What will studies of Fulani individuals naturally exposed to malaria teach us about protective immunity to malaria?

There are an estimated over 200 million yearly cases of malaria worldwide. Despite concerted international effort to combat the disease, it still causes approximately half a million deaths every year, the majority of which are young children with Plasmodium falciparum infection in sub-Saharan Africa. Successes are largely attributed to malaria prevention strategies, such as insecticide-treated mosquito nets and indoor spraying, as well as improved access to existing treatments. One important hurdle to new approaches for the treatment and prevention of malaria is our limited understanding of the biology of Plasmodium infection and its complex interaction with the immune system of its human host. Therefore, the elimination of malaria in Africa not only relies on existing tools to reduce malaria burden, but also requires fundamental research to develop innovative approaches. Here, we summarize our discoveries from investigations of ethnic groups of West Africa who have different susceptibility to malaria.     

The paradoxical role of radiation-induced cGAS–STING signalling network in tumour immunity

The cyclic GMP–AMP synthase–stimulator of interferon genes (cGAS–STING) pathway is an essential component of the innate immune system and is central to the identification of abnormal DNA leakage caused by ionising radiation (IR) damage. Cell-intrinsic cGAS–STING initiation has been revealed to have tremendous potential for facilitating interferon synthesis and T-cell priming. Targeting the cGAS–STING axis has been proposed as a strategy to improve radiosensitivity or enhance immunosurveillance. However, due to the complex biology of the irradiated tumour microenvironment and the extensive involvement of the cGAS–STING pathway in various physiological and pathological processes, many defects in this strategy limit the therapeutic effect. Here, we outline the molecular mechanisms by which IR activates the cGAS–STING pathway and analyse the dichotomous roles of the cGAS–STING pathway in modulating cancer immunity after radiotherapy (RT). Then, based on the crosstalk between the cGAS–STING pathway and other signalling events induced by IR, such as necroptosis, autophagy and other cellular effects, we discuss the immunomodulatory actions of the broad cGAS–STING signalling network in RT and their potential therapeutic applications. Finally, recent advances in combination therapeutic strategies targeting cGAS–STING in RT are explored.     

Cell-mediated immunity to chemically xenogenized tumors—VI. The effect of cell treatment with retroviral env antisense oligonucleotides

The occurence of aberrant, retrovirus-related proteins is a common finding in immunogenic clones of the triazene-xenogenized L5178Y lymphoma line (L5178Y/DTIC). In clone D-cells, newly expressed 80 kDa antigens related to xenotropic murine leukemia virus env gene products induce specific humoral and cell-mediated responses and possess biologic activity in vivo. To further clarify the relationship between immunogenic properties of clone D and retroviral gene expression, tumor cells were treated in vitro with antisense oligonucleotides complementary to xenotropic and/or polytropic env sequences of murine leukemia virus. The cells were then assayed for expression of antigens recognized by humoral and cell-mediated responses with specificity for clone D. The results demonstrated that inhibition of env mRNA translation adversely affected the expression of immunogenic determinants in the xenogenized tumor cells.     

Is the role of IgA in local immunity completely known?

IgA antibodies belong to the most important humoral immune factors present on mucosal surfaces. Different defence mechanisms are involved in the permanent and effective surveillance of mucosal surfaces. The robustness of local immunity homeostasis may also explain how the intestinal immune system is able to accommodate a wide range of microbes that have evolved a wide variety of intestinal lifestyles. Bacterial behaviours depend not only on the bacterial species, but also on the host. Commensal bacteria have been directly associated with the proper development of gut-associated lymphoid tissues.     

