Role of siderophores in cystic fibrosis pathogenesis: foes or friends?

Cystic fibrosis (CF) is one of the most common genetic disorders among Caucasians. CF patients are susceptible to chronic lung infections caused by diverse microorganisms, therefore CF should be regarded as a polymicrobial disease. Iron availability in the host is very limited, an obstacle for successful infection by pathogens. Siderophores are iron-binding low-molecular-weight compounds enabling microorganisms that produce them to grow under iron-limiting conditions. The aim of this review is to highlight the role of siderophores as virulence factors in CF pathogenesis, the siderophore ecology in CF lungs, the protective host mechanisms leading to iron-limiting conditions, and finally how siderophore-mediated iron uptake could be exploited for potential therapeutic interventions in cystic fibrosis.     

SARS-CoV-2 infection-induced immune responses: Friends or foes?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an emerging coronavirus that belongs to the β-genus, causing the outbreak of coronavirus disease 19 (COVID-19). SARS-CoV-2 infection can stimulate a pronounced immune response in the host, which embodies in the decrease of lymphocytes and aberrant increase of cytokines in COVID-19 patients. SARS-CoV-2 RNA and proteins interact with various pattern recognition receptors that switch on antiviral immune responses to regulate viral replication and spreading within the host in vivo. However, overactive and impaired immune responses also cause immune damage and subsequent tissue inflammation. This article focuses on the dual roles of immune system during SARS-CoV-2 infection, providing a theoretical basic for identifying therapeutic targets in a situation with an unfavourable immune reaction.     

Alveolar macrophages in diabetes: friends or foes?

AMs constitute an important bridge between innate and adaptive immunity. AMs patrol the lungs against pathogens, remove senescent cells, and help repair tissue. AM function is altered in many diseases, including DM, where AM abnormal immune responses may worsen infections or lead to exacerbation of inflammatory reactions. In vivo experimental models have greatly contributed to our knowledge of AM function. Studies have shown that during hyperglycemic states, the phagocytic function of AMs and the expression of adhesion molecules may be altered, interfering with the recruitment of immune cells to the inflammatory site. Insulin treatment seems to recover the normal function of impaired AMs. However, much research is still needed to characterize AMs and to better understand their role in inflammation and infection, particularly in diabetic patients. In this review, we attempt to explore recently accumulated knowledge about AM function and how this function is deficient in DM. Additionally, AM polarization is compared briefly with that of T cells, and this may interfere with how immune response is driven. This review discusses how impaired AMs lead to an aberrant immune response that contributes to worsening infection and autoimmunity, opening up discussion for future work in the field.     

γδ T cells and multiple sclerosis: Friends, foes, or both?

Multiple sclerosis (MS) is a debilitating CNS disease characterized by demyelination and neuro-axonal loss. Though the exact etiology is still unknown, accumulated evidence points to the immune system being involved in the MS disease-process. Both ill-fated adaptive and innate immune responses can potentially contribute to the etiopathogenesis. We have been interested in deciphering how innate immunity might be involved; in particular, the role of γδ T cells. In this review, we discuss the current understanding about γδ T cells and describe the evidence implicating them in myelin injury, neurotoxicity, and immunoregulation in the development of MS.     

Viral inhibitors of NKG2D ligands: Friends or foes of immune surveillance?

NKG2D is a potent activating receptor on NK cells and a co-stimulatory receptor on CD8+ T cells. Through its ability to recognize a panel of ligands inducible by stress or infection, it plays an important role in the control of viral infections. The viruses have evolved robust mechanisms to counteract NKG2D-dependent immune response. The functions of these viral inhibitors are well characterized during the early days post-infection but less so during the chronic viral infection.     

Autoantibodies in lupus: culprits or passive bystanders?

