ARHGAP42 encodes Rho GTPase activating protein 42 that belongs to a member of the GTPase Regulator Associated with Focal Adhesion Kinase (GRAF) family. ARHGAP42 is involved in blood pressure control by regulating vascular tone. Despite these findings, disorders of human variants in the coding part of ARHGAP42 have not been reported. Here, we describe an 8-year-old girl with childhood interstitial lung disease (chILD), systemic hypertension, and immunological findings who carries a homozygous stop-gain variant (c.469G>T, p.(Glu157Ter)) in the ARHGAP42 gene. The family history is notable for both parents with hypertension. Histopathological examination of the proband lung biopsy showed increased mural smooth muscle in small airways and alveolar septa, and concentric medial hypertrophy in pulmonary arteries. ARHGAP42 stop-gain variant in the proband leads to exon 5 skipping, and reduced ARHGAP42 levels, which was associated with enhanced RhoA and Cdc42 expression. This is the first report linking a homozygous stop-gain variant in ARHGAP42 with a chILD disorder, systemic hypertension, and immunological findings in human patient. Evidence of smooth muscle hypertrophy on lung biopsy and an increase in RhoA/ROCK signaling in patient cells suggests the potential mechanistic link between ARHGAP42 deficiency and the development of chILD disorder.
- MeSH
- dítě MeSH
- homozygot MeSH
- hypertenze genetika MeSH
- intersticiální plicní nemoci genetika patologie MeSH
- leukocytóza genetika imunologie MeSH
- lidé MeSH
- lymfocytóza genetika imunologie MeSH
- myši MeSH
- proteiny aktivující GTPasu genetika MeSH
- rhoA protein vázající GTP genetika metabolismus MeSH
- rodokmen MeSH
- sekvenování exomu MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- ARHGAP42 protein, human MeSH Prohlížeč
- Graf3 protein, mouse MeSH Prohlížeč
- proteiny aktivující GTPasu MeSH
- rhoA protein vázající GTP MeSH
- RHOA protein, human MeSH Prohlížeč
BACKGROUND: Natalizumab is an effective therapy in the treatment of relapsing-remitting multiple sclerosis; it induces lymphocytosis (NIL, natalizumab-induced lymphocytosis) and changes the peripheral lymphocyte pattern. METHODS: This study aims to evaluate NIL, peripheral blood lymphocyte subsets, CD4/CD8 ratio, and their impacts on JCV index and clinical data-No Evidence of Disease Activity (NEDA-3) and annualized relapse rate (ARR) in patients treated with natalizumab. RESULTS: Forty-one patients (33 women) were included in the study. The mean duration of follow-up on natalizumab treatment was 6.7 ± 3.2 years. Significant increases in relative lymphocytosis after 1 month, with a median of 40.4% (- 34.1 to + 145.5%) (p < 0.001), and after 1 year (49.0% (- 9.3 to + 127.6%)) (p < 0.001) were found. Significant differences were found after 1 month when comparing NIL between patients JCV-seroconverting (20.6% (- 17.7 to 72.7%)) and stable JCV-seronegative ones (43.5% (- 6.3 to +96.3%)) (p = 0.04). No significant difference NIL level was found between the patients exhibiting NEDA-3 status and those without it. ARR on natalizumab treatment correlated with CD4/CD8 ratio (r = 0.356; p = 0.021); patients who maintained NEDA-3 status over the whole treatment period exhibited a lower CD4/CD8 ratio (1.89 ± 1.08 vs. 2.5 ± 0.73; p < 0.04). CONCLUSION: This contribution reports the CD4/CD8 ratio as a possible biomarker for better clinical efficacy of natalizumab in patients exhibiting a lower CD4/CD8 ratio. NIL did not correlate with long-term therapeutic efficacy in patients treated with natalizumab, but was demonstrated as lower in patients JCV-seroconverting in the course of follow-up.
