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1.
Artigo em Inglês | MEDLINE | ID: mdl-32060950

RESUMO

BACKGROUND: There is no data regarding the prevalence of malignancies in patients with primary immunodeficiency (PID) in Turkey. Along with the prevalence of malignancy, we aimed to present the types of malignancy and define the underlying immune deficiency of the patients. METHOD: Between the years 1992 and 2018 years, from 5 tertiary immunology clinics, fifty-nine patients with PID who developed malignancy were included. All patients were evaluated for demographics, clinical features, and prognosis. RESULTS: The prevalence of malignancy in our cohort was detected as 0.9% (59/6392). The male to female ratio was 1.8 (38/21), and the median age of patients was 14 years (range: 1.5 - 51). The median age at diagnosis of malignancy was 10 years (range: 1.5 - 51). Ataxia-telangiectasia was the most frequent PID in patients with malignancy (n= 19, 32.2%), and non-Hodgkin lymphoma was the most common malignancy (n= 32, 51.6%). The rate of malignancy in DOCK8 deficiency (n=7/43, 16.3%) was higher than AT (n=19/193, 9.8%), WAS (n=2/22, 9.1%) and CVID (n=11/205, 5.4%). EBV quantitative PCR was positive in 16 out of 53 patients (30.2%). Three patients had secondary malignancies. Remission was achieved in 26 patients (44.1%). However, 31 patients (52.5%) died. Two patients (3.4%) are still on chemotherapy. CONCLUSION: This study is the largest cohort investigating the association of malignancy in patients with PID in Turkey. While lymphoid malignancies were the most common malignancy and observed more frequently in AT patients, the risk for malignancy was higher in patients with DOCK8 deficiency then AT.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31887391

RESUMO

BACKGROUND: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant. OBJECTIVE: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant. METHOD: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. RESULTS: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. CONCLUSION: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

3.
J Allergy Clin Immunol Pract ; 7(8): 2790-2800.e15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31238161

RESUMO

BACKGROUND: LPS-responsive beige-like anchor (LRBA) deficiency presents with susceptibility to infections, autoimmunity, and lymphoproliferation. The long-term efficacy of cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin (abatacept) as targeted therapy for its immune dysregulatory features remains to be established. OBJECTIVE: To determine the clinical and immunologic features of LRBA deficiency and long-term efficacy of abatacept treatment in controlling the different disease manifestations. METHODS: Twenty-two LRBA-deficient patients were recruited from different immunology centers and followed prospectively. Eighteen patients on abatacept were evaluated every 3 months for long-term clinical and immunologic responses. LRBA expression, lymphocyte subpopulations, and circulating T follicular helper cells were determined by flow cytometry. RESULTS: The mean age of the patients was 13.4 ± 7.9 years, and the follow-up period was 3.4 ± 2.3 years. Recurrent infections (n = 19 [86.4%]), immune dysregulation (n = 18 [81.8%]), and lymphoproliferation (n = 16 [72.7%]) were common clinical features. The long-term benefits of abatacept in 16 patients were demonstrated by complete control of lymphoproliferation and chronic diarrhea followed by immune dysregulation, most notably autoimmune cytopenias. Weekly or every other week administration of abatacept gave better disease control compared with every 4 weeks. There were no serious side effects related to the abatacept therapy. Circulating T follicular helper cell frequencies were found to be a reliable biomarker of disease activity, which decreased on abatacept therapy in most subjects. However, high circulating T follicular helper cell frequencies persisted in 2 patients who had a more severe disease phenotype that was relatively resistant to abatacept therapy. CONCLUSIONS: Long-term abatacept therapy is effective in most patients with LRBA deficiency.

