Translocating Lactobacillus torments tumors via tryptophan catabolism.

Variability in the efficacy of immune checkpoint inhibitors in cancer patients is associated with the human gut microbiota. However, detailed mechanisms are unclear. In this issue of Cell, Bender et al. uncovered that a probiotic Lactobacillus strain translocates into murine tumors to enhance immunotherapy via the tryptophan metabolite indole-3-aldehyde (I3A).

Within-host evolution of a gut pathobiont facilitates liver translocation.

Gut commensal bacteria with the ability to translocate across the intestinal barrier can drive the development of diverse immune-mediated diseases1-4. However, the key factors that dictate bacterial translocation remain unclear. Recent studies have revealed that gut microbiota strains can adapt and evolve throughout the lifetime of the host5-9, raising the possibility that changes in individual commensal bacteria themselves over time may affect their propensity to elicit inflammatory disease. Here we show that within-host evolution of the model gut pathobiont Enterococcus gallinarum facilitates bacterial translocation and initiation of inflammation. Using a combination of in vivo experimental evolution and comparative genomics, we found that E. gallinarum diverges into independent lineages adapted to colonize either luminal or mucosal niches in the gut. Compared with ancestral and luminal E. gallinarum, mucosally adapted strains evade detection and clearance by the immune system, exhibit increased translocation to and survival within the mesenteric lymph nodes and liver, and induce increased intestinal and hepatic inflammation. Mechanistically, these changes in bacterial behaviour are associated with non-synonymous mutations or insertion-deletions in defined regulatory genes in E. gallinarum, altered microbial gene expression programs and remodelled cell wall structures. Lactobacillus reuteri also exhibited broadly similar patterns of divergent evolution and enhanced immune evasion in a monocolonization-based model of within-host evolution. Overall, these studies define within-host evolution as a critical regulator of commensal pathogenicity that provides a unique source of stochasticity in the development and progression of microbiota-driven disease.

Subdoligranulum chews up joints: how a gut pathobiont can instigate arthritis.

The microbiota has been implicated in triggering certain autoimmune diseases. In rheumatoid arthritis (RA), the 'mucosal origins' hypothesis suggests that such a trigger can instigate systemic autoimmune responses that lead to synovial inflammation. Chriswell et al. recently identified a human gut commensal bound by monoclonal autoantibodies and eliciting autoantibody-mediated, transferable arthritis in gnotobiotic mouse models.

Supporting the differential diagnosis of connective tissue diseases with neurological involvement by blood and cerebrospinal fluid flow cytometry.

OBJECTIVE: Neurological manifestations of autoimmune connective tissue diseases (CTD) are poorly understood and difficult to diagnose. We here aimed to address this shortcoming by studying immune cell compositions in CTD patients with and without neurological manifestation. METHODS: Using flow cytometry, we retrospectively investigated paired cerebrospinal fluid (CSF) and blood samples of 28 CTD patients without neurological manifestation, 38 CTD patients with neurological manifestation (N-CTD), 38 non-inflammatory controls, and 38 multiple sclerosis (MS) patients, a paradigmatic primary neuroinflammatory disease. RESULTS: We detected an expansion of plasma cells in the blood of both N-CTD and CTD compared to non-inflammatory controls and MS. Blood plasma cells alone distinguished the clinically similar entities N-CTD and MS with high discriminatory performance (AUC: 0.81). Classical blood monocytes indicated higher disease activity in systemic lupus erythematosus (SLE) patients. Surprisingly, immune cells in the CSF did not differ significantly between N-CTD and CTD, while CD4+ T cells and the CD4+/CD8+ ratio were elevated in the blood of N-CTD compared to CTD. Several B cell-associated parameters partially overlapped in the CSF in MS and N-CTD. We built a machine learning model that distinguished N-CTD from MS with high discriminatory power using either blood or CSF. CONCLUSION: We here find that blood flow cytometry alone surprisingly suffices to distinguish CTD with neurological manifestations from clinically similar entities, suggesting that a rapid blood test could support clinicians in the differential diagnosis of N-CTD.

Research article network analysis of polymicrobial chronic wound infections in Masanga, Sierra Leone.