- Klíčová slova
- Flow cytometry, JC virus, Multiple sclerosis, Natalizumab, T lymphocytes,
- MeSH
- CD8-pozitivní T-lymfocyty MeSH
- imunologické faktory škodlivé účinky MeSH
- lidé MeSH
- lymfocytóza * chemicky indukované MeSH
- natalizumab škodlivé účinky MeSH
- progresivní multifokální leukoencefalopatie * MeSH
- relabující-remitující roztroušená skleróza * farmakoterapie MeSH
- roztroušená skleróza * MeSH
- virus JC * MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- imunologické faktory MeSH
- natalizumab MeSH
Infusion related adverse events (AE) with day 1 rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL) are common. The purpose of this study was to evaluate the AE occurring in patients with malignant B-cell lymphocytosis who received rituximab. Patients with a > or = 3 x 10(9)/L absolute lymphocyte count (ALC) receiving rituximab from 1998 to 1999 or participating in a phase I study of rituximab and interleukin-12 were reviewed. The AE occurring on the day of rituximab, the treatment provided (including hospitalization), and the subsequent ALC responses were recorded. Twenty-seven patients were identified; 14 had NHL, one Waldenstrom's macroglobulinemia, and 12 patients had chronic lymphocytic leukemia. The baseline median ALC was 9.58 x 10(9)/L (mean, 49.31; range, 3.56-380.95). All patients received rituximab as an outpatient. There were only two AE > or = grade 3. One patient was hospitalized for 1 day for i.v. fluids to treat an increase in creatinine that occurred with tumor lysis. A second patient developed a pulmonary syndrome five days after day 1 rituximab and required mechanical ventilation, but had no long-term lung toxicity. This study demonstrates that patients with high numbers of circulating blood B-lymphocytes can usually safely receive rituximab as outpatients. Patients who experience a rapid drop in ALC should be monitored closely for tumor lysis and the pulmonary syndrome.
- MeSH
- chronická lymfatická leukemie farmakoterapie MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocytóza farmakoterapie MeSH
- lymfom z plášťových buněk farmakoterapie MeSH
- monoklonální protilátky škodlivé účinky MeSH
- myší monoklonální protilátky MeSH
- protinádorové látky škodlivé účinky MeSH
- rituximab MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- Názvy látek
- monoklonální protilátky MeSH
- myší monoklonální protilátky MeSH
- protinádorové látky MeSH
- rituximab MeSH
Lymphoproliferative disorders of large granular lymphocytes (LGL) can arise from either CD3+ T cells or CD3- natural killer cells. Polyclonal proliferation of LG lymphocytes is called LGL lymphocytosis, monoclonal proliferation of LG lymphocytes is LGL leukaemia. Prominent clinical manifestations of LGL lymphocytosis and leukaemia are bacterial infections, splenomegaly, and may be connected with rheumatic or autoimmune disorders. Hematologic findings reveal particularly lymphocytosis, and severe neutropenia. The beta chain gene of T cell receptor rearrangement analysis is necessary for distinguishing of T LGL lymphocytosis from T LGL leukaemia. The authors report a case of young woman with T cells LGL lymphroproliferative disorder, bacterial infection, reactive lymphadenopathy, and spontaneous regression of the lymphocytosis within 6 months.
- MeSH
- diferenciální diagnóza MeSH
- dospělí MeSH
- genová přestavba T-lymfocytů MeSH
- lidé MeSH
- lymfocytóza diagnóza genetika patologie MeSH
- lymfocyty patologie MeSH
- prognóza MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- anglický abstrakt MeSH
- časopisecké články MeSH
- kazuistiky MeSH
- MeSH
- alergie etiologie MeSH
- časové faktory MeSH
- elektrokardiografie MeSH
- eozinofilie etiologie MeSH
- infarkt myokardu komplikace MeSH
- kouření komplikace MeSH
- lidé MeSH
- lymfocytóza etiologie MeSH
- počet leukocytů * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- dermatitida z povolání chemicky indukované MeSH
- dospělí MeSH
- ekzém krev etiologie mikrobiologie terapie MeSH
- eozinofilie MeSH
- hormony kůry nadledvin terapeutické užití MeSH
- leukocytóza MeSH
- lidé středního věku MeSH
- lidé MeSH
- lymfocytóza MeSH
- metody MeSH
- počet leukocytů MeSH
- vystavení vlivu životního prostředí MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- hormony kůry nadledvin MeSH
- MeSH
- diferenciální diagnóza MeSH
- hepatitida A diagnóza MeSH
- infekční nemoci epidemiologie MeSH
- lidé MeSH
- lymfocytóza diagnóza enzymologie MeSH
- metody MeSH
- počet leukocytů MeSH
- předškolní dítě MeSH
- Check Tag
- lidé MeSH
- předškolní dítě MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Československo MeSH
- Klíčová slova
- CHILD *, EOSINOPHILIA *, FEVER *, GASTROENTERITIS *, LEUKOCYTE COUNT *, LYMPHOCYTOSIS *,
- MeSH
- dítě MeSH
- eozinofilie * MeSH
- gastroenteritida * MeSH
- horečka * MeSH
- infekční nemoci * MeSH
- lidé MeSH
- lymfocytóza * MeSH
- počet leukocytů * MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Klíčová slova
- CEREBROSPINAL FLUID/chemistry *, LYMPHOCYTOSIS/cerebrospinal fluid *,
- MeSH
- leukocytóza * MeSH
- lidé MeSH
- lymfocytóza mozkomíšní mok MeSH
- mozkomíšní mok chemie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
