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Biomedical subjects

Hans D Ochs

Publications and source records attributed to Hans D Ochs.

At least 19 recordsLinked to original sources
PubMed2005

Rituximab inhibits the in vivo primary and secondary antibody response to a neoantigen, bacteriophage phiX174.

The response to primary immunization in patients treated with Rituximab (RIT) is not clear. We studied the in vivo antibody response of chronic renal failure (CRF) patients to the neoantigen bacteriophage phiX174 given alone or after ablation with RIT. Eighteen CRF subjects received two immunizations with phiX174 separated by 6 weeks. Nine subjects received a single dose of RIT. The intensity and immunoglobulin isotype of the antibody response (K(v)) were measured post-infusion. In addition, three subjects previously immunized and treated with RIT underwent a third and fourth immunization with phiX174 and a tetanus control 2 years later. RIT significantly decreased peak K(v) responses when compared to both historic non-CRF controls and to CRF subjects. CRF itself decreased peak K(v) responses compared to non-CRF controls. Percent-ratio of anti-phage IgM to IgG was significantly decreased in RIT treated subjects. One of three subjects treated with RIT was found to have developed a partial B cell tolerance to phiX174 administration 2 years later. RIT decreases antibody production and isotype switching to neoantigens and might be useful to prevent antibody response to therapeutic drugs and to newly transplanted organs.

Adult↗
PubMed2004

Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.

The hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.

Adult↗
PubMed2004

The hyper IgM syndrome--an evolving story.

The hyper IgM syndromes (HIGM) are a group of primary immune deficiency disorders characterized by defective CD40 signaling by B cells affecting class switch recombination and somatic hypermutation. As a consequence, patients with HIGM have decreased concentrations of serum IgG and IgA and normal or elevated IgM, leading to increased susceptibility to infections. The most common HIGM syndrome is X-linked and due to mutations of CD40 ligand (CD40L) expressed by activated CD4(+) T lymphocytes. Four other genes, expressed by B cells, have been associated with the HIGM phenotype. Mutations of CD40, the receptor for CD40L, cause a rare autosomal form of HIGM with a clinical phenotype similar to CD40L deficiency. Mutations of Activation-Induced Cytidine Deaminase (AICDA) and Uracil (DNA) Glycosylase (UNG), both expressed by follicular B lymphocytes, lead to defective class switch recombination and somatic hypermutation. Mutations of Nuclear Factor kappa B Essential Modulator (NEMO), an X-chromosome associated gene, result in hypohidrotic ectodermal dysplasia and immune deficiency. Thus, the molecular definition of these rare primary immune deficiency disorders has shed light on the complex events leading to the production of high-affinity, antigen-specific antibodies of different isotypes.

Child↗
PubMed2004

Mutations of the Wiskott-Aldrich Syndrome Protein (WASP): hotspots, effect on transcription, and translation and phenotype/genotype correlation.

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive immune deficiency disorder characterized by thrombocytopenia, small platelet size, eczema, recurrent infections, and increased risk of autoimmune disorders and malignancies. X-linked thrombocytopenia (XLT) is an allelic variant of WAS which presents with a milder phenotype, generally limited to thrombocytopenia. WAS and XLT are caused by mutations of the Wiskott-Aldrich syndrome protein (WASP) gene which encodes a 502-amino acid protein, named WASP. WASP is thought to play a role in actin cytoskeleton organization and cell signaling. Here, we report the identification of 141 unique mutations, 71 not previously reported, from 227 WAS/XLT families with a total of 262 affected members. When possible we studied the effects of these mutations on transcription, RNA splicing, and protein expression. By analyzing a large number of patients with WAS/XLT at the molecular level we identified 5 mutational hotspots in the WASP gene and have been able to establish a strong association between genotype and phenotype.

Child↗
PubMed2004

WAVE/Scars in platelets.