BACKGROUND: Chronic wounds are frequently colonized or infected with multiple bacterial or fungal species, which can both promote or inhibit each other. Network analyses are helpful to understand the interplay of these species in polymicrobial infections. Our aim was to analyse the network of bacterial and fungal species in chronic wounds. METHODS: Swabs (n = 163) from chronic wound infections (Masanga, Sierra Leone, 2019-2020) were screened for bacterial and fungal species using non-selective agars. Some of these wounds were suspected but not confirmed Buruli ulcer. Species identification was done with MALDI-TOF mass spectrometry. Network analysis was performed to investigate co-occurrence of different species within one patient. All species with n ≥ 10 isolates were taken into account. RESULTS: Of the 163 patients, 156 had a positive wound culture (median of three different species per patient; range 1-7). Pseudomonas aeruginosa (n = 75) was the dominating species with frequent co-detections of Klebsiella pneumoniae (21 cases; OR = 1.36, 95%CI: 0.63-2.96, p = 0.47), Staphylococcus aureus (14 cases; OR = 1.06, 95%CI: 0.44-2.55, p = 1) and Proteus mirabilis (13 cases; OR = 0.84, 95%CI: 0.35-1.99, p = 0.69). CONCLUSION: The culturome of chronic wounds in Sierra Leonean patients is highly diverse and characterized by the co-occurrence of P. aeruginosa, K. pneumoniae and S. aureus.

Exposure of operating room surgical staff to surgical smoke under different ventilation schemes.

In operating rooms (ORs), surgical smoke is released during electro and laser surgery as well as in ultrasound applications, which poses a health risk to the surgical personnel. In this experimental study, a surgical smoke substitute was developed. The particle concentration near the facial region of different OR staff members and the extract concentration were measured while varying the airflow (unidirectional air flow (UDAF), turbulent mixing ventilation (TMV), and displacement ventilation (DV)) as well as the OR light configuration (lamp positions and shapes). The lowest exposure was observed with DV due to the upward flow motion of contaminants toward the extract openings in the ceiling. UDAF was the only airflow scheme in which the presence of surgical lights affected personnel exposure to surgical smoke; where the presence of OR lights greatly increased surgical smoke exposure due to the wake below the lights. In summary, it was found that the highest exposure to surgical smoke occurred in UDAF and the surgeons were exposed to a significantly higher concentration of surgical smoke than the assistant and anesthesiologist.

[The role of the microbiome in lupus and antiphospholipid syndrome]. / Die Rolle des Mikrobioms bei Lupus und Antiphospholipidsyndrom.

Systemic lupus erythematosus (SLE) and antiphospholipid syndrome are related, systemic autoimmune diseases of unclear etiology. Genetically predisposing factors are known; however, these alone cannot be decisive for the onset and severity of these diseases. This article explains the role of the bacterial microbiome in the origin and progression of these rheumatic diseases. The most recent knowledge in the field of microbiome research based on animal experimental approaches, patient cohorts and human samples is summarized. Various commensal bacteria that promote autoimmunity, so-called pathobionts, which originate from the gut, the skin and the oral cavity, are described. Additionally, their different mechanisms of action are described: Enterococcus gallinarum and Limosilactobacillus reuteri induce adaptive autoimmunity and innate type I interferon pathways via translocation from the small intestine to the liver and spleen; Bacteroides thetaiotaomicron, Actinomyces massiliensis, Pseudopropionibacterium propionicum, Corynebacterium amycolatum, Ruminococcus gnavus and Roseburia intestinalis lead to the formation of pathogenic T­cell and autoantibody responses via the cross-reactivity with autoantigens (Ro60, dsDNA and ß2 glycoprotein I). Finally, potential future treatment approaches are also discussed, such as immunization against certain pathobionts or the targeted modulation of the microbiome via dietary approaches, which can successfully reduce autoimmune pathologies in animal models.

[Still's syndrome-similarities and differences between the juvenile and adult forms]. / Morbus Still ­ Ähnlichkeiten und Differenzen zwischen juveniler und adulter Form.

Still's syndrome includes systemic juvenile idiopathic arthritis (sJIA) and the adult form of Still's disease (adult-onset Still's disease, AOSD). Except for age, there are many similarities between sJIA and AOSD. A biphasic disease model is currently put forth. At disease onset, autoinflammation predominates, which is caused by dysregulation of the innate immune system. Later on, the disease can progress to a chronic-articular form, which is predominantly mediated by the adaptive immune system and is consequently due to autoimmunity. The "window-of-opportunity" hypothesis is based on this biphasic model and supports the assumption that an early, targeted therapy with cytokine blockade can prevent disease progression to chronic destructive arthritis. Macrophage activation syndrome (MAS) is a serious complication of the so-called cytokine storm during the systemic phase of the disease. Clinically, there are many similarities between sJIA and AOSD. Recurrent fever, a fleeting, salmon-colored rash, and arthralgia/arthritis are common signs and symptoms of both sJIA and AOSD. The few differences are mainly related to the therapies and their side effects in children versus adults. In addition, the contribution of genetics to pathogenesis is more pronounced in sJIA compared to AOSD, but there are also smooth transitions in this respect and both diseases are heavily influenced by exogenous factors such as microbial triggers. Future research aspects could include additional investigation of these triggers such as viruses, bacteria, or dysbiosis of the human microbiome.

