Category: Immune System

Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)

Background: Myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) is a disabling multi-system complex disorder with prevalence of 875 per 100,000 (up to 3.4 million people) in the United States. There are no known etiologic or risk factors and no approved treatments for ME/CFS. We conducted a molecular epidemiologic study to test the hypothesis that ME/CFS may be an autoimmune disease (AID) and explore the link between ME/CFS and cancer, specifically hematologic malignancies.Methods: Our clinic-based study involved carefully selected cases with confirmed diagnosis of ME/CFS (n=59) and healthy controls (n=54) frequency matched to cases on age, gender and ethnicity. During structured interviews, detailed multi-generation pedigrees, epidemiologic and medical questionnaires, and biospecimen were obtained on all subjects. Statistical analysis of pedigree data involved comparison of cases and controls with respect to the prevalence and cumulative incidence of AID and cancer among their first-degree relatives. For unadjusted analysis, risk ratios, 95% confidence intervals (CI), and p-values were calculated. For age-adjusted analyses, cumulative incidence estimates were compared using the log-rank test.

Results: The prevalence of AID was significantly higher among the first-degree relatives of cases compared to those of controls (OR=5.30; 95%CI: 1.83-15.38; p=0.001). The prevalence of AID among mothers was 14% for cases and 1.9% for controls (p=0.03). 11.2% of the first-degree relatives of cases had an AID compared to 3.1% of the relatives of controls (prevalence ratio=3.71; 95% CI: 1.74-7.88; p=0.0007). The cumulative incidence of AID among the first-degree relatives of ME/CFS cases was 9.4% compared to 2.7% for those of the controls (p=0.0025). First-degree relatives of ME/CFS cases had a significantly higher prevalence of any cancer compared to the relatives of unrelated controls (OR=4.06, 95%CI: 1.84-8.96, p=0.0005). Age-adjusted analysis revealed significantly higher (p=0.03) cumulative incidence of any cancer among the first-degree relatives of cases (20%) compared to the relatives of controls (15.4%). The cumulative incidence of hematologic cancers was also significantly higher among the relatives of cases (p<0.05).

Conclusions: We found statistically significant increased risks of AID and cancer among the first-degree relatives of ME/CFS cases. Our findings implicate immune dysregulation as an underlying mechanism, providing etiologic clues and leads for prevention. Given symptomatic similarities between ‘long COVID’ and ME/CFS, it is predicted that there will be a significant increase in incidence of ME/CFS as the result of COVID-19 pandemic. Our findings may enable defining a subset of COVID-19 patients who could be at risk of developing ME/CFS, and who may benefit from treatments used for certain AIDs.

Source: Roxana Moslehi, Anil Kumar, Amiran Dzutsev. Increased risks of cancer and autoimmune disease among the first-degree relatives of patients with myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 34. https://aacrjournals.org/cancerres/article/82/12_Supplement/34/700144

 

Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions

Abstract:

Background: Post-acute sequelae of COVID-19 (PASC) is a growing healthcare and economic concern affecting as many as 10%-30% of those infected with COVID-19. Though the symptoms have been well-documented, they significantly overlap with other common chronic inflammatory conditions which could confound treatment and therapeutic trials.

Methods: A total of 236 patients including 64 with post-acute sequelae of COVID-19 (PASC), 50 with myalgic encephalomyelitis-chronic fatigue syndrome (ME-CFS), 29 with post-treatment Lyme disease (PTLD), and 42 post-vaccine individuals with PASC-like symptoms (POVIP) were enrolled in the study. We performed a 14-plex cytokine/chemokine panel previously described to generate raw data that was normalized and run in a decision tree model using a Classification and Regression Tree (CART) algorithm. The algorithm was used to classify these conditions in distinct groups despite their similar symptoms.

Results: PASC, ME-CSF, POVIP, and Acute COVID-19 disease categories were able to be classified by our cytokine hub based CART algorithm with an average F1 score of 0.61 and high specificity (94%).

Conclusions: Proper classification of these inflammatory conditions with very similar symptoms is critical for proper diagnosis and treatment.

Source: Bruce K. Patterson, Jose Guevara-Coto, Edgar B. Francisco et al. Cytokine Hub Classification of PASC, ME-CFS and other PASC-like Conditions, 27 April 2022, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-1598634/v1]  https://www.researchsquare.com/article/rs-1598634/v1 (Full text)

Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis

Abstract:

Metabolic pathways related to energy production, amino acids, nucleotides, nitrogen, lipids, and neurotransmitters in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may contribute to the pathophysiology of ME/CFS. 4501 Northwestern University college students were enrolled in a prospective, longitudinal study.

