Chemokines in tuberculosis: The good,the bad and the ugly

Mycobacterium tuberculosis (Mtb) infects about one-third of the world's population, with a majority of infected individuals exhibiting latent asymptomatic infection, while 5–10% of infected individuals progress to active pulmonary disease. Research in the past two decades has elucidated critical host immune mechanisms that mediate Mtb control. Among these, chemokines have been associated with numerous key processes that lead to Mtb containment, from recruitment of myeloid cells into the lung to activation of adaptive immunity, formation of protective granulomas and vaccine recall responses. However, imbalances in several key chemokine mediators can alter the delicate balance of cytokines and cellular responses that promote mycobacterial containment, instead precipitating terminal tissue destruction and spread of Mtb infection. In this review, we will describe recent insights in the involvement of chemokines in host responses to Mtb infection and Mtb containment (the good), chemokines contributing to inflammation during TB (the bad), and the role of chemokines in driving cavitation and lung pathology (the ugly).     

Anxiety and outcome evaluation: The good, the bad and the ambiguous

Previous research has indicated that anxious individuals are more prone to evaluate ambiguous information as negative compared to non-anxious individuals. The feedback-related negativity (FRN) component of event-related brain potential (ERP) has been shown to be sensitive to outcome evaluation. The current ERP study aimed to test the hypothesis that the FRNs associated with ambiguous outcomes and negative outcomes are different between high-trait anxiety (HTA) and low-trait anxiety (LTA) individuals. The FRN was measured as a difference wave created across conditions. We found significantly different FRN responses between high-anxious and low-anxious participants in ambiguous outcome condition, as well as in negative outcome condition. Moreover, the HTA group's FRN responses under the ambiguous outcome condition were larger than the negative outcome condition. Nevertheless, the FRN following neutral outcome did not show any difference between the two groups. The present results support the idea that there is link between individual differences in anxiety and ambiguous outcome evaluation, which possibly reflects the adaptive function of anxiety. Additionally, the results indicate that the mechanisms underlying the evaluation of neutral outcomes and ambiguous outcomes might be different from each other.     

Triple negative breast carcinoma: the good,the bad and the ugly

Triple-negative breast cancers (TNBC) are a heterogeneous group of breast cancers defined by their lack of expression of oestrogen and progesterone receptors as well as human epidermal growth factor receptor 2 amplification, and therefore, are resistant to hormonal and Trastuzumab therapy. TNBC accounts for 15% of all breast cancers, and are more common in African-American women than in Whites. Also, BRCA-1 associated tumours are usually TNBC. Since the majority of TNBC fall into the basal-like breast cancer category by molecular studies, they are generally regarded as tumours of poor prognosis. However, some TNBC, such as adenoid cystic carcinoma and medullary carcinomas have excellent prognosis. Others, like metaplastic carcinoma have a prognosis that is comparable to infiltrating ductal carcinoma, not otherwise specified (NOS). Many immunohistochemical markers have been studied as an adjunct tool in classifying TNBC. However, microscopic evaluation remains an important tool in classifying these tumours and therefore predicting their prognosis.     

Fluid calories and energy balance: the good, the bad, and the uncertain

Energy-yielding fluids are a large and growing proportion of daily energy intake. The specific form and nutrient composition of fluids may hold divergent implications for energy balance. Ethanol elicits a weak compensatory dietary response, resulting in positive energy balance. However, its impact on body weight is unclear, possibly due to metabolic inefficiencies. In contrast, the weak dietary compensation for clear beverages containing other energy sources is associated with weight gain. How these beverages elude satiety mechanisms has not been studied. Soups hold higher satiating value, at least in part, due to cognitive factors. Nutrient dense beverages have been used successfully in meal replacement regimens for weight management, but due to their relatively weak satiety value, are widely consumed for weight gain and as nutrient supplements. A better understanding of the role of fluid calories in the diet is needed to improve dietary guidelines.     

