Mycobacterial diseases are a major public health concern. In the case of tuberculosis, the problem has been acerbated due to the emergence of drug-resistant strains of Mycobacterium tuberculosis, and Mycobacterium avium is the major opportunistic pathogen in HIV-1 infection in the United States. M. tuberculosis and M. avium replicate in human macrophages and induce apoptosis. Incubation of freshly added uninfected autologous macrophages with apoptotic M. avium-infected macrophages results in 90% inhibition of bacterial growth. Apoptosis also prevents the release of intracellular components and the spread of mycobacterial infection by sequestering the pathogens within apoptotic bodies. Consistent with the model that host cell apoptosis is a defense mechanism against mycobacteria is the finding that the virulent M. tuberculosis strain H37Rv induces substantially less macrophage apoptosis than the attenuated strain H37Ra. Evasion of apoptosis by this pathogen is achieved by enhanced release of sTNFR2 by H37Rv-infected macrophages and subsequent formation of inactive TNF-␣-TNFR2 complexes. These observations contribute to the hypothesis that apoptosis of the host macrophage is an important defense mechanism in mycobacterial infections, which prevents the spread of the infection.

We studied the role of CD43 (leukosialin/sialophorin), the negatively charged sialoglycoprotein of leukocytes, in the binding of mycobacteria to host cells. CD43-transfected HeLa cells bound Mycobacterium avium, but not Salmonella typhimurium or Shigella flexneri. Quantitative bacteriology showed that macrophages (Mφ) from wild-type mice (CD43+/+) bound M. avium, Mycobacterium bovis (bacillus Calmette-Guérin), and Mycobacterium tuberculosis (strain H37Rv), whereas Mφ from CD43 knockout mice (CD43−/−) did not. Fluorescence microscopy demonstrated that the associated M. avium had been ingested by the CD43+/+ Mφ. The inability of CD43−/− Mφ to bind M. avium could be restored by addition of galactoglycoprotein (Galgp), the extracellular mucin portion of CD43. The effect of Galgp is not due to opsonization of the bacteria, but required its interaction with the Mφ; other mucins had no effect. CD43 expression by the Mφ was also required for optimal induction by M. avium of tumor necrosis factor (TNF)-α production, which likewise could be reconstituted by Galgp. In contrast, interleukin (IL)-10 production by M. avium–infected Mφ was CD43 independent, demonstrating discordant regulation of TNF-α and IL-10. These findings describe a novel role of CD43 in promoting stable interaction of mycobacteria with receptors on the Mφ enabling the cells to respond specifically with TNF-α production.

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ImportanceThe effect of rationally defined nonpathogenic, nontoxigenic, commensal strains of Clostridia on prevention of Clostridioides difficile infection (CDI) is unknown.ObjectiveTo determine the efficacy of VE303, a defined bacterial consortium of 8 strains of commensal Clostridia, in adults at high risk for CDI recurrence. The primary objective was to determine the recommended VE303 dosing for a phase 3 trial.Design, Setting, and ParticipantsPhase 2, randomized, double-blind, placebo-controlled, dose-ranging study conducted from February 2019 to September 2021 at 27 sites in the US and Canada. The study included 79 participants aged 18 years or older who were diagnosed with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence (defined as aged ≥75 years or ≥65 years with ≥1 risk factors: creatinine clearance <60 mL/min/1.73 m2, proton pump inhibitor use, remote [>6 months earlier] CDI history).InterventionsParticipants were randomly assigned to high-dose VE303 (8.0 × 109 colony-forming units [CFUs]) (n = 30), low-dose VE303 (1.6 × 109 CFUs) (n = 27), or placebo capsules (n = 22) orally once daily for 14 days.Main Outcomes and MeasuresThe primary efficacy end point was the proportion of participants with CDI recurrence at 8 weeks using a combined clinical and laboratory definition. The primary efficacy end point was analyzed in 3 prespecified analyses, using successively broader definitions for an on-study CDI recurrence: (1) diarrhea consistent with CDI plus a toxin-positive stool sample; (2) diarrhea consistent with CDI plus a toxin-positive, polymerase chain reaction–positive, or toxigenic culture–positive stool sample; and (3) diarrhea consistent with CDI plus laboratory confirmation or (in the absence of a stool sample) treatment with a CDI-targeted antibiotic.ResultsBaseline characteristics were similar across the high-dose VE303 (n = 29; 1 additional participant excluded from efficacy analysis), low-dose VE303 (n = 27), and placebo (n = 22) groups. The participants’ median age was 63.5 years (range, 24-96); 70.5% were female; and 1.3% were Asian, 1.3% Black, 2.6% Hispanic, and 96.2% White. CDI recurrence rates through week 8 (using the efficacy analysis 3 definition) were 13.8% (4/29) for high-dose VE303, 37.0% (10/27) for low-dose VE303, and 45.5% (10/22) for placebo (P = .006, high-dose VE303 vs placebo).Conclusions and RelevanceAmong adults with laboratory-confirmed CDI with 1 or more prior CDI episodes in the last 6 months and those with primary CDI at high risk for recurrence, high-dose VE303 prevented recurrent CDI compared with placebo. A larger, phase 3 study is needed to confirm these findings.Trial RegistrationClinicalTrials.gov Identifier: NCT03788434