We collected data before illness, during infectious mononucleosis (IM), and at a 6 month follow-up for those who recovered (N = 18) versus those who went on to develop ME/CFS 6 months later (N = 18). Examining pre-illness blood samples, we found significant detectable metabolite differences between participants fated to develop severe ME/CFS following IM versus recovered controls. We identified glutathione metabolism, nucleotide metabolism, and the TCA cycle (among others) as potentially dysregulated pathways.

The pathways that differed between cases and controls are essential for proliferating cells, particularly during a pro-inflammatory immune response. Performing a series of binary logistic regressions using a leave-one-out cross-validation (LOOCV), our models correctly classified the severe ME/CFS group and recovered controls with an accuracy of 97.2%, sensitivity of 94.4%, and specificity of 100.0%. These changes are consistent with the elevations in pro-inflammatory cytokines that we have reported for patients fated to develop severe ME/CFS 6 months after IM.

Source: Jason LA, Conroy KE, Furst J, Vasan K, Katz BZ. Pre-illness data reveals differences in multiple metabolites and metabolic pathways in those who do and do not recover from infectious mononucleosis. Mol Omics. 2022 May 31. doi: 10.1039/d2mo00124a. Epub ahead of print. PMID: 35640165. https://pubmed.ncbi.nlm.nih.gov/35640165/

Chronic Fatigue Exhibits heterogeneous autoimmunity characteristics which reflect etiology

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease.
Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or “healthy but tired” (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999).
In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed.
An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
Source: Danilenko OV, Gavrilova NY, Churilov LP. Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology. Pathophysiology. 2022; 29(2):187-199. https://doi.org/10.3390/pathophysiology29020016 https://www.mdpi.com/1873-149X/29/2/16/htm (Full text)

Breast Implant-Associated Immunological Disorders

Abstract:

Background: Breast implants are commonly placed postbreast cancer reconstruction, cosmetic augmentation, and gender-affirming surgery. Breast implant illness (BII) is a systemic complication associated with breast implants. Patients with BII may experience autoimmune symptoms including fatigue, difficulty concentrating, hair loss, weight change, and depression. BII is poorly understood, and the etiology is unknown. The purpose of this literature review is to characterize BII autoimmune disorders and determine possible causes for its etiology.

Methods: The PubMed, Google Scholar, Embase, Web of Science, and OVID databases were interrogated from 2010 to 2020 using a query strategy including search term combinations of “implants,” “breast implant illness,” “autoimmune,” and “systemic illness.”

Results: BII includes a spectrum of autoimmune symptoms such as fatigue, myalgias/arthralgias, dry eyes/mouth, and rash. A review of epidemiological studies in the past ten years exhibited evidence affirming an association between breast implants and autoimmune diseases. The most commonly recognized were Sjogren’s syndrome, rheumatoid arthritis, systemic sclerosis, chronic fatigue syndrome, and Raynaud’s syndrome. Explantation resulted in alleviation of symptoms in over 50% of patients, strengthening the hypothesis linking breast implants to BII. Studies have shown that silicone is a biologically inert material and unlikely to be the cause of these symptoms. This is supported by the fact that increased risk of autoimmune disease was also reported in patients with other implantable biomaterials such as orthopedic implants. Recent studies shed light on a possible role of bacterial biofilm and subsequent host-pathogen interactions as a confounding factor to this problem.

Conclusion: BII could be dependent on biofilm infection and the microenvironment around the implants. The true pathophysiology behind these complaints must be further investigated so that alternative treatment regimens other than explantation can be developed. Translational significance of these studies is not limited to breast implants but extends to other implants as well.

Source: Suh LJ, Khan I, Kelley-Patteson C, Mohan G, Hassanein AH, Sinha M. Breast Implant-Associated Immunological Disorders. J Immunol Res. 2022 May 4;2022:8536149. doi: 10.1155/2022/8536149. PMID: 35571560; PMCID: PMC9095406. https://pubmed.ncbi.nlm.nih.gov/35571560/

Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Objectives: Studies have demonstrated immune dysfunction in adolescents with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); however, evidence is varied. The current study used network analysis to examine relationships between cytokines among a sample of pediatric participants with ME/CFS.