4.
Case Reports Immunol ; 2018: 6897935, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30405923

RESUMO

When caring for patients with life-limiting diseases, improving survival and optimizing quality of life are the primary goals. For patients with X-linked hyper-IgM syndrome (XHIGM), the treatment modality has to be decided for a particular patient regarding hematopoietic stem cell transplantation or intravenous immunoglobulin replacement therapy with P. jiroveci prophylaxis. A seven-year-old male patient was admitted with recurrent upper and lower respiratory tract infections and recurrent otitis media. His initial immunologic evaluation revealed low IgG and normal IgA and IgM levels with normal lymphocyte phenotyping and inadequate specific antibody responses. He was diagnosed as common variable immunodeficiency and began to receive intravenous immunoglobulin (IVIG) (0.5 gm/kg) with four-week intervals. During follow-up for 23 years under IVIG therapy, he was extremely well and never had severe infections. In 2017, targeted next generation sequencing was performed in order to understand his molecular pathology. A previously described hemizygous c.31C>T(p.Arg11Ter) mutation was found in CD40LG gene. The mother was heterozygous carrier for this mutation and his sister did not have any mutation. Flow cytometric analysis for CD40LG expression on activated T cells showed highly decreased, but not absent, CD40LG expression. In conclusion, diagnostic delay is a clinical problem for patients with CD40LG deficiency, because of low or normal IgM levels, showing that all the hypogammaglobulinemic patients, not only with high serum IgM levels, but also with normal to low IgM levels, have to be examined for CD40LG expression on activated T lymphocytes. Secondly, type of CD40LG mutations leads to enormous interpatient variations regarding serum IgM levels, CD40LG levels on activated T cells, age at diagnosis, severity of clinical findings, and follow-up therapies with or without hematopoietic stem cell therapy.

5.
Pediatr Int ; 60(10): 911-917, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30103264

RESUMO

BACKGROUND: Primary immunodeficiency disorder (PID), being a chronic disorder, may increase the prevalence of psychopathologies, but there are few studies on the effect of disease-related factors on psychopathology in this population. The aim of this study was therefore to assess and compare three groups: children with PID who receive i.v. immunoglobulin treatment; children with juvenile idiopathic arthritis (JIA); and healthy controls with respect to their mental health status. METHODS: Forty-four children with PID, 32 children with JIA and 30 healthy controls, underwent psychiatric evaluation. The Childhood Depression Inventory and the screen for child anxiety-related emotional disorders questionnaire were completed by the participants. The child behavior checklist was completed by the mothers of the participants. In addition, disease-related factors were identified. RESULTS: The frequency of mood disorders between the three groups differed. There was no difference between the PID and JIA groups with respect to the prevalence of mood disorders and other psychopathologies. The disease-related factors were associated with the frequency of mood disorder in PID patients. CONCLUSION: The rate of psychopathology was similar in patients with PID and JIA and higher than the controls. Some of the disease-related factors were associated with the frequency of mood disorders in the PID patients.


Assuntos
Síndromes de Imunodeficiência/psicologia , Transtornos Mentais/etiologia , Adolescente , Artrite Juvenil/psicologia , Estudos de Casos e Controles , Criança , Efeitos Psicossociais da Doença , Estudos Transversais , Feminino , Humanos , Masculino , Transtornos Mentais/diagnóstico , Transtornos Mentais/epidemiologia , Escalas de Graduação Psiquiátrica , Fatores de Risco
6.
Avicenna J Med Biotechnol ; 10(3): 192-195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30090215

RESUMO

Background: The Transmembrane Activator and Calcium modulator ligand Interactor (TACI), encoded by TNFRSF13B/TACI gene, is mutated in some patients with Common Variable Immunodeficiency (CVID) and IgA Deficiency (IgAD). The purpose of the study was to investigate for the first time in Turkish patients the prevalence of TNFRSF13B alterations in CVID, selective and partial IgAD patients. Methods: Forty two CVID, 36 selective IgAD, 34 partial IgAD and 25 healthy controls were included. All patients were examined for TNFRSF13B gene mutations by PCR. Results: The percentages of TNFRSF13B mutations in CVID, selective and partial IgAD patients were 7.1, 2.7 and 2.9%, respectively. No disease causing TNFRSF13B mutation in healthy controls was found. Patients with TACI mutations had recurrent respiratory tract infections. None of them experienced autoimmunity, bronchiectasis or granulomatous disease. In conclusion, TNFRSF13B mutations were present not only in CVID patients, but also in IgAD cases. Conclusion: Modifier genes as well as their combination with other genetic or environmental factors may play an important role in the development of the immunodeficiency phenotype.