Using specific antibodies against isoforms of WAVE (WASP [Wiskott-Aldrich syndrome protein] family Verprolin-homologous protein, also called Scar), we demonstrated that human platelets express all 3 isoforms. With the use of an in vitro pull-down technique, the src homology 3 (SH3) domain of insulin receptor substrate p53 (IRSp53) precipitated WAVE2 from platelet lysates more efficiently than did profilin I. The opposite was true for WAVE1, and neither precipitated WAVE3, suggesting that WAVE isoforms have different affinities to these ligands, while the SH3 domain of abl binds to all 3 isoforms. The 3 WAVE isoforms were distributed in the actin-rich Triton X-100-insoluble pellets following platelet aggregation induced by thrombin receptor-activating peptide. We also found that all 3 WAVE isoforms are substrates for calpain in vivo and in vitro. Although portions of these 3 isoforms were commonly distributed in the actin- and actin-related protein 2 and 3 (Arp2/3)-rich edge of the lamellipodia in spreading platelets, only WAVE2 remained in the cell fringe following detergent extraction or fixation of the cells. Finally, by mass spectrometry, we found that the proteins, which reportedly interact with WAVE/Scars, are present in platelets. These data suggest that the 3 WAVE isoforms exhibit common and distinct features and may potentially be involved in the regulation of actin cytoskeleton in platelets.

Actin Cytoskeleton↗
PubMed2004

Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome.

BACKGROUND: The immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare genodermatosis associated with dermatitis, enteropathy, type 1 diabetes, thyroiditis, hemolytic anemia, and thrombocytopenia. IPEX results from mutations of FOXP3, a gene located on the X chromosome that encodes a DNA-binding protein required for development of regulatory T cells. If untreated, affected males die early in life from malabsorption and other complications. To our knowledge, this syndrome has never been described in the dermatology literature. OBSERVATIONS: We studied an 11-year-old boy with IPEX. Mutation analysis revealed a G-->A transition (1150G>A) in exon 11, resulting in a putative substitution of Ala-->Thr at residue 384, within the DNA-binding site. Histopathologic examination of an active skin lesion revealed psoriasiform dermatitis. The lesions improved with clobetasol ointment. The patient also displayed alopecia universalis, which had been present since age 18 months, accompanied by longitudinal ridging of the nails. Lymphocyte challenge tests revealed a profound inability to synthesize interferon gamma (INF-gamma) and dysregulated production of other cytokines. CONCLUSIONS: IPEX is an often fatal genodermatosis associated with multiple autoimmune disorders. Cutaneous findings may include dermatitis, bullae, urticaria, alopecia universalis, and trachyonychia. Recognition of this life-threatening disorder is crucial for optimal treatment and genetic counseling.

Base Sequence↗
PubMed2004

X-linked immunodeficiencies.

Recent advances in molecular genetics have allowed identification of at least seven genes involved in X-linked immunodeficiencies. This has resulted not only in improved diagnostic possibilities but also in a better understanding of the pathophysiology of these disorders. In some cases, mutations in the same gene have been shown to cause distinct clinical and immunologic phenotypes, demonstrating a strong genotype-phenotype correlation. Identification of the molecular basis of these diseases has permitted creation of disease-specific registries, with a better characterization of the clinical and immunologic features associated with the various forms of X-linked immunodeficiencies. Additionally, gene therapy has been attempted in X-linked severe combined immune deficiency (XSCID), with clear evidence of successful correction of the pathology, and the appearance of severe adverse effects.

Agammaglobulinemia↗
PubMed2004

Naked DNA transfer of Factor VIII induced transgene-specific, species-independent immune response in hemophilia A mice.

