Explore the vast range of titles available.

Serum amyloid P component (SAP, also known as Pentraxin 2; APCS gene) is a component of the humoral arm of innate immunity involved in resistance to bacterial infection and regulation of tissue remodeling. Here we investigate the role of SAP in antifungal resistance. Apcs −/− mice show enhanced susceptibility to A. fumigatus infection. Murine and human SAP bound conidia, activate the complement cascade and enhance phagocytosis by neutrophils. Apcs −/− mice are defective in vivo in terms of recruitment of neutrophils and phagocytosis in the lungs. Opsonic activity of SAP is dependent on the classical pathway of complement activation. In immunosuppressed mice, SAP administration protects hosts against A . fumigatus infection and death. In the context of a study of hematopoietic stem-cell transplantation, genetic variation in the human APCS gene is associated with susceptibility to invasive pulmonary aspergillosis. Thus, SAP is a fluid phase pattern recognition molecule essential for resistance against A . fumigatus . Serum Amyloid P is a humoral component with established roles in the response to bacterial infection and regulation of tissue remodeling. Here the authors provide evidence to a further crucial role of serum amyloid P in the context of fungal pathogen Aspergillus fumigatus .

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) is the only curative therapy for many hematologic malignancies, whereby the Graft-versus-Leukemia (GVL) effect plays a pivotal role in controlling relapse. However, the success of GVL is hindered by Graft-versus-Host Disease (GVHD), where donor T cells attack healthy tissues in the recipient. The ability of natural regulatory T cells (Treg) to suppress immune responses has been exploited as a therapeutical option against GVHD. Still, it is crucial to evaluate if the ability of Treg to suppress GVHD does not compromise the benefits of GVL. Initial studies in animal models suggest that Treg can attenuate GVHD while preserving GVL, but results vary according to tumor type. Human trials using Treg as GVHD prophylaxis or treatment show promising results, emphasizing the importance of infusion timing and Treg/Tcon ratios. In this review, we discuss strategies that can be used aiming to enhance GVL post-Treg infusion and the proposed mechanisms for the maintenance of the GVL effect upon the adoptive Treg transfer. In order to optimize the therapeutic outcomes of Treg administration in allo-HSCT, future efforts should focus on refining Treg sources for infusion and evaluating their specificity for antigens mediating GVHD while preserving GVL responses.

Hematopoietic stem cells have been investigated and applied for the treatment of certain neurological disorders for a long time. Currently, their therapeutic potential is harnessed in autologous and allogeneic hematopoietic stem cell transplantation (HSCT). Autologous HSCT is helpful in immune-mediated neurological diseases such as Multiple Sclerosis. However, clinical benefits derive more from the immunosuppressive conditioning regimen than the interaction between stem cells and the central nervous system. Mainly used for hematological malignancies, Allogeneic HSCT explores the therapeutic potential of donor-derived hematopoietic stem cells. In the neurological setting, it has proven to be most valuable in Inborn Errors of Metabolism, a large spectrum of multisystem disorders characterized by congenital deficiencies in enzymes involved in metabolic pathways. Inborn Errors of Metabolism such as X-linked Adrenoleukodystrophy present with brain accumulation of enzymatic substrates that result in progressive inflammatory demyelination. Allogeneic HSCT can halt ongoing inflammatory neural destruction by replacing hematopoietic-originated microglia with donor-derived myeloid precursors. Microglia, the only neural cells successfully transplanted thus far, are the most valuable source of central nervous system metabolic correction and play a significant role in the crosstalk between the brain and hematopoietic stem cells. After transplantation, engrafted donor-derived myeloid cells modulate the neural microenvironment by recapitulating microglial functions and enhancing repair mechanisms such as remyelination. In some disorders, additional benefits result from the donor hematopoietic stem cell secretome that cross-corrects neighbouring neural cells via mannose-6-phosphatase paracrine pathways. The limitations of allogeneic HSCT in this setting relate to the slow turnover of microglia and toxicities such as graft-vs-host disease. These restraints have accelerated the development of hematopoietic stem cell gene therapy, where autologous hematopoietic stem cells are collected, manipulated ex vivo to overexpress the missing enzyme, and infused back into the patient. With this cellular drug vehicle strategy, the brain is populated by improved cells and exposed to supraphysiological levels of the flawed protein, resulting in metabolic correction. This review focuses on the current applications of HSCT and gene therapy for the treatment of central nervous system diseases, emphasizing the underlying mechanisms that result in brain repair.

