Immuno, Volume 2, Issue 3 (September 2022) – 8 articles

Systemic sclerosis (SSc) is a chronic disease characterized by microvasculopathy, autoantibodies (autoAbs), and fibrosis. The pathogenesis of the disease is incompletely understood. Microvasculopathy and autoAbs appear very early in the disease process. AutoAbs, such as those directed against DNA topoisomerase I (Topo I), are disease specific and associated with disease manifestations, and indicate activation of the adaptive immune system. B cells are involved in fibrosis in SSc. T cells are also involved in disease pathogenesis. T cells show signs of antigen-induced activation; T cells of TH2 type are increased and produce profibrotic cytokines interleukin (IL)-4, IL-13, and IL-31; CD4+ cytotoxic T lymphocytes are increased in skin lesions, and cause fibrosis and endothelial cell apoptosis; circulating T follicular helper (TFH) cells are increased in SSc produce IL-21 and promote plasmablast antibody production. On the other hand, regulatory T cells are impaired in SSc. These findings provide strong circumstantial evidence for T cell implication in SSc pathogenesis and encourage new T cell-directed therapeutic strategies for the disease. Full article

Long COVID, also referred to as Post-Acute Sequelae of COVID (PASC), is probably triggered during SARS-CoV-2 infection and acute COVID-19 by SARS-CoV-2 Spike-protein binding and hyper-activating the cell-membrane expressed Receptor for Advance Glycation End-products (mRAGE) and Toll-Like Receptor 4 (TLR4). SARS-CoV-2 infects lung monocytes by Spike binding to mRAGE (not ACE2). During acute COVID-19, high levels of IL-6 hyper-stimulate S100A8/A9 expression and secretion. Although no viral protein nor mRNA can be detected in half of long COVID (PASC) patients, there is a significant elevation of serum levels of IL-1b, IL-6, TNFa, and S100A8/A9. It appears that a pathological pro-inflammatory feedback loop (the TLR4/RAGE-loop) is established during acute COVID-19, which is maintained by S100A8/A9 > RAGE/TLR4 chronic inflammatory signalling, even after SARS-CoV-2 has been cleared from the body. During long COVID/PASC, Ca²⁺-binding protein S100A8/A9 chronically stimulates TLR4/RAGE-signalling to induce chronic expression of IL-1b, IL-6 and TNFa. Secreted IL-6 binds to its IL-6R receptor on the surface of other cells and signals via STAT3 and C/EBPb for more S100A8/A9 expression. Secreted IL-1b binds to its receptor IL-1R on other cells, and signals via NFkB for more mRAGE and TLR4 expression. New S100A8/A9 can bind and activate cell-surface mRAGE and TLR4 to stimulate expression of more IL-1b, IL-6 and TNFa. This process establishes a pathogenic pro-inflammatory TLR4/RAGE-loop: IL-1b + IL-6 > IL-1R + IL-6R > TLR4/mRAGE + S100A8/A9 > IL-1b + IL-6, which generates multi-organ inflammation that persists in the blood vessels, the brain, the liver, the heart, the kidneys, the gut and the musculo-skeletal system, and is responsible for all the complex pathologies associated with long COVID/PASC. Chronic expression of IL-1, IL-6 and TNFa is critical for the maintenance of the TLR4/RAGE-loop and persistence of long COVID/PASC. Ezrin peptides are inhibitors of IL-1, IL-6, IL-8 and TNFa expression, so are now being investigated as potential therapy for long COVID/PASC. There is preliminary anecdotal evidence of symptomatic relief (not confirmed yet by formal clinical trials) from a few long COVID/PASC patient volunteers, after treatment with ezrin peptide therapy. Full article

Under pathological conditions such as multiple sclerosis (MS), leukocytes infiltrate the central nervous system where they, in concert with activated microglia, promote inflammatory demyelination resulting in a broad spectrum of symptoms, including paralysis. Therefore, all current therapeutic approaches to MS target the immune system, blocking inflammation and paralysis progression, but may compromise the immune system. In this focused review, we present an underestimated compartment, the blood–brain barrier, which is compromised during MS and becomes permeable to leukocytes infiltrating the central nervous system. This barrier has the potential to offer new therapeutic strategies and is easily accessible for drugs. We highlight this paradigm using the example of the therapeutic anti-Reelin strategy we have developed. Reelin is a plasma protein that regulates the expression of adhesion markers on the endothelial surface, thus promoting the infiltration of inflammatory cells and propagating inflammation. Building Back a Better Blood–Brain Barrier (the “6B” strategy) may have advantages compared to actual immunosuppressive drugs because it restores a physiological function rather than suppressing the immune system. Full article

