Fernando Valentim Bitenco, Department of Dentistry and Oral Health

Periodontitis and Diabetes Complications: A Danish Population-Based Study.

Read the paper here.

Conflicting evidence suggests a link between diabetes-related microvascular complications and periodontitis. Reliable estimates have been hindered by small sample sizes and residual confounding. Moreover, the combined effects of microvascular complications and dyslipidemia on periodontitis have not been explored. Therefore, this study aimed to investigate the association between individual and combined diabetic microvascular complications (i.e., neuropathy and retinopathy) and moderate/severe periodontitis in a Danish population-based study. In addition, we assessed whether dyslipidemia modified these associations. This study comprised 15,922 participants with type 2 diabetes from the Health in Central Denmark study.

Anne Louise Hansen, Redox Biology

Development of nitralkene-based inhibitors to target STING-dependent inflammation.

Read the paper here

Stimulator of Interferon Genes (STING) is essential for the inflammatory response to cytosolic DNA. Despite that aberrant activation of STING is linked to an increasing number of inflammatory diseases, the development of inhibitors has been challenging, with no compounds in the pipeline beyond the preclinical stage. We previously identified endogenous nitrated fatty acids as novel reversible STING inhibitors. With the aim of improving the specificity and efficacy of these compounds, we developed and tested a library of nitroalkene-based compounds for in vitro and in vivo STING inhibition. The structure-activity relationship study revealed a robustly improved electrophilicity and reduced degrees of freedom of nitroalkenes by conjugation with an aromatic moiety. The lead compounds CP-36 and CP-45, featuring a β-nitrostyrene moiety, potently inhibited STING activity in vitro and relieved STING-dependent inflammation in vivo. This validates the potential for nitroalkene compounds as drug candidates for STING modulation to treat STING-driven inflammatory diseases, providing new robust leads for preclinical development.

David Olagnier: octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

Read the paper.

Oncolytic virotherapy is a unique immunotherapeutic approach to treat malignancies where viral agents are engineered to selectively target and eliminate cancer cells. Through their oncolytic activity and the release of tumour antigens, these viruses transform the tumour into an immunologically "hot" environment, making it more visible and recognizable to the immune system. The viral oncolytic agent used in the study is Vesicular Stomatitis Virus D51 (VSVD51), a virus that has high oncolytic capacities and displays less pre-existing immunity towards it in patients due to the low prevalence of VSV within humans. Specifically, VSVD51 represents an attenuated agricultural pathogen that is sensitive to the action of interferons (IFNs) to improve its safety profile for patients. Indeed, many tumours carry defects in their IFN signalling to promote a tumorogenic environment and can be targeted for this feature. However, VSVD51 did not enter clinical trials because of the heterogeneity of cancer disease where some tumour cells had intact IFN signalling and were resistant to VSVD51 infection. The given research represents a novel approach to enhance the effectiveness of oncolytic VSVD51 therapy with a metabolite-derived drug, 4-Octyl-Itaconate, that reduces the antiviral IFN-signaling through direct targeting of MAVS abd IKKb in cancers resistant to viral infections.

Marvin Werner

Bronchial asthma is a chronic inflammatory disease of the airways characterized by reversible bronchoconstriction. The pathophysiology involves various points, including bronchoconstriction, destruction of the epithelial layer and persistent inflammation, each of which has been well studied but whose interplay is not yet fully understood. Inflammation, which is partly triggered by allergic reactions, is one driving force behind bronchoconstriction. However, Bagley et al. now provide clear evidence that bronchoconstriction itself also contributes back to inflammation. In their work, published in Science, volume 384, they show how bronchoconstriction leads to inflammatory extrusion of epithelial cells which can be inhibited by gadolinium hexahydrate chloride or the peptide inhibitor GsMTx4. Bagley et al. thus provide a new basis for a mechano-inflammatory vicious cycle that directly links bronchospasm to the maintenance of inflammation. This work begins to close the loop in the pathogenesis of asthma and suggests new therapeutic targets for asthma treatment.

Bronchoconstriction damages airway epithelia by crowding-induced excess cell extrusion (science.org)

Torben Steiniche

Douglas Hanahan and Robert Weinberg initially proposed the "hallmarks of cancer" in 2000, outlining key physiological changes driving normal cells to become cancerous, and updated this concept in 2011. These hallmarks facilitate understanding cancer's development and progression, aiding in identifying therapeutic targets. In 2022, Hanahan introduced three additional dimensions to cancer understanding: Unlocking Phenotypic Plasticity, Nonmutational Epigenetic Reprogramming, and Polymorphic Microbiomes. Research, including fecal transplants from colon tumor patients to mice, highlighted the role of microbiomes in cancer, showing they can either protect against or promote tumor growth. Hanahan's inclusion of the microbiome as a potential new hallmark emphasizes the link between inflammation and cancer even further.

