CD4:CD8 ratio – American ME and CFS Society

Bamboo-based medicinal moxibustion for chronic fatigue syndrome: a randomized controlled trial

Abstract:

Objective: To observe the clinical efficacy of bamboo-based medicinal moxibustion for chronic fatigue syndrome (CFS), and to preliminarily explore its action mechanism.

Methods: Sixty-four patients with CFS were randomly divided into a moxibustion group (32 cases, 1 case dropped off, 1 case excluded) and an acupuncture group (32 cases, 2 cases dropped off). The patients in the moxibustion group were treated with bamboo-based medicinal moxibustion, while the patients in the acupuncture group were treated with routine acupuncture. Both groups were treated once a day, 6 days as a course of treatment with 1 day interval, for a total of 2 courses of treatment. Before treatment, 1 and 2 courses into treatment and in the follow-up of 14 days after treatment, the fatigue scale-14 (FS-14) and somatic and psychological health report (SPHERE) scores were observed in the two groups. Before and after treatment, the contents of CD⁺₃, CD⁺₄, CD⁺₈ of peripheral blood T lymphocyte subsets were measured and CD⁺₄/CD⁺₈ ratio was calculated; the clinical efficacy of the two groups was compared.

Results: Compared before treatment, the FS-14 and SPHERE scores in the two groups were decreased 1 and 2 courses into treatment and in the follow-up (P<0.01), and the FS-14 and SPHERE scores in the moxibustion group were lower than those in the acupuncture group (P<0.01, P<0.05). Compared before treatment, the contents of CD⁺₃, CD⁺₄ and CD⁺₄/CD⁺₈ ratio in the moxibustion group were increased after treatment (P<0.01). There was no significant difference of CD⁺₃, CD⁺₄, CD⁺₈ and CD⁺₄/CD⁺₈ ratio between before and after treatment in the acupuncture group (P>0.05). After treatment, the contents of CD⁺₃ and CD⁺₄ in the moxibustion group were higher than those in the acupuncture group (P<0.05). The total effective rate was 93.3% (28/30) in the moxibustion group, which was higher than 73.3% (22/30) in the acupuncture group (P<0.05).

Conclusion: Bamboo-based medicinal moxibustion could improve the physical and mental fatigue symptoms and psychological status in patients with CFS. Its effect may be related to regulating the contents of CD⁺₃, CD⁺₄ of peripheral blood T lymphocyte subsets and CD⁺₄/CD⁺₈ ratio.

Source: Xue KY, Quan F, Tang JX, Xiao CH, Lu CX, Cui J. [Bamboo-based medicinal moxibustion for chronic fatigue syndrome: a randomized controlled trial]. Zhongguo Zhen Jiu. 2023 May 12;43(5):493-8. Chinese. PMID: 37161800. https://pubmed.ncbi.nlm.nih.gov/37161800/

Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study

Abstract:

Background: We aimed to characterise the long-term health outcomes of survivors of severe acute respiratory syndrome (SARS) and determine their recovery status and possible immunological basis.

Methods: We performed a clinical observational study on 14 health workers who survived SARS coronavirus infection between Apr 20, 2003 and Jun 6, 2003 in Haihe Hospital (Tianjin, China). Eighteen years after discharge, SARS survivors were interviewed using questionnaires on symptoms and quality of life, and received physical examination, laboratory tests, pulmonary function tests, arterial blood gas analysis, and chest imaging. Plasma samples were collected for metabolomic, proteomic, and single-cell transcriptomic analyses. The health outcomes were compared 18 and 12 years after discharge. Control individuals were also health workers from the same hospital but did not infect with SARS coronavirus.