A civil paternity investigation involving the parents of the deceased alleged father in order to establish a family relationship is presented. On the basis of the 23 autosomal short tandem repeat (aSTR) genotyping results, conclusive proof of paternity was not achieved, as the probability of paternity (W) was calculated to 0.99988. Additional genetic data of 17 classical and non-classical human leukocyte alleles (HLA) typing by next-generation sequencing (NGS) at a high-resolution level supported the hypothesis of grandpaternity over the hypothesis of coincidental paternal obligate allele (POA) sharing (total W_aSTR&HLA = 0.9999998). The present study demonstrates the utility of 17 HLA genetic markers-typing in the solution of deficiency cases of disputed parentage. Full article

Bacterial lipopolysaccharides (LPS), also referred to as endotoxins, are major outer surface membrane components present on almost all Gram-negative bacteria and are major determinants of sepsis-related clinical complications including septic shock. LPS acts as a strong stimulator of innate or natural immunity in a wide variety of eukaryotic species ranging from insects to humans including specific effects on the adaptive immune system. However, following immune stimulation, lipopolysaccharide can induce tolerance which is an essential immune-homeostatic response that prevents overactivation of the inflammatory response. The tolerance induced by LPS is a state of reduced immune responsiveness due to persistent and repeated challenges, resulting in decreased expression of pro-inflammatory modulators and up-regulation of antimicrobials and other mediators that promote a reduction of inflammation. The presence of environmental-derived LPS may play a key role in decreasing autoimmune diseases and gut tolerance to the plethora of ingested antigens. The use of LPS may be an important immune adjuvant as demonstrated by the promotion of IDO1 increase when present in the fusion protein complex of CTB-INS (a chimera of the cholera toxin B subunit linked to proinsulin) that inhibits human monocyte-derived DC (moDC) activation, which may act through an IDO1-dependent pathway. The resultant state of DC tolerance can be further enhanced by the presence of residual E. coli lipopolysaccharide (LPS) which is almost always present in partially purified CTB-INS preparations. The approach to using an adjuvant with an autoantigen in immunotherapy promises effective treatment for devastating tissue-specific autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes (T1D). Full article

Multiple sclerosis (MS) is a multifactorial neurodegenerative disease. Low levels of vitamin D are a risk factor for MS and alterations in the vitamin D receptor (VDR) might be a risk factor as well. This study aimed to evaluate whether the VDR rs731236 (Taq-I) and rs4334089 (HpyCH4V) gene polymorphisms and VDR protein expression are associated with MS risk and severity. Vitamin D plasma levels were analyzed in a group of patients. Additional analyses of VDR protein expression and vitamin D levels of patients with different forms of MS (MSSS < 3 and MSSS ≥ 3) were performed. The analysis of the genotypic and allelic frequencies revealed that the rs731236 (Taq-I) gene polymorphism is significantly associated with MS presence. Although the total, cytosolic and nuclear VDR protein contents do not change between MS patients and healthy controls and between patients with different MS severity, vitamin D levels decrease in parallel with an increase in MSSS. Full article

Inflammation is a key factor in cancer promotion. Tumor-associated macrophages (TAMs), as part of the tumor microenvironment, are often associated with the progression of tumors and a worse prognosis in many cancers, namely on cervical cancer. This work exhaustively summarizes the conclusions of the different studies published concerning TAMs function in cervical cancer, from in vitro studies using cancer cell lines to the clinical perspective (histological samples-based studies). Most studies have led to the conclusion that TAMs increased density is directly related to increased severity of a malignant cervical lesion. Additionally, TAMs are normally polarized into an M2 phenotype, benefiting and promoting tumor progression, resulting in a worse disease outcome. The tumor microenvironment is also a highly critical contributor that not only influences tumor natural history but also modulates the specific immune response. Full article

Calcinosis cutis is the deposition of calcium salts in the skin and subcutaneous tissue, manifesting as variably shaped papules, nodules, and plaques that can substantially impair quality of life. The pathophysiology of calcinosis cutis involves dysregulation of proinflammatory cytokines, leukocytes, and other components of the innate immune system. In some conditions associated with calcinosis cutis, elevated serum calcium, phosphate, and vitamin D may also perturb innate immunity. The mechanisms by which these lead to cutaneous and subcutaneous calcification likely parallel those seen in vascular calcification. The role of aberrant innate immunity is further supported by the association between various autoantibodies with calcinosis cutis, such as anti-MDA5, anti-NXP2, anti-centromere, and anti-topoisomerase I. Treatments for calcinosis cutis remain limited and largely experimental, although mechanistically many therapies appear to focus on dampening innate immune responses. Further research is needed to better understand the innate immune pathophysiology and establish treatment options based on randomized-controlled trials. Full article