Hallmarks of Cancer: New Dimensions.

Hanahan D.Cancer Discov. 2022 Jan;12(1):31-46. doi: 10.1158/2159-8290.CD-21-1059.PMID: 35022204 Review.

Anne Troldborg

Kidney injury in systemic lupus erythematosus (SLE) occurs primarily due to the deposition of immune complexes and the subsequent activation of the complement pathway. The existence of antibodies targeting nuclear antigens leads to the formation of immune complexes that effectively activate the complement system, resulting in the generation of C5b-9 (the terminal complement complex, membrane attack complex). It has been demonstrated that the activation of C5b-9 plays a detrimental role in the pathogenesis of active lupus nephritis (LN).

Biomarkers can function as early indicators of the presence of specific diseases. However, in LN, specific biomarkers are lacking. In this new study, researchers assessed microvascular C5b-9 in individuals affected by active LN. Their hypothesis was the detection of C5b-9 in non-lesional skin (intact skin devoid of lesions) would have the potential to serve as a biomarker for LN activity.

Sixteen individuals diagnosed with lupus nephritis (LN) were enrolled in the study and were equally divided into two groups: those with active LN and those without active LN. Each participant underwent non-lesional skin biopsies, wherein intact skin devoid of lesions was examined for the presence of microvascular C5b-9.

The study findings revealed that the deposition of C5b-9 in non-lesional skin exhibited greater specificity in identifying active LN when compared to pyuria (an excessive presence of white blood cells in the urine), proteinuria, elevated levels of double-stranded DNA (a well-established diagnostic marker SLE), and hypocomplementemia (low levels of complement proteins C3 and/or C4).

The quest for novel biomarkers is of utmost importance, holding the potential to significantly enhance the diagnosis and assessment of LN. Although the results are preliminary and need validation, they hold great promise for the future.

Reference:

Meghan Anderson, Cynthia Magro, H Michael Belmont. Microvascular C5b-9 deposition in non lesional skin in patients with SLE and its correlation with active lupus nephritis: a prospective observational study. Lupus Sci Med. 2023 Oct;10(2):e000996. doi: 10.1136/lupus-2023-000996.

Fernando Valentim Bitencourt

Studies have shown that people with Type 2 Diabetes Mellitus (T2DM) are more likely to have gum disease, known as periodontitis, than those without diabetes. But how gum disease relates to other diabetes-related complications has yet to be explored. Our research group aimed to examine the clustering of periodontitis with other diabetes-related complications and understand how they are linked through common risk factors.

In this study, involving 2,429 people from the National Health and Nutrition Examination Survey (NHANES), we modelled direct and indirect pathways from risk factors to diabetes-related complications, a latent construct comprising periodontitis, retinopathy, cardiovascular diseases, proteinuria, and hypertension. We found that periodontitis co-occurs and clusters with other diabetes complications. Furthermore, we identified risk factors directly affecting diabetes-related complications, including age, sex, smoking, BMI, HbA1c levels, SES, dyslipidemia, healthy diet, and physical activity.

Incorporating periodontitis to target diabetes-related complications prevention and management via their common risk factors represents a potential approach for systemic and oral chronic diseases. It may be a valuable screening tool for other well-known diabetes-related complications since the oral cavity is easy to access.

Reference:

Bitencourt FV, Nascimento GG, Costa SA, Andersen A, Sandbæk A, Leite FRM. Co-occurrence of Periodontitis and Diabetes-Related Complications. J Dent Res. 2023 Sep;102(10):1088-1097. doi: 10.1177/00220345231179897. Epub 2023 Jul 14. PMID: 37448314.

Holger Brüggemann 

A recent study published in Science reported on the engineering of skin commensals to elicit antitumor immunity. The bacterium Staphylococcus epidermidis, a commensal abundantly present on the skin of virtually every human being was genetically manipulated to express distinct tumor-specific antigens. The topical application of the engineered bacteria was able to elicit organism-wide, T cell-driven antitumor responses. More specifically, S. epidermidis was engineered to express melanoma tumor antigens; the engineered bacteria applied to mouse skin generated tumor-specific T cells that infiltrated and reduced the growth of localized as well as metastatic melanoma in a mouse model. 

In contrast to other approaches employing microorganisms to elicit or boost anti-tumor responses, the presented approach with S. epidermidis did not result in an infection or any (local skin) inflammation, nor did it require intratumoral delivery of the microorganism. Thus, this approach could be more safe (and much simpler) compared to other approaches. 