The development of antibodies to a previously unexpressed protein product may limit the success of human gene therapy approaches. We inserted B-domain-deleted factor VIII (FVIII) cDNA of human, canine, or murine origin into the multiple cloning site of a liver-specific vector, pBS-HCRHPI-A, to yield plasmids pBS-HCRHPI-FVIIIA, pBS-HCRHPI-cFVIIIA, and pBS-HCRHPI-mFVIIIA, respectively. Fifty micrograms of each plasmid in 2 ml of solution was rapidly injected into the tail vein of three groups of hemophilia A mice. Factor VIII levels ranging from 3 to 12 IU/ml were obtained from all three groups (normal is 1 IU/ml in human plasma) 3 days after treatment. These initial very high levels of functional human, canine, or murine factor VIII, however, fell gradually to undetectable levels within 2-3 weeks, and their disappearance correlated with the generation of high-titer, inhibitory anti-FVIII antibodies. Notably, this immune response occurred independent of the species of origin of the exogenous factor VIII. Antibody titers to factor VIII were detected beginning at 2 weeks, reached a plateau and remained at high levels for over 6 months. The majority of anti-hFVIII IgG was IgG1 isotype specific, suggesting a humoral response mediated by Th2-induced signals. Consistent with this idea, in a separate group of mice treated with pBS-HCRHPI-FVIIIA, transient immunosuppression by cyclophosphamide significantly delayed (5/6) or abolished (1/6) inhibitory antibody formation against the transgene.

Animals↗
PubMed2004

Octagam 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases.

Octagam is an intravenous immunoglobulin preparation registered in Europe for treating primary immunodeficiency diseases (PID). The present clinical trial was designed to demonstrate that Octagam meets the minimal efficacy requirement of the U.S. Food and Drug Administration-that treatment should result in </=1 serious infection/subject/year. The objectives of this clinical trial were to show that Octagam meets this requirement, and to confirm the safety of Octagam. Forty-six subjects with well-defined PID received Octagam (either 400-600 mg/kg every 28 days or 300-450 mg/kg every 21 days) for 12 months. The primary efficacy variable was the number of serious infections/subject/year. The estimated infection rate was 0.1 serious infections/subject/year. The half-life ( T (1/2)) of total IgG was 41 days. Adverse events potentially related to Octagam occurred in 5% of infusions, either during or within 30 min of the procedure. Octagam meets the Food and Drug Administration minimal requirement for efficacy. In addition, Octagam had a T (1/2) (IgG) comparable with published data, and was well tolerated. Octagam treatment is safe and resulted in 0.1 serious infections/subject/year in primary immunodeficient subjects.

Adolescent↗
PubMed2003

Clinical course of patients with WASP gene mutations.

Mutations of the Wiskott-Aldrich syndrome protein (WASP) gene result either in the classic Wiskott-Aldrich syndrome (WAS) or in a less severe form, X-linked thrombocytopenia (XLT). A phenotype-genotype correlation has been reported by some but not by other investigators. In this study, we characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive. In contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient was correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival and survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients. This analysis provides evidence for a strong phenotype-genotype correlation and demonstrates that WAS protein expression is a useful tool for predicting long-term prognosis for patients with WAS/XLT. Based on data presented here, hematopoietic stem cell transplantation should be considered, especially for WASP-negative patients, while the patients are young to improve prognosis.

Adolescent↗
PubMed2003

Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination.

Activation-induced cytidine deaminase (AID) is a 'master molecule' in immunoglobulin (Ig) class-switch recombination (CSR) and somatic hypermutation (SHM) generation, AID deficiencies are associated with hyper-IgM phenotypes in humans and mice. We show here that recessive mutations of the gene encoding uracil-DNA glycosylase (UNG) are associated with profound impairment in CSR at a DNA precleavage step and with a partial disturbance of the SHM pattern in three patients with hyper-IgM syndrome. Together with the finding that nuclear UNG expression was induced in activated B cells, these data support a model of CSR and SHM in which AID deaminates cytosine into uracil in targeted DNA (immunoglobulin switch or variable regions), followed by uracil removal by UNG.

Adult↗
PubMed2003

Novel Artemis gene mutations of radiosensitive severe combined immunodeficiency in Japanese families.