The Portuguese donor Registry of CEDACE was the fifth largest bone marrow donor Registry of the WMDA as of 2019 and has yet to be thoroughly analyzed. We aimed to characterize its various aspects, including demographics and HLA allele and haplotype frequencies, to evaluate the genetic matching propensity score and ultimately further develop it. We described and compared characteristics of the donor population with census data and used an Expectation-Maximization algorithm and analyses of molecular variance to assess haplotype frequencies and establish phylogenetic distances between regions and districts within the country. We identified 396545 donors, corresponding to 3.85% of the Portuguese population; the median donor age was 39 years, with 60.4% of female donors. Most donors were Portuguese nationals, although 40 other nationalities were present, with a significant proportion of donors from Brazil and Portuguese-speaking African Countries; almost all donors self-reported as Western, with the second largest group reporting African ancestry. There was an asymmetric contribution of donors from different districts and regions, with most coming from coastal districts and few from the southern districts and autonomous regions; foreign and self-declared non-Western donors were mainly located in the Metropolitan Area of Lisbon and the South. Although most donors were typed in three (HLA-A, HLA-B and HLA-DRB1), only 44% were also typed in HLA-C, 1.28% in HLA-DQB1 and only 0.77% in all five and in high-resolution. There were varying allele and haplotype frequencies across districts and regions, with the most common three , low-resolution haplotypes, being HLA-A*01~B*08~DRB1*03, A*29~B*44~DRB1*07 and HLA-A*02~B*44~DRB1*04; some haplotypes were more prevalent in the South, others in the North and a few in the autonomous regions; African and foreign donors presented relevant differences in haplotype frequency distributions, including rare haplotypes of potential interest. We also report on four , low-resolution frequency distributions. Using AMOVA, we compared genetic distances between districts and regions, which recapitulated the country's geography. Our analysis showed potential paths to optimization of the Registry, including increasing the male donor pool and focusing on underrepresented districts and particular populations of interest, such as donors from Portuguese-speaking African countries.

The C-type lectin receptor MelLec recognizes DHN-melanin in conidial spores of Aspergillus fumigatus and other DHN-melanized fungi, revealing an important role for this receptor in antifungal immunity in both mice and humans. Cell receptor triggers antifungal immunity Defence against fungal pathogens in mammals relies on pattern recognition receptors, which are often activated by pathogen virulence factors. One such factor is melanin, a component of the fungal cell wall. Gordon Brown and colleagues identify the melanin-sensing C-type lectin receptor (MelLec) as an endothelial cell receptor for fungal melanin. Activation of this receptor triggers a protective inflammatory response against infection by Aspergillus fungi in mice and humans. MelLec thereby has an important role in host defence against disseminated Aspergillosis . Resistance to infection is critically dependent on the ability of pattern recognition receptors to recognize microbial invasion and induce protective immune responses. One such family of receptors are the C-type lectins, which are central to antifungal immunity 1 . These receptors activate key effector mechanisms upon recognition of conserved fungal cell-wall carbohydrates. However, several other immunologically active fungal ligands have been described; these include melanin 2 , 3 , for which the mechanism of recognition is hitherto undefined. Here we identify a C-type lectin receptor, melanin-sensing C-type lectin receptor (MelLec), that has an essential role in antifungal immunity through recognition of the naphthalene-diol unit of 1,8-dihydroxynaphthalene (DHN)-melanin. MelLec recognizes melanin in conidial spores of Aspergillus fumigatus as well as in other DHN-melanized fungi. MelLec is ubiquitously expressed by CD31 + endothelial cells in mice, and is also expressed by a sub-population of these cells that co-express epithelial cell adhesion molecule and are detected only in the lung and the liver. In mouse models, MelLec was required for protection against disseminated infection with A. fumigatus . In humans, MelLec is also expressed by myeloid cells, and we identified a single nucleotide polymorphism of this receptor that negatively affected myeloid inflammatory responses and significantly increased the susceptibility of stem-cell transplant recipients to disseminated Aspergillus infections. MelLec therefore recognizes an immunologically active component commonly found on fungi and has an essential role in protective antifungal immunity in both mice and humans.

In response to infection, macrophages adapt their metabolism rapidly to enhance glycolysis and fuel specialized antimicrobial effector functions. Here we show that fungal melanin is an essential molecule required for the metabolic rewiring of macrophages during infection with the fungal pathogen Aspergillus fumigatus . Using pharmacological and genetic tools, we reveal a molecular link between calcium sequestration by melanin inside the phagosome and induction of glycolysis required for efficient innate immune responses. By remodeling the intracellular calcium machinery and impairing signaling via calmodulin, melanin drives an immunometabolic signaling axis towards glycolysis with activation of hypoxia-inducible factor 1 subunit alpha (HIF-1α) and phagosomal recruitment of mammalian target of rapamycin (mTOR). These data demonstrate a pivotal mechanism in the immunometabolic regulation of macrophages during fungal infection and highlight the metabolic repurposing of immune cells as a potential therapeutic strategy. Macrophages undergo a Warburg-like switch from oxidative phosphorylation to glycolysis in response to inflammatory stimulus. Here the authors show that fungal melanin can trigger this switch in human macrophages by sequestering calcium in the phagosome and enabling protection against Aspergillus fumigatus infection.

