Tag: cytokines

A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls

Abstract:

Background: Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM) are debilitating disorders that significantly affect the daily lives of those suffering from them, as well as their loved ones. Both conditions have overlapping clinical features that resemble inflammatory disorders, and overlapping symptoms, such as depression, suggest central nervous system (CNS) involvement. The role of the immune system’s soluble messengers in the pathogenesis of CFS and FM has been under investigation, but so far the results are inconclusive. In addition, there is growing evidence that the kynurenine pathway is involved in the pathology of diseases related to the CNS, yet the role of each metabolite is not clear. The relationship between kynurenine metabolism and CFS and FM has not been extensively explored. Few studies have simultaneously examined the immunological status in both CFS and FM, making this thesis the first to comprehensively evaluate the potential distinct immunological differences between the two disorders.

Objective: The objective of this study was to compare the CFS and FM with healthy controls, regarding the levels of several soluble blood markers related to the immune system. The markers chosen were:

  • The inflammatory marker high-sensitive CRP (hsCRP)
  • The following cytokines and chemokines: Interferon (IFN)-γ, Interleukin (IL)-1β, IL1ra, IL-4, IL-6, IL-8, IL-10, IL-17, Interferon gamma-induced protein (IP)-10, Monocyte Chemoattractant Protein (MCP)-1, Transforming Growth Factor (TGF)-β1, TGF-β2, TGF-β3 and Tumour Necrosis Factor (TNF)-α
  • The metabolites and their ratios of the kynurenine pathway: Tryptophan (Try), kynurenine (Kyn), kynurenic acid (KA), 3-hydroxykykynurenine (HK), anthranilic acid (AA), xanthurenic acid (XA), 3-hydroxyanthranilic acid (HAA), quinolinic acid (QA) and picolinic acid (Pic).

Method: The population consisted of three groups: CFS patients (n = 49), FM patients (n = 58), and healthy controls (n = 54). All participants were females aged 18–60. Patients were recruited from a specialised university hospital clinic and controls were recruited by advertisement among the staff and students at the hospital and university.

Plasma levels of hsCRP were analysed at the hospital. The cytokines and chemokines IFN-γ, IL-1β, IL-1ra, xii IL-4, IL-6, IL-8, IL-10, IL-17, IP-10, MCP-1, TGF-β1, TGF-β2, TGF-β3, and TNF-α were analysed by multiplex. Kynurenine metabolites were analysed by LC-MS/MS.

Linear regression models of log-transformed data for hsCRP and the kynurenine metabolites were conducted for comparison of the three groups CFS, FM and controls. The Kruskal-Wallis test was used to analyse differences of cytokines between the three groups. Main findings were controlled for age, body mass index (BMI), and symptoms of anxiety and depression.

Results: hsCRP levels were significantly higher for both the CFS and FM groups compared to healthy controls when adjusting for age and BMI (p = .006). There was no difference between the two patient groups. Level of hsCRP was affected by BMI (p < .001) but not age.

MCP-1 was significantly increased in both patient groups compared to healthy controls (p < .001). IL-1β, Il-4, IL-6, TNF-α, TGF-β1, TGF-β2, TGF-β3 (all p < .001), IL-10 (p = .003) and IL17 (p = .002) all were significantly lower in the patient groups compared to healthy controls. IFN-γ was significantly lower in the FM group (p < .001). For IL-8, IP-10 and IL1ra there were no significant difference.

QA differed between CFS and FM patients (p = .036) and was related to higher levels of BMI (p = .002). The KA/QA ratio was lower for CFS patients compared to healthy controls (p = .016). The KA/HK ratio was lower for FM patients compared to healthy controls, and this lower ratio was associated with increased symptoms of pain (p = .002). The kynurenine aminotransferase II (KAT II) enzymatic activity given by XA/HK was lower for FM patients compared to healthy controls (p = .013). In addition, BMI was negatively associated with enhanced KAT II enzymatic activity (p = .039).

Symptoms of anxiety and depression were not associated with any of the immune markers studied.

Conclusion: In our material hsCRP and MCP-1 are increased in patients both with CFS and with FM, while several other cytokines are either similar or significantly lower in patients than controls. Our study also indicates associations between kynurenine metabolism and CFS and FM. Kynurenine also is associated with single symptoms such as fatigue and pain. Forthcoming studies indicating interactions and causative effects, or restoration of the inflammatory status, may place cytokines and kynurenine metabolites as a target for treatment as well as prevention of these conditions in the future.