Findings: Fatigue was the most common symptom in SARS survivors 18 years after discharge, with osteoporosis and necrosis of the femoral head being the main sequelae. The respiratory function and hip function scores of the SARS survivors were significantly lower than those of the controls. Physical and social functioning at 18 years was improved compared to that after 12 years but still worse than the controls. Emotional and mental health were fully recovered. Lung lesions on CT scans remained consistent at 18 years, especially in the right upper lobe and left lower lobe lesions. Plasma multiomics analysis indicated an abnormal metabolism of amino acids and lipids, promoted host defense immune responses to bacteria and external stimuli, B-cell activation, and enhanced cytotoxicity of CD8⁺ T cells but impaired antigen presentation capacity of CD4⁺ T cells.

Interpretation: Although health outcomes continued to improve, our study suggested that SARS survivors still suffered from physical fatigue, osteoporosis, and necrosis of the femoral head 18 years after discharge, possibly related to plasma metabolic disorders and immunological alterations.

Funding: This study was funded by the Tianjin Haihe Hospital Science and Technology Fund (HHYY-202012) and Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-063B, TJYXZDXK-067C).

Source: Li K, Wu Q, Li H, Sun H, Xing Z, Li L, Chen H. Multiomic characterisation of the long-term sequelae of SARS survivors: a clinical observational study. EClinicalMedicine. 2023 Apr;58:101884. doi: 10.1016/j.eclinm.2023.101884. Epub 2023 Feb 27. PMID: 36873427; PMCID: PMC9969173.

Associations Between Psychological and Immunological Variables in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Systematic Review

Abstract:

Background: Little emphasis has been given to the fact that various psychological processes and behaviors in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) have neural correlates that affect-and are affected by-the immune system. The aim of this paper is to provide a systematic review of the literature on cross-sectional and longitudinal associations between psychological and immunological variables/changes in CFS/ME.

Methods: The systematic literature search was conducted on Dec 10, 2020 using PubMed. Original research studies investigating associations between a predefined set of psychological and immunological variables in CFS/ME were included. Specifically, the review was focused on studies examining the following psychological variables: executive function, emotion regulation, interpersonal function, sleep, mental health, anxiety, depression, and/or other psychiatric symptoms. In terms of immunological variables, studies investigating interleukin (IL)-1, IL-2, IL-4, IL-6, tumor necrosis factor (TNF), CD4⁺, and/or CD8⁺ were included. Besides original research papers, other potentially relevant papers (e.g., literature reviews) were carefully read and reference lists were checked in order to identify any additional relevant studies. Available data was summarized in text and tables.

Results: The literature search identified 897 potentially relevant papers. Ultimately, 14 studies (807 participants in total) were included in the review of which only two were longitudinal in nature. The review indicated that executive function is associated with IL-1 and IL-6, and interpersonal function is associated with IL-6 and TNF-α. Further, the available data suggested that emotion regulation is associated with IL-2 and sleep is associated with IL-1, IL-6, TNF-α, and IL-2. Interestingly, poorer emotion regulation, interpersonal function, and sleep have all been found to be associated with higher cytokine levels. Executive function has shown both positive and negative relationships with cytokines and among these psychological constructs, it is also the only one that has been found to be associated with CD4⁺ and CD8⁺ counts/percentages.

Conclusions: Correlations exist between psychological and immunological variables in CFS/ME. However, there are few consistent findings and there is almost a complete lack of longitudinal studies. This review points to a gap in existing CFS/ME research and hopefully, it will inspire to the generation of innovative, psychoneuroimmunological hypotheses within the CFS/ME research field.

Source: Raanes EFW, Stiles TC. Associations Between Psychological and Immunological Variables in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Systematic Review. Front Psychiatry. 2021 Nov 23;12:716320. doi: 10.3389/fpsyt.2021.716320. PMID: 34887782; PMCID: PMC8650213. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650213/ (Full text)

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions.

We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation.

Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity).

