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BACKGROUND: Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. METHODS: We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. RESULTS: We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis. CONCLUSIONS: The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype.

MeSH
agamaglobulinemie genetika imunologie MeSH
aktivace lymfocytů genetika imunologie MeSH
B-lymfocyty imunologie MeSH
buněčná diferenciace genetika imunologie MeSH
dítě MeSH
dospělí MeSH
fosfatidylinositol-3-kinasy genetika MeSH
fosforylace genetika MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mutace genetika imunologie MeSH
plazmatické buňky imunologie MeSH
předškolní dítě MeSH
prekurzorové B-lymfoidní buňky imunologie MeSH
přesmyk imunoglobulinových tříd genetika imunologie MeSH
protoonkogenní proteiny c-akt genetika MeSH
recidiva MeSH
signální transdukce genetika MeSH
somatická hypermutace imunoglobulinových genů genetika imunologie MeSH
Check Tag
dítě MeSH
dospělí MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
předškolní dítě MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH

Kapitola

Proměny léčby Brutonovy agamaglobulinemie

Skáčiková, Lucia
Autor Autorita Ústav imunologie a mikrobiologie 1. LF UK a VFN, Praha

Imunopatologické stavy v kazuistikách. 2016 ; () : 46-52.

ISBN 978-80-204-4124-9
Medvik
Zdroj

MeSH
agamaglobulinemie * diagnóza farmakoterapie genetika MeSH
anamnéza MeSH
antibakteriální látky farmakologie terapeutické užití MeSH
ateroskleróza farmakoterapie MeSH
chronická obstrukční plicní nemoc farmakoterapie MeSH
dospělí MeSH
genetické testování využití MeSH
intravenózní imunoglobuliny farmakologie terapeutické užití MeSH
klinické laboratorní techniky MeSH
lidé MeSH
výsledek terapie MeSH
Check Tag
dospělí MeSH
lidé MeSH
mužské pohlaví MeSH
Publikační typ
kazuistiky MeSH

Článek

X-linked agammaglobulinemia caused by new mutation in BTK gene: a case report

Biomedical papers of the Medical Faculty of the University Palacký, Olomouc Czech Republic. 2014 ; 158 (3) : 470-473. [pub] 20130322

Biomed. Pap. Fac. Med. Palacký Univ. Olomouc Czech Repub. (Print)
ISSN 1213-8118
Medvik
Zdroj

AIM: Primary immunodeficiencies (PID) are becoming a recognized public health problem worldwide. The most important subgroup of these disorders are the antibody deficiencies. X-linked agammaglobulinaemia was the first described entity of this group and is characterised by early onset of recurrent bacterial infections, profound deficiency of all immunoglobulin isotypes and markedly reduced number of peripheral B-lymphocytes. CASE REPORT: We report the case of a 10-year old boy with X-linked agammaglobulinaemia caused by a previously non-described mutation in BTK gene with typical clinical presentation but delayed diagnosis. Following diagnosis, substitution therapy with intravenous immunoglobulins was started and the clinical status of the patient improved. CONCLUSION: We reported a case of X-linked agammaglobulinaemia with delayed diagnosis despite the typical anamnestic signs for primary humoral immunodeficiency. The disease was caused by a previously non-reported mutation in the BTK gene. Measurement of serum immunoglobulins should be performed in all children with recurrent, complicated respiratory infections as a screening test for humoral immunodeficiencies.

MeSH
agamaglobulinemie farmakoterapie genetika MeSH
dítě MeSH
genetické nemoci vázané na chromozom X farmakoterapie genetika MeSH
intravenózní imunoglobuliny terapeutické užití MeSH
lidé MeSH
mutace * MeSH
tyrosinkinasy genetika MeSH
Check Tag
dítě MeSH
lidé MeSH
mužské pohlaví MeSH
Publikační typ
časopisecké články MeSH
kazuistiky MeSH

Článek

Exon first nucleotide mutations in splicing: evaluation of in silico prediction tools

PLoS One. 2014 ; 9 (2) : e89570.

