Complexity and Controversies over the Cytokine Profiles of T Helper Cell Subpopulations in Tuberculosis

Tuberculosis (TB) is a contagious infectious disease caused by the TB-causing bacillusMycobacterium tuberculosisand is considered a public health problem with enormous social impact. Disease progression is determined mainly by the balance between the microorganism and the host defense systems. Although the immune system controls the infection, this control does not necessarily lead to sterilization. Over recent decades, the patterns of CD4+ T cell responses have been studied with a goal of complete understanding of the immunological mechanisms involved in the maintenance of latent or active tuberculosis infection and of the clinical cure after treatment. Conflicting results have been suggested over the years, particularly in studies comparing experimental models and human disease. In recent years, in addition to Th1, Th2, and Th17 profiles, new standards of cellular immune responses, such as Th9, Th22, and IFN-γ-IL-10 double-producing Th cells, discussed here, have also been described. Additionally, many new roles and cellular sources have been described for IL-10, demonstrating a critical role for this cytokine as regulatory, rather than merely pathogenic cytokine, involved in the establishment of chronic latent infection, in the clinical cure after treatment and in keeping antibacillary effector mechanisms active to prevent immune-mediated damage.

Download Full-text

Immune-Mediated Drug-Induced Liver Injury: Immunogenetics and Experimental Models

International Journal of Molecular Sciences ◽

10.3390/ijms22094557 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4557

Author(s):

Alessio Gerussi ◽

Ambra Natalini ◽

Fabrizio Antonangeli ◽

Clara Mancuso ◽

Elisa Agostinetto ◽

...

Keyword(s):

Liver Injury ◽

Experimental Models ◽

Clinical Event ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Immune Mediated ◽

Liver Injuries ◽

Immunological Mechanisms ◽

Molecular Aspects ◽

Therapeutic Tools

Drug-induced liver injury (DILI) is a challenging clinical event in medicine, particularly because of its ability to present with a variety of phenotypes including that of autoimmune hepatitis or other immune mediated liver injuries. Limited diagnostic and therapeutic tools are available, mostly because its pathogenesis has remained poorly understood for decades. The recent scientific and technological advancements in genomics and immunology are paving the way for a better understanding of the molecular aspects of DILI. This review provides an updated overview of the genetic predisposition and immunological mechanisms behind the pathogenesis of DILI and presents the state-of-the-art experimental models to study DILI at the pre-clinical level.

Download Full-text

Skin Immunity to Dermatophytes: From Experimental Infection Models to Human Disease

Frontiers in Immunology ◽

10.3389/fimmu.2020.605644 ◽

2020 ◽

Vol 11 ◽

Author(s):

Verónica L. Burstein ◽

Ignacio Beccacece ◽

Lorena Guasconi ◽

Cristian J. Mena ◽

Laura Cervi ◽

...

Keyword(s):

Immune Response ◽

Human Disease ◽

Current Knowledge ◽

Skin Inflammation ◽

Experimental Models ◽

Fungal Virulence ◽

Lectin Receptors ◽

Immunological Mechanisms ◽

Human Infections ◽

Cellular Immune

Dermatophytoses (ringworms) are among the most frequent skin infections and are a highly prevalent cause of human disease worldwide. Despite the incidence of these superficial mycoses in healthy people and the compelling evidence on chronic and deep infections in immunocompromised individuals, the mechanisms controlling dermatophyte invasion in the skin are scarcely known. In the last years, the association between certain primary immunodeficiencies and the susceptibility to severe dermatophytosis as well as the evidence provided by novel experimental models mimicking human disease have significantly contributed to deciphering the basic immunological mechanisms against dermatophytes. In this review, we outline the current knowledge on fungal virulence factors involved in the pathogenesis of dermatophytoses and recent evidence from human infections and experimental models that shed light on the cells and molecules involved in the antifungal cutaneous immune response. The latest highlights emphasize the contribution of C-type lectin receptors signaling and the cellular immune response mediated by IL-17 and IFN-γ in the anti-dermatophytic defense and skin inflammation control.