There is still a long way to clinical application; there are several issues, such as the substantial differences between mouse and human (skin) immunity, the genetic instability of the engineered bacteria in vivo, and ethical issues regarding the use of GMOs. Future research is needed to uncover if engineered skin commensal bacteria can be used as a reliable therapeutic option to promote antigen-specific immune cell responses resulting in potent antitumor activity.  

Chen et al. 2023: Engineered skin bacteria induce antitumor T cell responses against melanoma. Science 380, 203-210

Christian Lodberg Hvas

Fecal microbiota transplantation (FMT) is highly effective against recurrent Clostridioides difficile infection and a promising treatment for other microbiome-related disorders, but a comprehensive understanding of microbial engraftment dynamics is lacking.

In this Paper of the Month, Ianiro et al. performed an integrated shotgun metagenomic systematic meta-analysis of new and publicly available stool microbiomes collected from 226 triads of donors, pre-FMT recipients and post-FMT recipients across eight different disease types.

By exploring the dynamics of microbiome engraftment after FMT and their association with clinical variables, the study uncovered species-specific engraftment patterns and presented machine learning models able to predict donors that might optimize post-FMT specific microbiome characteristics for disease-targeted FMT protocols.

Ianiro et al. 2022: Variability of strain engraftment and predictability of microbiome composition after fecal microbiota transplantation across different diseases Nature Medicine 28, 1913-1923

For more information about FMT in Denmark and Europe, please see the Centre for Faecel Microbioata Transplantation website

Anne Margrethe Troldborg

VEXAS is a newly described complex clinical syndrome caused by variations in the UBA1 gene. Patients experience macrocytic anemia, fever, elevated inflammatory markers and a plethora of different systemic rheumatic, dermatologic and pulmonary symptoms. Before the current publication, VEXAS has been described as a rare disease almost exclusively affecting men and very little was known about penetrance of the genetic variations causing VEXAS.

In this paper of the month, David Beck and colleagues, who originally described the VEXAS syndrome, examine prevalence and penetrance of the UBA1 variations by retrospectively investigating genetic data from 163.000 individuals in Pennsylvania, US.

Among the 163.000 individuals, who in the period 1996-2012 gave a blood sample for genetic research (protocolized research project), 11 people had one of the known VEXAS variants in the UBA1 gene. All 11 individuals had clinical disease (100%). In two cases, the mutation was present before the onset of the clinical symptoms. Two out of the 11 people were women with a heterozygous mutation. The estimated prevalence for people over 50 was 1/4269 for men and 1/26,238 for women.

The study offers the first real estimate of VEXAS prevalence, which is significantly higher than first assumed. In addition, the study answers the question of penetrance, as all carriers of a described VEXAS mutation had or developed clinical disease (100% penetrance). The finding of detectable variants before clinical disease and the higher female representation among VEXAS are new aspects that need confirmation in other large cohorts.

Beck DB, Bodian DL, Shah V, et al.: Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population - JAMA 2023;329:318-324.

Vivi Schlünssen

The paper of the month is a systematic review (SR) and meta-analysis compiling data from both observational and intervention studies on the association between chronic low-grade inflammation and working conditions. The paper reflects an increasing interest within the environmental and occupational field for inflammatory markers possible preceding chronic disease with potentially important windows of opportunity for prevention of chronic disease.

The most interesting part of the SR is the work place intervention studies (16, including 8 RCT), where physical interventions (e.g. aerobic training, cycling to work) or mental interventions (e.g. stress resilience training, Yoga training) were investigated. The most commonly used markers for low grade inflammation was high sensitivity CRP, TNf-α and  IL-6

Workplace physical exercise interventions were associated with a decrease in C-reactive protein (P<0.001). For other workplace interventions, i.e. .mental and organizational/structural, results were inconclusive.

The authors conclude that the research base is still limited, but the SR support that exercise interventions at or relate to the workplace might be able to reduce chronic low-grade inflammation.

Kaltenegger et al: Associations of working conditions and chronic low-grade inflammation among employees: a systematic review and meta-analysis - PubMed (nih.gov)

Thomas Vorup-Jensen 

The laboratory of Prof. Simon J. Davis, University of Oxford (Davis Lab Oxford), has focused on describing the function co-stimulatory molecules in the cell membrane of especially T cells. Among many important contributions, the so-called kinetic segregation (ks) model describes T cell signaling because of intramembrane reorganization of receptors with an intracellular part containing either kinases or phosphatases. A net signaling occurs when large phosphatase-containing molecules such as CD45 are denied access to the smaller, kinase-containing CD3. This happens when the immunological synapse is formed where simple geometry forces larger molecules out of the contact zone between an antigen-presenting cell and the T cell. In their recent paper, Sušac et al. now investigates the role of conformational change in the T cell receptor as part of the signaling. From high-resolution structures, they show that such signaling can occur without conformational change. As concluded in the study, the data are consistent with the notion that a T cell receptor ligand may need only to bind the receptor, holding the TCR in regions of the membrane that favor signaling in accordance with the ks model.   

