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Janine Reichenbach

Publications and source records attributed to Janine Reichenbach.

12 recordsLinked to original sources
PubMed2006

Fatal neonatal-onset mitochondrial respiratory chain disease with T cell immunodeficiency.

We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8(+) T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8(+) T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.

CD8-Positive T-Lymphocytes↗
PubMed2006

The NEMO mutation creating the most-upstream premature stop codon is hypomorphic because of a reinitiation of translation.

Amorphic mutations in the NF- kappa B essential modulator (NEMO) cause X-dominant incontinentia pigmenti, which is lethal in males in utero, whereas hypomorphic mutations cause X-recessive anhidrotic ectodermal dysplasia with immunodeficiency, a complex developmental disorder and life-threatening primary immunodeficiency. We characterized the NEMO mutation 110_111insC, which creates the most-upstream premature translation termination codon (at codon position 49) of any known NEMO mutation. Surprisingly, this mutation is associated with a pure immunodeficiency. We solve this paradox by showing that a Kozakian methionine codon located immediately downstream from the insertion allows the reinitiation of translation. The residual production of an NH(2)-truncated NEMO protein was sufficient for normal fetal development and for the subsequent normal development of skin appendages but was insufficient for the development of protective immune responses.

Amino Acid Sequence↗
PubMed2006

Treatment of HCV infection with interferon alpha-2b and ribavirin in a patient with X-linked lymphoproliferative syndrome.

Chronic hepatitis C (HCV) infection in patients with primary immunodeficiency increases the risk of an accelerated progression of HCV-related liver disease. Here, we report a patient with X-linked lymphoproliferative syndrome infected with HCV and Epstein-Barr virus (EBV). After combination treatment with interferon alpha-2b and ribavirin, clearance of HCV-RNA was achieved, and noteworthily, EBV DNA also became undetectable.

Antiviral Agents↗
PubMed2006

Immunoglobulins and inflammatory cytokines in nasal secretions in humoral immunodeficiencies.

OBJECTIVE: Chronic respiratory tract infections are a common problem in patients with severe humoral immunodeficiency despite intravenous immunoglobulin therapy (IVIG), often presenting as rhinosinusitis. METHODS: Because it is unclear whether IVIG is a good substitute at the mucosal surface, we analyzed immunoglobulin levels and inflammatory cytokines (ECP, IL-8, and TNF-alpha) in nasal secretions of 13 patients with common variable immunodeficiency (CVID) and in 10 patients with IgA deficiency. RESULTS: In patients with CVID, median IgG and IgM levels did not differ significantly from controls, whereas inflammatory cytokines were markedly elevated, reflecting persistent inflammation at the mucosal site. In contrast, patients with IgA deficiency showed significantly raised IgG and IgM levels, whereas ECP and TNF-alpha were only slightly increased. CONCLUSION: Low levels of SIgA might be compensated locally at the mucosal site by high levels of IgM and IgG. Our findings implicate that adequate IVIG is not sufficient to prevent chronic inflammation of the sinuses in patients with severe humoral immunodeficiency.

Adolescent↗
PubMed2005

From idiopathic infectious diseases to novel primary immunodeficiencies.

Primary immunodeficiencies are typically seen as rare monogenic conditions associated with detectable immunologic abnormalities, resulting in a broad susceptibility to multiple and recurrent infections caused by weakly pathogenic and more virulent microorganisms. By opposition to these conventional primary immunodeficiencies, we describe nonconventional primary immunodeficiencies as Mendelian conditions manifesting in otherwise healthy patients as a narrow susceptibility to infections, recurrent or otherwise, caused by weakly pathogenic or more virulent microbes. Conventional primary immunodeficiencies are suspected on the basis of a rare, striking, clinical phenotype and are defined on the basis of an overt immunologic phenotype, often leading to identification of the disease-causing gene. Nonconventional primary immunodeficiencies are defined on the basis of a more common and less marked clinical phenotype, which remains isolated until molecular cloning of the causal gene reveals a hitherto undetected immunologic phenotype. Similar concepts can be applied to primary immunodeficiencies presenting other clinical features, such as allergy and autoimmunity. Nonconventional primary immunodeficiencies thus expand the clinical boundaries of this group of inherited disorders considerably, suggesting that Mendelian primary immunodeficiencies are more common in the general population than previously thought and might affect children with a single infectious, allergic, or autoimmune disease.

Agammaglobulinemia↗
PubMed2005

Autosomal-dominant primary immunodeficiencies.

