TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cellspecific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clinical presentation of TACI deficiency prompted us to evaluate the genetic, immunologic, and clinical condition in 50 individuals with TNFRSF13B alterations, following screening of 564 unrelated patients with hypogammaglobulinemia. We identified 13 new sequence variants. The most frequent TNFRSF13B variants (C104R and A181E; n ؍ 39; 6.9%) were also present in a heterozygous state in 2% of 675 controls. All patients with biallelic mutations had hypogammaglobulinemia and nearly all showed impaired binding to a proliferationinducing ligand (APRIL). However, the majority (n ؍ 41; 82%) of the patients carried monoallelic changes in TNFRSF13B. Presence of a heterozygous mutation was associated with antibody deficiency (P <.001 , relative risk 3.6). Heterozygosity for the most common mutation, C104R, was associated with disease (P < .001, relative risk 4.2). Furthermore, heterozygosity for C104R was associated with low numbers of IgD ؊ CD27 ؉ B cells (P ؍ .019), benign lymphoproliferation (P < .001), and autoimmune complications (P ؍ .001). These associations indicate that C104R heterozygosity increases the risk for common variable immunodeficiency disorders and influences clinical presentation. (Blood.
To date, 86 of 7,746 macrolide-resistant Streptococcus pneumoniae isolates from 1999 to 2002 PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) surveillance studies were negative for methylase and efflux mechanisms. Mutations in 23S rRNA or the genes encoding riboprotein L4 or L22 were found in 77 of 86 isolates. Six isolates were resistant to quinupristin-dalfopristin and two were resistant to linezolid, while telithromycin demonstrated good activities against all isolates.Macrolide, lincosamide, and streptogramin B (MLS B ) resistance in Streptococcus pneumoniae occurs predominantly by modification of the drug binding site and/or by drug efflux. Drug efflux is encoded by the mef(A) gene, while target modification is usually the result of methylation of the 23S rRNA, mostly by the product of the erm(B) gene and rarely by the erm(A) subclass erm(TR) gene. In vitro studies have demonstrated that target modification can also be achieved by mutations in domains II and V of 23S rRNA (in one to four of the four copies of this gene present in S. pneumoniae) and in the genes encoding riboproteins L4 and L22 (1, 11). These mutations can confer resistance to MLS B antibacterials and, in some cases, to ketolides (1, 11). Ribosomal mutations have also been found in MLS B -resistant clinical isolates, although reports are rare at present (2, 9, 10).PROTEKT (Prospective Resistant Organism Tracking and Epidemiology for the Ketolide Telithromycin) is a longitudinal, multicenter surveillance study of antibacterial resistance among respiratory tract pathogens from numerous countries worldwide. PROTEKT US is a sister study involving the United States only and began in 2000. All macrolide-resistant S. pneumoniae strains isolated during year 1 of the PROTEKT study (1999 to 2000) were screened for the common efflux and methylase genes associated with macrolide resistance to determine the global distributions of these mechanisms. Of 1,043 macrolide-resistant isolates screened, 16 (1.5%) isolates repeatedly tested negative for the erm and mef genes, while the remaining isolates were resistant to macrolides (4, 5). All isolates were found to harbor ribosomal mutations, most commonly A2059G (12 isolates) (4).(Preliminary data were presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy, Chi (32.9%) were macrolide resistant; 86 (0.37%) macrolide-resistant isolates (including the 16 isolates reported previously) were negative for methylase and efflux mechanisms. The ribosomal mutations associated with macrolide resistance in these isolates were determined in this study. Before the isolates were sequenced for ribosomal mutations, macrolide resistance was confirmed by repeating the MIC determinations and comparing the MIC data with the initial results. Detection of L4 and L22 riboprotein and 23S rRNA gene mutations was performed as described previously (3). Briefly, the complete L4 and L22 operons and all four 23S rRNA operons were sequenced.