Methods: 10,119 youth aged 5-17 in the Chicagoland area were screened for ME/CFS; 111 subjects and controls were brought in for a physician examination and completed a blood draw. Youth were classified as controls (Cs, N = 43), ME/CFS (N = 23) or severe (S-ME/CFS, N = 45). Patterns of plasma cytokine networks were analyzed.

Results: All participant groups displayed a primary network of interconnected cytokines. In the ME/CFS group, inflammatory cytokines IL-12p70, IL-17A, and IFN-γ were connected and included in the primary membership, suggesting activation of inflammatory mechanisms. The S-ME/CFS group demonstrated a strong relationship between IL-17A and IL-23, a connection associated with chronic inflammation. The relationships of IL-6 and IL-8 in ME/CFS and S-ME/CFS participants also differed from Cs. Together, these results indicate pro-inflammatory responses in our illness populations.

Discussion: Our data imply biological differences between our three participant groups, with ME/CFS and S-ME/CFS participants demonstrating an inflammatory profile. Examining co-expression of cytokines may aid in the identification of a biomarker for pediatric ME/CFS.

Source: Jason LA, Gaglio CL, Furst J, Islam M, Sorenson M, Conroy KE, Katz BZ. Cytokine network analysis in a community-based pediatric sample of patients with myalgic encephalomyelitis/chronic fatigue syndrome. Chronic Illn. 2022 May 16:17423953221101606. doi: 10.1177/17423953221101606. Epub ahead of print. PMID: 35570777.  https://pubmed.ncbi.nlm.nih.gov/35570777/

EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating multisystem illness of unknown etiology for which there is no cure and no diagnostic tests available. Despite increasing evidence implicating EBV and human herpesvirus-6A (HHV-6A) as potential causative infectious agents in a subset of ME/CFS patients, there are few mechanistic studies to address a causal relationship.

In this study we examined a large ME/CFS cohort (n=351) and 77 controls and demonstrate a significant increase in activin A and IL-21serum levels, which correlated with seropositivity for antibodies to the EBV and HHV-6 protein deoxyuridine-triphosphate nucleotidohydrolase (dUTPase), but not CXCL13. These cytokines are critical for T follicular helper (TFH) cell differentiation, generation of high-affinity antibodies and long-lived plasma cells. Notably, ME/CFS serum was sufficient to drive TFH cell differentiation via an activin A-dependent mechanism.

The lack of simultaneous CXCL13 increase with IL-21 indicates impaired TFH-function in ME/CFS. In vitro studies revealed that virus-dUTPases strongly induced activin A secretion while in vivo, EBV-dUTPase induced the formation of splenic marginal zone B and invariant NKTFH cells. Altogether, our data indicate abnormal germinal center (GC) activity in ME/CFS subjects and highlight a mechanism by which EBV and HHV6-dUTPases may alter GC and extrafollicular Ab responses.

Source: Cox BS, Alharshawi K, Mena-Palomo I, Lafuse WP, Ariza ME. EBV/HHV-6A dUTPases contribute to Myalgic Encephalomyelitis/Chronic-Fatigue-Syndrome pathophysiology by enhancing TFH cell differentiation and extrafollicular activities. JCI Insight. 2022 Apr 28:e158193. doi: 10.1172/jci.insight.158193. Epub ahead of print. PMID: 35482424. https://pubmed.ncbi.nlm.nih.gov/35482424/

No difference in serum levels of B-cell activating receptor and antibodies against cytolethal distending toxin B and flagellin in post-infectious irritable bowel syndrome and chronic fatigue syndrome after Giardia infection

Abstract :

Background and Aim: Functional gastrointestinal disorders (FGIDs) and chronic fatigue syndrome (CFS) frequently occur as comorbid conditions to each other. A shared etiology of these syndromes has been proposed because of their shared symptomatology and triggering by infections.

Antibodies against the bacterial antigens cytolethal distending toxin B (CdtB) and flagellin have been proposed to be biomarkers of irritable bowel syndrome (IBS), especially diarrhea-predominant IBS (IBS-D). It is unknown if they may also be associated with comorbid conditions such as CFS. On the other hand, elevated level of B-cell activating factor (BAFF) has been associated with CFS and inflammatory bowel disease (IBD) and subjective food intolerance.

Methods: We evaluated serum levels of anti-flagellin and anti-CdtB using an in-house enzyme-linked immunosorbent assay (ELISA) and BAFF with a commercially available ELISA kit in a cohort of patients who developed fatigue syndromes and/or FGIDs after Giardia infection, by comparing them with healthy controls without these conditions.