Current concepts in the management of patellofemoral pain — The role of alignment

BackgroundPatellofemoral pain is a prevalent and significant clinical problem that is often reported to persist even following evidence based intervention. It is clear therefore that there is much about this complex patient group that is not presently fully understood. This is particularly concerning given the reported links between patellofemoral pain in adolescence and the subsequent development of osteoarthritis and anxiety.AssessmentClinical assessment has historically focussed on biomechanical factors such as altered lower limb kinematics, muscle weakness and late muscle ‘onset or activation’ during activity. However when examined it is clear that study findings from patellofemoral populations are often inconsistent. Reasons for this are discussed and specifically the limitations around current ‘gold standard’ measurement methods, such as motion capture are outlined. A biomechanical approach is applied to demonstrate the importance of ensuring optimal patient alignment during rehabilitation, where optimal is defined as ensuring the most energy efficient muscle or muscles are used by the patient to perform a movement. This in turn ensures that the direction, magnitude and location of load applied to the skeleton during activity is optimal and therefore less likely to lead to injury.TreatmentThe role of alignment in patellofemoral pain and the importance of correcting this during rehabilitation is discussed, and examples provided. Validated, reliable, and reproducible methods of measuring skeletal geometry, muscle geometry, muscle force and direction, and kinematics of activity must be developed as a priority in order for us to further our understanding and improve outcomes in this complex clinical population.     

The effect of IκK-16 on lipopolysaccharide-induced impaired monocytes

This study focuses on impaired monocyte function, which occurs in some patients after trauma, major elective surgery, or sepsis. This monocyte impairment increases the risk of secondary infection and death. We aimed to determine the influence IκK-16 had on monocytes using an ex-vivo model of human monocyte impairment. We included the effects of the well-studied comparators interferon-gamma (IFN-γ) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on impaired monocytes. Primary human monocytes were stimulated with 10 ng/mL of lipopolysaccharide (LPS) for 16 h and then challenged with 100 ng/mL LPS to assess the monocyte inflammatory response. Treatment regimens, consisting of either IκK-16, IFN-γ, or GM-CSF, were administered to impaired monocytes near the time of initial LPS stimulation. Stimulation with 10 ng/mL LPS initially promoted a pro-inflammatory response but subsequently impaired production of both tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) and decreased HLA-DR expression. IκK-16 treatment attenuated TNF-α production and programmed death-ligand 1 (PD-L1) expression and increased IL-10 and CD14 expression. IFN-γ treatment increased TNF-α production as well as PD-L1 and HLA-DR expression. In conclusion, limiting early inflammation with IκK-16 suppresses TNF-α production and PD-L1 expression but enhances IL-10 production and preserves CD14 expression for potential future exposure to infective stimuli.     

From cellular senescence to Alzheimer’s disease: The role of telomere shortening

The old age population is increasing worldwide as well as age related diseases, including neurodegenerative disorders, such as Alzheimer’s disease (AD), which negatively impacts on the health care systems. Aging represents per se a risk factor for AD. Thus, the study and identification of pathways within the biology of aging represent an important end point for the development of novel and effective disease-modifying drugs to treat, delay, or prevent AD. Cellular senescence and telomere shortening represent suitable and promising targets. Several studies show that cellular senescence is tightly interconnected to aging and AD, while the role of telomere dynamic and stability in AD pathogenesis is still unclear. This review will focus on the linking mechanisms between cellular senescence, telomere shortening, and AD.     

Channel-induced apoptosis of infected host cells—the case of malaria

Infection of erythrocytes by the malaria pathogen Plasmodium falciparum leads to activation of several distinct anion channels and a non-selective, Ca²⁺-permeable cation channel. All channel types are presumably activated by the oxidative stress generated by the pathogen. Similar or identical channels are activated by oxidation of non-infected erythrocytes. Activation of the non-selective cation channel allows entry of Ca²⁺ and Na⁺, both of which are required for intracellular growth of the pathogen. The entry of Ca²⁺ stimulates an intraerythrocytic scramblase that facilitates bi-directional phospholipid migration across the bilayer, resulting in breakdown of the phosphatidylserine asymmetry of the cell membrane. The exposure of phosphatidylserine at the outer surface of the cell membrane is presumably followed by binding to phosphatidylserine receptors on macrophages and subsequent phagocytosis of the affected erythrocyte. The lysosomal degradation may eventually eliminate the pathogen. The channel may thus play a dual role in pathogen survival. Absence of the channels is not compatible with pathogen growth, enhanced channel activity accelerates erythrocyte apoptosis that may represent a host defence mechanism serving to eliminate infected erythrocytes.     