8.
Int J Immunopathol Pharmacol ; 32: 2058738418779458, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29978731

RESUMO

Common variable immunodeficiency (CVID) and immunoglobulin A deficiency (IgAD) are the most prevalent primary immunodeficiency disorders. High rates of familial inheritance have been described in CVID and IgAD, but it is unknown in different ethnic populations. We aimed to determine the prevalence of familial cases and whether they showed more severe clinical characteristics than sporadic ones in Turkish patients. A total of 40 CVID and 70 IgAD patients and their 251 first-degree relatives (FDRs) were evaluated. Demographic, clinical, and laboratory data were reviewed. A familial case was defined as a patient with at least one affected FDR (A-FDR). The rate of parental consanguinity was 19.1%. There were 37 familial cases (37/110) (33.6%) with at least one A-FDR. There were 48 A-FDRs who had immunoglobulins lower than age-related normals (48/251) (19.1%). Pulmonary infections were significantly higher in familial cases. To our knowledge, this study includes the highest number of CVID/IgAD patients and their FDRs in literature. Familial cases are at least 30% of the IgAD and CVID patients, and they have more frequent lower respiratory tract infections than sporadic ones, so these patients have to be evaluated depending on their being familial or sporadic for better management. The risk of carrying any immunologic alterations in relatives of patients with IgAD and CVID is approximately 20%. Although most A-FDRs are asymptomatic, considering the risk of progression to CVID by age, we highly recommend routine screening for FDRs.


Assuntos
Imunodeficiência de Variável Comum/epidemiologia , Consanguinidade , Deficiência de IgA/epidemiologia , Imunoglobulina A/sangue , Adulto , Imunodeficiência de Variável Comum/genética , Imunodeficiência de Variável Comum/imunologia , Feminino , Hereditariedade , Humanos , Deficiência de IgA/genética , Deficiência de IgA/imunologia , Masculino , Pessoa de Meia-Idade , Linhagem , Turquia
9.
Turk Pediatri Ars ; 52(3): 138-144, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29062247

RESUMO

AIM: Susceptibility to mycobacterial diseases is observed in some primary immunodeficiency diseases. In this study, we aimed to evaluate mycobacterial infections in primary immunodeficiency diseases. MATERIAL AND METHODS: Patients under follow-up by Ege University Pediatric Immunology Department for severe combined and combined immunodeficiencies, interleukin 12/ interferon gamma receptor deficiency, nuclear factor kappa-beta essential modulator deficiency and chronic granulomatosis disease were evaluated retrospectively in terms of the frequency and characteristics of mycobacterial infections using a questionnaire form for demographic properties, clinical features and laboratory tests. RESULTS: A diagnosis of mycobacterial infection was made clinically in a total of 25 patients including five (11.3%) of 45 patients who had severe combined immune deficiency, 12 (52.3%) of 21 patients who had chronic granulomatous disease, four patients (100%) who had interferon gamma receptor 2 partical deficiency, two patients (100%) who had interleukin 12 receptor beta 1 deficiency and one patient (100%) who had nuclear factor kapa-beta essential modulator deficiency. Mycobacterium strain could be typed in 14 (33%) of these 25 patients including Mycobacterium bovis, Mycobacterium chelonea, Mycobacterium elephantis, Mycobacterium fortuitum, and Mycobacterium tuberculosis. All patients were treated with anti-tuberculosis therapy. Thirty-six percent of these 25 patients underwent hematopoietic stem cell transplantation. Eight patients (five before, three after transplantation) died. CONCLUSIONS: Non-tuberculosis mycobacteria including mainly Mycobacterium bovis were observed with a higher rate compared to Mycobacterium tuberculosis in primary immunodeficiencies, especially in those affecting the interleukin 12/interferon gamma pathway. Early diagnosis of primary immunodeficiencies with neonatal screening program and preventing administration of the Bacille Calmette-Guerin vaccine in these patients is important.

