Enter your email address below and we will send you the reset instructions. If the address matches an existing account you will receive an email with instructions to reset your password Close. Request Username Can't sign in? Forgot your username? Enter your email address below and we will send you your username. Human Gene Therapy Vol. Taizo Wada Search for more papers by this author. Jayashree Jagadeesh Search for more papers by this author.
David L. Nelson Search for more papers by this author. Fabio Candotti Search for more papers by this author. Somatic mosaicism in the Wiskott—Aldrich syndrome: Molecular and functional characterization of genotypic revertants. Wiskott—Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation. Recent advances in understanding the pathophysiology of Wiskott-Aldrich syndrome. Ten years of gene therapy for primary immune deficiencies.
WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function. Hematopoietic Progenitor Cells. Gene therapy of inherited immunodeficiencies. Wiskott-Aldrich syndrome. The Wiskott—Aldrich syndrome: from genotype—phenotype correlation to treatment. Current understanding of the Wiskott—Aldrich syndrome and prospects for gene therapy. Lentiviral vectors targeting WASp expression to hematopoietic cells, efficiently transduce and correct cells from WAS patients.
Read the latest chapters of Clinical Immunobiology at dipotsdern.ga, Elsevier's leading platform of peer-reviewed scholarly literature. Specific sections focus on basic, applied, and clinical immunology. Volume 1: Development and phylogeny of the Immune System, edited by.
Stem cell transplantation for the Wiskott—Aldrich syndrome: a single-center experience confirms efficacy of matched unrelated donor transplantation. Retroviral WASP gene transfer into human hematopoietic stem cells reconstitutes the actin cytoskeleton in myeloid progeny cells differentiated in vitro. WASP and the phenotypic range associated with deficiency. A lentiviral vector encoding the human Wiskott—Aldrich syndrome protein corrects immune and cytoskeletal defects in WASP knockout mice.
Lentiviral vectors for the treatment of Wiskott—Aldrich syndrome. Perspectives of gene therapy for primary immunodeficiencies. X-linked immunodeficiencies. The Molecular Pathology of Primary Immunodeficiencies. The pathogenic process leading to the production of Gd-IgA1 involves dysregulated expression of several key glycosyltransferases.
The Gd-IgA1 is recognized by glycan-specific autoantibodies, a pathogenic process that leads to formation of nephritogenic immune complexes. Further definition of the nature of abnormal O -glycosylation of IgA1 and the pathways enhancing autoantigen production may uncover potential disease-specific therapeutic targets in future studies.
Numerous lines of evidence support a strong genetic contribution to IgAN First, significant geographic and ethnic differences exist in the prevalence of IgAN: it occurs with greatest frequency in East Asians, is relatively common in Europeans, and is infrequent in individuals of African ancestry 55 , Second, familial aggregation of the disease has been well recognized In most reported families, IgAN follows autosomal dominant transmission with incomplete penetrance.
The recognition of familial disease has many clinical implications, particularly for the selection of living, related donors for kidney transplantation. Despite numerous efforts at gene mapping using linkage approaches, Mendelian defects responsible for familial IgAN remain elusive 59 — Linkage studies of IgAN have been limited because definitive diagnosis requires an invasive procedure, which often precludes reliable screening of asymptomatic relatives of affected individuals and increases chances of phenotype misclassification.
Newer approaches, such as linkage analysis with phenotyping enhanced by determination of serum Gd-IgA1 levels, in combination with exome or genome sequencing may prove more fruitful The GWAS approach has emerged as a powerful alternative to family-based studies for complex traits and has been successfully applied to IgAN.
By design, the major limitation of GWAS is that they detect only common susceptibility variants, and these typically have relatively small effects Nevertheless, a well-executed GWAS may provide unbiased insights into the biology of human disease that could be clinically relevant regardless of the fraction of risk explained In the case of IgAN, this approach is further motivated by the success of GWAS in the field of autoimmune and inflammatory diseases, with well over genome-wide significant susceptibility loci discovered to date. New biology arising from GWAS allowed for the identification of previously unrecognized pathways that are shared between different autoimmune disorders, shedding light on the common underlying mechanisms that can now be targeted pharmaceutically Notably, the discovery sample size for all three studies combined consisted of only 3, IgAN cases and thus is approximately ten-fold smaller compared with the aforementioned studies of IBD and MS, which each included over 30, cases.
Notably, this is a substantially greater fraction compared with other GWAS of kidney phenotypes — for example, a study of 60, individuals reported 13 loci that explained only 1.
Nonetheless, a large portion of IgAN risk remains unexplained, and there are likely additional loci that have not yet been discovered. These observations clearly motivate even larger studies of IgAN. Although the fraction of the overall risk explained to date by GWAS is relatively small, systematic ethnic differences in IgAN risk allele frequencies correlate well with disease epidemiology Strikingly, East Asians carry the highest average number of risk alleles and have the greatest prevalence of IgAN, while Africans have the lowest burden of risk alleles and are rarely affected.