A subgroup of patients with severe combined immunodeficiency (SCID) and increased cellular radiation sensitivity (RS-SCID) have mutations of Artemis, a gene that encodes a protein essential for V(D)J recombination and DNA double-strand break repair. RS-SCID described to date are either of European origin or are Athabascan-speaking native Americans belonging to the Navajo and Apache tribes. We have identified three Japanese boys and one girl from four unrelated families with RS-SCID caused by a genomic exon 3 deletion of the Artemis gene, resulting in loss of exon 3 and skipping of exon 4. Two patients were homozygous and two patients were heterozygous for this novel mutation. Those parents studied were heterozygous for this mutation. These findings suggest the genomic exon 3 deletion is unique to Japan and may be considered as a founder haplotype. Although two infants underwent successful bone marrow transplantation and immune reconstitution, the long-term outcome of this procedure is uncertain, because Artemis is expressed in most tissues and lack of its function in cells other than those derived from hematopoietic stem cells may increase the risk of malignancies.

Antigens, CD↗
PubMed2003

Inducible CO-stimulator molecule, a candidate gene for defective isotype switching, is normal in patients with hyper-IgM syndrome of unknown molecular diagnosis.

BACKGROUND: Inducible CO-stimulatory molecule (ICOS), the third member of the CD28/CTLA4 family, is expressed by activated T cells and interacts with its ligand (ICOSL, B7-related protein-1 [B7RP-1]) that is constitutively expressed by B cells. The interaction of ICOS with its ligand leads to terminal differentiation of B cells to plasma cells. ICOS-deficient mice fail to undergo immunoglobulin-class switch recombination (CSR) and germinal center formation, suggesting that ICOS could be a candidate gene for phenotypic hyper-IgM (HIGM) syndromes characterized by recurrent infections, low serum IgG and IgA, and normal or elevated IgM. Genetically, at least 4 distinct molecular defects have been identified that result in defective CSR and present as HIGM syndromes: defects of the CD40 ligand gene (CD40L; HIGM1, X-linked), the activation-induced cytidine deaminase gene (AID; HIGM2, autosomal recessive), the CD40 gene (HIGM3, autosomal recessive), and the nuclear factor-kappaB (NF-kappaB) essential modulator gene (NEMO, or IKK-gamma, X-linked). In a substantial subgroup of HIGM patients, these 4 genes are normal, and the genetic defect is unknown. OBJECTIVE: We sought to investigate the possibility that mutations of ICOS could account for some patients' belonging to this HIGM subgroup. METHODS: The expression of ICOS protein by activated peripheral blood mononuclear cells and/or interleukin-2-dependent T cell lines derived from these patients was estimated by flow cytometery after incubation of the cells with the ICOS ligand fusion protein B7RP-1 Fc. The coding region and exon-intron boundaries of ICOS were assessed by sequence analysis. RESULTS: We studied 33 HIGM patients from 30 families, selected from an original cohort of 136 patients from 113 families, by excluding mutations of CD40L, AID, CD40, and NEMO. Activated T cells from all 33 patients expressed ICOS normally, and sequence analysis of the coding region and exon-intron boundaries revealed only wild-type ICOS, predicting that the protein structure is normal in this patient population. CONCLUSION: These findings strongly suggest that ICOS does not belong to the group of genes that, if mutated, present clinically as the HIGM syndrome.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2003

CD4+ T-cell-directed antibody responses are maintained in patients with psoriasis receiving alefacept: results of a randomized study.