Several autoantibodies are culprits in the pathogenesis of organ damage in systemic lupus erythematosus, by means of established or postulated mechanisms, whereby inducing a perturbation of cell structure and function, with consequent tissue-organ impairment. Common autoantibody-mediated mechanisms of damage include cell surface binding with or without cytolysis, immune complex-mediated damage, penetration into living cells, binding to cross-reactive extracellular molecules. Experimental data from both murine models and humans have recently clarified the key role of autoantibodies in severe organ involvements, including nephritis, neuropsychiatric (NP) dysfunction, and cerebrovascular disease (CVD). In lupus nephritis early and late phases are distinguishable and mediated by different processes in which anti-chromatin antibodies are both inducing and perpetuating agents, by immune-complex formation and massive deposition in mesangial matrix at first, and in glomerular basement membrane at end-stage. Also NP abnormalities occur very early, much earlier than other systemic manifestations, and exacerbate with the increase in autoantibody titers. Among the autoantibodies mainly implicated in neurolupus, anti-β2 glycoprotein I (β2GPI) antibodies are preferentially involved in focal NP events which are a consequence of non-inflammatory microangiopathy; otherwise, anti-ribosomal P protein antibodies and N-methyl-d-aspartate receptor (NMDAR) antibodies cause diffuse NP events through a direct cytotoxic effect on neuronal cells at specific brain zones.     

Dendritic cells in viral pathogenesis: protective or defective?

Dendritic cells (DC) are potent antigen-presenting cells that are critical in the initiation of immune responses to control and/or eliminate viral infections. Recent studies have investigated the effects of virus infection on the biology of DC. This review summarizes these changes, focusing on both the DC parameters affected and the viral factors involved. In addition, the central role of DC biology in the pathogenesis of several viral families, including herpesviruses, paramyxoviruses and retroviruses, is explored. The field of pathogen recognition by DC is addressed, focusing on its role in protecting the host from viral infection, as well as the ability of viruses to exploit such host receptor ligation and signalling to their replicative advantage. The hypothesis is proposed that virus and host have evolved a symbiotic relationship to ensure both viral transmission and host survival.     

Tumor-infiltrating T lymphocytes: friends or foes?

The prognostic significance of tumor-infiltrating lymphocytes (TILs) has been a longstanding topic of debate. In cases where TILs have improved patient outcome, T lymphocytes are recognized as the main effectors of antitumor immune responses. However, recent studies have revealed that a subset of CD4(+) T cells, referred to as CD4(+)CD25(+) regulatory T cells (Treg), may accumulate in the tumor environment and suppress tumor-specific T-cell responses, thereby hindering tumor rejection. Hence, predicting tumor behavior on the basis of an indiscriminate evaluation of tumor-infiltrating T cells may result in inconsistent prognostic accuracy. The presence of infiltrating CD4(+)CD25(+) Treg may be detrimental to the host defense against the tumor, while the presence of effector T lymphocytes, including CD8(+) T cells and non-regulatory CD4(+) helper T cells may be beneficial. Enhanced recruitment of antitumor effector T lymphocytes to tumor tissue in addition to inhibition of local Treg, may therefore be an ideal target for improving cancer immunotherapy. This article reviews the antitumor functions of T-lymphocytes, with special attention given to CD4(+) regulatory T-cells within the tumor environment.     

Tumors and inflammatory infiltrates: friends or foes?

The recognition of a role for inflammation in the natural history of a tumor has a long record, stretching from the mid-19th century. From the times of Virkow, who postulated that cancer originates from inflamed tissues, to Metchnikoff and many others, this field has continued to excite (and divide) the scientific community. The question as to whether the inflammatory infiltrate helps or hinders tumors is still open. In a sense, modern molecular biology has, if anything, worsened this dualism, and the literature on this issue shows a plethora of conflicting reports. We would like to provide another contribution to this topic, which was the subject of a recent brilliant review (Balkwill F and Mantovani A. Lancet 2001; 357: 539–45 [1]), by focussing more specifically to the relation between inflammation and tumor invasion and how this could drive rational therapeutic approaches. This revised version was published online in July 2006 with corrections to the Cover Date.     

Toll-like receptor 3 in viral pathogenesis: friend or foe?