High‐dose methylprednisolone plus rituximab (R‐HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) patients unfit for chemo‐immunotherapy and has proven its utility on the treatment of CLL/SLL complicated by auto‐immune cytopenias. We performed a retrospective, single‐centre study, of CLL/SLL patients treated with R‐HDMP for 9 years. Thirty‐nine patients were included, median age at time of treatment was 77 years. Most patients had stage Rai III/IV and Binet C disease. Twenty‐eight patients had relapsed/refractory disease at time of treatment with a median of 1 previous line of therapy; 53.8% had prior exposure to fludarabine and 25% to rituximab. Grade 3–4 neutropenia and thrombocytopenia were recorded in 10.2% and 17.9% patients, respectively. While on treatment, 51.3% had documented infectious complications, but no other non‐haematological toxicities grades 3–4 were identified. Overall response rate was 64%. Median overall survival and progression‐free survival were 24 and 13 months, respectively. Twenty four patients relapsed and 16 received another line of treatment after R‐HDMP, with median time to next treatment of 13.5 months. Thirteen out of the 24 patients improved performance status and were subsequently considered fit for chemo‐immunotherapy. R‐HDMP is a valuable option for elderly and frail patients, with low risk of severe myelotoxicity and other severe adverse events. It was shown to work as a bridge to other lines of treatment, including chemo‐immunotherapy. High dose methylprednisolone plus rituximab (R‐HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma patients unfit for chemo‐immunotherapy. We present a cohort of patients with median age of 77 years, most with stage Rai III/IV and Binet C disease. Overall response rate was 64% and median overall survival and progression‐free survival were 24 and 13 months, respectively, with an acceptable toxicity profile, highlighting R‐HDMP utility for elderly and frail patients.

Invasive aspergillosis (IA) is a severe infection that can occur in severely immunocompromised patients. Efficient immune recognition of Aspergillus is crucial to protect against infection, and previous studies suggested a role for NOD2 in this process. However, thorough investigation of the impact of NOD2 on susceptibility to aspergillosis is lacking. Common genetic variations in NOD2 has been associated with Crohn’s disease and here we investigated the influence of these  genetic variations on the anti- Aspergillus host response. A  NOD2 polymorphism reduced the risk of IA after hematopoietic stem-cell transplantation. Mechanistically, absence of NOD2 in monocytes and macrophages increases phagocytosis leading to enhanced fungal killing, conversely, NOD2 activation reduces the antifungal potential of these cells. Crucially, Nod2 deficiency results in resistance to Aspergillus infection in an in vivo model of pulmonary aspergillosis. Collectively, our data demonstrate that genetic deficiency of NOD2 plays a protective role during Aspergillus infection. NOD2 has been shown to be crucial for immune recognition of Aspergillus infection. Here the authors show that a common NOD2 genetic variant associated with Crohn’s disease is associated with reduced risk of disease due to enhanced antifungal activates of monocytes and macrophages.

[...]the combination of 5-Aza and DZNep enhanced the prophylactic effect on aGvHD. In this issue,Hippen et al.present an exhaustive revision on the different translational strategies used for the adoptive transfer of Tregs, including the manipulation of their TCR and cytokine signaling as well as the implementation of CAR technology, resulting in CAR-Tregs such as HLA-A2-CAR-Tregs and CD19 CAR-Tregs. [...]they review the clinical trials involving adoptive Treg therapy already completed (as of March 2022), and discuss the different approaches to enhance Tregs´ suppressive efficacy, specificity, stability, migration, survival and expansion capacity, and the post-transplant treatments used to increase the Treg function and number. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. Activation of immune cells in response to fungal infection involves the reprogramming of their cellular metabolism to support antimicrobial effector functions. Although metabolic pathways such as glycolysis are known to represent critical regulatory nodes in antifungal immunity, it remains undetermined whether these are differentially regulated at the interindividual level. In this study, we identify a key role for 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in the immunometabolic responses to Aspergillus fumigatus . A genetic association study performed in 439 recipients of allogeneic hematopoietic stem cell transplantation (HSCT) and corresponding donors revealed that the donor, but not recipient, rs646564 variant in the PFKFB3 gene increased the risk of invasive pulmonary aspergillosis (IPA) after transplantation. The risk genotype impaired the expression of PFKFB3 by human macrophages in response to fungal infection, which was correlated with a defective activation of glycolysis and the ensuing antifungal effector functions. In patients with IPA, the risk genotype was associated with lower concentrations of cytokines in the bronchoalveolar lavage fluid samples. Collectively, these findings demonstrate the important contribution of genetic variation in PFKFB3 to the risk of IPA in patients undergoing HSCT and support its inclusion in prognostic tools to predict the risk of fungal infection in this clinical setting. IMPORTANCE The fungal pathogen Aspergillus fumigatus can cause severe and life-threatening forms of infection in immunocompromised patients. Activation of glycolysis is essential for innate immune cells to mount effective antifungal responses. In this study, we report the contribution of genetic variation in the key glycolytic activator 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) to the risk of invasive pulmonary aspergillosis (IPA) after allogeneic hematopoietic stem cell transplantation. The PFKFB3 genotype associated with increased risk of infection was correlated with an impairment of the antifungal effector functions of macrophages in vitro and in patients with IPA. This work highlights the clinical relevance of genetic variation in PFKFB3 to the risk of IPA and supports its integration in risk stratification and preemptive measures for patients at high risk of IPA.