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The complement system was examined in a group of eight patients (six with lymphoadenopathy syndrome (LAS); two with acquired immunodeficiency syndrome (AIDS)-related complex (ARC], who were found to be human immunodeficiency virus (HIV)-positive, for the presence of specific HIV-anti-HIV complexes. A significant impairment of the classical and/or alternative pathway was found associated with the presence of cleavage fragments of C3 and/or B and a significant reduction in the complement factors studied. Ultracentrifugation fractions of serum samples obtained from one of the patients were assessed for the detection of specific HIV-anti-HIV (GP41-anti-GP41) complexes and were incubated with normal human serum to determine their complement activation capacity. A clear complement activation was found with the fraction in which a clear peak of HIV-anti-HIV (GP41-anti-GP41) immune complexes was present. The results demonstrate that specific immune complexes and complement activation are sometimes concomitantly present in patients with AIDS-related disease and that specific immune complexes may be one of the causal factors of the pathogenesis of complement activation in these patients. Possible consequences for the severe immune regulation with relevance to the dramatic failure in treating the virus effectively are discussed.

Despite evidence for the expression of the low-affinity Fc receptor for IgE (FcεRII/CD23) in several pathological conditions, the role played by CD23 in normal human T cells is still unclear. We studied the effect of a stomal-derived cytokine, interleukin (IL-7), on the expression of CD23 in human T cells stimulated with 10 μg/ml phytohemagglutinin (PHA). The results demonstrate that IL-7 did not induce CD23 expression in the resting T cells. However, PHA-induced CD23 expression was enhanced by costimulation with IL-7 (1,000 U/ml). Cytofluorometric analysis revealed that CD23 expression in activated T cells was enhanced by the addition of IL-7 (from 2% to 18%). It was also observed that the effect of IL-7 on CD23 expression is exclusively on CD4+ T cells. The enhanced expression of CD23 was blocked by an anti-IL-7 monoclonal antibody (mAb), but not by IL-2 and IL-4 mAbs. This suggests that IL-7 is a potent regulatory cytokine capable of acting independently of IL-2 and IL-4 in the expression of CD23. Northern blot analysis showed an increase in CD23 mRNA when activated T cells were cultured in the presence of IL-7. A significant increase in receptor numbers on activated T cells was detected by Scatchard analysis when IL-7 was added to the cell cultures. The induction of CD23 expression by IL-1, 1L-3, IL-4, IL-5, IL-6, interferon-8 and OKT3 on PHA-activated T cells was not of the same magnitude as observed in the presence of IL-7. These results demonstrate a selective induction of CD23 expression on activated human T cells cultured in the presence of IL-7. These data indicate that the stromal-derived growth factor points to an important role of CD23 in the regulatory network of the immune response.

Significantly increased levels of IgG anti-IgE were seen in atopic patients as compared with controls. A correlation was observed between the levels of anti-IgE autoantibodies and serum IgE in the groups of atopic patients studied. No significant correlation was found between IgG anti-IgE levels and severity of the disease or between IgG subclasses with anti-IgE activity and clinical status. Analysis of IgG subclasses with anti-IgE activity showed that IgG1 and IgG4 were clearly factors in differentiating the atopies from the controls. IgG2 and IgG3 anti-IgE levels were not statistically significantly elevated. The lack of these autoantibodies may be explained by the presence of immune complexes or the lack of specificity of the monoclonal antibodies used in this study. These observations have not yet determined whether these autoantibodies and the isotypic selection and restriction observed play a role in the dysregulation of the immune response and in the evolution towards atopy.