10.
Int J Immunopathol Pharmacol ; 30(2): 194-200, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28449602

RESUMO

In order to evaluate B-lymphocyte subsets of patients with primary immunodeficiencies, the normal values for national healthy children have to be used as a reference. Recently, B-cell co-receptor markers (CD19, CD21, and CD81) and CD20, CD22, and CD27 deficiencies have been reported in relation with different primary immunodeficiency diseases. The objective of this study was to establish national reference values for B-lymphocyte co-receptors and some surface markers, CD20, CD22, CD27, as well as classic lymphocyte subsets in the peripheral blood of healthy children. A total of 90 healthy children were included in this study. Complete blood counts were performed and cells with CD3, CD4, CD8, CD19, CD16/56, CD20, CD21, CD22, CD27, and CD81 surface markers were simultaneously detected by flow cytometry. The children were evaluated in three age subgroups, 0-1, 1-6, and >6 years, and minimum, maximum, mean, mean minus standard deviation, and 2.5-97.5 percentile values were all determined. By establishing reliable reference ranges for these surface markers, we hoped to help identifying and classifying some primary immunodeficiency patients, especially those defined as unclassified hypogammaglobulinemia and those without definite diagnosis.


Assuntos
Antígenos de Superfície/sangue , Proteínas de Membrana/sangue , Adolescente , Antígenos de Superfície/imunologia , Linfócitos B/imunologia , Criança , Pré-Escolar , Feminino , Voluntários Saudáveis , Humanos , Síndromes de Imunodeficiência/sangue , Síndromes de Imunodeficiência/imunologia , Lactente , Recém-Nascido , Masculino , Proteínas de Membrana/imunologia , Valores de Referência , Turquia
11.
Case Reports Immunol ; 2016: 5459029, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27699073

RESUMO

Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

12.
J Clin Med Res ; 8(5): 379-84, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-27081423

RESUMO

BACKGROUND: Severe combined immunodeficiency (SCID) syndromes are a heterogenous group of diseases characterized by impairment in both cellular and humoral immunity with a range of genetic disorders. Complete recombinase activating gene (RAG) deficiency is associated with classical T(-)B(-)NK(+) SCID which is the most common phenotype of Turkish SCID patients. There is a broad spectrum of hypomorfic RAG mutations including Omenn syndrome, leaky or atypical SCID with expansion of γδ T cells, autoimmunity and cytomegalovirus (CMV) infections. METHODS: Twenty-one (44%) patients had RAG1 deficiency of all 44 SCID patients followed up by pediatric immunology department. A retrospective analysis was conducted on the medical records of all SCID patients with RAG1 deficiency. RESULTS: Eight patients were classified as T(-)B(-)NK(+) SCID, five patients as T(+)B(-)NK(+) SCID (three of these were Omenn phenotype), and eight patients as T(+)B(+)NK(+) SCID phenotype. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were 87.7 ± 73.8 (12 - 256), 4.4 ± 8.2 (1 - 36) and 29.1 ± 56.8 (1 - 244) months, respectively. Consanguinity was present in 11 (52%) of 21 patients. Autoimmunity was found in six patients (28%). Ten patients (47%) had CMV infection, four (19%) had Epstein-Barr virus (EBV) infections and three (14%) had Bacillus Calmette-Guerin (BCG) infections. Seven patients who had refractory cytopenia (two pancytopenia and five bicytopenia) underwent bone marrow biopsy, three of whom had bone marrow fibrosis. Future evaluations must be considered about bone marrow fibrosis in RAG1 deficiency patients. Eosinophilia was observed in 10 patients, seven of whom did not have Omenn phenotype. CONCLUSION: Non-Omenn phenotype RAG1 deficiencies can also present with eosinophilia. This report is presented to emphasize that RAG1 mutations may lead to diverse clinical phenotypes.

