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Challenges and Opportunities in Immune Regulation

Challenges and Opportunities in Immune Regulation

Walker, M., Peppercorn, K., Kleffmann, T., Edgar, C. D., & Tate, W. P. (2023b)

Abstract

Viral infection in most people results in a transient immune/inflammatory response resulting in elimination of the virus and recovery where the immune system returns to that of the pre-infectious state. In susceptible people by contrast there is a transition from an acute immune response to a chronic state that can lead to an ongoing lifelong complex post-viral illness, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. This susceptibility is proposed to be genetic or be primed by prior health history. Complex abnormalities occur in immune cell functions, immune cell metabolism and energy production, and in cytokine immune modulator regulation. The immune system of the brain/central nervous system becomes activated leading to dysfunction in regulation of body physiology and the onset of many neurological symptoms.

A dysfunctional immune system is core to the development of the post-viral condition as shown with diverse strategies of immune profiling.  Many studies have shown changes in numbers and activity of immune cells of different phenotypes and their metabolism. Immune regulating cytokines show complex altered patterns and vary with the stage of the disease, and there are elements of associated autoimmunity.  These complex changes are accompanied by an altered molecular homeostasis with immune cell transcripts and proteins no longer produced in a tightly regulated manner, reflected in the instability of the epigenetic code that controls gene expression. Potential key elements of the altered immune function in this disease needing further exploration are changes to the gut-brain-immune axis as a result of changes in the microbiome of the gut, and viral reactivation from latent elements of the triggering virus or from a prior viral infection. Long COVID, an Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-like illness, is the post-viral condition that has arisen in large numbers solely from the pandemic virus Severe Acute Respiratory Syndrome Coronovirus-2. With over 760 million cases worldwide, an estimated ~100 million cases of Long COVID have occurred within a short period. This now provides an unprecedented opportunity to understand the progression of these post-viral diseases, and to progress from a research phase mainly documenting the immune changes to considering potential immunotherapies that might improve the overall symptom profile of affected patients, and provide them with a better quality of life.

Rosenthal, K. S., & Zimmerman, D. H. (2022)

Abstract

Autoimmune disease disrupts the normal immunological balance by promoting a perpetual cycle of innate/immune/inflammatory responses that continues due to the continued presence of antigen. The disease cycle is in turn amplified and regulated by cycles of antigen-specific T cell mediated immune responses. Removal of the stimuli or regulation of the disease drivers can stop the cycle to allow rebalancing and prevent the progression or chronicity of disease. As an alternative to the current treatments for autoimmune and inflammatory disease, which reduce, inhibit or eliminate the triggers, drivers or antigens, newer approaches stimulate regulatory responses, or inhibit or repurpose the effector/inflammatory responses to control the immune disease cycle. LEAPS (Ligand Epitope Antigen Presentation System) therapeutic vaccines for rheumatoid arthritis are presented as examples of therapies that elicit antigen specific T cell modulation of autoimmune and inflammatory responses to treat disease.

Walker, M., Hall, K. S., Peppercorn, K., & Tate, W. P. (2022)

Abstract

Long COVID is now well accepted as an ongoing post-viral syndrome resulting from infection of a single virus, the pandemic SARS-CoV-2. It mirrors the post-viral fatigue syndrome, Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome, a global debilitating illness arising mainly from sporadic geographically-specific viral outbreaks, and from community endemic infections, but also from other stressors. Core symptoms of both syndromes are post-exertional malaise (a worsening of symptoms following mental or physical activity), pervasive fatigue, cognitive dysfunction (brain fog), and sleep disturbance. Long COVID patients frequently also suffer from shortness of breath, relating to the lung involvement of the SARS-CoV-2 virus. There is no universally accepted pathophysiology, or recognized biomarkers yet for Long COVID or indeed for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Clinical case definitions with very similar characteristics for each have been defined. Chronic inflammation, immune dysfunction, and disrupted energy production in the peripheral system has been confirmed in Long COVID and has been well documented in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.     Neuroinflammation occurs in the brain in Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome as shown from a small number of positron emission tomography and magnetic resonance spectroscopy studies, and has now been demonstrated for Long COVID. Oxidative stress, an increase in reactive oxygen and reactive nitrogen species, and free radicals, has long been suggested as a potential cause for many of the symptoms seen in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, resulting from both activation of the brain’s immune system and dysregulation of mitochondrial function throughout the body. The brain as a high producer of energy may be particularly susceptible to oxidative stress. It has been shown in peripheral immune cells that the balanced production of proteins involved in regulation of the reactive oxygen species in mitochondria is disturbed in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Fluctuations in the chronic low level neuroinflammation during the ongoing course of Long COVID as well as Myalgic Encephalomyelitis/Chronic Fatigue Syndrome have been proposed to cause the characteristic severe relapses in patients. This review explores oxidative stress as a likely significant contributor to the pathophysiology of Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and the mechanisms by which oxidative stress could cause the symptoms seen in both syndromes. Treatments that could mitigate oxidative stress and thereby lessen the debilitating symptoms to improve the life of patients are discussed.