BACKGROUND: Alefacept, human LFA-3/IgG(1) fusion protein, selectively reduces memory-effector (CD45RO(+)) T cells, a source of the pathogenic mediators of psoriasis. OBJECTIVE: To evaluate the effect of alefacept on immune function, T-cell-dependent humoral responses to a neoantigen (PhiX174) and recall antigen (tetanus toxoid) were assessed. METHODS: Patients with psoriasis were randomized to the control group or to receive alefacept (7.5 mg intravenously weekly for 12 weeks). The alefacept group received PhiX174 immunizations at weeks 6, 12, 20, and 26 and tetanus toxoid at week 21; control subjects received PhiX174 at weeks 6 and 12 and tetanus at week 10. RESULTS: Mean anti-PhiX174 titers were comparable in both groups. There was no difference in the percentage of responders (anti-PhiX174 IgG >/=30% of the total anti-PhiX174) between the alefacept group and the control group (86% and 82%, respectively; P =.73). The percentage of patients with anti-tetanus toxoid titer increases >/=2 times baseline also was similar (alefacept, 89%; control 91%). CONCLUSION: A single 12-week course of alefacept did not impair primary or secondary antibody responses to a neoantigen or memory responses to a recall antigen. The selective immunomodulatory effect of alefacept against a potentially pathogenic T-cell subset is associated with maintenance of a significant aspect of immune function (antibody response) to fight infection and respond to vaccinations.

Adult↗
PubMed2003

Wiskott-Aldrich Syndrome: a model for defective actin reorganization, cell trafficking and synapse formation.

Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders and increased incidence of malignancies. Classic WAS, and a milder form, X-linked thrombocytopenia, are caused by mutations of the WAS protein (WASP) gene. Recent investigations have provided evidence that WASP and several related proteins are involved in the reorganization of the actin cytoskeleton by activating Arp2/3-mediated actin polymerization. This function is controlled by the small GTPase Cdc42, which regulates the autoinhibitory loop formation of WASP. In addition, WASP is involved in cytoplasmic signaling via its interaction with a variety of adaptor molecules. Mutation analysis of large cohorts of WAS/X-linked thrombocytopenia patients has provided evidence for a strong correlation between phenotype and genotype.

Actins↗
PubMed2003

Functional analysis of human memory B-cell subpopulations: IgD+CD27+ B cells are crucial in secondary immune response by producing high affinity IgM.

The number of memory B cells in peripheral blood has been assayed in various diseases by using CD27 as a memory B-cell marker. However, the defining differences of characteristic and function between the two memory B-cell subpopulations separated by immunoglobulin (Ig)D expression remain to be clearly elucidated. We analyzed here IgD(+)CD27(+) B cells (circulating B cells 2, cB2) and IgD(-)CD27(+) memory B cells (cB3) in comparison with IgD(+)CD27(-) naive B cells (cB1). cB2 were found to be morphologically similar to cB3 with abundant cytoplasm, whereas cB3 expressed CD80, CD86, and CD95 on their surface more predominantly than cB2. A majority of cB2 expressed both IgD and IgM, and cB3 expressed IgA or IgG. Mature gamma1 and gamma2 transcripts were found in cB3, but at very low levels in cB2, and activation-induced cytidine deaminase (AID) mRNA expression was recognized only in cB3. The frequencies of somatic hypermutation in cB2 and cB3 were comparable levels studied by VH5. cB2 did not shift to cB3 in vitro by the stimuli such as via B-cell receptor or CD40. cB2 produced large amounts of IgM predominantly and promptly, which is in accordance with the known characteristics of memory B cells. Taken together, although cB2 are unclass-switched, cB2 have the functions of memory B cells and are not in the process of transition from naive to switched memory B cells, playing a crucial role in secondary immune response by producing high-affinity IgM in the early phase of infections.

Adolescent↗
PubMed2003

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis.

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX) is one of a group of clinical syndromes that present with multisystem autoimmune disease suggesting a phenotype of immune dysregulation. Clinically, IPEX manifests most commonly with diarrhea, insulin-dependent diabetes mellitus, thyroid disorders, and eczema. FOXP3, the gene responsible for IPEX, maps to chromosome Xp11.23-Xq13.3 and encodes a putative DNA-binding protein of the forkhead family. Recent data indicate that FOXP3 is expressed primarily in the CD4+CD25+ regulatory T-cell subset, where it may function as a transcriptional repressor and key modulator of regulatory T-cell fate and function. This review describes the clinical features of IPEX and the structure, function, and known mutations of FOXP3 that provide important insights into its role in maintenance of immune homeostasis.

Animals↗