Download Full-text

Pathogenesis of Onchocercal Keratitis (River Blindness)

Clinical Microbiology Reviews ◽

10.1128/cmr.12.3.445 ◽

1999 ◽

Vol 12 (3) ◽

pp. 445-453 ◽

Cited By ~ 69

Author(s):

Laurie R. Hall ◽

Eric Pearlman

Keyword(s):

Inflammatory Response ◽

Clinical Symptoms ◽

Corneal Stroma ◽

Public Health Problem ◽

Experimental Models ◽

World Health ◽

River Blindness ◽

Anterior Portion ◽

Immunological Mechanisms ◽

Interstitial Keratitis

SUMMARY Onchocerciasis is a major cause of blindness. Although the World Health Organization has been successful in reducing onchocerciasis as a public health problem in parts of West Africa, there remain an estimated 17 million people infected with Onchocerca volvulus, the parasite that causes this disease. Ocular pathology can be manifested in any part of the eye, although disease manifestations are frequently characterized as either posterior or anterior eye disease. This review focuses on onchocerca-mediated keratitis that results from an inflammatory response in the anterior portion of the eye and summarizes what is currently known about human disease. This review also describes studies with experimental models that have been established to determine the immunological mechanisms underlying interstitial keratitis. The pathogenesis of keratitis is thought to be due to the host inflammatory response to degenerating parasites in the eye; therefore, the primary clinical symptoms of onchocercal keratitis (corneal opacification and neovascularization) are induced after injection of soluble O. volvulus antigens into the corneal stroma. Experimental approaches have demonstrated an essential role for sensitized T helper cells and shown that cytokines can regulate the severity of keratitis by controlling recruitment of inflammatory cells into the cornea. Chemokines are also important in inflammatory cell recruitment to the cornea, and their role in onchocerciasis is being examined. Further understanding of the molecular basis of the development of onchocercal keratitis may lead to novel approaches to immunologically based intervention.

Download Full-text

The Role of T Helper (TH)17 Cells as a Double-Edged Sword in the Interplay of Infection and Autoimmunity with a Focus on Xenobiotic-Induced Immunomodulation

Clinical and Developmental Immunology ◽

10.1155/2013/374769 ◽

2013 ◽

Vol 2013 ◽

pp. 1-13 ◽

Cited By ~ 9

Author(s):

Nasr Y. A. Hemdan ◽

Ahmed M. Abu El-Saad ◽

Ulrich Sack

Keyword(s):

Immune Cell ◽

Critical Role ◽

Cell Subset ◽

Epidemiologic Studies ◽

Experimental Models ◽

Cell Responses ◽

Th 17 ◽

Xenobiotic Exposure ◽

Occupationally Exposed

Extensive research in recent years suggests that exposure to xenobiotic stimuli plays a critical role in autoimmunity induction and severity and that the resulting response would be exacerbated in individuals with an infection-aroused immune system. In this context, heavy metals constitute a prominent category of xenobiotic substances, known to alter divergent immune cell responses in accidentally and occupationally exposed individuals, thereby increasing the susceptibility to autoimmunity and cancer, especially when accompanied by inflammation-triggered persistent sensitization. This perception is learned from experimental models of infection and epidemiologic studies and clearly underscores the interplay of exposure to such immunomodulatory elements with pre- or postexposure infectious events. Further, theTH17 cell subset, known to be associated with a growing list of autoimmune manifestations, may be the “superstar” at the interface of xenobiotic exposure and autoimmunity. In this review, the most recently established links to this nomination are short-listed to create a framework to better understand new insights intoTH17’s contributions to autoimmunity.

Download Full-text

Towards Improved Use of Vaccination in the Control of Infectious Bronchitis and Newcastle Disease in Poultry: Understanding the Immunological Mechanisms

Vaccines ◽

10.3390/vaccines9010020 ◽

2021 ◽

Vol 9 (1) ◽

pp. 20

Author(s):

Anthony C. Ike ◽

Chukwuebuka M. Ononugbo ◽

Okechukwu J. Obi ◽

Chisom J. Onu ◽

Chinasa V. Olovo ◽

...

Keyword(s):

Immune Responses ◽

Newcastle Disease ◽

Viral Infections ◽

Advanced Technology ◽

Global Food Security ◽

Infectious Bronchitis ◽

Immunological Mechanisms ◽

Inactivated Vaccines ◽

Successful Control ◽

Cellular Immune

Infectious bronchitis (IB) and Newcastle disease (ND) are two important diseases of poultry and have remained a threat to the development of the poultry industry in many parts of the world. The immunology of avian has been well studied and numerous vaccines have been developed against the two viruses. Most of these vaccines are either inactivated vaccines or live attenuated vaccines. Inactivated vaccines induce weak cellular immune responses and require priming with live or other types of vaccines. Advanced technology has been used to produce several types of vaccines that can initiate prime immune responses. However, as a result of rapid genetic variations, the control of these two viral infections through vaccination has remained a challenge. Using various strategies such as combination of live attenuated and inactivated vaccines, development of IB/ND vaccines, use of DNA vaccines and transgenic plant vaccines, the problem is being surmounted. It is hoped that with increasing understanding of the immunological mechanisms in birds that are used in fighting these viruses, a more successful control of the diseases will be achieved. This will go a long way in contributing to global food security and the economic development of many developing countries, given the role of poultry in the attainment of these goals.