In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

Source: Ece Karhan, Courtney L Gunter, Vida Ravanmehr, Meghan Horne, Lina Kozhaya, Stephanie Renzullo, Lindsey Placek, Joshy George, Peter N Robinson, Suzanne D Vernon, Lucinda Bateman, Derya Unutmaz. Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)
bioRxiv 2019.12.23.887505; doi: https://doi.org/10.1101/2019.12.23.887505 https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1 (Full text available as PDF file)

Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers

Abstract:

BACKGROUND: There is now evidence that specific subgroups of patients with Myalgic Encephalomyelitis / chronic fatigue syndrome (ME/CFS) suffer from a neuro-psychiatric-immune disorder. This study was carried out to delineate the expression of the activation markers CD38 and human leukocyte antigen (HLA) DR on CD4+ and CD8+ peripheral blood lymphocytes in ME/CFS.

METHODS: Proportions and absolute numbers of peripheral lymphocytes expressing CD3+, CD19+, CD4+, CD8+, CD38+ and HLA-DR+ were measured in ME/CFS (n=139), chronic fatigue (CF, n=65) and normal controls (n=40).

RESULTS: The proportions of CD3+, CD8+, CD8+CD38+ and CD8+HLA-DR+ were significantly higher in ME/CFS patients than controls, while CD38+, CD8+CD38+, CD8+HLA-DR+ and CD38+HLA-DR+ were significantly higher in ME/CFS than CF. The percentage of CD19+ cells and the CD4+/CD8+ ratio were significantly lower in ME/CFS and CF than in controls. There were highly significant inverse correlations between the increased expression of CD38+, especially that of CD8+CD38+, and the lowered CD4+/CD8+ ratio and CD19+ expression. There were no significant associations between the flow cytometric results and severity or duration of illness and peripheral blood biomarkers of oxidative and nitrosative stress (O&NS, i.e. IgM responses to O&N modified epitopes), leaky gut (IgM or IgA responses to LPS of gut commensal bacteria), cytokines (interleukin-1, tumor necrosis factor-α), neopterin, lysozyme and autoimmune responses to serotonin.

CONCLUSIONS: The results support that a) increased CD38 and HLA-DR expression on CD8+ T cells are biomarkers of ME/CFS; b) increased CD38 antigen expression may contribute to suppression of the CD4+/CD8+ ratio and CD19+ expression; c) there are different immune subgroups of ME/CFS patients, e.g. increased CD8+ activation marker expression versus inflammation or O&NS processes; and d) viral infections or reactivation may play a role in a some ME/CFS patients.

Source: Maes M, Bosmans E, Kubera M. Increased expression of activation antigens on CD8+ T lymphocytes in Myalgic Encephalomyelitis/chronic fatigue syndrome: inverse associations with lowered CD19+ expression and CD4+/CD8+ ratio, but no associations with (auto)immune, leaky gut, oxidative and nitrosative stress biomarkers. Neuro Endocrinol Lett. 2015;36(5):439-46. https://www.ncbi.nlm.nih.gov/pubmed/26707044

A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes

Abstract:

Participants with CFS were grouped into viral and non-viral onset fatigue categories and assessed for differential immunological marker expression. Peripheral Blood Mononuclear Cells were assessed for differential phenotypic expression of surface adherence glycoproteins on circulating lymphocytes. The flow cytometric analysis employed fluorescent monoclonal antibody labeling.

The viral in comparison to the non-viral group demonstrated significant elevations in several Th1 type subsets including: the percentage and number of CD4+ cells, the percentage and number of CD2+CD26+ cells, the percentage and number of CD2+CD4+CD26+ cells, the percentage and number of CD4+ CD26+ cells, and the percentage of Th2 naïve cells (CD4+ CD45RA+CD62L+).

Of the remaining significant findings, the non viral group demonstrated significant elevations in comparison to the viral group for the following Th1 type subsets: the percentage of CD8+ cells, the percentage of T-cytotoxic suppressor cells (CD3+8+), and the percentage and number of Th1 memory cells (CD8+CD45RA-CD62L-).