13.
Int J Immunopathol Pharmacol ; 29(2): 241-51, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26684629

RESUMO

Common variable immunodeficiency (CVID) is a heterogeneous group of primary antibody deficiencies characterized by decreased serum immunoglobulin G along with a decrease in serum IgA and/or IgM, defective specific antibody production, and recurrent bacterial infections. Abnormal lymphocyte trafficking, dysregulated cellular responses to chemokines, and uncontrolled T cell polarization may be involved in the pathogenesis and may help to understand the clinical complications. We evaluated T helper cell subsets (chemokine receptors CCR4, CCR5, and CCR7), expressions on T lymphocytes, intracellular cytokines - IL-2, IL-4, IL-13, IFN- γ-on CD4(+) T cells, and expression of CD4(+)CD25(+)Foxp3(+) regulatory T cells of 20 CVID patients and 26 healthy controls. Autoimmune clinical findings and other complications were also determined. Percentages and absolute numbers of CD4(+)CD25(+) Foxp3(+) cells did not show any significant difference between CVID cases and healthy controls nor between severe and moderate disease patients. The only significant difference regarding Th1 and Th2 type intracellular cytokines was the decreased absolute numbers of CD3(+)CD4(+)IL4(+) cells in CVID cases. There were some findings about T helper cell type dominance in CVID patients such as positive correlation between hepatomegaly and high IL-2 and IFN-γ in CD3(+)CD4(+) cells and very high expression of CCR5 (Th1) on CD3(+)CD4(+) cells in patients with granuloma. Th1 (CCR5) and Th2 (CCR4) type chemokine receptors did not show any dominance in CVID cases. However, frequencies of CCR7 expressing CD3(+) T cells, CD3(+)CD4(+) T helper cells and CD3(+)CD8(+) T cytotoxic cells were significantly lower in severe CVID patients. In addition, presence of autoimmune clinical findings was negatively correlated with CCR7(+) cells. As CCR7 is a key mediator balancing immunity and tolerance in the immune system, the abnormality of this mediator may contribute to the profound immune dysregulation seen in CVID. In addition, Th1 cells seem to be more involved in the disease pathogenesis than Th2 cells.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Imunodeficiência de Variável Comum/imunologia , Citocinas/imunologia , Receptores de Quimiocinas/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Interferon gama/imunologia , Interleucina-13/imunologia , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Interleucina-4/imunologia , Ativação Linfocitária/imunologia , Masculino , Receptores CCR4/imunologia , Receptores CCR5/imunologia
14.
Asian Pac J Allergy Immunol ; 33(4): 312-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26708396

RESUMO

BACKGROUND: Patients with transient hypogammaglobulinaemia of infancy (THI) may have mild infections or be asymptomatic. About 20% of THI patients have very severe and recurrent infections and receive intravenous immunoglobulins (IVIg) for replacement therapy and infection prophylaxis. It is still not clear why some THI patients are severely symptomatic; it has been suggested that there might be additional immunologic or environmental factors or other co-morbidities. OBJECTIVE: As an immunological factor, Fcγ receptor polymorphisms (H/H-131, H/R-131 and R/R-131 for FcγIIa; V/V-158, V/F-158 and F/F-158 for FcγRIIIa; NA1/NA1, NA1/NA2 and NA2/NA2 for FcγRIIIb) were analysed in THI patients who had very severe infections and need hospitalisation (treated with IVIg) (n:18) and in THI patients who were asymptomatic or had mild infections (treated with antibiotics or received no medication) (n:25). RESULTS: Genotypic distributions between two groups did not deviate significantly from the Hardy-Weinberg equilibrium expectations (p > 0.05) and odds ratios for "disease risk estimate" did not show any dominance for any genotype. Allele frequencies did not show any significant difference between the two groups (p >0.05). The number of infections per year for each Fcγ receptor genotype was not significantly different between both groups. CONCLUSION: There is no association between the heterogeneous clinical picture of THI patients and Fcγ receptor gene polymorphisms.


Assuntos
Agamaglobulinemia/genética , Polimorfismo Genético , Receptores de IgG/genética , Criança , Pré-Escolar , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Masculino
15.
J Med Case Rep ; 9: 145, 2015 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-26100510