Download Full-text

Microglial Pruning: Relevance for Synaptic Dysfunction in Multiple Sclerosis and Related Experimental Models

Cells ◽

10.3390/cells10030686 ◽

2021 ◽

Vol 10 (3) ◽

pp. 686

Author(s):

Maria Concetta Geloso ◽

Nadia D’Ambrosi

Keyword(s):

Multiple Sclerosis ◽

Neuronal Death ◽

Environmental Changes ◽

Experimental Models ◽

Synaptic Dysfunction ◽

Synapse Elimination ◽

Neurodegenerative Process ◽

Immune Mediated ◽

Wide Range ◽

Demyelinating Lesions

Microglia, besides being able to react rapidly to a wide range of environmental changes, are also involved in shaping neuronal wiring. Indeed, they actively participate in the modulation of neuronal function by regulating the elimination (or “pruning”) of weaker synapses in both physiologic and pathologic processes. Mounting evidence supports their crucial role in early synaptic loss, which is emerging as a hallmark of several neurodegenerative diseases, including multiple sclerosis (MS) and its preclinical models. MS is an inflammatory, immune-mediated pathology of the white matter in which demyelinating lesions may cause secondary neuronal death. Nevertheless, primitive grey matter (GM) damage is emerging as an important contributor to patients’ long-term disability, since it has been associated with early and progressive cognitive decline (CD), which seriously worsens the quality of life of MS patients. Widespread synapse loss even in the absence of demyelination, axon degeneration and neuronal death has been demonstrated in different GM structures, thus raising the possibility that synaptic dysfunction could be an early and possibly independent event in the neurodegenerative process associated with MS. This review provides an overview of microglial-dependent synapse elimination in the neuroinflammatory process that underlies MS and its experimental models.

Download Full-text

Microwave-Assisted Synthesis of (Piperidin-1-yl)quinolin-3-yl)methylene)hydrazinecarbothioamides as Potent Inhibitors of Cholinesterases: A Biochemical and In Silico Approach

Molecules ◽

10.3390/molecules26030656 ◽

2021 ◽

Vol 26 (3) ◽

pp. 656

Author(s):

Rubina Munir ◽

Muhammad Zia-ur-Rehman ◽

Shahzad Murtaza ◽

Sumera Zaib ◽

Noman Javid ◽

...

Keyword(s):

Neurodegenerative Disorder ◽

Critical Role ◽

Public Health Problem ◽

Microwave Assisted Synthesis ◽

Major Public Health Problem ◽

Spectroscopic Techniques ◽

Dual Inhibitor ◽

Microwave Assisted ◽

Ic50 Values

Alzheimer’s disease (AD), a progressive neurodegenerative disorder, characterized by central cognitive dysfunction, memory loss, and intellectual decline poses a major public health problem affecting millions of people around the globe. Despite several clinically approved drugs and development of anti-Alzheimer’s heterocyclic structural leads, the treatment of AD requires safer hybrid therapeutics with characteristic structural and biochemical properties. In this endeavor, we herein report a microwave-assisted synthesis of a library of quinoline thiosemicarbazones endowed with a piperidine moiety, achieved via the condensation of 6/8-methyl-2-(piperidin-1-yl)quinoline-3-carbaldehydes and (un)substituted thiosemicarbazides. The target N-heterocyclic products were isolated in excellent yields. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). Anti-Alzheimer potential of the synthesized heterocyclic compounds was evaluated using acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. The in vitro biochemical assay results revealed several compounds as potent inhibitors of both enzymes. Among them, five compounds exhibited IC50 values less than 20 μM. N-(3-chlorophenyl)-2-((8-methyl-2-(piperidin-1-yl)quinolin-3-yl)methylene)hydrazine carbothioamide emerged as the most potent dual inhibitor of AChE and BChE with IC50 values of 9.68 and 11.59 μM, respectively. Various informative structure–activity relationship (SAR) analyses were also concluded indicating the critical role of substitution pattern on the inhibitory efficacy of the tested derivatives. In vitro results were further validated through molecular docking analysis where interactive behavior of the potent inhibitors within the active pocket of enzymes was established. Quinoline thiosemicarbazones were also tested for their cytotoxicity using MTT assay against HepG2 cells. Among the 26 novel compounds, there were five cytotoxical and 18 showed proliferative properties.