Source: Groven, Nina. A Thesis on Immune Differences in Chronic Fatigue Syndrome, Fibromyalgia and Healthy Controls. PhD Thesis [Norwegian University of Science and Technology] https://ntnuopen.ntnu.no/ntnu-xmlui/handle/11250/3072207 (Full text available as PDF file)

Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

Abstract:

COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID.

At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation.

Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.

Source: Marianna Santopaolo, Michaela Gregorova, Fergus Hamilton, David Arnold, Anna Long, Aurora Lacey, Alice Halliday, Holly Baum, Kristy Hamilton, Rachel Milligan, Elizabeth Oliver, Olivia Pearce, Lea Knezevic, Begonia Morales Aza, Alice Milne, Emily Milodowski, Eben Jones, Rajeka Lazarus, Anu Goenka, Adam Finn, Nicholas Maskell, Andrew D Davidson, Kathleen Gillespie, Linda Wooldridge, Laura Rivino (2023) Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months eLife 12:e85009 https://doi.org/10.7554/eLife.85009 https://elifesciences.org/articles/85009

Increasing serum soluble CD40 ligand (sCD40L) may be a biomarker of ME/CFS and chronic Long COVID progression

Abstract:

To date, no single blood lab test exists to diagnose or track ME/CFS or chronic Long COVID. Based on existing literature, this article brings together evidence that a molecule secreted by the immune system called sCD40L tends to become increasingly elevated in ME/CFS, Long COVID, and Multiple Sclerosis.

These studies, along with what’s known about the role of sCD40L in health and other diseases, suggest sCD40L may be useful to track over time in ME/CFS and Long COVID patients.

Source: Vijay Iyer. Increasing serum soluble CD40 ligand (sCD40L) may be a biomarker of ME/CFS and chronic Long COVID progression. Patient-Generated Hypotheses Journal | Issue 1, May 2023. https://patientresearchcovid19.com/storage/2023/05/Patient-Generated-Hypotheses-Issue-1-May-2023.pdf#page=42 (Full text)

Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics

Abstract:

Background: SARS-CoV-2 is a highly infectious respiratory virus associated with coronavirus disease (COVID-19). Discoveries in the field revealed that inflammatory conditions exert a negative impact on bone metabolism; however, only limited studies reported the consequences of SARS-CoV-2 infection on skeletal homeostasis. Inflammatory immune cells (T helper—Th17 cells and macrophages) and their signature cytokines such as interleukin (IL)-6, IL-17, and tumor necrosis factor-alpha (TNF-α) are the major contributors to the cytokine storm observed in COVID-19 disease. Our group along with others has proven that an enhanced population of both inflammatory innate (Dendritic cells—DCs, macrophages, etc.) and adaptive (Th1, Th17, etc.) immune cells, along with their signature cytokines (IL-17, TNF-α, IFN-γ, IL-6, etc.), are associated with various inflammatory bone loss conditions. Moreover, several pieces of evidence suggest that SARS-CoV-2 infects various organs of the body via angiotensin-converting enzyme 2 (ACE2) receptors including bone cells (osteoblasts—OBs and osteoclasts—OCs). This evidence thus clearly highlights both the direct and indirect impact of SARS-CoV-2 on the physiological bone remodeling process. Moreover, data from the previous SARS-CoV outbreak in 2002–2004 revealed the long-term negative impact (decreased bone mineral density—BMDs) of these infections on bone health.

Methodology: We used the keywords “immunopathogenesis of SARS-CoV-2,” “SARS-CoV-2 and bone cells,” “factors influencing bone health and COVID-19,” “GUT microbiota,” and “COVID-19 and Bone health” to integrate the topics for making this review article by searching the following electronic databases: PubMed, Google Scholar, and Scopus.

Conclusion: Current evidence and reports indicate the direct relation between SARS-CoV-2 infection and bone health and thus warrant future research in this field. It would be imperative to assess the post-COVID-19 fracture risk of SARS-CoV-2-infected individuals by simultaneously monitoring them for bone metabolism/biochemical markers. Importantly, several emerging research suggest that dysbiosis of the gut microbiota—GM (established role in inflammatory bone loss conditions) is further involved in the severity of COVID-19 disease. In the present review, we thus also highlight the importance of dietary interventions including probiotics (modulating dysbiotic GM) as an adjunct therapeutic alternative in the treatment and management of long-term consequences of COVID-19 on bone health.