Lukas Susac et al.: Structure of a fully assembled tumor-specific T cell receptor ligated by pMHC - ScienceDirect

Søren Egedal Degn

The production of highly specific antibodies is one of the most striking features of our immune response to infectious microorganisms. The presence of such antibodies can provide long-lived protection against the eliciting pathogen (sometimes life-long!), a feature which we also harness through vaccination. The first step in activation of this antibody response is the engagement of the B cell receptor (BCR) by antigen. Surprisingly, to this day, there is no broad consensus on how this engagement triggers activation of the BCR. Despite the pervasive text-book description of a mechanism of activation driven by ‘clustering’, this model is not supported by data, and numerous competing modes of activation have been proposed in the field. The BCR is in essence a membrane-bound version of the respective antibody produced by a given B cell, with the important addition of a transmembrane domain and direct association with essential signaling components called CD79a and CD79b (or Iga and Igb, respectively). Although the structure of antibodies has been known for well over 50 years, since Gerald M. Edelman and Rodney R. Porter’s Nobel Prize winning work, the elucidation of the precise mechanism of antigen triggering of the BCR has been severely hampered by the paucity of structural information on the precise configuration and conformation of the receptor.

This past month, two back-to-back Science papers blasted through this impasse using Cryo-electron microscopy (Cryo-EM), a relatively new weapon in the arsenal of structural biologists, which allows the resolution of previously unattainable targets. The structures presented provide important new insights about the organization of the transmembrane domain of the BCR and its interaction with CD79. However, as they only present the resting (non-antigen-engaged) configuration of the complex, they do fall short of providing the smoking gun evidence for any of the proposed mechanisms of activation. Nonetheless, the success of this ‘impossible’ step holds the promise to provide the final evidence shortly down the road, as the antigen-engaged conformation will undoubtedly soon be revealed!

Xinyu Ma et al.: Cryo-EM structures of two human B cell receptor isotypes | Science

Qiang Su et al.: Cryo-EM structure of the human IgM B cell receptor | Science

Related perspective: Unveiling the B cell receptor structure | Science

Rikke Nørregaard

Acute kidney injury (AKI) is defined by an abrupt decrease in renal function. The incidence of AKI varies from 5% in all hospitalized patients to 30-50% in intensive care units. Most interventional trails in AKI have failed in humans so there is a need for better therapeutic approaches to prevent or treat AKI.

There is an increasing evidence for an important role for the innate immune cells in propagation of AKI. Following acute injury to the kidney, macrophages plan an important role in recovery of functional and structural integrity, but renal fibrosis and progressive functional decline occur with incomplete recovery

This paper described a novel mechanism by which prostaglandins modulate macrophage phenotype following AKI and provide new insight into mechanisms underlying detrimental kidney effects of non-steroidal anti-inflammatory (NSAID) drugs that inhibit cyclooxygenase activity. 

Yu Pan et al.: Myeloid cyclooxygenase-2/prostaglandin E2/E-type prostanoid receptor 4 promotes transcription factor MafB-dependent inflammatory resolution in acute kidney injury

Joanna Maria Kalucka

Breast cancer (BC) is the most frequently diagnosed cancer in women in the US and Europe. Despite improvements in anti-tumour therapy, BC remains the second leading cause of cancer deaths in women. Metastatic relapse is the leading cause of this high mortality and occurs for long periods after removing the primary tumour. Therefore, understanding the mechanisms that control metastasis is pivotal for designing an improved and safe BC treatment regimen.

Changes in cell metabolism have been shown to be essential for several steps of metastasis: metabolism can support tumour growth and facilitate cancer-cell survival in the bloodstream and help to disseminate to distant organs. However, so far, no one has addressed whether a cellular metabolism can influence cancer cell abilities to metastasize.