Download Full-text

Innate cell microenvironments in lymph nodes shape the generation of T cell responses during type I inflammation

Science Immunology ◽

10.1126/sciimmunol.abb9435 ◽

2021 ◽

Vol 6 (56) ◽

pp. eabb9435

Author(s):

Joseph M. Leal ◽

Jessica Y. Huang ◽

Karan Kohli ◽

Caleb Stoltzfus ◽

Miranda R. Lyons-Cohen ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Lymph Nodes ◽

Critical Role ◽

Myeloid Cell ◽

T Cell Responses ◽

Type I ◽

Cell Responses ◽

Inflammatory Monocytes ◽

Cell Effector

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections.

Download Full-text

Comprehensive Epitope Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T-Cell Responses Directed against the Entire Expressed HIV-1 Genome Demonstrate Broadly Directed Responses, but No Correlation to Viral Load

Journal of Virology ◽

10.1128/jvi.77.3.2081-2092.2003 ◽

2003 ◽

Vol 77 (3) ◽

pp. 2081-2092 ◽

Cited By ~ 513

Author(s):

M. M. Addo ◽

X. G. Yu ◽

A. Rathod ◽

D. Cohen ◽

R. L. Eldridge ◽

...

Keyword(s):

T Cell ◽

T Cell Responses ◽

Protein Subunits ◽

Cell Responses ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Total Magnitude ◽

Cellular Immune ◽

Hiv 1

ABSTRACT Cellular immune responses play a critical role in the control of human immunodeficiency virus type 1 (HIV-1); however, the breadth of these responses at the single-epitope level has not been comprehensively assessed. We therefore screened peripheral blood mononuclear cells (PBMC) from 57 individuals at different stages of HIV-1 infection for virus-specific T-cell responses using a matrix of 504 overlapping peptides spanning all expressed HIV-1 proteins in a gamma interferon-enzyme-linked immunospot (Elispot) assay. HIV-1-specific T-cell responses were detectable in all study subjects, with a median of 14 individual epitopic regions targeted per person (range, 2 to 42), and all 14 HIV-1 protein subunits were recognized. HIV-1 p24-Gag and Nef contained the highest epitope density and were also the most frequently recognized HIV-1 proteins. The total magnitude of the HIV-1-specific response ranged from 280 to 25,860 spot-forming cells (SFC)/106 PBMC (median, 4,245) among all study participants. However, the number of epitopic regions targeted, the protein subunits recognized, and the total magnitude of HIV-1-specific responses varied significantly among the tested individuals, with the strongest and broadest responses detectable in individuals with untreated chronic HIV-1 infection. Neither the breadth nor the magnitude of the total HIV-1-specific CD8+-T-cell responses correlated with plasma viral load. We conclude that a peptide matrix-based Elispot assay allows for rapid, sensitive, specific, and efficient assessment of cellular immune responses directed against the entire expressed HIV-1 genome. These data also suggest that the impact of T-cell responses on control of viral replication cannot be explained by the mere quantification of the magnitude and breadth of the CD8+-T-cell response, even if a comprehensive pan-genome screening approach is applied.

Download Full-text

Prediction of IL4 Inducing Peptides

Clinical and Developmental Immunology ◽

10.1155/2013/263952 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 57

Author(s):

Sandeep Kumar Dhanda ◽

Sudheer Gupta ◽

Pooja Vir ◽

G. P. S. Raghava

Keyword(s):

Mhc Class Ii ◽

Critical Role ◽

Interleukin 4 ◽

Th2 Response ◽

Data Set ◽

T Helper 2 ◽

Cell Responses ◽

Antibody Class ◽

First Time ◽

Motif Information

The secretion of Interleukin-4 (IL4) is the characteristic of T-helper 2 responses. IL4 is a cytokine produced by CD4+ T cells in response to helminthes and other extracellular parasites. It has a critical role in guiding antibody class switching, hematopoiesis and inflammation, and the development of appropriate effector T-cell responses. In this study, it is the first time an attempt has been made to understand whether it is possible to predict IL4 inducing peptides. The data set used in this study comprises 904 experimentally validated IL4 inducing and 742 noninducing MHC class II binders. Our analysis revealed that certain types of residues are preferred at certain positions in IL4 inducing peptides. It was also observed that IL4 inducing and noninducing epitopes differ in compositional and motif pattern. Based on our analysis we developed classification models where the hybrid method of amino acid pairs and motif information performed the best with maximum accuracy of 75.76% and MCC of 0.51. These results indicate that it is possible to predict IL4 inducing peptides with reasonable precession. These models would be useful in designing the peptides that may induce desired Th2 response.

Download Full-text