The microbiome in systemic autoimmune disease: mechanistic insights from recent studies.

PURPOSE OF REVIEW: The resident bacterial communities and the host immune system have coevolved for millennia. However, recent changes in modern societies have disrupted this coevolutionary homeostasis and contributed to a rise in immune-mediated conditions. The purpose of this review is to provide an overview of recently elucidated mechanisms of how certain taxa within the bacterial microbiome propagate autoimmunity. RECENT FINDINGS: Interactions between the bacterial microbiome with innate and adaptive immune cells propagate autoreactivity, chronic inflammation, and tissue damage in susceptible hosts. These interactions contribute to autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus, which are the focus of this review. Recent findings suggest that autoimmune manifestations in genetically susceptible individuals can arise through cross-reactivity with commensal orthologs of autoantigens or commensal-mediated posttranslational modification of autoantigens. Physiologic responses to gut, oral, or skin commensal bacteria can thus be misdirected toward such autoantigens in susceptible hosts. In addition, recent studies highlight that a breach of the gut barrier and translocation of commensal bacteria to non-gut organs can trigger several autoimmune pathways that can be prevented by commensal vaccination or dietary interventions. SUMMARY: Complex host-microbiota interactions contribute to systemic autoimmunity outside the gut. On a molecular level, posttranslational modification of, and cross-reactivity with, autoantigens represent mechanisms of how the microbiota mediates autoimmunity. On a cellular level, translocation of live gut bacteria across a dysfunctional gut barrier allows for direct interactions with immune and tissue cells, instigating autoimmunity systemically.

The role of the gut microbiota in the pathogenesis of antiphospholipid syndrome.

Infectious triggers are associated with the induction of transient antiphospholipid antibodies. One therefore wonders if microbes that permanently colonize us play a role in the pathogenesis of antiphospholipid syndrome (APS). The microbiota represents the collection of all microorganisms colonizing humans and is necessary for normal host physiology. The microbiota, however, is a constant stress on the immune system, which is tasked with recognizing and eliminating pathogenic microbes while tolerating commensal populations. A growing body of literature supports a critical role for the commensal-immune axis in the development of autoimmunity against colonized barriers (e.g., gut or skin) and sterile organs (e.g., pancreas or joints). Whether these interactions affect the development and sustainment of autoreactive CD4(+) T cells and pathogenic autoantibodies in APS is unknown. This review provides an overview of the current understanding of the commensal-immune axis in autoimmunity with a focus on the potential relevance to APS. Additionally, we discuss emerging findings supporting the involvement of the gut microbiota in a spontaneous model of APS, the (NZW × BXSB)F1 hybrid, and formalize hypotheses to explain how interactions between the immune system and the microbiota may influence human APS etiopathogenesis.

Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c+ CD11b+ dendritic cells.

Development of type 1 diabetes in the nonobese diabetic (NOD) mouse is preceded by an immune cell infiltrate in the pancreatic islets. The exact role of the attracted cells is still poorly understood. Chemokine CCL2/MCP-1 is known to attract CCR2(+) monocytes and dendritic cells (DCs). We have previously shown that transgenic expression of CCL2 in pancreatic islets via the rat insulin promoter induces nondestructive insulitis on a nonautoimmune background. We report here an unexpected reduction of diabetes development on the NOD background despite an increased islet cell infiltrate with markedly increased numbers of CD11c(+) CD11b(+) DCs. These DCs exhibited a hypoactive phenotype with low CD40, MHC II, CD80/CD86 expression, and reduced TNF-α but elevated IL-10 secretions. They failed to induce proliferation of diabetogenic CD4(+) T cells in vitro. Pancreatic lymph node CD4(+) T cells were down-regulated ex vivo and expressed the anergy marker Grail. By using an in vivo transfer system, we show that CD11c(+) CD11b(+) DCs from rat insulin promoter-CCL2 transgenic NOD mice were the most potent cells suppressing diabetes development. These findings support an unexpected beneficial role for CCL2 in type 1 diabetes with implications for current strategies interfering with the CCL2/CCR2 axis in humans, and for dendritic cell biology in autoimmunity.

Naturally transmitted segmented filamentous bacteria segregate with diabetes protection in nonobese diabetic mice.