The vast majority of known primary immunodeficiencies (PIDs) are autosomal or X-linked recessive Mendelian traits. Only four classical primary immunodeficiencies are thought to be autosomal-dominant, three of which still lack a well-defined genetic etiology: isolated congenital asplenia, isolated chronic mucocutaneous candidiasis, and hyper IgE syndrome. The large deletions on chromosome 22q11.2 associated with Di George syndrome suggest that this disease may be dominant but not Mendelian, possibly involving several genes. The clinical and genetic features of six novel autosomal-dominant primary immunodeficiencies have however been described in recent years. These primary immunodeficiencies are caused by germline mutations in seven genes: ELA2, encoding a neutrophil elastase, and GFI1, encoding a regulator of ELA2 (mutations associated with severe congenital neutropenia); CXCR4, encoding a chemokine receptor (warts, hypogammaglobulinemia, infections and myelokathexis syndrome); LCRR8, encoding a key protein for B-cell development (agammaglobulinemia); IFNGR1, encoding the ligand-binding chain of the interferon-gamma receptor; STAT1, encoding the signal transducer and activator of transcription 1 downstream from interferon-gammaR1 (Mendelian susceptibility to mycobacterial diseases); and IKBA, encoding IkappaBalpha, the inhibitor alpha of NF-kappaB (anhidrotic ectodermal dysplasia with immunodeficiency). These recent data suggest that many more autosomal-dominant PIDs are likely to be identified in the near future.

Genes, Dominant↗
PubMed2004

Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.

The IL-12/IFN-gamma axis is crucial for protective immunity to Mycobacterium in humans and mice. Our goal was to analyze the relative contribution of various human blood cell subsets and molecules to the production of, or response to IL-12 and IFN-gamma. We designed an assay for the stimulation of whole blood by live M. bovis Bacillus Calmette-Guerin (BCG) alone, or BCG plus IL-12 or IFN-gamma, measuring IFN-gamma and IL-12 levels. We studied patients with a variety of specific inherited immunodeficiencies resulting in a lack of leukocytes, or T, B, and/or NK lymphocytes, or polymorphonuclear cells, or a lack of expression of key molecules such as HLA class II, CD40L, NF-kappaB essential modulator (NEMO), and IL-1 receptor-associated kinase-4 (IRAK-4). Patients with deficiencies in IL-12p40, IL-12 receptor beta1 chain (IL-12Rbeta1), IFN-gammaR1, IFN-gammaR2, and STAT-1 were used as internal controls. We showed that monocytes were probably the main producers of IL-12, and that NK and T cells produced similar amounts of IFN-gamma. NEMO and IRAK-4 were found to be important for IL-12 production and subsequent IFN-gamma production, while a lack of CD40L or HLA class II had no major impact on the IL-12/IFN-gamma axis. The stimulation of whole blood by live BCG thus triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes.

Adult↗
PubMed2004

Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia.

BACKGROUND: Amorphic mutations in the X-linked nuclear factor kappaB essential modulator ( NEMO ) gene cause Incontinentia pigmenti, which is lethal in hemizygous male patients. Hypomorphic NEMO mutations in male patients lead to anhidrotic ectodermal dysplasia (EDA) with immunodeficiency. OBJECTIVE: To report the clinical features of a child bearing a NEMO mutation who displayed an immunodeficiency without EDA. METHODS: Documentation of clinical care, chart review, standard immunologic and microbiological laboratory techniques, mutation analysis of the NEMO gene. RESULTS: Since the age of 15 months, the patient had Mycobacterium avium disease, beginning with multiple adenitis, later followed by disseminated osteomyelitis and dermatitis. In addition, Haemophilus influenzae and Streptococcus pneumoniae infections led to bronchiectasis. An immunologic work-up revealed a low production of IFN-gamma by PBMCs associated with a hyper-IgM phenotype. Despite treatment using repeated cycles of a 4-drug antimycobacterial regimen, continuous subcutaneous IFN-gamma, repeated antibiotic treatment, and intravenous immunoglobulin substitution, the boy remained chronically ill. At the age of 12 years, the disease was complicated by severe autoimmune hemolytic anemia and eventually fatal herpes simplex virus 1 encephalitis despite high-dose acyclovir therapy. Although he did not present any sign of EDA, a novel type of disease-causing hypomorphic NEMO mutation (110-111insC in exon 2) was identified. CONCLUSION: This case demonstrates that patients hemizygous for NEMO mutations can present with an immunodeficiency without EDA. An investigation of NEMO should thus be undertaken in selected children with immunodeficiency despite the lack of EDA.

