Search

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD[8.sup.+] T cell cytotoxicity, CD[4.sup.+] T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency., Introduction Primary immunodeficiencies (PIDs) or inborn errors of immunity (IEI) are caused by mutations in single genes that compromise the function of the immune system (1). Somatic reversion is the [...]

Rotavirus-induced diarrhea is a life-threatening disease in immunocompromised individuals and in children in developing countries. We have developed a system for prophylaxis and therapy against rotavirus disease using transgenic rice expressing the neutralizing variable domain of a rotavirus-specific llama heavy-chain antibody fragment (MucoRice-ARP1). MucoRice-ARP1 was produced at high levels in rice seeds using an overexpression system and RNAi technology to suppress the production of major rice endogenous storage proteins. Orally administered MucoRice-ARP1 markedly decreased the viral load in immunocompetent and immunodeficient mice. The antibody retained in vitro neutralizing activity after long-term storage (>1 yr) and boiling and conferred protection in mice even after heat treatment at 94°C for 30 minutes. High-yield, water-soluble, and purification-free MucoRice-ARP1 thus forms the basis for orally administered prophylaxis and therapy against rotavirus infections., Introduction Rotavirus is the leading cause of diarrhea in infants and young children worldwide, causing more than 114 million episodes of diarrhea annually in children under the age of 5 [...]

B-cell survival depends on signals induced by B-cell activating factor (BAFF) binding to its receptor (BAFF-R). In mice, mutations in BAFF or BAFF-R cause B-cell lymphopenia and antibody deficiency. Analyzing BAFF-R expression and BAFF-binding to B cells in common variable immunodeficiency (CVID) patients, we identified two siblings carrying a homozygous deletion in the BAFF-R gene. Removing most of the BAFF-R transmembrane part, the deletion precludes BAFF-R expression. Without BAFF-R, B-cell development is arrested at the stage of transitional B cells and the numbers of all subsequent B-cell stages are severely reduced. Both siblings have lower IgG and IgM serum levels but, unlike most CVID patients, normal IgA concentrations. They also did not mount a T-independent immune response against pneumococcal cell wall polysaccharides but only one BAFF-R-deficient sibling developed recurrent infections. Therefore, deletion of the BAFF-R gene in humans causes a characteristic immunological phenotype but it does not necessarily lead to a clinically manifest immunodeficiency. B lymphopenia | primary immunodeficiency | recessive mutation

Ig class switch recombination (CSR) and somatic hypermutation serve to diversify antibody responses and are orchestrated by the activity of activation-induced cytidine deaminase and many proteins involved in DNA repair and genome surveillance. Msh5, a gene encoded in the central MHC class III region, and its obligate heterodimerization partner Msh4 have a critical role in regulating meiotic homologous recombination and have not been implicated in CSR. Here, we show that MRL/Ipr mice carrying a congenic [H-2.sup.b/b] MHC interval exhibit several abnormalities regarding CSR, including a profound deficiency of IgG3 in most mice and long micro-homologies at Ig switch (S) joints. We found that Msh5 is expressed at low levels on the [H-2.sup.b] haplotype and, importantly, a similar long S joint microhomology phenotype was observed in both Msh5 and Msh4-null mice. We also present evidence that genetic variation in MSH5 is associated with IgA deficiency and common variable immune deficiency (CVID) in humans. One of the human MSH5 alleles identified contains two nonsynonymous polymorphisms, and the variant protein encoded by this allele shows impaired binding to MSH4. Similar to the mice, Ig S joints from CVID and IgA deficiency patients carrying disease-associated MSH5 alleles show increased donor/acceptor microhomology, involving pentameric DNA repeat sequences and lower mutation rates than controls. Our findings suggest that Msh4/5 heterodimers contribute to CSR and support a model whereby Msh4/5 promotes the resolution of DNA breaks with low or no terminal microhomology by a classical nonhomologous end-joining mechanism while possibly suppressing an alternative microhomology-mediated pathway. immunoglobulin subclass deficiency | mismatch repair | Msh4

Only three Ig isotypes, IgM, IgX, and IgY, were previously known in amphibians. Here, we describe a heavy-chain isotype in Xenopus tropicalis, IgF (encoded by [C.sub.[phi]]), with only two constant region domains. IgF is similar to amphibian IgY in sequence, but the gene contains a hinge exon, making it the earliest example, in evolution, of an Ig isotype with a separately encoded genetic hinge. We also characterized a gene for the heavy chain of IgD, located immediately 3' of [C.sub.[mu]], that shares features with the [C.sub.[delta]] gene in fish and mammals. The latter gene contains eight constant-region-encoding exons and, unlike the chimeric splicing of [mu][C.sub.H]1 onto the IgD heavy chain in teleost fish, it is expressed as a unique IgD heavy chain. The IgH locus of X. tropicalis shows a 5' [V.sub.H]-[D.sub.H]-[J.sub.H]-[C.sub.[mu]]-[C.sub. [delta]]-[C.sub.x]-[C.sub.v]-[C.sub.[phi]], 3' organization, suggesting that the mammalian and amphibian Ig heavy-chain loci share a common ancestor. amphibians | antibody evolution

Helicobacter pylori adherence in the human gastric mucosa involves specific bacterial adhesins and cognate host receptors. Here, we identify sialyl-dimeric-Lewis x glycosphingolipid as a receptor for H. pylori and show that H. pylori infection induced formation of sialyl-Lewis x antigens in gastric epithelium in humans and in a Rhesus monkey. The corresponding sialic acid--binding adhesin (SabA) was isolated with the 'retagging' method, and the underlying sabA gene (JHP662/HP0725) was identified. The ability of many H. pylori strains to adhere to sialylated glycoconjugates expressed during chronic inflammation might thus contribute to virulence and the extraordinary chronicity of H. pylori infection., Helicobacter pylori persistently infects the gastric mucosa of more than half of all people worldwide, causes peptic ulcer disease, and is an early risk factor for gastric cancer (1). Many [...]