Vertebrates typically harbor a rich gastrointestinal microbiota, which has coevolved with the host over millennia and is essential for several host physiological functions, in particular maturation of the immune system. Recent studies have highlighted the importance of a single bacterial species, segmented filamentous bacteria (SFB), in inducing a robust T-helper cell type 17 (Th17) population in the small-intestinal lamina propria (SI-LP) of the mouse gut. Consequently, SFB can promote IL-17-dependent immune and autoimmune responses, gut-associated as well as systemic, including inflammatory arthritis and experimental autoimmune encephalomyelitis. Here, we exploit the incomplete penetrance of SFB colonization of NOD mice in our animal facility to explore its impact on the incidence and course of type 1 diabetes in this prototypical, spontaneous model. There was a strong cosegregation of SFB positivity and diabetes protection in females, but not in males, which remained relatively disease-free regardless of the SFB status. In contrast, insulitis did not depend on SFB colonization. SFB-positive, but not SFB-negative, females had a substantial population of Th17 cells in the SI-LP, which was the only significant, repeatable difference in the examined T-cell compartments of the gut, pancreas, or systemic lymphoid tissues. Th17-signature transcripts dominated the very limited SFB-induced molecular changes detected in SI-LP CD4(+) T cells. Thus, a single bacterium, and the gut immune system alterations associated with it, can either promote or protect from autoimmunity in predisposed mouse models, probably reflecting their variable dependence on different Th subsets.

Sex-specific environmental influences on the development of autoimmune diseases.

Sex differences in autoimmune diseases are evolutionarily tied to the fact that the female immune system is confronted with intense alterations during menstrual cycles, pregnancy and childbirth. These events may be associated with breaches in the mucosal epithelial layers that are shielding us from environmental factors. Associations between environmental agents and autoimmune diseases have been described extensively in prior studies. Little evidence, however, exists for sex-specific environmental effects on autoimmune diseases. In this review, we summarize studies involving this often-neglected aspect. We give examples of environmental factors that may influence the sex bias in autoimmunity. We conclude that most studies do not give insight into sex-specific environmental effects due to the influence of gender-selective social, occupational or other exposures. Prospective studies are needed in order to determine true sex-biased environmental influences. Finally, humanized murine models might aid in better understanding the mechanisms involved in sex-specific environmental effects on autoimmune diseases.

Evolving concepts of host-pathobiont interactions in autoimmunity.

Autoimmune diseases are complex, multifactorial diseases with a polygenic trait and diverse environmental factors that contribute to triggering and exacerbating each disorder. The human microbiome is increasingly implicated in the multistep pathogenesis of autoimmune diseases. We summarize here the latest developments in the field of how the microbiota interacts with the host on a cellular and molecular level. We review how pathobionts evolve within the gut of autoimmune-prone hosts to translocate to secondary lymphoid tissues. On mucosal sites and in non-gut tissues, pathobionts trigger autoimmune pathways through various mechanisms, including cross-reactivity with autoantigens and secretion of metabolites that alter immune functions. A better understanding of these mechanisms will hasten the development of unconventional therapeutic approaches for autoimmune diseases.

The Influence of Ventilation Measures on the Airborne Risk of Infection in Schools: A Scoping Review.

OBJECTIVES: To review the risk of airborne infections in schools and evaluate the effect of intervention measures reported in field studies. BACKGROUND: Schools are part of a country's critical infrastructure. Good infection prevention measures are essential for reducing the risk of infection in schools as much as possible, since these are places where many individuals spend a great deal of time together every weekday in a small area where airborne pathogens can spread quickly. Appropriate ventilation can reduce the indoor concentration of airborne pathogens and reduce the risk of infection. METHODS: A systematic search of the literature was conducted in the databases Embase, MEDLINE, and ScienceDirect using keywords such as school, classroom, ventilation, carbon dioxide (CO2) concentration, SARS-CoV-2, and airborne transmission. The primary endpoint of the studies selected was the risk of airborne infection or CO2 concentration as a surrogate parameter. Studies were grouped according to the study type. RESULTS: We identified 30 studies that met the inclusion criteria, six of them intervention studies. When specific ventilation strategies were lacking in schools being investigated, CO2 concentrations were often above the recommended maximum values. Improving ventilation lowered the CO2 concentration, resulting in a lower risk of airborne infections. CONCLUSIONS: The ventilation in many schools is not adequate to guarantee good indoor air quality. Ventilation is an important measure for reducing the risk of airborne infections in schools. The most important effect is to reduce the time of residence of pathogens in the classrooms.

Human Th17- and IgG3-associated autoimmunity induced by a translocating gut pathobiont.

