TNF-α and Chronic Fatigue Syndrome

Based upon the clinical presentation of chronic fatigue syndrome (CFS), we hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. We therefore undertook a retrospective cross-sectional study to examine the role of TNF- in patients with CFS. Our results suggest a significant increase serum TNF- in patients with CFS (P < 0.0001) compared to non-CFS controls. This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF- blockers and other antiinflammatory agents for the treatment of this disease is warranted.     

A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ß2-adrenergic receptors

Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiology of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system.We found elevated ß2 adrenergic receptor (ß2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ß2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia.Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ß2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiology of ME/CFS without an autoimmune pathogenesis.     

When is an autoimmune disease not an autoimmune disease?

What are the enviromental triggers and genetic susceptibilities underlying the development of autoimmune diseases? These and other questions were addressed at a recent meeting in Finland¹.     

Chronic Fatigue Syndrome – A clinically empirical approach to its definition and study

Background

The lack of standardized criteria for defining chronic fatigue syndrome (CFS) has constrained research. The objective of this study was to apply the 1994 CFS criteria by standardized reproducible criteria.

Methods

This population-based case control study enrolled 227 adults identified from the population of Wichita with: (1) CFS (n = 58); (2) non-fatigued controls matched to CFS on sex, race, age and body mass index (n = 55); (3) persons with medically unexplained fatigue not CFS, which we term ISF (n = 59); (4) CFS accompanied by melancholic depression (n = 27); and (5) ISF plus melancholic depression (n = 28). Participants were admitted to a hospital for two days and underwent medical history and physical examination, the Diagnostic Interview Schedule, and laboratory testing to identify medical and psychiatric conditions exclusionary for CFS. Illness classification at the time of the clinical study utilized two algorithms: (1) the same criteria as in the surveillance study; (2) a standardized clinically empirical algorithm based on quantitative assessment of the major domains of CFS (impairment, fatigue, and accompanying symptoms).

Results

One hundred and sixty-four participants had no exclusionary conditions at the time of this study. Clinically empirical classification identified 43 subjects as CFS, 57 as ISF, and 64 as not ill. There was minimal association between the empirical classification and classification by the surveillance criteria. Subjects empirically classified as CFS had significantly worse impairment (evaluated by the SF-36), more severe fatigue (documented by the multidimensional fatigue inventory), more frequent and severe accompanying symptoms than those with ISF, who in turn had significantly worse scores than the not ill; this was not true for classification by the surveillance algorithm.

Conclusion

The empirical definition includes all aspects of CFS specified in the 1994 case definition and identifies persons with CFS in a precise manner that can be readily reproduced by both investigators and clinicians.     

Chronic Obstructive Pulmonary Disease： Evidence for an Autoimmune Component

Chronic obstructive pulmonary disease （COPD） is characterized by an irreversible limitation on pulmonary airflow associated with chronic inflammation and mucous hypersecretion （chronic bronchitis） and/or the pathological destruction of alveolar airspaces leading to emphysema. COPD, predominantly as a result of tobacco smoke exposure, represents the fourth leading cause of mortality worldwide and its prevalence is increasing. Despite this, much of the basic mechanisms which contribute to disease progression remain to be elucidated and current therapeutic approaches are, for the most part, based upon alleviating patient symptoms （bronchodilators） as opposed to treating the underlying pathological mechanisms triggered in response to cigarette smoke exposure. The classic disease paradigm suggests that an imbalance of pulmonary matrix proteases versus anti-proteases underlies the tissue destruction and inflammation associated with COPD. However, there is a growing appreciation of the complex and multifaceted nature of the pathological mechanisms associated with disease progression. Recently, there has been mounting evidence indicating that COPD patients exhibit many of the characteristics of a classical autoimmune response. We will discuss current evidence in support of this paradigm and outline how future therapeutic approaches may be tailored to address this.     

Chronic spontaneous urticaria: an autoimmune disease? A revision of the literature

The cause of chronic spontaneous urticaria has been an enigma for decades, but the recognition of functional autoantibodies in some patients with the spontaneous chronic urticaria has opened up a new concept of autoimmune urticaria. Clinical and laboratory features are in keeping with an autoimmune aetiology for many patients with otherwise inexplicable disease, but there is still debate about the importance of functional autoantibodies in the disease pathogenesis, how to test them and the clinical implications for treatment and prognosis. This review will look at the evidence for there being an autoimmune subset of urticaria, the strengths and weaknesses of the available tests in current use.     

