• MeSH
• Agammaglobulinemia diagnosis   drug therapy   MeSH
• Common Variable Immunodeficiency diagnosis   immunology   therapy   MeSH
• IgA Deficiency MeSH
• Hyper-IgM Immunodeficiency Syndrome diagnosis   therapy   MeSH
• Immunologic Tests methods   MeSH
• Humans MeSH
• Neonatal Screening MeSH
• Primary Immunodeficiency Diseases diagnosis   therapy   MeSH
• Antibodies analysis   blood   MeSH
• Immunologic Deficiency Syndromes * diagnosis   therapy   MeSH
• Vaccination methods   MeSH
• Check Tag
• Humans MeSH

An association between movement disorders and immune-system dysfunction has been described in the context of rare genetic diseases such as ataxia telangiectasia as well as infectious encephalopathies. We encountered a male patient who presented immunodeficiency of unknown etiology since childhood. A medication-refractory, progressive choreodystonic movement disorder emerged at the age of 42 years and prompted an exome-wide molecular testing approach. This revealed a pathogenic hemizygous variant in CD40LG, the gene implicated in X-linked hyper-IgM syndrome. Only two prior reports have specifically suggested a causal relationship between CD40LG mutations and involuntary hyperkinetic movements. Our findings thus confirm the existence of a particular CD40LG-related condition, combining features of compromised immunity with neurodegenerative movement abnormalities. Establishing the diagnosis is crucial because of potential life-threatening immunological complications.

• MeSH
• Child MeSH
• Adult MeSH
• Hyper-IgM Immunodeficiency Syndrome, Type 1 * genetics   pathology   MeSH
• Humans MeSH
• CD40 Ligand genetics   MeSH
• Mutation MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients. OBJECTIVES: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT. METHODS: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression. RESULTS: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation. CONCLUSION: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates.

• MeSH
• Time MeSH
• Child MeSH
• Adult MeSH
• Hyper-IgM Immunodeficiency Syndrome mortality   therapy   MeSH
• Kaplan-Meier Estimate MeSH
• Cohort Studies MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Proportional Hazards Models MeSH
• Retrospective Studies MeSH
• Hematopoietic Stem Cell Transplantation mortality   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Observational Study MeSH

Časná diagnostika vrozených poruch imunity umožňuje adekvátní cílenou léčbu a zabránění infekčním komplikacím. Poruchy tvorby protilátek jsou nejčastější. Imunoglobuliny a specifické protilátky jsou sníženy nebo chybí. Proto je nezbytné přistoupit k substituční imunoglobulinové léčbě. Buněčné poruchy specifické imunity se projeví jako kombinované T a B buněčné imunodeficience.

1st part: Diagnostic approach Early diagnosis of immunodeficiency makes possible early definitive therapy and avoids the complications of pretreatment infections. B-cell defects constitute the majority of primary immunodeficiencies. All are characterized by the reduction in or absence of immunoglobulins and/or specific antimicrobial antibodies. Consequently, substitution of immunoglobulin G (IgG) is the pillar of treatment. T-cell immunodeficiency defects become apparent as combined T- and B-cell deficiencies.

• MeSH
• Agammaglobulinemia diagnosis   MeSH
• Autoantibodies analysis   immunology   MeSH
• Common Variable Immunodeficiency diagnosis   MeSH
• IgA Deficiency MeSH
• IgG Deficiency MeSH
• Child MeSH
• Hyper-IgM Immunodeficiency Syndrome diagnosis   MeSH
• Infections immunology   MeSH
• Infant MeSH
• Humans MeSH
• Child, Preschool MeSH
• Immunologic Deficiency Syndromes * diagnosis   physiopathology   MeSH
• Congenital, Hereditary, and Neonatal Diseases and Abnormalities MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Child, Preschool MeSH
• Publication type
• Review MeSH