Carrier Proteins↗
PubMed2003

A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency.

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by hypomorphic mutations in the gene encoding NEMO/IKKgamma, the regulatory subunit of the IkappaB kinase (IKK) complex. IKK normally phosphorylates the IkappaB-inhibitors of NF-kappaB at specific serine residues, thereby promoting their ubiquitination and degradation by the proteasome. This allows NF-kappaB complexes to translocate into the nucleus where they activate their target genes. Here, we describe an autosomal-dominant (AD) form of EDA-ID associated with a heterozygous missense mutation at serine 32 of IkappaBalpha. This mutation is gain-of-function, as it enhances the inhibitory capacity of IkappaBalpha by preventing its phosphorylation and degradation, and results in impaired NF-kappaB activation. The developmental, immunologic, and infectious phenotypes associated with hypomorphic NEMO and hypermorphic IKBA mutations largely overlap and include EDA, impaired cellular responses to ligands of TIR (TLR-ligands, IL-1beta, and IL-18), and TNFR (TNF-alpha, LTalpha1/beta2, and CD154) superfamily members and severe bacterial diseases. However, AD-EDA-ID but not XL-EDA-ID is associated with a severe and unique T cell immunodeficiency. Despite a marked blood lymphocytosis, there are no detectable memory T cells in vivo, and naive T cells do not respond to CD3-TCR activation in vitro. Our report highlights both the diversity of genotypes associated with EDA-ID and the diversity of immunologic phenotypes associated with mutations in different components of the NF-kappaB signaling pathway.

Child↗
PubMed2002

Serum ECP levels and methacholine challenge in infants with recurrent wheezing.

BACKGROUND: High levels of serum eosinophil cationic protein (sECP) as a marker of eosinophilic airway inflammation have been described as a predictor of childhood asthma. Bronchial hyperreactivity (BHR) appears to be secondary to the release of inflammatory mediators. OBJECTIVE: We investigated the possible correlation between eosinophilic inflammation and BHR in 72 infants with recurrent wheezing. METHODS: To determine bronchial reactivity, lung function measurements with methacholine challenge were performed in 72 infants, aged 12 to 30 months, and the degree of BHR to methacholine was compared with sECP values. Patients were grouped according to low (group 1, <10 microg/L, n = 22), medium (group 2, 10 to 20 microg/L, n = 23), and high (group 3, >20 microg/L, n = 27) sECP values. RESULTS: In group 1, sECP levels ranged from 3.1 to 9.9 microg/L, mean 6.6 microg/L +/- standard deviation [SD] 2.3, in group 2, from 10.3 to 19.8 microg/L, mean 14.3 microg/L +/- SD 2.8, and in group 3 from 23.0 to 66.7 microg/L, mean 34.5 microg/L +/- SD 9.5. Distribution of provocative methacholine concentration among groups was as follows: group 1, 30 to 976 microg, mean 350.9 microg +/- SD 258.3; group 2, 36 to 752 microg, mean 340.7 microg +/- SD 226.3; group 3, 41 to 848 microg, mean 301.3 microg +/- SD 189.8 methacholine. CONCLUSION: There was no significant correlation between sECP levels and bronchial reactivity in all groups (r = -0.076, P = 0.6), indicating that these parameters reflect two independent pathogenic mechanisms in the etiology of childhood asthma.

Blood Proteins↗
PubMed2002

Elevated oxidative stress in patients with ataxia telangiectasia.

Ataxia telangiectasia (AT) is a pleiotropic genetic disorder characterized by progressive neurodegeneration, especially of cerebellar Purkinje cells, immunodeficiency, increased incidence of cancer, and premature aging. The disease is caused by functional inactivation of the ATM (AT-mutated) gene product, which is thought to act as a sensor of reactive oxygen species and oxidative damage of cellular macromolecules and DNA. The compound phenotype of AT might thus be linked to a continuous state of oxidative stress leading to an increase of programmed cell death (apoptosis). To assess this hypothesis, we analyzed lipid peroxidation products and the oxidative stress associated DNA base damage 8-hydroxy-2-deoxyguanosine in patients with AT. Oxidative damage to lipids and DNA was found to be markedly increased in AT patients. These results indicate that ATM might play an important role in the maintenance of cell homeostasis in response to oxidative damage. In this context, a better control of levels of reactive oxygen species could be a rational foundation of therapeutic intervention to help alleviate some of the symptoms associated with AT.

8-Hydroxy-2'-Deoxyguanosine↗