ISSN 1932-6203
Medvik
Zdroj

Mutations in the first nucleotide of exons (E(+1)) mostly affect pre-mRNA splicing when found in AG-dependent 3' splice sites, whereas AG-independent splice sites are more resistant. The AG-dependency, however, may be difficult to assess just from primary sequence data as it depends on the quality of the polypyrimidine tract. For this reason, in silico prediction tools are commonly used to score 3' splice sites. In this study, we have assessed the ability of sequence features and in silico prediction tools to discriminate between the splicing-affecting and non-affecting E(+1) variants. For this purpose, we newly tested 16 substitutions in vitro and derived other variants from literature. Surprisingly, we found that in the presence of the substituting nucleotide, the quality of the polypyrimidine tract alone was not conclusive about its splicing fate. Rather, it was the identity of the substituting nucleotide that markedly influenced it. Among the computational tools tested, the best performance was achieved using the Maximum Entropy Model and Position-Specific Scoring Matrix. As a result of this study, we have now established preliminary discriminative cut-off values showing sensitivity up to 95% and specificity up to 90%. This is expected to improve our ability to detect splicing-affecting variants in a clinical genetic setting.

MeSH
agamaglobulinemie genetika MeSH
bodová mutace * MeSH
exony MeSH
genetické nemoci vázané na chromozom X genetika MeSH
HeLa buňky MeSH
lidé MeSH
místa sestřihu RNA * MeSH
modely genetické MeSH
molekulární sekvence - údaje MeSH
počítačová simulace MeSH
sekvenční analýza DNA MeSH
sestřih RNA MeSH
software * MeSH
tyrosinkinasy genetika MeSH
Check Tag
lidé MeSH
Publikační typ
časopisecké články MeSH
hodnotící studie MeSH
práce podpořená grantem MeSH

Článek

X-linked agammaglobulinemia in community-acquired pneumonia cases revealed by immunoglobulin level screening at hospital admission

Klinische Pädiatrie. 2013 ; 225 (6) : 339-42.

Klin Padiatr
ISSN 1439-3824
Medvik
Zdroj

In children with primary immunodeficiencies, the onset of symptoms precedes the diagnosis and the initiation of appropriate treatment by months or years. This delay in diagnosis is due to the fact that while these disorders are rare, some of the infections seen in immunodeficient patients are common. Defective antibody production represents the largest group among these disorders, with otitis, sinusitis and pneumonia as the most frequent initial manifestation. We performed a prospective study of humoral immunity in children hospitalized due to community-acquired pneumonia in tertiary care hospital. Out of 254 patients (131 boys, 123 girls, median age 4.5 years) recruited over 3 years, we found 2 boys (age 11 and 21 months) lacking serum immunoglobulins and circulating B cells. Subsequent genetic analysis confirmed diagnosis of X-linked agammaglobulinemia. Despite their immunodeficiency, the pneumonia was uncomplicated in both patients and did not call for immunological evaluation. However, the immunoglobulin screening at admission allowed for an early diagnosis of the immunodeficiency and timely initiation of immunoglobulin substitution, the key prerequisite for a favorable course of the disease.Simple and inexpensive immuno-globulin measurement during the manage-ment of hospitalized children with community-acquired pneumonia may help in early identification of patients with compromised humoral immunity and prevent serious complications.

Článek

Protilátkové imunodeficience
[Antibody immunodeficiencies]

Postgraduální medicína. 2012 ; 14 (9) : 980-988.

Postgraduální med.
ISSN 1212-4184
Medvik
Zdroj

Článek shrnuje diagnostická kritéria, etiopatogenezi, klinické projevy a léčbu primárních i sekundárních poruch tvorby protilátek. Humorální imunodeficity obecně spojuje náchylnost k infekcím způsobeným opouzdřenými baktériemi. Dominují infekce dýchacích cest a trávicího ústrojí. U řady klinických jednotek je zvýšená náchylnost k autoimunitním či alergickým onemocněním. Základem léčby jsou substituce imunoglobuliny a cílená antibiotická terapie. Díky včasnější diagnostice a lepší dostupnosti léčby se prognóza i kvalita života těchto nemocných výrazně zlepšily.

The article summarises diagnostic criteria, etiopathogenesis, clinical symptoms, and management of primary and secondary humoural immunodeficiencies. Humoural immunodeficiencies are connected with higher susceptibility to infections caused by encapsulated bacteria. Infections of respiratory and gastrointestinal tract have been predominant. There is also a trend to autoimmune complications and allergies in patients with this diagnosis. The therapy is based on immunoglobulin substitution and targeted antibiotic treatment. Due to earlier diagnosis and better availability of therapeutic options in recent years, the prognosis of patients with primary immunodeficiencies and their quality of life has improved significantly.