Cognitive Behavior Therapy for Chronic Fatigue Syndrome: Where to Go From Here?

[Clin Psychol Sci Prac 18: 325–330, 2011] The meta‐analytic review of Castell, Kazantzis, and Moss‐Morris (2011) is a valuable contribution to the debate about the efficacy of behavioral interventions for chronic fatigue syndrome (CFS). Again it is found that cognitive behavior therapy (CBT) has a positive effect on the outcomes of patients with CFS. However, a substantial number of patients do not profit (enough) from this intervention. Increasing our knowledge about the mechanisms of change and other relevant aspects related to the treatment response could help to improve further the efficacy and applicability of CBT for CFS. This commentary discusses some of these aspects and, where possible, research strategies are proposed.     

Is autism an autoimmune disease?

Autism spectrum disorder (ASD) is a spectrum of behavioral anomalies characterized by impaired social interaction and communication, often accompanied by repetitive and stereotyped behavior. The condition manifests within the first 3 years of life and persists into adulthood. There are numerous hypotheses regarding the etiology and pathology of ASD, including a suggested role for immune dysfunction. However, to date, the evidence for involvement of the immune system in autism has been inconclusive. While immune system abnormalities have been reported in children with autistic disorder, there is little consensus regarding the nature of these differences which include both enhanced autoimmunity and reduced immune function. In this review, we discuss current findings with respect to immune function and the spectrum of autoimmune phenomena described in children with ASD.     

Psychosis: an autoimmune disease?

Psychotic disorders are common and disabling. Overlaps in clinical course in addition to epidemiological and genetic associations raise the possibility that autoimmune mechanisms may underlie some psychoses, potentially offering novel therapeutic approaches. Several immune loci including the major histocompatibility complex and B‐cell markers CD19 and CD20 achieve genome‐wide significance in schizophrenia. Emerging evidence suggests a potential role via neurodevelopment in addition to classical immune pathways. Additionally, lymphocyte biology is increasingly investigated. Some reports note raised peripheral CD19⁺ and reduced CD3⁺ lymphocyte counts, with altered CD4 : CD8 ratios in acute psychosis. Also, post‐mortem studies have found CD3⁺ and CD20⁺ lymphocyte infiltration in brain regions that are of functional relevance to psychosis. More specifically, the recent paradigm of neuronal surface antibody‐mediated (NSAb) central nervous system disease provides an antigen‐specific model linking adaptive autoimmunity to psychopathology. NSAbs bind extracellular epitopes of signalling molecules that are classically implicated in psychosis such as NMDA and GABA receptors. This interaction may cause circuit dysfunction leading to psychosis among other neurological features in patients with autoimmune encephalitis. The detection of these cases is crucial as autoimmune encephalitis is ameliorated by commonly available immunotherapies. Meanwhile, the prevalence and relevance of these antibodies in people with isolated psychotic disorders is an area of emerging scientific and clinical interest. Collaborative efforts to achieve larger sample sizes, comparison of assay platforms, and placebo‐controlled randomized clinical trials are now needed to establish an autoimmune contribution to psychosis.     

Is celiac disease an autoimmune disorder?

Celiac disease, which results from an immune reaction to ingested cereal gluten proteins, has several autoimmune features. In particular, celiac disease patients produce highly disease specific IgA and IgG autoantibodies to tissue transglutaminase when they are on a gluten-containing diet, and they have small intestinal intraepithelial lymphocytes which can mediate direct cytotoxicity of enterocytes expressing MIC molecules in an antigen non-specific manner. Similar to typical autoimmune disorders, celiac disease has a multifactorial aetiology with complex genetics, and several autoimmune diseases are commonly presented by patients with celiac disease. Much has been learned about the immunology of celiac disease in recent years, and there is overwhelming evidence that the immune response to gluten is central to the pathogenesis. In light of this, the many autoimmune phenomena associated with celiac disease are thought-provoking, and they challenge us to rethink the boundaries between autoimmunity and immunopathology.     

Postpartum depression, an autoimmune disease?