The good, the bad and the ugly--APCs of the eye

Dendritic-cell (DC) populations throughout the body have a wide range of features in common, which are associated with their primary function in antigen presentation. The unique immune milieu of the anterior segment of the eye is characterized by a selective DC-dependent inability to develop delayed hypersensitivity responses following antigen invasion into the eye. Recent research papers provide evidence that different maturation stages of DC subsets are detectable at different corneal sites. Thus, the corneal DC, as well as the DC and the macrophages in the iris and ciliary body, have the potential of determining the outcome of immunity or tolerance within this organ.     

Effects of stress on immune function: the good,the bad,and the beautiful

Although the concept of stress has earned a bad reputation, it is important to recognize that the adaptive purpose of a physiological stress response is to promote survival during fight or flight. While long-term stress is generally harmful, short-term stress can be protective as it prepares the organism to deal with challenges. This review discusses the immune effects of biological stress responses that can be induced by psychological, physiological, or physical (including exercise) stressors. We have proposed that short-term stress is one of the nature’s fundamental but under-appreciated survival mechanisms that could be clinically harnessed to enhance immunoprotection. Short-term (i.e., lasting for minutes to hours) stress experienced during immune activation enhances innate/primary and adaptive/secondary immune responses. Mechanisms of immuno-enhancement include changes in dendritic cell, neutrophil, macrophage, and lymphocyte trafficking, maturation, and function as well as local and systemic production of cytokines. In contrast, long-term stress suppresses or dysregulates innate and adaptive immune responses by altering the Type 1–Type 2 cytokine balance, inducing low-grade chronic inflammation, and suppressing numbers, trafficking, and function of immunoprotective cells. Chronic stress may also increase susceptibility to some types of cancer by suppressing Type 1 cytokines and protective T cells and increasing regulatory/suppressor T cell function. Here, we classify immune responses as being protective, pathological, or regulatory, and discuss “good” versus “bad” effects of stress on health. Thus, short-term stress can enhance the acquisition and/or expression of immunoprotective (wound healing, vaccination, anti-infectious agent, anti-tumor) or immuno-pathological (pro-inflammatory, autoimmune) responses. In contrast, chronic stress can suppress protective immune responses and/or exacerbate pathological immune responses. Studies such as the ones discussed here could provide mechanistic targets and conceptual frameworks for pharmacological and/or biobehavioral interventions designed to enhance the effects of “good” stress, minimize the effects of “bad” stress, and maximally promote health and healing.     

Gut permeability and mucosal inflammation: bad,good or context dependent

Inflammatory bowel disease (IBD) is a multifactorial disease. A breach in the mucosal barrier, otherwise known as “leaky gut,” is alleged to promote mucosal inflammation by intensifying immune activation. However, interaction between the luminal antigen and mucosal immune system is necessary to maintain mucosal homeostasis. Furthermore, manipulations leading to deregulated gut permeability have resulted in susceptibility in mice to colitis as well as to creating adaptive immunity. These findings implicate a complex but dynamic association between mucosal permeability and immune homeostasis; however, they also emphasize that compromised gut permeability alone may not be sufficient to induce colitis. Emerging evidence further supports the role(s) of proteins associated with the mucosal barrier in epithelial injury and repair: manipulations of associated proteins also modified epithelial differentiation, proliferation, and apoptosis. Taken together, the role of gut permeability and proteins associated in regulating mucosal inflammatory diseases appears to be more complex than previously thought. Herein, we review outcomes from recent mouse models where gut permeability was altered by direct and indirect effects of manipulating mucosal barrier-associated proteins, to highlight the significance of mucosal permeability and the non-barrier-related roles of these proteins in regulating chronic mucosal inflammatory conditions.     

Autoimmune effector memory T cells: the bad and the good

Immunological memory is a hallmark of adaptive immunity, a defense mechanism endowed to vertebrates during evolution. However, an autoimmune pathogenic role of memory lymphocytes is also emerging with accumulating evidence, despite reasonable skepticism on their existence in a chronic setting of autoimmune damage. It is conceivable that autoimmune memory would be particularly harmful since memory cells would constantly “remember” and attack the body’s healthy tissues. It is even more detrimental given the resistance of memory T cells to immunomodulatory therapies. In this review, we focus on self-antigen-reactive CD4⁺ effector memory T (T_EM) cells, surveying the evidence for the role of the T_EM compartment in autoimmune pathogenesis. We will also discuss the role of T_EM cells in chronic and acute infectious disease settings and how they compare to their counterparts in autoimmune diseases. With their long-lasting potency, the autoimmune T_EM cells could also play a critical role in anti-tumor immunity, which may be largely based on their reactivity to self-antigens. Therefore, although autoimmune T_EM cells are “bad” due to their role in relentless perpetration of tissue damage in autoimmune disease settings, they are unlikely a by-product of industrial development along the modern surge of autoimmune disease prevalence. Rather, they may be a product of evolution for their “good” in clearing damaged host cells in chronic infections and malignant cells in cancer settings.     