In a recent study published in Nature, by Rossi et al., investigated the role of the metabolic enzyme phosphoglycerate dehydrogenase (PHGDH), which is known to be overexpressed and/or amplified in 70% of triple-negative breast cancers (TNBC). The authors report that intra-tumour heterogeneity and low expression of PHGDH protein in primary TNBC correlate with poor metastasis-free survival in patients. Strikingly loss of PHGDH in mice promotes cancer cell dissemination and metastasis formation. Furthermore, the changes in PHGDH expression associated with metastatic stage of cancer cells, for example, early metastatic lesions and circulating cancer cells, show low or no PHGDH expression, while advanced proliferating metastases express PHGDH. Furthermore, the downstream analysis revealed that cancer cells lacking PHGDH enzyme had higher expression of genes associated with cell migration, invasion and transformation. The authors also reported that cells with low PHGDH expression showed more migratory capacity than those with high PHGDH from the same tumour. These results elegantly link metabolic heterogeneity with gene-expression programs related to tumour metastasis, and these findings showcased that low enzyme levels are sufficient to induce aggressive features in cancer cells.

Mechanistically, PHGDH altered cell migration by directly binding to another metabolic enzyme:  phosphofructokinase (PFK), a key glycolytic pathway component. Upon loss of PHGDH, the activity of PFK decreases which redirects the carbon flux into another metabolic pathway: the hexosamine-sialic acid pathway. Consequently,  glycosylation (sialylation) of integrin alpha-v-beta-3, a key component for cell migration, is increased, which inhibits the invasiveness of PHGDH low cancer cells and metastasis formation.

Intriguingly, the authors report that cancer cells with low levels of the PHGDH tended to locate near vascular tissue. This implies that endothelial cells can modulate PHGDH expression and thus have an effect on cancer cell invasiveness. Even though the factors and the insights on this mechanisms still have to be defined, this study highlights a possibility of signalling from endothelial cells that directly affects the expression of a metabolic enzyme in tumour cells.

Taken together, while the catalytic activity of PHGDH supports cancer cell proliferation, low PHGDH protein expression non-catalytically potentiates cancer dissemination and metastasis formation. This study broadens our understanding of the role of metabolic heterogeneity in cancer and might point toward new approaches for targeting diverse tumour-cell populations in order to suppress tumor metastases.

Rossi, M. et al.: PHGDH heterogeneity potentiates cancer cell dissemination and metastasis https://www.nature.com/articles/s41586-022-04758-2

Karina Dalsgaard Sørensen

Cancer has long been perceived as a disease of the human genome. However, recent lines of evidence point to a more prominent role of the human microbiota in cancer development and progression. This novel insight has significant clinical implications for patient treatment and early detection of cancer. Nevertheless, the field of microbiome research in cancer is still in its infancy and its relevance to prostate carcinogenesis is far from being understood.

A recent study aimed to map the microbial composition within malignant and benign prostate tissue from patients suffering from prostate cancer, in the hope of finding associations between cancer development/progression and the composition of the prostate tissue microbiome. The authors identified several microbial species to be in dysbiosis within malignant compared to benign prostate tissue. Microbial dysbiosis was also associated with altered immune regulation within the prostate tissue.

These findings point to the future possibility of using certain microbial species as diagnostic/prognostic biomarkers in prostate cancer, or even as novel treatment targets for achieving better response. Immunomodulatory effects of certain species could also be targets for future immunotherapy.

Salachan et al.: Microbiota of the prostate tumor environment investigated by whole-transcriptome profiling

https://pubmed.ncbi.nlm.nih.gov/35078527/

Holger Jon Møller

Immunotherapy, a type of intervention that unleashes the body’s own immune cells to better fight cancer, has revolutionized the treatment of certain metastatic cancers such as advanced melanoma.

The focus for treatment has primarily been on adaptive immune checkpoints such as PD-1, but it doesn’t work for all. Researchers are therefore investigating options to improve current immunotherapy – e.g. by combined modulation of the innate immune defense (such as tumor associated macrophages) to support the T-cell responses.

Macrophage checkpoints - such as SIRPα that binds to CD47 on the tumor cells - are promising targets for increasing phagocytosis of tumor cells. However such therapy has hitherto been limited to a subset of patients

A new study in mice has now shown that combining CD47 targeted therapy with the well known chemotherapeutic Paclitaxel (Taxol) dramatically enhance the anti-cancer efficacy as compared to CD47 targeting alone.

This immunotherapeutic strategy may lead to a new paradigm of using Paclitaxel to activate TAMs and thereby in combination with macrophage immune checkpoint inhibitors, improve cancer treatment.

Xu Cao et al.: Targeting macrophages for enhancing CD47 blockade-elicited lymphoma clearance and overcoming tumor-induced suppression 

Fabio Renato Manzolli Leite

The oral mucosa is a poorly studied barrier tissue with an important role in training immune tolerance due to large exposure to antigens of a stable commensal community. Periodontitis, a chronic inflammatory condition of the teeth supporting tissues associated with a microbial dysbiosis, is modified by multiple host response genes combined with lifestyle and environmental factors. Periodontal diseases share common inflammatory components with other chronic diseases, such as rheumatoid arthritis, inflammatory bowel disease, and diabetes. Some studies demonstrate that individuals susceptible to chronic inflammatory diseases present signs of periodontitis before the clinical systemic manifestations.