Hyper-IgM syndrom (HIGM) je skupina vzácných a závažných vrozených imunodeficiencí, pro které jsou typické velmi nízké hladiny imunoglobulinu tříd IgG, IgA a IgE s normální nebo zvýšenou hladinou IgM. Příčinou onemocnění je porucha mechanismu izotypového přesmyku. Defekt postihuje signalizační dráhu molekuly CD40 nebo vnitřní signalizaci B-lymfocytů, případně buněčný DNA reparační mechanismus. Nejčastější poruchou je poškození ligandu pro CD40 (X-vázaný hyper-IgM syndrom). Kromě humorální imunity je postižena i složka buněčná, takže pacienti jsou ohroženi oportunními infekcemi (především Pneumocystis jirovecii, CMV, kryptokoky nebo mykobakteriemi). Typické jsou Časté recidivující respirační infekce a chronický průjem doprovázený neprospíváním. Více než u poloviny pacientů nalézáme chronickou neu"''^penii, dále se vyskytují artritidy, trombocytopenie, hemolytické anemie a nefritidy. Pacienti s deficitem CD40L jsou také zvýšeně ohroženi vznikem maligních onemocnění. Základem léčby jsou režimová opatření, antibiotická profylaxe a substituční léčba imunoglobuliny. Jediná kauzální terapie je alogenní transplantace hematopoetických buněk. V letech 1993 až 2011 bylo v České republice diagnostikováno pět pacientů s vrozeným deficitem CD40 ligandu. Tři pacienti byli po stanovení diagnózy indikováni k transplantaci hematopoetických buněk. V článku předkládáme přehled průběhu onemocnění, diagnostiky a léčby těchto pacientů.

Hyper-IgM syndrome (HIGM) is a group of rare and serious primary immunodeficiencies. It is characterised by very low levels of IgG, IgA and IgE immunoglobulins whereas the level of IgM is normal or elevated. It is caused by impairment of immunoglobulin isotype sw itching. Either the signalling pathway of CD40 molecule, intrinsic B-cell signalling or DNA reparation mechanism are defective. The most frequent defect lies in the gene coding for CD40 ligand (X-linked Hyper-IgM syndrome). Apart from humoral immunity also the T-cell funct ion is affected. Thus, the patients suffer from infections caused by opportunistic pathogens (most frequently Pneumocystic jirovecii , CMV, Crypto- cocci, Mycobacteria). Recurrent respiratory tract infections are frequently seen. Chronic diarrhoea may be present as well and may associate with failure to thrive. More than a half of the patients suffer from chronic neutropenia. Arthritis, thrombocytopenia, haemolyt ic anaemia and nephritis are documented in some patients. Patients with CD40 ligand deficiency have increased risk of malignant diseases. The cornerstones of the therapy are preventive measures, antibiotic prophylaxis and immunoglobulin substitution. The haematopoietic stem cell tr ansplantation is the only curative therapy currently available. Between 1993 and 2011 there were 5 patients with CD40 ligand deficiency diagnosed and treated in the Czech Republic. Three pati ents were indicated for haematopoietic stem cell transplantation. The authors present an overview of the disease’s course, diagnostic pro cess and treatment of these patients.

• Keywords
• deficit CD40L,
• MeSH
• CD4 Antigens genetics   chemistry   MeSH
• B-Lymphocytes metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Child MeSH
• Dysgammaglobulinemia MeSH
• Financing, Organized MeSH
• Hyper-IgM Immunodeficiency Syndrome epidemiology   genetics   immunology   MeSH
• Immunoglobulins, Intravenous administration & dosage   MeSH
• Humans MeSH
• CD40 Ligand metabolism   MeSH
• Young Adult MeSH
• Frameshift Mutation genetics   immunology   MeSH
• Child, Preschool MeSH
• Flow Cytometry MeSH
• Hematopoietic Stem Cell Transplantation utilization   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Publication type
• Case Reports MeSH