The viral group demonstrated a pattern of activation that differed from that of the group with a non-viral etiology, as evidenced by an elevated and out of range percentage and number of CD4+ cells, the percentage of CD2+CD26+, and the percentage of Th2 naïve cells (CD4+CD45RA+CD62L+). Both groups demonstrated reduced and out of range Natural Killer Cell Cytotoxicity and percentage of B-1 cells (CD5+CD19).

In addition, both groups demonstrated an elevated and out of range percentage of CD2+CD8+CD26+, percentage of the Th1 memory subset (CD4+CD45RA-CD62L-), the percentage of Th1 memory and naïve cells (CD8+CD45RA-CD62L-, CD8+CD45RA+CD62L-), the percentage and number of Th2 memory cells (CD4+CD45RA-CD62L+), and the percentage of Th2 memory and naïve cells (CD8+CD45RA-CD62L+, CD8+CD45RA+CD62L+).

These findings imply that the homeostatic mechanism responsible for the regulation of the Th1 (cell mediated) and Th2 (humoral) immune responses is disturbed in CFS. The implications of these findings are discussed.

Source: Porter N, Lerch A, Jason LA, Sorenson M, Fletcher MA, Herrington J. A Comparison of Immune Functionality in Viral versus Non-Viral CFS Subtypes. J Behav Neurosci Res. 2010 Jun 1;8(2):1-8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3951052/ (Full article)

Study of immune alterations in patients with chronic fatigue syndrome with different etiologies

Abstract:

The Chronic Fatigue Syndrome (CFS) is characterized by symptoms lasting for at least six months and accompanied by disabling fatigue. The etiology of CFS is still unclear.

At the National Center for Study of the Infectious Diseases Department of the Chieti University some immune investigations were performed with the purpose of detecting markers of the disease. CD4+, CD8+, NK CD56+ and B CD19+ lymphocytes were studied in 92 male and 47 female patients and in 36 control subjects. CFS patients were divided in three groups with a post-infectious onset (PI-CFS), an non post-infectious onset (NPI-CFS) and a non post-infectious onset with associated infections (NPI-CFS + AI).

Both CD4+ and CD8+ lymphocytes were reduced in the CFS patients. However, the CD4+/CD8+ ratio was increased in the CFS patients without difference between males and females. CD56+ cells of CFS patients were also reduced. In particular, blood CD56+ cells counts were significantly higher in PI-CFS patients than in the NPI-CFS subjects. These data confirm our preliminary results suggesting a key-role of a dysfunction of the immune system as a precipitating and-or perpetuating factor of the syndrome.

Source: Racciatti D, Dalessandro M, Delle Donne L, Falasca K, Zingariello P, Paganelli R, Pizzigallo E, Vecchiet J. Study of immune alterations in patients with chronic fatigue syndrome with different etiologies. Int J Immunopathol Pharmacol. 2004 May-Aug;17(2 Suppl):57-62. http://www.ncbi.nlm.nih.gov/pubmed/15345193

Immunity Impairment as a Result of Neurohormonal Disorders

Abstract:

An important principle of psychoneuroimmunologic interaction is that immunocytes act as if they were mobile sensitive organs for the central nervous system, producing local and systemic neuropeptides and immunological transmitters with appropriate stimulation. They inform the brain of local damage and mobilize the neuroendocrine system for protection. Their list is long and continues to grow. It includes: somatostatin, vasoactive intestinal peptide, thyroid stimulating hormone, human chorionic gonadotropin, follicle stimulating hormone, luteinizing hormone and other neurotransmitters and hormones, having immunomodulating properties.

This may indicate to close interaction between the immune and neuroendocrine systems, which may be involved into the disease process. A bright example of this may be a disease that has not been closely studied in our country, but is widespread throughout the world. This is the chronic fatigue syndrome, at the base of which lie disturbances of the central nervous, endocrine and immune systems. The idea that the chronic fatigue syndrome is a disturbance of the production of cytokines is related to a number of disturbances in the T system of immunity. It was found back in 1987-1988 that there is an increase in the level of HLA DR and IL-2 receptors and an increase in the ratio CD4/CD8 in patients suffering from this syndrome.