RESUMO

INTRODUCTION: Interleukin-1 receptor antagonist deficiency is a rare autoinflammatory disease involving neonatal onset of pustulosis, periostitis, and sterile osteomyelitis. The underlying genetic abnormality involves a recessive mutation in IL1RN, which encodes interleukin-1 receptor antagonist. In this case report, we describe a case of a 12-year-old Turkish girl who initially was presented at 1 year of age, older than previously reported children with interleukin-1 receptor antagonist deficiency, and with a novel mutation, p.R26X, in ILR1N. CASE PRESENTATION: Our patient developed pustular cutaneous lesions at 1 year of age. At the age of 12 years, she was hospitalized for arthralgia of her knees, elbows, and ankles and arthritis of the left knee, with simultaneous pustular cutaneous lesions. She was admitted to the intensive care unit because of septicemia and respiratory insufficiency during follow-up. A skin biopsy of hyperpigmented lesions demonstrated neutrophil infiltration in the epidermis and subepidermal pustular dermatosis. Interleukin-1 receptor antagonist deficiency was suspected, and genetic analysis revealed a homozygous mutation (p.R26X) in IL1RN, which led to a diagnosis of interleukin-1 receptor antagonist deficiency. Treatment with canakinumab (recombinant human anti-human interleukin-1ß monoclonal antibody) 150 mg subcutaneously once every 6 weeks was initiated. Our patient did not experience further cutaneous lesions or arthritis. Her post-treatment inflammatory markers were normal; she gained weight; and she was able to walk independently. CONCLUSIONS: In this case report, we describe a patient with interleukin-1 receptor antagonist deficiency who responded excellently to canakinumab treatment. We believe more awareness is warranted for interleukin-1 receptor antagonist deficiency in children. It is possible that the mutation in our patient was a founder mutation that may lead to diagnosis of additional cases in Turkey.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Proteína Antagonista do Receptor de Interleucina 1/genética , Mutação/genética , Anticorpos Monoclonais Humanizados , Criança , Feminino , Humanos , Resultado do Tratamento , Turquia
16.
Front Immunol ; 6: 145, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25964782

RESUMO

Defective adaptive immune responses are well studied in common variable immunodeficiency (CVID) patients; however, more focus is needed on innate immune system defects to explain CVID's clinical and laboratory heterogeneity. This is the first study comparing migratory function of granulocytes, oxidative burst activity of phagocytic cells, surface integrin expressions on neutrophils and lymphocytes, natural killer (NK) cell numbers and cytotoxic activity, natural killer T cells, lymphocyte subsets such as CD8(+)CD28(+), CD4(+)CTLA-4(+) cells in CVID patients (n: 20) and healthy controls (n: 26). The relationship between laboratory findings and some clinical was also investigated. CD3(+)CD8(+) T cytotoxic cells were found to be elevated in CVID patients, but CD3(+)CD8(+)CD28(+) or CD3(+)CD8(+)CD28(-) cells did not show any significant difference. CD4(+)CTLA-4(+) cell percentages were significantly lower in CVID patients compared to healthy controls. Severe CVID patients had decreased percentages of NK cells with increased NK cell cytotoxicity suggesting possibly increased activation. Furthermore, CD3(-)CD16(+)CD56(+)CD28(+) cells of CVID patients were elevated while percentage of CD28(-) NK cells was decreased. Neutrophil migration percentages were lower but and oxidative burst activity was not affected. CD11a expressions on these cells were depressed in contrast to increased expression of CD18. Innate immunity defects may affect the extent of recurrence and severity of infections in CVID. Our observations highlight some of these associations and indicate the need for further similar studies for improving better innate system evaluation batteries for these patients. Further phenotypic correlations of these analyses will help clinicians reach a more definitive target for the molecular genetic diagnostic of pediatric CVID patients.

17.
J Clin Immunol ; 33(1): 74-83, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22983506

RESUMO

PURPOSE: Primary immunodeficiency diseases (PIDs) are inherited disorders of the immune system resulting in increased susceptibility to unusual infections and predisposition to autoimmunity and malignancies. The European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This study aimed to provide a minimum estimate of the prevalence of each disorder and to determine the clinical characteristics and outcomes of patients with PID in Turkey. METHODS: Clinical features of 1435 patients with primary immunodeficiency disorders are registered in ESID Online Patient Registry by the Pediatric Immunology Departments of the Medical Faculties of Uludag University and Ege University Between 2004 and 2010. These two centers are the major contributors reporting PID patients to ESID database from Turkey. RESULTS: Predominantly antibody immunodeficiency (73.5 %) was the most common category followed by autoinflammatory disorders (13.3 %), other well defined immunodeficiencies (5.5 %), congenital defects of phagocyte number, function or both 3.5 %), combined T and B cell immunodeficiencies (2 %), defects in innate immunity (1 %), and diseases of immune dysregulation (0.7 %). Patients between 0 and 18 years of age constitued 94 % of total and the mean age was 9.2 ± 6 years. The consanguinity rate within the registered patients was 14.3 % (188 of 1130 patients). The prevalance of all PID cases ascertained from the registry was 30.5/100.000. The major cause of the mortality was severe infection which was seen in forty-two of seventy five deceased patients. The highest mortality was observed in patients with severe combined immunodeficiencies and ataxia-telangiectasia. CONCLUSION: Promoting the awareness of PID among the medical professionals and the general public is required if premature death and serious morbidity occurs due to late diagnosis of the wider spectrum of PID are to be avoided.