RIPK3 in cell death and inflammation: the good,the bad,and the ugly

Necroptosis is a form of cell death that can be observed downstream of death receptor or pattern recognition receptor signaling under certain cellular contexts, or in response to some viral and bacterial infections. The receptor interacting protein kinases-1 (RIPK1) and RIPK3 are at the core of necroptotic signaling, among other proteins. Because this pathway is normally halted by the pro-apoptotic protease caspase-8 and the IAP ubiquitin ligases, how and when necroptosis is triggered in physiological settings are ongoing questions. Interestingly, accumulating evidence suggests that RIPK3 has functions beyond the induction of necroptotic cell death, especially in the areas of tissue injury and sterile inflammation. Here, we will discuss the role of RIPK3 in a variety of physiological conditions, including necroptotic and non-necroptotic cell death, in the context of viral and bacterial infections, tissue damage, and inflammation.     

Animal models of multiple sclerosis: the good, the bad and the bottom line

Multiple sclerosis (MS) is a spontaneous, acquired, inflammatory demyelinating disease of the human CNS. Because it involves a complex interaction between two of the most intricate biological systems, immune system and CNS, animal modeling has been critical for addressing MS pathogenesis. MS models were originally developed serendipitously more than 75 years ago. Immune-mediated, toxic, viral and genetic models of demyelination are now used to understand the manifold aspects of MS. MS treatments evolved in part from animal model research, and further progress is envisaged in large part because these systems have been continually refined and their use focused on questions whose relevance was established by studying the human disease.     

E-cadherin, N-cadherin, and calretinin in pleural effusions: the good, the bad, the worthless

The distinction between reactive mesothelial cells (RMC), malignant mesothelioma (MM), and metastatic adenocarcinoma (ACA) in pleural effusions may be impossible based on morphology alone. E-cadherin, N-cadherin, and calretinin are newly described immunocytochemical markers which can potentially be utilized for facilitating this distinction. E-cadherin and N-cadherin are calcium-dependent intercellular adhesion molecules expressed in epithelial cells and mesenchymal/mesothelial cells, respectively. The differential expression of E-cadherins in epithelial cells and N-cadherins in mesothelial cells has been utilized to differentiate reactive mesothelial cells, MMs and ACAs. Calretinin is a calcium-binding protein within the family of EF-hand proteins. It is abundantly expressed in peripheral and central nervous tissues, and has been shown to consistently immunoreact with mesothelial cells. We studied cell block sections from 77 pleural effusions (22 RMC, 26 MM, and 29 ACA) to investigate the potential immunocytochemical use of anti-E-cadherin, anti-N-cadherin, and anti-calretinin antibodies for differentiating between RMC, MM, and ACA in pleural effusions. A modified avidin-biotin peroxidase complex (ABC) method was used. E-cadherin immunostaining was observed in 14% of RMC, 46% of MMs, and 97% of ACAs. A distinct membrane staining pattern was seen in ACAs. The pattern of staining was cytoplasmic in all reactive RMC and varied from membrane to cytoplasmic in MMs. Anti-N-cadherin immunoreacted with 77% of RMC, 35% of MMs, and 48% of ACAs. Twenty-seven percent of RMC, 58% of MMs, and 31% of ACAs immunoreacted with anti-calretinin. Based on these results, we conclude that anti-E-cadherin is a potentially useful marker in the distinction of ACA cells from RMC. However, it is not as useful for the distinction of ACA and MM. Anti-N-cadherin and anti-calretinin did not reliably distinguish between reactive mesothelial, MM, and ACA cells in pleural effusions.