Viral infections frequently induce acute and chronic inflammatory diseases, yet the contribution of the innate immune response to a detrimental host response remains poorly understood. In virus‐infected cells, double‐stranded RNA (dsRNA) is generated as an intermediate during viral replication. Cell necrosis (and the release of endogenous dsRNA) is a common event during both sterile and infectious inflammatory processes. The discovery of Toll‐like receptor 3 (TLR3) as an interferon‐inducing dsRNA sensor led to the assumption that TLR3 was the master sentinel against viral infections. This simplistic view has been challenged by the discovery of at least three members of the DExd/H‐box helicase cytosolic sensors of dsRNA that share with TLR3 the Toll–interleukin‐1 receptor (TIR) ‐adapter molecule TIR domain‐containing adaptor protein interferon‐β (TRIF) for downstream type I interferon signalling. Data are conflicting on the role of TLR3 in protective immunity against viruses in the mouse model. Varying susceptibility to infection and disease outcomes have been reported in TLR3‐immunodeficient mice. Surprisingly, the susceptibility to develop herpes simplex virus‐1 encephalitis in humans with inborn defects of the TLR3 pathway varies, and TLR3‐deficient humans do not show increased susceptibility to other viral infections. Therefore, a current challenge is to understand the protective versus pathogenic contribution of TLR3 in viral infections. We review recent advances in the identification of TLR3‐signalling pathways, endogenous and virus‐induced negative regulators of the TLR3 cascade, and discuss the protective versus pathogenic role of TLR3 in viral pathogenesis.     

Regulatory T cells: Friends or foe in human Mycobacterium leprae infection?

Regulatory T cells (Tregs) are known to control immune responses by suppressing the antigen-presenting and effector T cells. Some mechanisms adopted by Tregs in combating Mycobacterium infections have been proposed. Nevertheless, in M. leprae infection, also known as leprosy or Hansen’s disease, the role of Tregs has not been completely elucidated. Using multicolor flow cytometry, we evaluated the expression of different cell surface and intracellular molecules present in Tregs from peripheral blood samples of leprosy patients. Before initiating treatment, thirteen new cases of leprosy were grouped according to the Ridley–Jopling classification in to the paucibacilary (PB) or multibacilary (MB) group. Fifteen non-infected individuals (NI) were included as control subjects. Tregs were higher in the MB group than in the NI group. Tregs also co-expressed high amounts of PD1 and PDL-1, indicating that these cells could induce apoptosis of effector cells and simultaneously prevent their own apoptosis. Our data showed that compared to the NI group, Tregs from the PB group expressed higher levels of CD95L, which may be associated with other apoptotic pathways that may decrease Tregs in these patients. Correlation analysis reinforced that PD1 and CD95L are efficient apoptosis' pathway that decreased levels of Tregs in the NI and PB groups. We also observed significant differences in cytokine expression of Tregs from the PB and MB groups. Compared to the NI group, Tregs from the MB group showed higher IL-17 expression; however, compared to the PB group, the expression of IL-10 in Tregs from the MB group was lower, suggesting inefficient control of inflammation. Therefore, we concluded that different pathways were involved in Treg-induced suppression of leprosy. Moreover, Treg-mediated regulation of inflammation via IL-10 and IL-17 expression in leprosy patients was inefficient. Thus, we propose that during M. leprae infection, Tregs may impair the immune responses elicited against this bacillus, favor bacterial replication, and aid in persistence of a disseminated multibacillary disease.     

Dendritic cells and viral immunity: friends or foes?

Dendritic cells (DC) residing in epithelial tissues of various mucosae and the skin are characterized by the unique ability to capture antigens and migrate to draining lymph nodes, where they can activate naive and memory T cells. Although DC play a pivotal role in inducing protective immunity to viral infection, they can also be exploited by viruses to evade the host immune response, induce immune suppression, or serve as latent viral reservoirs. Thus, virus interactions with DC may lead to an immune response that can be protective, but does not necessarily lead to complete virus elimination, resulting in immunopathology.     

Immune cells and molecules in pregnancy: friends or foes to the fetus?

Considering allograft rejection as a basic feature of the immune system, the mammalian pregnancy is an immunological paradox where the semi-allogeneic fetus is not rejected. How are the demands of pregnancy solved in the context of maternal immunity? Medawar’s original proposal of maternal immune inertness during pregnancy should be revised to active materno-placental tolerance. Multiple mechanisms are involved in peripheral and local tolerance induction that prevents fetal rejection while maintaining competent immune surveillance and protection. The goal of this review is to discuss the major cellular and molecular components of the immune system that control and promote fetal survival.