Assuntos
Imunodeficiência de Variável Comum/diagnóstico , Imunodeficiência de Variável Comum/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Imunodeficiência de Variável Comum/imunologia , Bases de Dados Factuais , Feminino , Hospitais Universitários , Humanos , Lactente , Masculino , Prevalência , Sistema de Registros , Turquia/epidemiologia , Adulto Jovem
18.
Ital J Pediatr ; 38: 8, 2012 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-22424479

RESUMO

BACKGROUND: Severe combined immunodeficiency is within a heterogeneous group of inherited defects throughout the development of T- and/or B-lymphocytes. Mutations in recombinase-activating genes 1 or 2 (RAG1/2) represent approximately 10% of all SCID cases. RAG1/2 are essential for V(D)J rearrangement of the B- and T-cell receptors. OBJECTIVES: The aim of this study was to review clinical, immunological and molecular findings of Turkish SCID patients with RAG1 defects and to draw attention to novel mutations, genotype-phenotype correlations and the high rate of BCG infections within this group. METHODS: Eleven patients (F/M: 6/5) were included. Molecular, immunological and clinical data were evaluated. RESULTS: Five patients were classified as T-B-NK + SCID, four patients as T + B-NK + SCID (two of these patients were diagnosed as classical Omenn syndrome) and two patients as T + B + NK + SCID with respect to clinical presentations and immunological data. Mean age of the whole study group, mean age at onset of symptoms and mean age at diagnosis were: 33.0 ± 42.8, 3.1 ± 3.3 and 10.4 ± 13.5 months, respectively. Consanguinity rate was 54%. Some novel mutations were found in RAG1 gene in addition to previously reported mutations. Genotype-phenotype correlation was not significantly apparent in most of the cases. BCG infection was observed in 36.4% of patients (two BCG-osis and two BCG-itis). CONCLUSION: Epigenetic factors such as compound genetic defects, enviromental factors, and exposure to recurrent infections may modify phenotypical characteristics of RAG deficiencies. Inoculation of live vaccines such as BCG should be postponed until primary immunodeficiency disease is excluded with appropriate screening tests in suspected cases.


Assuntos
Genes RAG-1/genética , Mutação , Imunodeficiência Combinada Severa/genética , Adulto , Linfócitos B/imunologia , Vacina BCG , Consanguinidade , Epigênese Genética , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Imunodeficiência Combinada Severa/classificação , Imunodeficiência Combinada Severa/imunologia , Imunodeficiência Combinada Severa/terapia , Linfócitos T/imunologia , Turquia
19.
Int Immunopharmacol ; 11(11): 1747-51, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21771668

RESUMO

BACKGROUND: IgA deficiency (IgAD) is the most common primary antibody deficiency. Although two-third of the cases are reported to be asymptomatic, some IgAD children may have frequent infections that urge the clinicians to search for prophylactic measures. OM-85 BV is one of these agents that is known to stimulate mucosa associated lymphoid tissue, and upregulate Th-1 response. This study was performed to determine a possible role of OM-85 BV in triggering autoimmunity in IgAD children within a four-year-follow up period. METHODS: Sixty-three children (34 males (54%), 29 females (46%)) with sporadic IgAD and recurrent febrile infections were included. Patients were carefully screened for autoimmunity both on admission and in follow-up: Those with autoimmune features or under immunosuppressant treatment were excluded. Patients were randomly divided into two groups: Group I received bacterial lysate propylaxis (OM-85 BV) (n:37), and Group 2 received no prophylactic regimen (n:26). Development of clinical autoimmune findings or autoantibodies (anti-nuclear antibody (ANA), ANA profile (14 antigens), anti-cytoplasmic antibodies (ANCA), anti-cardiolipin antibodies IgG and IgM (aCL), rheumatoid factor (RF), direct Coombs test, anti-thyroglobulin (anti-T) and anti-thyroid microsomal antigen (anti-M)) were evaluated. RESULTS: Mean age of the study group, age at the onset of infectious symptoms and at admission were 102.9±42.2, 27.1±24.9, and 55.2±25.1 months, respectively. Follow-up duration of the whole study group was 48.3±23.1 months. Number of infections was 6.2±2.7 per year in the whole study group. Sixteen patients (25.4%) of the whole study group showed ANA positivity in different patterns and titers. Frequency of ANA, ANCA and RF positivity was 24.3%, 5.4%, 2.7% in Group 1, and 26.9%, 11.5%, 3.8% in Group 2, respectively. Statistical comparisons revealed no significant difference between the two groups. CONCLUSION: Significant clinical or laboratory markers for autoimmunity in follow-up were not observed between receivers or non-receivers of OM-85 BV. Frequency of ANA positivity was comparable to the previously reported values in IgAD children which was not affected by OM-85 BV usage. Possible effect of triggering autoimmunity with repeated cures of bacterial lysates needs to be further clarified. Side effects requiring the cessation of treatment were not recorded.