Source: Sapra L, Saini C, Garg B, Gupta R, Verma B, Mishra PK, Srivastava RK. Long-term implications of COVID-19 on bone health: pathophysiology and therapeutics. Inflamm Res. 2022 Sep;71(9):1025-1040. doi: 10.1007/s00011-022-01616-9. Epub 2022 Jul 28. PMID: 35900380; PMCID: PMC9330992. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9330992/ (Full text)

Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID

Simple Summary:

In this study, we looked at how persistent inflammation affects peripheral body temperature and sympathovagal balance in individuals with long COVID. Increased temperature and reduced heart rate variability were directly related to the increase in inflammatory cytokines and reduction in anti-inflammatory cytokines. We identified a possible “molecular signature” for long COVID, characterised by a Th17 inflammatory profile with a reduced anti-inflammatory response, resulting in alterations in homeostatic functions and sympathovagal balance.

Abstract:

A persistent state of inflammation has been reported during the COVID-19 pandemic. This study aimed to assess short-term heart rate variability (HRV), peripheral body temperature, and serum cytokine levels in patients with long COVID. We evaluated 202 patients with long COVID symptoms categorized them according to the duration of their COVID symptoms (≤120 days, n = 81; >120 days, n = 121), in addition to 95 healthy individuals selected as controls.
All HRV variables differed significantly between the control group and patients with long COVID in the ≤120 days group (p < 0.05), and participants in the long COVID ≤120 days group had higher temperatures than those in the long COVID >120 days group in all regions analysed (p < 0.05).
Cytokine analysis showed higher levels of interleukin 17 (IL-17) and interleukin 2 (IL-2), and lower levels of interleukin 4 (IL-4) (p < 0.05). Our results suggest a reduction in parasympathetic activation during long COVID and an increase in body temperature due to possible endothelial damage caused by the maintenance of elevated levels of inflammatory mediators.
Furthermore, high serum levels of IL-17 and IL-2 and low levels of IL-4 appear to constitute a long-term profile of COVID-19 cytokines, and these markers are potential targets for long COVID-treatment and prevention strategies.
Source: Neves PFMd, Quaresma JAS, Queiroz MAF, Silva CC, Maia EV, Oliveira JSdS, Neves CMAd, Mendonça SdS, Falcão ASC, Melo GS, Santos IBF, Sousa JRd, Santos EJMd, Vasconcelos PFdC, Vallinoto ACR, Falcão LFM. Imbalance of Peripheral Temperature, Sympathovagal, and Cytokine Profile in Long COVID. Biology. 2023; 12(5):749. https://doi.org/10.3390/biology12050749 https://www.mdpi.com/2079-7737/12/5/749 (Full text)

Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis

Abstract:

Background: Coronavirus disease 2019 (COVID-19) can involve persistence, sequelae, and other clinical complications that last weeks to months to evolve into long COVID-19. Exploratory studies have suggested that interleukin-6 (IL-6) is related to COVID-19; however, the correlation between IL-6 and long COVID-19 is unknown. We designed a systematic review and meta-analysis to assess the relationship between IL-6 levels and long COVID-19.

Methods: Databases were systematically searched for articles with data on long COVID-19 and IL-6 levels published before September 2022. A total of 22 published studies were eligible for inclusion following the PRISMA guidelines. Analysis of data was undertaken by using Cochran’s Q test and the Higgins I-squared (I2) statistic for heterogeneity. Random-effect meta-analyses were conducted to pool the IL-6 levels of long COVID-19 patients and to compare the differences in IL-6 levels among the long COVID-19, healthy, non-postacute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (non-PASC), and acute COVID-19 populations. The funnel plot and Egger’s test were used to assess potential publication bias. Sensitivity analysis was used to test the stability of the results.

Results: An increase in IL-6 levels was observed after SARS-CoV-2 infection. The pooled estimate of IL-6 revealed a mean value of 20.92 pg/ml (95% CI = 9.30-32.54 pg/ml, I2 = 100%, P < 0.01) for long COVID-19 patients. The forest plot showed high levels of IL-6 for long COVID-19 compared with healthy controls (mean difference = 9.75 pg/ml, 95% CI = 5.75-13.75 pg/ml, I2 = 100%, P < 0.00001) and PASC category (mean difference = 3.32 pg/ml, 95% CI = 0.22-6.42 pg/ml, I2 = 88%, P = 0.04). The symmetry of the funnel plots was not obvious, and Egger’s test showed that there was no significant small study effect in all groups.