Results: We did not find significant differences in circulating BAFF, anti-CdtB, or anti-flagellin antibody levels in these patient groups compared to healthy controls. Therefore, our results do not support a role for BAFF, anti-CdtB, or anti-flagellin antibodies as universal biomarkers for IBS or CFS.

Conclusion: BAFF, anti-CdtB, or anti-flagellin antibodies cannot be considered as universal biomarkers for IBS or CFS.

Source: Hanevik, K., Saghaug, C., Aaland, M., Morch, K. and Langeland, N. (2022), No difference in serum levels of B-cell activating receptor and antibodies against cytolethal distending toxin B and flagellin in post-infectious irritable bowel syndrome and chronic fatigue syndrome after Giardia infection. JGH Open, 6: 185-188. https://doi.org/10.1002/jgh3.12724 (Full text)

Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis, or chronic fatigue syndrome (ME/CFS) is a serious disease whose cause has yet to be identified. Objective markers of the disease are also not well understood and would serve as important tools in diagnosis and management.

One potential biomarker or transmitter of immune signals in ME/CFS is the extracellular vesicle (EV) compartment. These small, membrane bound particles have been shown to play a key role in intercellular signaling. Our laboratory has focused on methods of detection of EVS in clinical samples. In this study we explored whether the prevalence of EVs in the plasma of participants with mild or severe ME/CFS differed from the plasma of healthy control participants. By staining for multiple cell surface molecules, plasma EVs could be fingerprinted as to their cell of origin.

Our study revealed a significant correlation between severe ME/CSF and levels of EVs bearing the B cell marker CD19 and the platelet marker CD41a, though these changes were not significant after correction for multiple comparisons. These findings point to potential dysregulation of B cell and platelet activation or homeostasis in ME/CFS, which warrants validation in a replication cohort and further exploration of potential mechanisms underlying the association.

Source: Bonilla H, Hampton D, Marques de Menezes EG, Deng X, Montoya JG, Anderson J, Norris PJ. Comparative Analysis of Extracellular Vesicles in Patients with Severe and Mild Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front Immunol. 2022 Mar 4;13:841910. doi: 10.3389/fimmu.2022.841910. PMID: 35309313; PMCID: PMC8931328. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8931328/ (Full text)

Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis

Abstract:

Background: About 10% of individuals who contract infectious mononucleosis (IM) have symptoms 6 months later that meet criteria for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).  Our study for the first time examined whether it is possible to predict who will develop ME/CFS following IM.

Methods: We have reported on a prospectively recruited cohort of 4,501 college students, of which 238 (5.3%) developed IM.  Those who developed IM were followed-up at six months to determine whether they recovered or met criteria for ME/CFS. The present study focuses on 48 students who after six months had a diagnosis of ME/CFS, and a matched control group of 58 students who had no further symptoms after their IM. All of these 106 students  had data at baseline (at least 6 weeks prior to the development of IM), when experiencing IM, and 6 months following IM. Of those who did not recover from IM, there were two groups: 30 were classified as ME/CFS and 18 were classified as severe ME/CFS. We measured the results of 7 questionnaires, physical examination findings, the severity of mononucleosis and cytokine analyses at baseline (pre-illness) and at the time of IM.  We examined predictors (e.g., pre-illness variables as well as variables at onset of IM) of  those who developed ME/CFS and severe ME/CFS following IM.

Results: From analyses using receiver operating characteristic statistics, the students who had had severe gastrointestinal symptoms of stomach pain, bloating, and an irritable bowel at baseline  and who also had abnormally low levels of the immune markers IL-13 and/or IL-5 at baseline, as well as severe gastrointestinal symptoms when then contracted IM,  were found to have a nearly 80% chance of having severe ME/CFS persisting six months following IM.

Conclusions: Our findings are consistent with emerging literature that gastrointestinal distress and autonomic symptoms, along with several immune markers, may be implicated in the development of severe ME/CFS.

Source: Jason, Leonard & Cotler, Joseph & Islam, Mohammed & Furst, Jacob & Katz, Ben. (2022). Predictors for Developing Severe Myalgic Encephalomyelitis/Chronic Fatigue Syndrome following Infectious Mononucleosis. Journal of Rehabilitation Therapy. 4. 1-5. 10.29245/2767-5122/2021/1.1129. https://www.rehabiljournal.com/articles/predictors-for-developing-severe-myalgic-encephalomyelitischronic-fatigue-syndrome-following-infectious-mononucleosis.html  (Full text)