Little is known about why 10%-20% of the population develops a moderate to severe periodontitis and usually they are unresponsive to current therapies targeted at the microbial community. Leite et al. showed that some people from their very young adulthood have an exaggerated immune response to biofilm accumulation. These individuals showed a distinct profile of pro-and anti-inflammatory cytokine release. The two cytokine profiles were dubbed "non-organized response" with an aggregation of IL-4, IL-6, IL-8, IL-12, and IL-13 and "organized response" IL-2, IL-10, and TNF-α. Participants with fast development of inflammation presented a higher "non-organized response" factor and a lower "organized response" factor.

Williams et al. compiled a single-cell transcriptome atlas of human oral mucosa in healthy individuals and patients with periodontitis. They describe the epithelial and stromal cell populations with inflammatory signatures that promote antimicrobial defences and neutrophil recruitment. They corroborate the exaggerated stromal cell responsiveness with enhanced neutrophil and leukocyte infiltration in periodontitis opening a new field of studies for oral and systemic manifestation of some inflammatory conditions.

Leite et al.: Cytokine profiles and the dynamic of gingivitis development in humans

Williams et al.: Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity

Trine Mogensen

The paper by Ablasser and co-workers from Swiss Federal Institute of Technology Lausanne published in Nature, identifies a novel mechanism whereby SARS-CoV-2 induces mitochondrial DNA release, cell death and type I interferon (IFN) production in COVID-19 and further demonstrates that pharmacological inhibition of DNA sensing pathways alleviates pathology and may represent a therapeutic target.

Whereas type I IFN is essential for mounting antiviral responses early during SARS-CoV-2 infection, these same IFNs may be deleterious later during infection and contribute to inflammation, immunopathology, and tissue damage. In this work the authors investigated skin tissue from patients with dermatological manifestations of COVID-19, post mortem lung samples from patients with severe disease, as well as a mouse model.  They identify the cyclic GMP-AMP synthase (cGAS)-Stimulator of interferon genes (STING)-pathway, which controls immunity to cytosolic DNA, as a major mediator of aberrant type I IFN responses and pathology in COVID-19. Through immunological profiling of COVID-19 skin manifestations, they uncover a STING-dependent type I IFN signature primarily generated by macrophages residing in areas of endothelial cell damage. They further show that SARS-CoV-2 infection activates cGAS-STING signaling in endothelial cells through mitochondrial DNA release, resulting in cell death and excessive type I IFN production. This is complemented by data from a mouse model, in which pharmacological inhibition of STING reduces SARS-CoV-2-induced lung inflammation and improves disease outcome.

Collectively, this study establishes a mechanistic basis of pathological type I IFN production in COVID-19, by identifying the cytosolic cGAS-STING pathway as responsible for virus-induced mitochondrial DNA-mediated triggering of pathological type I IFN responses and tissue immunopathology, and finally demonstrate that pharmacological inhibition of this pathway reduces type I IFN and tissue pathology, thereby suggesting that the cGAS-STING pathway may represent a therapeutic target of potential clinical relevance.

Domizio  et al. The cGAS-STING pathway drives type I IFN immunopathology in COVID-19

Vivi Schlünssen

Exposure to respirable crystalline silica is suggested to increase the risk of Inflammatory disease including rheumatic diseases. In this nationwide register-based study, Boudigaard et al examined the association between respirable crystalline silica and systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and small vessel vasculitis. The authors included 1,541,505 male and 1,470,769 female workers followed since entering the labour market 1979–2015. Each worker was annually assigned a level of respirable crystalline silica exposure estimated with a quantitative job exposure matrix. 4673 male and 12 268 female cases were identified in the Danish patient register.

Boudigaard et al observed increasing risk of autoimmune rheumatic diseases following increasing occupational exposure to respirable crystalline silica, strongest for systemic sclerosis and rheumatoid arthritis, and most pronounced for men. 

Boudigaard et al.: Occupational exposure to respirable crystalline silica and risk of autoimmune rheumatic diseases: a nationwide cohort study

Torben Steiniche

Systemic inflammation measured by the acute-phase protein CRP associates with poor outcome across cancer types. In contrast, local tumor-associated inflammation, primarily evaluated by T-lymphocytes, correlates with favorable prognosis. Yet, little is known whether these two responses are related or opposing processes and why elevated CRP in relation to cancer is detrimental for clinical outcome. This article presents a platform combining multiplexed immunohistochemistry and digital imaging, enabling a virtual readout of both lymphoid and myeloid immune markers and their spatial patterns in the primary tumors of resected stage II and III colon cancer (CC) patients with and without accompanying systemic inflammation. The data in the article highlight the importance of a comprehensive immune classification of tumors including players of innate immunity and support a role for CRP as an informative biomarker of the immune response taking place at the tumor site. 