Conclusions: This study showed that increased IL-6 correlates with long COVID-19. Such an informative revelation suggests IL-6 as a basic determinant to predict long COVID-19 or at least inform on the “early stage” of long COVID-19.

Source: Yin JX, Agbana YL, Sun ZS, Fei SW, Zhao HQ, Zhou XN, Chen JH, Kassegne K. Increased interleukin-6 is associated with long COVID-19: a systematic review and meta-analysis. Infect Dis Poverty. 2023 Apr 24;12(1):43. doi: 10.1186/s40249-023-01086-z. PMID: 37095536; PMCID: PMC10123579. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10123579/ (Full text)

Unique immune and inflammatory cytokine profiles may define long COVID syndrome

Abstract:

Purpose: Long COVID is estimated to occur in 5-10% of individuals after acute SARS-CoV-2 infection. However, the pathophysiology driving the disease process is poorly understood.

Methods: We evaluated urine and plasma inflammatory and immune cytokine profiles in 33 individuals with long COVID compared to 33 who were asymptomatic and recovered, and 34 without prior infection.

Results: Mean urinary leukotriene E4 was significantly elevated among individuals with long COVID compared to asymptomatic and recovered individuals (mean difference 774.2 pg/mL; SD 335.7) and individuals without prior SARS-CoV-2 infection (mean difference 503.1 pg/ml; SD 467.7). Plasma chemokine ligand 6 levels were elevated among individuals with long COVID compared to individuals with no prior SARS-CoV-2 infection (mean difference 0.59 units; SD 0.42). We found no significant difference in angiotensin-converting enzyme 2 antibody levels. Plasma tumor necrosis factor receptor-associated factor 2 (TRAF2) levels were reduced among individuals with long COVID compared to individuals who were asymptomatic and recovered (mean difference = 0.6 units, SD 0.46). Similarly, the mean level of Sarcoma Homology 2-B adapter protein 3 was 3.3 units (SD 1.24) among individuals with long COVID, lower than 4.2 units (SD 1.1) among individuals with recovered, asymptomatic COVID.

Conclusion: Our findings suggest that further studies should be conducted to evaluate the role of leukotriene E4 as a potential biomarker for a diagnostic test. Furthermore, based on reductions in TRAF2, long COVID may be driven in part by impaired TRAF2-dependent immune-mediated inflammation and potentially immune exhaustion.

Source: Allan-Blitz LT, Akbari O, Kojima N, Saavedra E, Chellamuthu P, Denny N, MacMullan MA, Hess V, Shacreaw M, Brobeck M, Turner F, Slepnev VI, Ibrayeva A, Klausner JD. Unique immune and inflammatory cytokine profiles may define long COVID syndrome. Clin Exp Med. 2023 Apr 16:1–6. doi: 10.1007/s10238-023-01065-6. Epub ahead of print. PMID: 37061998; PMCID: PMC10105906. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10105906/ (Full text)

Cytokine deficiencies in patients with Long-COVID

Abstract:

Up to half of individuals who contract SARS-CoV-2 develop symptoms of long-COVID approximately three months after initial infection. These symptoms are highly variable, and the mechanisms inducing them are yet to be understood. We compared plasma cytokine levels from individuals with long-COVID to healthy individuals and found that those with long-COVID had 100% reductions in circulating levels of Interferon Gamma (IFNγ) and Interleukin-8 (IL-8). Additionally, we found significant reductions in levels of IL-6, IL-2, IL-17, IL-13, and IL-4 in individuals with long-COVID.

We propose immune exhaustion as the driver of long-COVID, with the complete absence of IFNγ and IL-8 preventing the lungs and other organs from healing after acute infection, and reducing the ability to fight off subsequent infections, both contributing to the myriad of symptoms suffered by those with long-COVID.

Source: Williams ES, Martins TB, Shah KS, Hill HR, Coiras M, Spivak AM, Planelles V. Cytokine Deficiencies in Patients with Long-COVID. J Clin Cell Immunol. 2022;13(6):672. Epub 2022 Nov 18. PMID: 36742994; PMCID: PMC9894377. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9894377/ (Full text)

A review of cytokine-based pathophysiology of Long COVID symptoms

Abstract:

The Long COVID/Post Acute Sequelae of COVID-19 (PASC) group includes patients with initial mild-to-moderate symptoms during the acute phase of the illness, in whom recovery is prolonged, or new symptoms are developed over months. Here, we propose a description of the pathophysiology of the Long COVID presentation based on inflammatory cytokine cascades and the p38 MAP kinase signaling pathways that regulate cytokine production.