Medical conditions with known etiology and typical peripartal/postpartal disease exacerbations are now, without exception, considered autoimmune in etiology. Postpartum psychiatric conditions, and especially postpartum depression, currently, however, are still not understood in their etiology. This paper suggests that the typical postpartum flare pattern, and other clinical characteristics, point towards an autoimmune etiology for (postpartum) depression. The high prevalence of (postpartum) depression led to its designation as a major public health problem. A better understanding of etiology and pathophysiology would greatly advance the, currently still inaccurate, diagnosis of the condition, and improve approaches towards prevention and treatment.     

Immune aging – A mechanism in autoimmune disease

Evidence is emerging that the process of immune aging is a mechanism leading to autoimmunity. Over lifetime, the immune system adapts to profound changes in hematopoiesis and lymphogenesis, and progressively restructures in face of an ever-expanding exposome. Older adults fail to generate adequate immune responses against microbial infections and tumors, but accumulate aged T cells, B cells and myeloid cells. Age-associated B cells are highly efficient in autoantibody production. T-cell aging promotes the accrual of end-differentiated effector T cells with potent cytotoxic and pro-inflammatory abilities and myeloid cell aging supports a low grade, sterile and chronic inflammatory state (inflammaging). In pre-disposed individuals, immune aging can lead to frank autoimmune disease, manifesting with chronic inflammation and irreversible tissue damage. Emerging data support the concept that autoimmunity results from aging-induced failure of fundamental cellular processes in immune effector cells: genomic instability, loss of mitochondrial fitness, failing proteostasis, dwindling lysosomal degradation and inefficient autophagy. Here, we have reviewed the evidence that malfunctional mitochondria, disabled lysosomes and stressed endoplasmic reticula induce pathogenic T cells and macrophages that drive two autoimmune diseases, rheumatoid arthritis (RA) and giant cell arteritis (GCA). Recognizing immune aging as a risk factor for autoimmunity will open new avenues of immunomodulatory therapy, including the repair of malfunctioning mitochondria and lysosomes.     

Is peripartum cardiomyopathy an organ-specific autoimmune disease?

Peripartum cardiomyopathy (PPCM) is a rare and serious heart disease that exclusively afflicts women during childbearing years. Symptoms include rapid onset of cardiovascular insufficiency occurring during pregnancy, initiated anytime between the third trimester until 5 months post-partum in the absence of any other signs or history of heart disease. The rare incidence of PPCM and the absence of any relevant animal models have limited research and understanding of the pathogenic mechanisms involved. Several compelling sets of data support the view that PPCM is a form of autoimmune IDCM. However, PPCM differs from autoimmune IDCM in that (a) it is associated with unique sets of autoantibodies and autoantigens, (b) it has a relatively rapid onset, and (c) it exclusively affects pregnant women. Furthermore, the etiology of PPCM is dependent on the interaction of pregnancy associated factors, e.g. increased hemodynamic stress, vasoactive hormones and fetal microchimerism, that co-operate in the context of essential immune and genetic environments for disease progression. Our model of PPCM attempts to represent how multiple factors, e.g. pregnancy, genetics, immune dysregulation, and fetal microchimerism are held in a complex dynamic balance that can co-operate towards the maintenance of cardiovascular health or disease in the mother (Fig. 1). A more thorough study of the precise nature of the cardiac tissue autoantigens may lead to the identification of the mechanisms of breakdown of self-tolerance and perhaps also the putative etiologic agent(s). Further studies of the precise nature of the cardiac tissue autoantigens and the specific factors governing the balance between tolerance and autoimmunity in the periphery, e.g. expression of PD-L1 on cardiac tissues and the role of regulatory T cells, may help to elucidate the autoimmune mechanisms of PPCM.     

Idiopathic bilateral vestibulopathy: an autoimmune disease?

Bilateral vestibulopathy (BV) is the loss of function of both peripheral labyrinths or of the eighth nerves. Its etiology remains obscure in approximately 20% to 50% of cases (so-called idiopathic bilateral vestibulopathy, IBV). Alternatively, the cause could be viral or vascular; to date, causative gene mutations have not been identified.     

Could diabetic retinopathy be an autoimmune disease?