Cardozo, D. M., De Barros-Mazon, S., Guimarães, F., Visentainer, J. E. L., & De Souza, C. A. (2024)

Abstract

The Natural Killer cells are innate lymphoid cells that play essential roles in defense against viral and parasitic infections, elimination of tumor cells, regulation of adaptive immunity through cytotoxicity, and cytokine secretion. Fundamental knowledge about the regulation of Natural Killer cells can be applied to study their function in patients undergoing hematopoietic stem cell transplantation, with or without Cytomegalovirus reactivation. The function of Natural Killer cells is governed by a repertoire of receptors responsible for initiating intracellular activating or inhibitory signaling. The balance of this signaling directs the cytotoxic activity of these cells, as well as cell proliferation and cytokine release.Understanding the interaction of receptors expressed on the surface of Natural Killer cells with their ligands expressed on target cells is a topic of discussion in the context of alloreactivity and the graft-versus-leukemia effect in transplant patients. Recent investigations have shown that KIR/HLA interactions go beyond affinity and describe that many of them depend on the peptide being presented by the HLA at that moment. Analysis of the peptidome (HLA class I + bound peptide) has demonstrated that some Natural Killer cell receptors are peptide-dependent. Therefore, understanding these interactions by considering the entire Natural Killer cell receptor + HLA class I + peptide complex is crucial in the reestablishment of immune cells after hematopoietic stem cell transplantation, especially in the context of Cytomegalovirus reactivation, which is very common in these patients. Hence, the aim of this study is to deepen our understanding of the specificity of interactions between human Natural Killer cell KIR receptors and the peptidome in the context of Cytomegalovirus reactivation after allogeneic, related, HLA-compatible hematopoietic stem cell transplantation without T-cell depletion. For the analysis of interactions between Natural Killer cell receptors and peptidomes, specific peptide libraries for HLA class I alleles will be created to evaluate the specificities of interactions between KIR + HLA class I + peptide.

Davis, P. J., Hercbergs, A., Lin, H., Leinung, M. C., & Mousa, S. A. (2023)

Abstract

Thyroid hormone as L-thyroxine (T4) at physiological concentrations acts at its cell surface receptor on integrin avb3  to stimulate cancer cell proliferation1. These proliferation studies have been conducted in vitro, but pharmacological reduction of T4 and substitution of nuclear receptor ligand 3,3’,5-triiodo-L-thyronine (T3) is a state of euthyroid hypothyroxinemia that has been shown clinically to arrest tumor growth in patients with cancer. T3 is inactive at physiological levels at the plasma membrane integrin receptor. A preclinical study of human basal cell carcinoma (BCC) cells has shown that the integrin thyroid hormone receptor regulates BCC radiosensitivity. While the large majority of BCCs are very manageable clinically, a small number of such tumors are aggressive. In this review of documented and proposed effects of T4 on BCC cells, we raise the possibility that BCC aggressiveness reflects T4 actions on its thyrointegrin target. The functions affected by T4 at the integrin in other human cancers include enhanced cell proliferation, anti-apoptosis, immune checkpoint regulation and metastasis, as well as state of radiosensitivity. The importance of investigating this possible pathophysiology is that euthyroid hypothyroxinemia may be tested as a treatment option.

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