Assuntos
Adjuvantes Imunológicos/efeitos adversos , Autoimunidade/efeitos dos fármacos , Extratos Celulares/efeitos adversos , Deficiência de IgA/prevenção & controle , Imunidade nas Mucosas/efeitos dos fármacos , Adjuvantes Imunológicos/uso terapêutico , Autoanticorpos/sangue , Extratos Celulares/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Deficiência de IgA/imunologia , Imunidade nas Mucosas/imunologia , Imunoglobulina A/sangue , Masculino , Estudos Prospectivos
20.
Eur J Pediatr ; 170(8): 1039-47, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21274562

RESUMO

UNLABELLED: Hyper-IgM syndromes are characterized by normal or elevated serum IgM levels with the absence or reduced levels of other immunoglobulins. There are some patients with defective class-switch recombination (CSR) who do not have CD40L, CD40, AID, and UNG defects. The aim of this study is to determine the B-cell functions of patients with Hyper-IgM type 4 phenotype. Ten patients (seven males and three females) 84.2 ± 16.5 months of age with initial low serum IgG and IgA and high or normal IgM levels were included. Clinically, 50% had recurrent upper respiratory tract, 10% urinary tract, 10% lower respiratory tract infections, and 30% had mixed type infections. Lymphoid hyperplasia, overt autoimmune manifestations, or malignancy was not noted. Seven of 10 patients were studied twice; at the age of 34.2 ± 13.7 and at 86.6 ± 12.3 months. Absolute lymphocyte counts and lymphocyte subsets were normal in all cases. All of them had normal expression of CD40 on B cells and CD40L on activated T cells for males. At first examination, all patients had normal in vitro sCD40L+rIL-4-induced B cell proliferation response and somatic hypermutation but CSR towards IgE was absent. AID and UNG genes did not show any abnormalities. All showed improvement in both clinical findings and Ig levels during the follow-up period of 55.8 ± 14.8 months. Ages for normalization of IgG and IgA were 68.2 ± 8.7 and 70.2 ± 21.6 months, respectively. During the second evaluation: In vitro sCD40L+rIL-4-induced B-cell proliferation was normal in all cases, whereas CSR was still abnormal in five of eight patients. Two of the patients had an increase in in vitro CSR response but still low IgG2 subclass levels. Three patients with initially absent in vitro CSR response also normalized. CONCLUSION: Clinical manifestations and immunoglobulin levels of the patients with Hyper-IgM type 4 phenotype recovered in late childhood at about 6 years of age. There was a transient CSR defect which was not observed in cases with transient hypogammaglobulinemia of infancy. Detection of a non-AID or non-UNG associated CSR defect in infancy should be confirmed later on since spontaneous recovery may occur.


Assuntos
Síndrome de Imunodeficiência com Hiper-IgM/imunologia , Imunoglobulinas/sangue , Subpopulações de Linfócitos B/metabolismo , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Síndrome de Imunodeficiência com Hiper-IgM/complicações , Síndrome de Imunodeficiência com Hiper-IgM/genética , Contagem de Linfócitos , Masculino , Fenótipo , Remissão Espontânea , Estudos Retrospectivos
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