Extraintestinal autoimmune diseases are multifactorial with translocating gut pathobionts implicated as instigators and perpetuators in mice. However, the microbial contributions to autoimmunity in humans remain largely unclear, including whether specific pathological human adaptive immune responses are triggered by such pathobionts. We show here that the translocating pathobiont Enterococcus gallinarum induces human IFNγ + Th17 differentiation and IgG3 subclass switch of anti- E. gallinarum RNA and correlating anti-human RNA autoantibody responses in patients with systemic lupus erythematosus and autoimmune hepatitis. Human Th17 induction by E. gallinarum is cell-contact dependent and involves TLR8-mediated human monocyte activation. In murine gnotobiotic lupus models, E. gallinarum translocation triggers IgG3 anti-RNA autoantibody titers that correlate with renal autoimmune pathophysiology and with disease activity in patients. Overall, we define cellular mechanisms of how a translocating pathobiont induces human T- and B-cell-dependent autoimmune responses, providing a framework for developing host- and microbiota-derived biomarkers and targeted therapies in extraintestinal autoimmune diseases. One Sentence Summary: Translocating pathobiont Enterococcus gallinarum promotes human Th17 and IgG3 autoantibody responses linked to disease activity in autoimmune patients.

Emerging therapies for systemic lupus erythematosus--focus on targeting interferon-alpha.

Current therapies for systemic lupus erythematosus (SLE), a debilitating, potentially lethal, multifactorial systemic autoimmune disease, are limited to suppressing disease activity and are associated with multiple adverse effects. Recent advances in basic and translational sciences have elucidated a crucial role for the interferon-alpha (IFNα) pathway in the pathogenesis of this enigmatic disease. The so-called "type I interferon signature" has emerged as a major risk factor for disease activity of SLE. Multiple genes encoding for molecules within the type I interferon pathway have been associated with SLE in genome wide association studies. In addition, innate immune receptors are thought to be triggered by either endogenous and/or exogenous stimuli that lead to hypersecretion of IFNα. We review the multiple emerging treatment strategies targeting IFNα-related pathways. These include monoclonal antibodies against IFNα, anti-IFNα antibody-inducing vaccines, and inhibitors of Toll-like receptors. We also summarize the current status of these pharmaceutical agents in early clinical trials.

E3 ubiquitin ligase GRAIL controls primary T cell activation and oral tolerance.

T cell unresponsiveness or anergy is one of the mechanisms that maintain inactivity of self-reactive lymphocytes. E3 ubiquitin ligases are important mediators of the anergic state. The RING finger E3 ligase GRAIL is thought to selectively function in anergic T cells but its mechanism of action and its role in vivo are largely unknown. We show here that genetic deletion of Grail in mice leads not only to loss of an anergic phenotype in various models but also to hyperactivation of primary CD4(+) T cells. Grail(-/-) CD4(+) T cells hyperproliferate in vitro to TCR stimulation alone or with concomitant anti-CD28 costimulation, with transient increased survival. In vitro differentiated T helper 1 cells show slight but significant hypersecretion of IFN-gamma in Grail(-/-) mice whereas Th2 and Th17 cytokine secretions are unchanged. Consistent with defective in vitro anergy, oral tolerance is abolished in vivo in OT-II TCR transgenic Grail(-/-) mice fed with ovalbumin. In experimental allergic encephalitis, a model of organ-specific autoimmunity, oral tolerization with myelin basic protein was abrogated as well in Grail(-/-) mice. On the protein level, Grail(-/-) naïve T cells show no significant differences of total and phosphorylated levels of ZAP70, phospholipase Cgamma1, and MAP kinases p38 and JNK but elevated baseline levels of MAP kinase ERK1/2. In summary, we define a role for GRAIL in primary T cell activation, survival, and differentiation. In addition, we formally prove an indispensable role for GRAIL in T cell anergy and oral tolerance-a promising, antigen-specific strategy to treat autoimmune diseases.

Skin Deep: The Role of the Microbiota in Cutaneous Autoimmunity.

The skin microbiota is thought to possibly contribute to the pathogenesis of skin autoimmune diseases. The gut microbiota affects systemically the development and function of the immune system, thereby potentially influencing cutaneous autoimmunity as well. In this paper, we review the role of the gut and skin microbiota in cutaneous autoimmune diseases. Besides direct inflammatory effects at the skin barrier, microbiota may contribute to the pathogenesis of skin autoimmune diseases by metabolites, recall immune cell responses, and permeation of antigens to the subepidermal space. Skin and gut barrier dysfunction may represent a common pathophysiologic process allowing microbiota or its particles to promote autoimmune diseases at barrier surfaces.