Of a total of 1,043 macrolide-resistant Streptococcus pneumoniae isolates collected from 24 countries as part of PROTEKT 1999-2000, 71 isolates tested positive for both the mef(A) and erm(B) genes. Of 69 isolates subjected to further molecular investigations, all were resistant to tetracycline, 63 (91.3%) were resistant to penicillin, and 57 (82.6%) were resistant to trimethoprim-sulfamethoxazole. One isolate was also fluoroquinolone resistant, and another was resistant to quinupristin-dalfopristin. The ketolide telithromycin retained activity against all of the isolates. Of the 69 of these 71 isolates viable for further testing, 46 were from South Korea, 13 were from the United States, 8 came from Japan, and 1 each came from Mexico and Hungary. One major clonal complex (59 [85.5%] of 69 isolates) was identified by serotyping (with 85.5% of the isolates being 19A or 19F), pulsed-field gel electrophoresis, and multilocus sequence typing. The remaining isolates were less clonal in nature. Representative isolates were shown to carry the mobile genetic elements Tn1545 and mega, were negative for Tn1207.1, had tetracycline resistance mediated by tet(M), and contained the mef(E) variant of mef(A). All isolates were positive for mel, a homologue of the msr(A) efflux gene. These clones are obviously very efficient at global dissemination, and hence it will be very important to monitor their progress through continued surveillance. Telithromycin demonstrated high levels of activity (MIC for 90% of the strains tested, 0.5 g/ml; MIC range, 0.06 to 1 g/ml) against all isolates.
The ROB-1 beta-lactamase was found almost exclusively in North America and was more active against cefaclor and cefprozil than the TEM-1 beta-lactamase.
SummaryCommon variable immunodeficiency (CVID) is a primary immunodeficiency that typically affects adults and is characterized by abnormalities of quantative and qualitative humoral function that are heterogeneous in their immunological profile and clinical manifestations. The recent identification of four monogenic defects that result in the CVID phenotype also demonstrates that the genetic basis of CVID is highly variable. Mutations in the genes encoding the tumour necrosis factor (TNF) superfamily receptors transmembrane activator and calcium-modulating ligand interactor (TACI) and B cell activation factor of the TNF family receptor (BAFF-R), CD19 and the co-stimulatory molecule inducible co-stimulator molecule (ICOS) all lead to CVID and illustrate the complex interplay required to co-ordinate an effective humoral immune response. The molecular mechanisms leading to the immune defect are still not understood clearly and particularly in the case of TACI, where a number of heterozygous mutations have been found in affected individuals, the molecular pathogenesis of disease requires further elucidation. Together these defects account for perhaps 10-15% of all cases of CVID and it is highly likely that further genetic defects will be identified.
Fluoroquinolone resistance in 23F -1-14 variant). All the isolates were multidrug resistant but were susceptible to quinupristin-dalfopristin, linezolid, and telithromycin. The Spain 23F -1 clone also occurred among antimicrobial-susceptible isolates, which suggests that the primary source of this clone may have been Asia rather than Iberia.
B cell activating factor belonging to the TNF family (BAFF) and a proliferation inducing ligand (APRIL), and their receptors BAFF receptor (BAFFR), B cell maturation antigen (BCMA), and transmembrane activator and CAML interactor (TACI) are involved in the regulation of B cell homeostasis and differentiation. BAFF overexpression leads to systemic lupus erythematosus (SLE) in mice and elevated BAFF levels have been observed in human SLE and mouse models for SLE. Furthermore, genetic inactivation of TACI in mice results in a SLE-like phenotype. Based on our recent finding that TACI is mutated in patients with common variable immunodeficiency, of whom more than 30% suffer from autoimmune conditions, we analyzed TACI in humans with SLE. Sequence analysis of TNFRSF13b/TACI in 119 unrelated SLE patients revealed four variants: R20C in exon 1, R72H in exon 3, the silent variation c.327 G > A in exon 3, and A181E in exon 4. No significant association with any of these variants was found, when compared to the frequencies of the variants in a healthy control cohort. Furthermore, the mutated alleles R20C and R72H did not segregate with the SLE phenotype in familial cases of SLE. Thus, our evaluation of the coding region of TNFRSF13b/TACI did not reveal any deleterious or disease-associated mutations.
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