Several pathogenic mechanisms have been identified that correlate immunoglobulin A deficiency (IgAD) and disease predisposition. Studies using transmission/disequilibrium testing indicates family-based associations, with affected mothers more likely to produce IgAD offspring than affected fathers. Anti-IgA-positive status also affects transmission, as does increased allele sharing at 6p21 witnessed in affected individuals.

A gene belonging to the src group of proto-oncogenes has been associated with X-linked agammaglobulinemia (XLA), a hereditary immunodeficiency disease occurring in males. The gene, which was isolated in yeast artificial chromosome using complementary DNA and which has been designated atk, probably produces the defective development of B cells in the bone marrow that causes XLA. Furthermore, atk also carries the genetic information for a protein-tyrosine kinase.

The human leukocyte antigen (HLA) class II association of common variable immunodeficiency (CVID) was investigated. A previous study has shown that susceptibility and resistance to IgA deficiency (IgA-D) were related to different amino acids at position 57 of the HLA-DQ-beta chain. The observation of familial predisposition to both IgA-D and CVID indicated that susceptibilityand resistance to CVID could also be associated with HLA loci. The results showed that IgA-D and CVID are related disorders based on allelic variability at HLA loci.

Many human diseases are preferentially associated with certain genes of the major histocompatibility complex. This is especially true for diseases with a strong immunological component. It has become common for researchers to correlate disease occurrence with the presence of particular human leukocyte antigens, or HLA. The HLA are the products of the major histocompatibility complex genes. An investigation was carried out to explore the relationship between immunoglobulin A deficiency (IgA), the most common form of human immunodeficiency, and the HLA haplotypes. (Since immunoglobulin A is a secretory protein, the deficiency of this antibody is reflected in infections of the mouth, respiratory tract, and gastrointestinal system.) The investigation focused on the class II antigens, which include DP, DQ, and DR antigens. The discussion can be complicated by the fact that each individual inherits a haplotype, that is, half of his or her MHC genes, from each parent, and thus there are always two DP, DQ, and DR haplotypes in each patient. The investigation of 95 patients with IgA deficiency led to the observation that the disease was strongly correlated with the presence of DRw17. In addition, the haplotypes DR7, DQw2 and DR1, DQw5 were found to be positively associated with IgA deficiency. The haplotype DR15, DQw6 had a strong negative association, that is, subjects with this haplotype are very unlikely to have IgA deficiency. Interestingly, the influence of one haplotype could add to the influence of the haplotype from the other parent. They could even be synergistic; for example, the risk associated with having both DRw17, DQw2 and DR1, DQw5 is far greater than the sum of the risks of either set of genes separately. The molecules associated with IgA deficiency were compared for common features. These molecules were found to have either alanine or valine at position 57 of the DQ-beta chain. Both these amino acids are uncharged. DQ-beta chains negatively associated with susceptibility have a charged aspartic acid at position 57. Curiously, this is the same amino acid position in the protein chain which has been found to be altered in patients with insulin-dependent diabetes. The results indicate the far-reaching consequences of alterations in the protein structure of the HLA histocompatibility antigens. (Consumer Summary produced by Reliance Medical Information, Inc.)

Background. Previous studies have shown that selected strains of lactobacilli that are administered orally result in a modest reduction of diarrhea duration. However, duration alone is not considered optimal for therapeutic evaluation of any agent in diarrhea. Objective. To examine the effect of a new probiotic, Lactobacillus paracasei strain ST11 (ST11), in acute childhood diarrhea by using evaluation criteria recommended by the World Health Organization. Methods. In a randomized, double-blind, placebo-controlled clinical trial, 230 male infants and young children, 4 to 24 months of age, presenting with diarrhea of Results. No effect of ST11 treatment on severe rotavirus diarrhea was observed. However, the probiotic treatment did significantly reduce cumulative stool output (225 [+ or -] 218 vs 381 [+ or -] 240 mL/kg), stool frequency (27.9 [+ or -] 17 vs 42.5 [+ or -] 26), and oral rehydration solution intake (180 [+ or -] 207 vs 331 [+ or -] 236 mL/kg) in children with less-severe nonrotavirus diarrhea compared with those receiving placebo treatment. A significantly higher proportion of nonrotavirus children receiving ST11 had their diarrhea resolve within 6 days of therapy (ST11 versus placebo: 76% vs 49%). Conclusions. ST11 has a clinically significant benefit in the management of children with nonrotavirus-induced diarrhea, but it is ineffective in those with rotavirus diarrhea. Pediatrics 2005;116:e221-e228. URL: www.pediatrics.org/cgi/doi/10.1542/peds.2004-2334; children, diarrhea, rotavirus, lactobacillus, probiotic.