Cíl práce: Molekula CD154 (CD40L) je transmembránový glykoprotein přítomný především v aktivovaných lymfocytech T CD4+. Jeho receptorem je molekula CD40, která je v membráně lymfocytů B, ale též jiných buněk. Interakce CD154-CD40 je podmínkou optimálního rozvoje adaptivní imunitní reakce, jejím důsledkem je však i ovlivnění zánětlivého procesu. Porucha funkce CD154 je patognomická pro závažnou primární imunodeficienci – syndrom hyperimunoglobulinémie M. Odhalení abnormality CD154 je základem pro stanovení diagnózy tohoto syndromu. Materiál a metodika: Vypracovali jsme mikrometodu, která umožňuje průkaz CD154 na lymfocytech aktivovaných in vitro v plné krvi a srovnali ji s metodou vyšetření CD154 na izolovaných lymfocytech. Periferní heparinizovaná krev je inkubována 4 hodiny s aktivačními činidly (phorbol-myristat-acetat, ionomycin), inkubována s monoklonálními protilátkami a vyšetřena na průtokovém cytometru. Vzhledem k tomu, že v průběhu stimulace dochází ke ztrátě molekul CD4 v plazmatické membráně, jsou CD4+ lymfocyty identifikovány jako CD5+/CD8. Jejich aktivace je sledována expresí CD69. K simultánnímu hodnocení přítomnosti CD154 se používá tříbarevná průtoková cytometrie. Výsledky: Metodika byla aplikována u deseti zdravých dárců krve. K provedení testu stačí 0,5 ml heparinizované krve. Optimální doba aktivace, která umožňuje detegovatelnou expresi CD154 na lymfocytech T, jsou 4 hodiny. Zjistili jsme, že v průběhu této aktivace dochází ke snížení množství CD4 molekul na lymfocytech T. Hodnoty exprese CD154 jsou plně srovnatelné při použití naší metody s plnou krví i metody s izolovanými leukocyty. Závěr: Naše metodika k průkazu CD154 na lymfocytech aktivovaných v plné krvi je časově nenáročná, vyžaduje malé množství (0,5 ml) krve a lze ji doporučit při vstupním vyšetření dětí s podezřením na syndrom hyperimunoglobulinémie M. Umožňuje také záchyt přenašeček XHIGM.

Objective: CD154 (also called CD40L) is a transmembrane glycoprotein predominantly expressed on the surface membrane of activated CD4+ T cells. Its receptor CD40 is present on all B cells, but also on other cells. The interaction CD154-CD40 is necessary for the optimal development of the adaptive immune response and also has consequences for the modulation of the inflammatory response. A defect in the expression of CD154 is pathognomonic of congenital immunodeficiency called X-linked Hyper-IgM syndrome (XHIGM). To detect the abnormality of CD154 is essential for making the diagnosis of XHIGM. Material and methods: We worked out a microtest for the detection of CD154 expression on in vitro activated CD4+ T cells in whole blood and compared it with that on isolated cells from peripheral blood. Heparinized peripheral blood was activated with phorbol 12-myristate 13-acetate and ionomycin for 4 hours, labeled with monoclonal antibodies and analyzed by flow cytometry. Considering that the CD4 marker on the plasma membrane surface decreases during the activation, CD4+ T cells are mostly recognized as CD5+/CD8- cells. Their activation is monitored based on the expression of CD69. Three-?-colour immunofluorescence staining was used for simultaneous detection of CD154. Results: Ten blood donors were tested. As little as 0.5 ml of heparinized whole blood is needed to complete the test. Optimal time for activation and detection of CD154 on T lymphocytes is 4 hours. We found that the number of CD4 molecules on the surface of T cells decreases during the activation. The expression of CD154 in our whole blood microtest is fully comparable with that in the test on isolated leukocytes. Conclusion: The presented microtest for the detection of CD154 on activated lymphocytes in whole blood is fast and blood saving, since as little as 0.5 ml of blood is needed to complete it. It can be recommended as the initial test for suspected hyper-IgM syndrome in children. We demonstrate that this screening method can help to detect also carriers of XHIGM.

• Keywords
• syndrom hyperimunoglobulinémie M, CD40,
• MeSH
• Lymphocyte Activation immunology   MeSH
• CD4-Positive T-Lymphocytes immunology   classification   MeSH
• Fluorescent Antibody Technique MeSH
• Hyper-IgM Immunodeficiency Syndrome, Type 1 diagnosis   MeSH
• Immunophenotyping methods   MeSH
• Humans MeSH
• CD40 Ligand analysis   MeSH
• Lymphocytes immunology   classification   MeSH
• Flow Cytometry MeSH
• Check Tag
• Humans MeSH