In this model, the SARS-CoV-2 viral infection is hypothesized to trigger a dysregulated peripheral immune system activation with subsequent cytokine release. Chronic low-grade inflammation leads to dysregulated brain microglia with an exaggerated release of central cytokines, producing neuroinflammation. Immunothrombosis linked to chronic inflammation with microclot formation leads to decreased tissue perfusion and ischemia. Intermittent fatigue, Post Exertional Malaise (PEM), CNS symptoms with “brain fog,” arthralgias, paresthesias, dysautonomia, and GI and ophthalmic problems can consequently arise as result of the elevated peripheral and central cytokines.

There are abundant similarities between symptoms in Long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). DNA polymorphisms and viral-induced epigenetic changes to cytokine gene expression may lead to chronic inflammation in Long COVID patients, predisposing some to develop autoimmunity, which may be the gateway to ME/CFS.

Source: Low RN, Low RJ, Akrami A. A review of cytokine-based pathophysiology of Long COVID symptoms. Front Med (Lausanne). 2023 Mar 31;10:1011936. doi: 10.3389/fmed.2023.1011936. PMID: 37064029; PMCID: PMC10103649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10103649/ (Full text)

High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients

Abstract:

Background: Cytokines induced by SARS-CoV-2 infection play a crucial role in the pathophysiology of COVID-19 and hyperinflammatory responses have been associated with poor clinical outcomes, with progression to severe conditions or long-term subacute complications named as long-COVID-19.

Methods: In this cross-sectional study, we aimed to evaluate a set of antigen-specific inflammatory cytokines in blood from recovered COVID-19 individuals or who suffered a post-acute phase of SARS-CoV-2 infection compared to healthy individuals with no history of COVID-19 exposition or infection. Interferon-gamma (IFN-γ), IFN-γ-induced protein 10 (IP-10), tumor necrosis factor (TNF), IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, and IL-17A were quantified by multiplex cytometric bead assay and enzyme-linked immunosorbent assay after stimulation of whole blood with recombinant Spike protein from SARS-CoV-2. Additionally, all participants have evaluated for anti-(S) protein-specific IgG antibodies. Clinical specimens were collected within two months of COVID-19 diagnosis.

Results: A total of 47 individuals were enrolled in the study, a median age of 43 years (IQR = 14.5), grouped into healthy individuals with no history of infection or exposure to SARS-CoV-2 (unexposed group; N = 21); and patients from the Health Complex of the Rio de Janeiro State University (UERJ), Brazil, who were SARS-CoV-2 positive by RT-PCR (COVID-19 group)–categorized as recovered COVID-19 (N = 11) or long-COVID-19 (N = 15). All COVID-19 patients presented at least one signal or symptom during the first two weeks of infection. Six patients were hospitalized and required invasive mechanical ventilation.

Our results showed that COVID-19 patients had significantly higher levels of IFN-γ, TNF, IL-1β, IL-2, IL-6, IL-8, and IP-10 than the unexposed group. The long-COVID-19 group has presented significantly high levels of IL-1β and IL-6 compared to unexposed individuals, but not from recovered COVID-19. A principal-component analysis demonstrated 84.3% of the total variance of inflammatory-SARS-CoV-2 response in the first two components, and it was possible to stratify IL-6, TNF, IL-1β, IL-10, and IL-2 as the top-five cytokines which are candidates to discriminate COVID-19 group (including long-COVID-19 subgroup) and healthy unexposed individuals.

Conclusion: We revealed important S protein-specific differential biomarkers in individuals affected by COVID-19, bringing new insights into the inflammatory status or SARS-CoV-2 exposition determination.

Source: Gomes SMR, Brito ACdS, Manfro WFP, Ribeiro-Alves M, Ribeiro RSdA, da Cal MS, et al. (2023) High levels of pro-inflammatory SARS-CoV-2-specific biomarkers revealed by in vitro whole blood cytokine release assay (CRA) in recovered and long-COVID-19 patients. PLoS ONE 18(4): e0283983. https://doi.org/10.1371/journal.pone.0283983 (Full text)