Moreover, careful dissection of ethnicity-specific effects will be important, because the disease appears to have different features in East Asians and Europeans. For example, apart from dramatic differences in prevalence, biopsy series as well as ESRD registries indicate that the disease is equally frequent in males and females in East Asia 69 — In contrast, IgAN is strikingly more common in European males, with a male-to-female ratio often exceeding 73 — These data suggest a complex interaction between gender and ethnicity on disease risk in IgAN.
To date, no one has examined whether these patterns are mediated by a genetic effect. Moreover, prior GWAS showed no significant associations for markers on the sex chromosomes, suggesting that gender differences may be mediated by autosomal SNPs with gender-specific effects. The studies of gender-genotype interactions, as well as careful analysis of sex chromosomes in larger GWAS, may potentially provide some answers as to the origin of these intriguing epidemiologic patterns.
Finally, although GWAS have defined several susceptibility loci, the discovery of specific causal alleles within each locus awaits additional fine mapping or re-sequencing efforts, in addition to functional follow-up studies.
Nevertheless, through careful analysis and annotation of the detected loci, several causal candidate genes have been prioritized, providing novel insights into the pathways driving the pathogenesis of IgAN. These are interferon-regulated genes involved in antigen processing for presentation by MHC-I molecules, and these genes also play an important role in modulation of cytokine production and cytotoxic T cell response. Secretory IgA is central to intestinal homeostasis between the host and commensal bacteria, playing a critical role in regulating the intestinal microbiome and preventing pathogen overgrowth Figure 2.
The inability of secretory IgA to activate the classical complement pathway may also play a role in creating a more tolerant non-inflammatory host-microbial relationship. Intestinal network of IgA production. IgA is the most abundant antibody isotype in the body, with the majority of IgA found in mucosal secretions.
Mucosal IgA production is induced by T cell—dependent or T cell—independent mechanisms.
IgA-secreting plasma cells migrate to lamina propria, where they release dimeric IgA. The dimers are formed through an interaction of two IgA molecules with a joining chain, which is synthesized by plasma cells. IgA dimers can bind to the polymeric Ig receptor pIgR on the basolateral surface of the mucosal epithelium and undergo transcytosis to the apical surface, where they dissociate from pIgR and are secreted into the lumen, carrying the secretory component of the receptor.
The secretory component protects IgA molecules from proteolytic enzymes in the gut lumen. The bacteriostatic effects of secretory IgA are accompanied by antimicrobial peptides, such as defensins, secreted into the gut lumen by Paneth cells. The key molecules involved in the intestinal network of IgA production are indicated in orange; molecules implicated by GWAS are indicated in red. This hypothesis is also supported by GWAS.
Inactivation of Tnfsf13 in mice produces partial IgA deficiency and reduced IgA antibody responses to mucosal immunization Conversely, overexpression of B cell activation factor BAFF , a related molecule with overlapping functions and receptors with APRIL, results in autoimmune disease with commensal flora-dependent mesangial IgA deposits in mice These cytokines are members of the IL-6 family, are expressed in mucosal tissues, and have immunoregulatory properties 95 , Interestingly, OSM- deficient mice develop autoimmune disease with positive anti-dsDNA antibodies and glomerulonephritis with mesangial IgG deposits We hypothesize that increased IgA production conferred by this allele has protective local anti-inflammatory effects, but the concomitant increase in the circulating IgA results in a higher risk of nephritis.
Additional functional studies are clearly needed to test this hypothesis. High rates of copy number variation are attributable to long runs of repetitive sequence in this region. The gene copy is also correlated with the expression level of these peptides , GWAS strongly implicate dysregulation of mucosal IgA production as one of the causes of IgAN and suggest that the interplay of mucosal immunity with the commensal microbiome may represent an important disease modifier.
Future efforts will focus on defining causal alleles at the identified loci by fine mapping, sequencing, and functional studies. Additional work is also needed to test the effects of these loci on the synthesis and O -glycosylation of IgA1. It binds activated surface-fixed C3b and inhibits formation of C3 convertase while targeting C3b for inactivation by Factor I—mediated cleavage Considering the high level of sequence similarity between CFH and CFHR s, these genes are believed to have originated through segmental duplications and, similar to the DEFA locus, this region is prone to recurrent structural rearrangements.
A similar protective effect of the deletion was reported for age-related macular degeneration AMD , a complement-mediated retinal disease and a major cause of blindness in the elderly , Structural studies revealed that FHR1, FHR2, and FHR5 share highly conserved dimerization domains, which enable formation of head-to-tail homo- and heterodimers of different combinations of these proteins The dimeric forms are secreted by FHR-producing cells and are present in circulation in vivo.