Who are you talking to? The role of addressee identity in utterance comprehension

Experimental evidence suggests that speaker and addressee quickly adapt to each other from the earliest moments of sentence processing, and that interlocutor-related information is rapidly integrated with other sources of nonpragmatic information (e.g., semantic, morphosyntactic, etc.). These findings have been taken as support for one-step models of sentence comprehension. The results from the present event-related potential study challenge this theoretical framework providing a case where discourse level information is integrated only at a late stage of processing, when morphosyntactic analysis has been already initiated. We considered the case of Basque allocutive agreement, where information about addressee gender is encoded in verbal inflection. Two different types of Basque grammatical violations were presented together with the corresponding control conditions: one could be detected based on a morphosyntactic mismatch (person agreement violation), while the other could be detected only if the addressee's gender was considered (allocutive violation). Morphosyntactic violations elicited greater N400 effects followed by P600 effects, while allocutive violations elicited only P600 effects. These results provide new constraints to one-step accounts as they represent a case where speakers do not immediately adjust to the addressee's perspective. We propose that the relevance of discourse-level information might be a crucial variable to reconcile the dichotomy between one- and two-step models.     

Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease

Autophagy and endocytosis deliver unneeded cellular materials to lysosomes for degradation. Beyond processing cellular waste, lysosomes release metabolites and ions that serve signaling and nutrient sensing roles, linking the functions of the lysosome to various pathways for intracellular metabolism and nutrient homeostasis. Each of these lysosomal behaviors is influenced by the intraluminal pH of the lysosome, which is maintained in the low acidic range by a proton pump, the vacuolar ATPase (v-ATPase). New reports implicate altered v-ATPase activity and lysosomal pH dysregulation in cellular aging, longevity, and adult-onset neurodegenerative diseases, including forms of Parkinson disease and Alzheimer disease. Genetic defects of subunits composing the v-ATPase or v-ATPase-related proteins occur in an increasingly recognized group of familial neurodegenerative diseases. Here, we review the expanding roles of the v-ATPase complex as a platform regulating lysosomal hydrolysis and cellular homeostasis. We discuss the unique vulnerability of neurons to persistent low level lysosomal dysfunction and review recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum.     

β-Thalassemia trait association with autoimmune diseases: β-globin locus proximity to the immunity genes or role of hemorphins?

Thalassemia major continues to be a significant health problem for Mediterranean, Afro-Arabic countries, India and South Easth Asia. It was generally assumed that the β-thalassemia heterozygotes do not bear significant medical risks except a mild microcytic anemia. Nonetheless, increasing number of reports associate β-thalassemia trait with autoimmune conditions, nephritis, diabetes, arthritis, fibromyalgia and asthma. Available sparse data indicate reduced incidence of systemic lupus erythematosus (SLE) in β-thalassemia heterozygotes; yet, if two conditions coexist, the SLE manifestations occur much severer. These associations make sense when considering that the hemoglobin β-chain locus at 11p15.5 resides in close proximity to eight genes with profound roles in immune regulation: STIM1, CD151, TC21/RRAS2, SIGIRR/TOLL/IL1R8, pp52/LSP1 (lymphocyte specific protein), TRIM21, toll interacting protein (TOLLIP) and SLEN3. β-Thalassemia trait accompaniment to autoimmune disease may be the result of haplotypal associations between the close proximity genes. An alternative explanation to thalassemia heterozygosity: autoimmune disease association may be the changed concentrations of hemorphins. Hemorphins are endogenous opioid peptides derived via proteolytical cleavage of hemoglobin. They are shown to bind diverse opioid receptors and act anti-inflammatory. Their reduced expression in thalassemia heterozygosity may explain a proinflammatory stage and autoimmunity vulnerability.