Oral tolerance induction is a key feature of intestinal immunity, generating systemic nonresponsiveness to ingested antigens. In this study, we report that orally applied soluble antigens are exclusively recognized in the intestinal immune system, particularly in the mesenteric lymph nodes. Consequently, the initiation of oral tolerance is impeded by mesenteric lymphadenectomy. Small bowel transplantation reveals that mesenteric lymph nodes require afferent lymph to accomplish the recognition of orally applied antigens. Finally, oral tolerance cannot be induced in CCR7-deficient mice that display impaired migration of dendritic cells from the intestine to the mesenteric lymph nodes, suggesting that immunologically relevant antigen is transported in a cell-bound fashion. These results demonstrate that antigen transport via afferent lymphatics into the draining mesenteric lymph nodes is obligatory for oral tolerance induction, inspiring new therapeutic strategies to exploit oral tolerance induction for the prevention and treatment of autoimmune diseases.

In mammals, the master clock of the suprachiasmatic nuclei (SCN) and subordinate clocks found throughout the body coordinate circadian rhythms of behavior and physiology. We characterize the clock of the adrenal, an important endocrine gland that synchronizes physiological and metabolic rhythms. Clock gene expression was detected in the outer adrenal cortex prefiguring a role of the clock in regulating gluco- and mineral corticoid biogenesis. In Per2/Cry1 double mutant mice, which lack a circadian clock, hypothalamus/pituitary/adrenal axis regulation was defective. Organ culture and tissue transplantation suggest that the adrenal pacemaker gates glucocorticoid production in response to adrenocorticotropin (ACTH). In vivo the adrenal circadian clock can be entrained by light. Transcriptome profiling identified rhythmically expressed genes located at diverse nodes of steroid biogenesis that may mediate gating of the ACTH response by the adrenal clock.

Abstract1 2 6 0 VOLUME 22 | NUMBER 11 | NOVEMBER 2016 nature medicine a r t i c l e s bnAbs have become blueprints for vaccine design owing to their unequalled activity against divergent HIV-1 strains and proven potency in preventing and suppressing HIV-1 infection after in vivo administration [1][2][3][4][5][6][7][8] . Elicitation of potent bnAb activity is relatively rare in natural HIV-1 infection: only 10-25% of infected individuals develop breadth, and an estimated 1% generate highly potent bnAb, or 'elite neutralization' , activity 9,10 . Although much is known about the functional properties of bnAbs, the parameters that govern their evolution in natural infection remain unknown, which is a critical limitation for vaccine development. To date, no vaccine approach has induced bnAb responses that match those elicited in natural infection 1,11 . Defining what restricts and promotes bnAb evolution in certain individuals will be crucial for devising successful vaccine regimens, as the same restrictions are likely to be encountered during immunization.Observations that bnAb activity arises predominantly in viremic individuals after several years of infection and is linked to lower CD4 + cell counts (referred to here as CD4 levels) 4,12-14 strongly suggest that prolonged exposure to viral antigen is needed for induction of bnAbs.Broadly neutralizing antibodies (bnAbs) are a focal component of HIV-1 vaccine design, yet basic aspects of their induction remain poorly understood. Here we report on viral, host and disease factors that steer bnAb evolution using the results of a systematic survey in 4,484 HIV-1-infected individuals that identified 239 bnAb inducers. We show that three parameters that reflect the exposure to antigen-viral load, length of untreated infection and viral diversity-independently drive bnAb evolution. Notably, black participants showed significantly (P = 0.0086-0.038) higher rates of bnAb induction than white participants. Neutralization fingerprint analysis, which was used to delineate plasma specificity, identified strong virus subtype dependencies, with higher frequencies of CD4-binding-site bnAbs in infection with subtype B viruses (P = 0.02) and higher frequencies of V2-glycan-specific bnAbs in infection with non-subtype B viruses (P = 1 × 10 −5 ). Thus, key host, disease and viral determinants, including subtypespecific envelope features that determine bnAb specificity, remain to be unraveled and harnessed for bnAb-based vaccine design.This may be necessary in part to allow the extensive antibody-affinity maturation that is characteristic of many HIV-1-specific bnAbs 15,16 . Similarly, antigen levels may be relevant, as bnAbs have been found to evolve less frequently in individuals with lower viral loads 1,4,13,17 . Individual case studies delineating pathways of bnAb maturation have highlighted the tight interplay between virus escape and antibody adaptation that precedes the development of a broad neutralization response [18][19][20][21][22][23] . In line with this, the viral envelop...

Background Understanding the drivers of SARS-CoV-2 transmission is crucial for control policies but evidence of transmission rates in different settings remains limited. Methods We conducted a systematic review to estimate secondary attack rates (SAR) and observed reproduction numbers (Robs) in different settings exploring differences by age, symptom status, and duration of exposure. To account for additional study heterogeneity, we employed a Beta-Binomial model to pool SARs across studies and a Negative-binomial model to estimate Robs. Results Households showed the highest transmission rates, with a pooled SAR of 21.1% (95%CI:17.4%-24.8%). SARs were significantly higher where the duration of household exposure exceeded 5 days compared with exposure of ≤5 days. SARs related to contacts at social events with family and friends were higher than those for low-risk casual contacts (5.9% vs. 1.2%). Estimates of SAR and Robs for asymptomatic index cases were approximately a seventh, and for pre-symptomatic two thirds of those for symptomatic index cases. We found some evidence for reduced transmission potential both from and to individuals under 20 years of age in the household context, which is more limited when examining all settings. Conclusions Our results suggest that exposure in settings with familiar contacts increases SARS-CoV-2 transmission potential. Additionally, the differences observed in transmissibility by index case symptom status and duration of exposure have important implications for control strategies such as contact tracing, testing and rapid isolation of cases. There was limited data to explore transmission patterns in workplaces, schools, and care-homes, highlighting the need for further research in such settings.

We identified 5 risk factors for nocardiosis after SOT. Low-dose cotrimoxazole was not found to prevent Nocardia infection. These findings may help improve management of transplant recipients.