Source: Artsimovich NG, Galushina TS, Matvienko MA, Nastoyaschaya NN, Fadeeva TA, Shneidorova MA. Immunity Impairment as a Result of Neurohormonal Disorders. Russ J Immunol. 1999 Dec;4(4):343-345. http://www.ncbi.nlm.nih.gov/pubmed/12687153

Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling

Abstract:

Ten adult patients with persistent active HHV-6 variant A infection and clinical chronic fatigue syndrome (CFS) were studied over a period of 24 months after initial clinical diagnosis. CFS was diagnosed according to IIIP-revised CDC-criteria as defined by the CFS Expert Advisory Group to the German Federal Ministry of Health in 1994. Changes in HHV-6 antibody titer, viral DNA load, peripheral blood T lymphocytes and subpopulations, as well as CD4/CD8 cell ratio and cell death (apoptosis) were monitored. Data were collected for comparison with respective changes in acute HHV-6 infection and as a basis for future computer simulation studies.

The results showed variable but slightly elevated numbers of HHV-6 DNA copies in the blood of patients with CFS, while PBL (peripheral blood lymphocyte) apoptosis rates were clearly increased. CD4/CD8 cell ratios varied from below 1 up to values as seen in autoimmune disorders. Contrary to acute HHV-6 infection, T lymphocytes do not exhibit the usual response to HHV-6, that is elevation of mature and immature populations suggesting a certain degree of unresponsiveness.

The data suggest that persistent low-dose stimulation by HHV-6 may favor imbalanced immune response rather than overt immune deficiency. This hypothesis requires confirmation through additional functional studies.

Source: Krueger GR, Koch B, Hoffmann A, Rojo J, Brandt ME, Wang G, Buja LM. Dynamics of chronic active herpesvirus-6 infection in patients with chronic fatigue syndrome: data acquisition for computer modeling. In Vivo. 2001 Nov-Dec;15(6):461-5. http://www.ncbi.nlm.nih.gov/pubmed/11887330

Chronic fatigue syndrome following a toxic exposure

Abstract:

Chronic fatigue syndrome (CFS) is a clinical entity characterized by severe fatigue lasting more than 6 months and other well-defined symptoms. Even though in most CFS cases the etiology is still unknown, sometimes the mode of presentation of the illness implicates the exposure to chemical and/or food toxins as precipitating factors: ciguatera poisoning, sick building syndrome, Gulf War syndrome, exposure to organochlorine pesticides, etc.

In the National Reference Center for CFS Study at the Department of Infectious Diseases of ‘G. D’Annunzio’ University (Chieti) we examined five patients (three females and two males, mean age: 37.5 years) who developed the clinical features of CFS several months after the exposure to environmental toxic factors: ciguatera poisoning in two cases, and exposure to solvents in the other three cases. These patients were compared and contrasted with two sex- and age-matched subgroups of CFS patients without any history of exposure to toxins: the first subgroup consisted of patients with CFS onset following an EBV infection (post-infectious CFS), and the second of patients with a concurrent diagnosis of major depression.

All subjects were investigated by clinical examination, neurophysiological and immunologic studies, and neuroendocrine tests. Patients exposed to toxic factors had disturbances of hypothalamic function similar to those in controls and, above all, showed more severe dysfunction of the immune system with an abnormal CD4/CD8 ratio, and in three of such cases with decreased levels of NK cells (CD56+). These findings may help in understanding the pathogenetic mechanisms involved in CFS.

Source: Racciatti D, Vecchiet J, Ceccomancini A, Ricci F, Pizzigallo E. Chronic fatigue syndrome following a toxic exposure. Sci Total Environ. 2001 Apr 10;270(1-3):27-31. http://www.ncbi.nlm.nih.gov/pubmed/11327394