with ARTEMIS mutations. Clinicians should consider the possibility that an immunodeficiency with a clinically mild initial presentation could be a combined immunodeficiency, so as to provide appropriate care for affected patients.


Assuntos
Proteínas Nucleares/genética , Imunodeficiência Combinada Severa/genética , Linfócitos B/metabolismo , Criança , Pré-Escolar , Endonucleases , Feminino , Humanos , Imunoglobulina A/metabolismo , Masculino , Mutação/genética
20.
J Clin Immunol ; 35(5): 439-44, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25943627

RESUMO

PURPOSE: X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was originally described in male patients with X-linked lymphoproliferative syndrome type 2 (XLP2). Recent observations have highlighted a critical role of XIAP for the regulation of NOD2 signaling and are probably the molecular basis for increasingly recognized further immune dysregulatory symptoms of XIAP deficient patients, such as inflammatory bowel disease (IBD). We describe a large Caucasian family in which IBD and erythema nodosum (EN) also manifested in female carriers of XIAP mutations. METHODS: Clinical data and laboratory findings including flow cytometric analysis of XIAP protein expression and sequencing of the BIRC4 gene. NOD2 signaling was investigated by determination of TNFα production in monocytes upon L18-MDP stimulation in vitro. RESULTS: The BIRC4 nonsense mutation p.P225SfsX226 was identified as the genetic cause of XIAP deficiency in our family. Surprisingly, clinical symptoms were not restricted to male patients, but also occurred in several female carriers. The most severely affected carrier demonstrated random X-inactivation, leading to a significant expression of mutated XIAP protein in monocytes, and consequently to impaired NOD2 responses in vitro. CONCLUSION: Our report provides further evidence that clinical symptoms of XIAP deficiency are not restricted to male patients. Random X-inactivation may be associated with EN and mild IBD also in female carriers of BIRC4 mutations. Analysis of the X-inactivation pattern reflected by XIAP protein expression can identify such carriers and the analysis of NOD2 signaling by flow cytometry can confirm the functional significance. XIAP expression patterns should be investigated in female patients with a family history of EN and/or IBD.


Assuntos
Eritema Nodoso/diagnóstico , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Doenças Inflamatórias Intestinais/diagnóstico , Transtornos Linfoproliferativos/diagnóstico , Monócitos/metabolismo , Viroses/diagnóstico , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/genética , Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Acetilmuramil-Alanil-Isoglutamina/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Portador Sadio , Células Cultivadas , Criança , Pré-Escolar , Eritema Nodoso/etiologia , Eritema Nodoso/genética , Grupo com Ancestrais do Continente Europeu , Evolução Fatal , Feminino , Doenças Genéticas Ligadas ao Cromossomo X/complicações , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Doenças Inflamatórias Intestinais/etiologia , Doenças Inflamatórias Intestinais/genética , Transtornos Linfoproliferativos/complicações , Transtornos Linfoproliferativos/genética , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Mutação/genética , Proteína Adaptadora de Sinalização NOD2/metabolismo , Linhagem , Fatores Sexuais , Transdução de Sinais/genética , Fator de Necrose Tumoral alfa/metabolismo , Viroses/etiologia , Viroses/genética
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