Diabetic retinopathy is a common and progressive complication of diabetes mellitus. It is characterized by the loss of pericytes, hypertrophy of basement membrane, microaneurysms formation, increased vascular permeability, capillary occlusions, neovascularisation and fibrovascular proliferation. The pathogenesis of diabetic retinopathy is still insufficiently understood, although some reports have implicated the role of the immune system. We hypothesize that, according to some current data diabetic retinopathy could also be considered as an autoimmune disease. The finding of antipericyte and antiendothelial cell autoantibodies in the circulation of diabetic patients strongly suggests that some autoimmune activity has been involved in the early pathophysiology of diabetic retinopathy. There is even more evidence that implicates the presence of autoimmune mechanisms in the proliferative stage of this disease: elevated levels of tumor necrosis factor-alpha, interleukin-8 and soluble interleukin-2 receptor in the serum of diabetic patients, increased vitreous concentration of the interleukin-6 and interleukin-8 in patients with proliferative retinopathy. Furthermore, preretinal membranes in diabetic patients contain deposits of immunoglobulins, activated complement components, monocytes, T and B lymphocytes, fibroblastes and lymphokynes. In diabetic patients human leukocyte antigen DR and DQ expression on the retinal vascular endothelial cells as well as on pigment and nonpigment epithelial cells was found. These antigens are normally restricted to immunocompetent cells and play an important regulatory role in the immune response. Their aberrant expression has been found on nonlymphoid cells in various autoimmune diseases whilst abnormal expression of DR and DQ antigens at sites where they do not normally exist would result in autoimmunity by converting the target cell into a functional antigen-presenting cell. In conclusion, although the pathogenesis of diabetic retinopathy is not completely understood it is known that the immune system is certainly involved in its development. However, there is increasing evidence of the presence of some autoimmune processes in the early stages of diabetic retinopathy and particularly in its proliferative phases. Consequently, diabetic retinopathy could also be considered as an autoimmune disease.     

Meniere's disease might be an autoimmune condition?

OBJECTIVES: To review our current knowledge of the pathogenesis of Meniere's disease, including viral infection and immune system-mediated mechanisms, and to discuss the pathogenesis as it relates to pharmacotherapy. SYSTEMATIC REVIEW METHODOLOGY: Relevant publications on the aetiopathogenesis, molecular biology, genetics and histopathology of Meniere's disease from 1861 to 2011 were analysed. RESULTS AND CONCLUSIONS: Meniere's disease is characterised by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural pressure. The aetiology and pathogenesis remain unknown. Proposed theories of causation include viral infections and immune system-mediated mechanisms. The immune response in Meniere's disease is focused on inner ear antigens. Approximately one-third of Meniere's disease cases seem to be of an autoimmune origin although the immunological mechanisms involved are not clear. The diagnosis of autoimmune inner ear disease is based either on clinical criteria or on a positive response to steroids. The antiviral approach has virtually eliminated the use of various surgical methods used in the past. Steroid responsiveness is high, and with prompt treatment, inner ear damage may be reversible. The administration of etanercept improves or stabilises symptoms in treated patients. Treatment of antiphospholipid syndrome can be directed toward preventing thromboembolic events by using antithrombotic medications. Only warfarin has been shown to be effective. Gene therapy can be used to transfer genetic material into inner ear cells using viral vectors and to protect, rescue, and even regenerate hair cells of the inner ear.     

Sudden sensorineural hearing loss: an autoimmune disease?

Objectives

To review our current knowledge of the pathogenesis of sudden sensorineural hearing loss, including viral infection, vascular occlusion and immune system-mediated mechanisms, and to discuss the pathogenesis as it relates to pharmacotherapy.

Systematic review methodology

Relevant publications on the pathogenesis of sudden sensorineural hearing loss from 1944 to 2010 were analysed.

Results and conclusions

Sudden sensorineural hearing loss is defined as hearing loss of 30 dB in three sequential frequencies over 3 days or less. It can be an isolated symptom or the presenting symptom of a systemic disease. The aetiology and pathogenesis remain unknown. Detailed investigation typically reveals a specific cause in about 10% of patients. Proposed theories of causation include viral infections, vascular occlusion and immune system-mediated mechanisms. A variety of therapies have been proposed based on the various proposed aetiologies.