Køstner et al.: Systemic Inflammation Associates With a Myeloid Inflamed Tumor Microenvironment in Primary Resected Colon Cancer—May Cold Tumors Simply Be Too Hot?

Thomas Vorup-Jensen

Immunological tolerance is a physiological mechanism of immense impact our health. Failure is associated with autoimmune disease, several of considerable burden to our health care system such as rheumatoid arthritis and multiple sclerosis. Available therapies are almost entirely acting on the symptoms by lowering inflammation. However, a new direction has been taken by David C. Wraith, whose work enabled clinical trials in restoring tolerance in multiple sclerosis patients. In the Paper of the Month, Schurgers and Wraith give a succinct review of state of the art and point to a new application of tolerance inducing therapies, namely to permit reconstitution with Factor VIII, a protein of the coagulation cascade. Undoubtedly, these directions will take immunotherapies into new territories.

Schurgers and Wraith.: Induction of Tolerance to Therapeutic Proteins With Antigen-Processing Independent T Cell Epitopes: Controlling Immune Responses to Biologics

Søren Egedal Degn

Antibodies produced in response to infection or vaccination are a central component of our immune defense against infectious pathogens. However, they can also wreak havoc when erroneously targeted towards components of our own cells or tissues, as seen in a broad spectrum of autoimmune diseases. High quality antibodies are produced by B cells in induced microanatomical structures called germinal centers, within our secondary lymphoid tissues. In germinal centers, B cells undergo a Darwinian process of somatic hypermutation of their immunoglobulin genes followed by selection of variants with improved affinity for antigen. Over the course of the immune response, this drives the process of affinity maturation, which improves the specificity and affinity of antibodies produced. The length of the duration of this process determines, on one hand, the degree of affinity maturation towards the eliciting antigen, on the other, the risk of inadvertently generating novel potentially autoreactive specificities, due to the random nature of hypermutation. For this reason, the duration of the germinal center response has to be tightly controlled, but it has been unclear what determines this critical timing. Using intravital imaging of mouse germinal centers and single-cell RNA sequencing, Gabriel Victora’s group recently reported in Science, that termination of germinal centers coincides with upregulation of the transcription factor FoxP3 in T follicular helper cells. Surprisingly, these cells acquire a regulatory T cell–like phenotype, yet are distinct from T follicular regulatory cells, and are absolutely required to shut down the GC reaction. Tweaking this process may be key to extending germinal center lifetimes to enhance antibody responses in the context of vaccination, as well as controlling hyperactive and chronic germinal center responses associated with autoimmunity and chronic infections.

Jacobsen et al.: Expression of Foxp3 by T follicular helper cells in end-stage germinal centers

Rikke Nørregaard

Chronic kidney disease (CKD) affects approximately 10% of the adult population worldwide and is characterized by the development of renal injury and fibrosis and progressive loss of renal function, ultimately CKD leads to end-stage renal disease (ESRD). The incidence and prevalence of CKD has been increasing concurrently with the increase in lifestyle diseases such as diabetes, hypertension, obesity and longer lifespan.

It is now recognized that CKD is not always progressive, but that regression of albuminuria and improvement in renal function can occur if the injurious stimulus is removed. However, the cellular and molecular pathways mediating injury regression are poorly understood, partly because renal biopsies are rarely performed in patients who are clinically improving.

This paper shows that the innate immune system is central to injury and repair in the kidney and describe the heterogeneity of myeloid cell subsets behind these processes. Using complementary technologies, including bulk tissue transcriptomics, integrated droplet– and plate-based single-cell RNA sequencing, and paired blood exchange, the authors resolved myeloid cell heterogeneity in a murine model of reversible unilateral ureteral obstruction by creating a single-cell atlas.

Taken together this paper identifies novel myeloid subtypes, based on transcriptomics in single cells, that represent therapeutic targets to inhibit progression or promote regression of kidney disease.

Conway et al.: Kidney single-cell atlas reveals myloid heterogeneity in progression and regression of kidney disease

Karina Dalsgaard Sørensen

Checkpoint inhibitors (CPI) have revolutionized cancer treatment, leading to longterm survival for many patients who were previously left with very little hope. However, not all cancers respond to CPI and acquired resistance to CPI treatment is a considerable challenge. Hence, in order to select the right patient for the right CPI at the right time (personalized medicine), there is a need for better and more accurate biomarkers that can predict response to CPI and hence guide treatment selection.

Litchfield et al. used a “big data” approach to search for novel biomarkers of CPI response through a meta-analysis of whole-exome sequencing (WES) and transcriptomic (RNA sequencing) data from over 1000 CPI-treated patients across seven cancer types (urothelial cancer, malignant melanoma, head and neck cancer, non-small cell lung cancer, renal cell carcinom, colorectal cancer, and breast cancer).

The meta-analysis revealed that clonal tumor mutation burden (TMB) was the strongest predictor of CPI response, followed by total TMB and bulk tumor CXCL9 gene expression. Copy number analyses also identified TRFA2 loss and CCND1 amplification in the tumor to be associated with CPI resistance across multiple cancer types. Finally, transcriptomic analyses of clonal neoantigen-reactive CD8 tumor-infiltrating lymphocytes (TILs) identified CCR5 and CXCL13 as T-cell intrinsic markers of response to CPI.

Although further clinical validation is needed, the study provides important novel insights into the molecular and cellular mechanisms that control CPI response, including complex crosstalks between cancer cells and infiltrating immune cells in the tumor microenvironment.

Litchfield et al.: Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition

Joanna Kalucka

The immune system has crucial homeostatic functions in adipose tissue. Inflammation of white adipose tissue is a hallmark of obesity. In a recently published study, Hildreth et al. by employing single-cell RNA-sequencing, report new subsets of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage that accumulate in obese white adipose tissue. This new perspective on the cellular landscape of adipose tissue provides novel insights into potential functions, regulation and interaction of known and newely identified immune cells clusters that residue in white adipose tissue. Furthermore, this study offers a valuable resource for further investigation regarding mechanisms and therapeutic targets that may help reduce inflammation in obese patients.

Hildreth et al.: Single-cell seguencing af human white adipose tissue identifies new cell states in health and obesity

Holger Jon Møller

Immunotherapy, a type of intervention that unleashes the body’s own immune cells to better fight cancer, has revolutionized the treatment of certain metastatic cancers such as advanced melanoma.

The focus for treatment has primarily been on adaptive immune checkpoints such as PD-1, but it doesn’t work for all. Researchers are therefore investigating options to improve current immunotherapy – e.g. by combined modulation of the innate immune defense to support the T-cell responses.

Another surprising option for increasing the efficacy of current immunotherapy was presented in Science in February 2021. In two small, uncontrolled trials, patients with PD-1-refractory melanoma showed improvement in response to anti-PD-1, if treatment was combined with a fecal microbiota transplant. This suggests that the microbiome may influence the tumor-micro environment and thereby increase the effect of immunotherapy. 

Davar et al.: Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients

Baruch et al.: Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients

Fábio R. M. Leite

Inflammatory oral diseases share common causes with many systemic conditions, such as diabetes, metabolic disorders, and arthritis. In some cases, the initiation and exacerbation of oral tissues' destruction are observed even before detecting other clinical signs of such conditions. Dysfunctions in blood microcirculation and connective tissue metabolism are the most probable causes. Treatment for such conditions usually influences the progression of oral inflammatory diseases. The mouth may play a role in understanding the initiation and resolution of inflammation related to systemic conditions. These papers are based on one of our established cohorts, and they illustrate that systemic health and socioeconomic status play a significant role in developing inflammatory-driven destruction of the tissues around the teeth, known as periodontitis. To validate the close link between oral and systemic conditions, the authors demonstrate the size of the effect of interventions in common risk factors, such as obesity, alcohol, and smoking, in the prevention of oral inflammation.

Leite et al.: Prediction of periodontitis occurrence: influence of classification and sociodemographic and general health information

Nascimento et al.: Diet-induced overweight and obesity and periodontitis risk: an application of the parametric g-formula in the 1982 Pelotas Birth Cohort

Ellen-Margrethe Hauge

A recent publication in NEJM identified a genetic background for a treatment-refractory and often fatal autoinflammatory syndrome developing in men with a mutation in UBA1 on the X chromosome, that codes for the major E1 enzyme initiating ubiquitylation. The clinical presentation includea adult-onset relapsing polychondritis, Sweet’s syndrome, polyarteritis nodosa, giant-cell arteritis or a hematologic condition such as myelodysplastic syndrome or multiple myeloma. The disorder was named VEXAS, which relates to the vacuoles in myeloid and erythroid precursor cells, the E1 enzyme, X-linked phenotype, autoinflammatory presentation and the somatic mutation.

Beck et al.: Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease