Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers.

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

The advantage of specific intravenous immunoglobulin (sIVIG) on regular IVIG: experience of the last decade.

During the last decade it has been shown that some components of intravenous immunoglobulin (IVIG) are responsible for their broadly therapeutic application. Currently, such specific subfractions are defined as specific IVIG (sIVIG) and are affinity-purified from commercial IVIGs that target specific antigens/antibodies related to a specific autoimmune disease. A remarkable example of the therapeutic potential of sIVIG is the proven enhanced anti-inflammatory potency of sialylated and recombinant sialylated IVIG obtained from total IVIG. In other experimental models, it has also been demonstrated that sIVIG work in many other contrivances, such as revealing anti-idiotypic networks blocking pathogenic antibodies ameliorating disease activity. sIVIG has also been shown to exert its action by modulating specific receptors expressed on immune cells in both inflammatory and autoimmune diseases. Indeed, sIVIG has emerged as a novel approach to treat different immune-mediated conditions in a more accurate antigen-specific manner. Herein we review experimental evidence supporting sIVIG-efficacy in treating autoimmune diseases and inflammation.

Mixed connective tissue disease: an overview of clinical manifestations, diagnosis and treatment.

The most common clinical manifestations of mixed connective disease are Raynaud's phenomenon, arthralgias, swollen joints, esophageal dysfunction, muscle weakness and fingers sausage-like appearance together with the presence of anti-ribonucleoprotein (RNP) antibodies. However, organ involvement is more extensive than first descriptions reported. The disease can be serious with development of pulmonary, kidney, cardiovascular, gastrointestinal and central nervous system manifestations. The worst prognosis and high mortality are associated with the presence of pulmonary disease. Although a different set of clinical criteria have been proposed, there is no consensus about the most accurate. There is no full agreement about treatment and the initial impression of a satisfactory response to low doses of steroids is not always the rule. Herein, we review available evidence to a better approach to all previous topics.

Immunology, autoimmunity, and autoantibodies in Parkinson's disease.

Recent revelations of immune alterations in Parkinson's disease have led to the convergence that an autoimmune mechanism may play a role in the etiopathogenesis of this neurodegenerative disease. In the current study, 77 Parkinson's disease patients and 77 matched healthy controls were analyzed for the presence of seven autoantibodies previously found to be associated with central nervous system manifestations namely: antineuronal-cells, anti-brain lysate, anti-dsDNA, anti-phosphatidylserine, anti-cardiolipin, anti-serotonin, and anti-melanocytes antibodies. Patients underwent systematic assessments of demographics, clinical, and biochemical manifestations. Three autoantibodies were found to be more prevalent among Parkinson's disease patients (antineuronal cells10.3% vs. 1.3%, p = 0.017; anti-brain lysate 9.1% vs. 1.3%, p = 0.032; anti-dsDNA 10.3% vs. 2.6%, p = 0.049). Clinical manifestations of Parkinson's disease, particularly dyskinesia and depression, were found to be associated with the presence of these autoantibodies.

Infectious agents in the pathogenesis of primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a chronic progressive cholestatic liver disease which is characterized by the breakdown of self-tolerance to the highly conserved pyruvate dehydrogenase complex, specially the pyruvate dehydrogenase E2 complex (PDC-E2). The breakdown of the tolerance to such antigens leads to an autoimmune process characterized by portal inflammation and immune-mediated destruction of the intrahepatic bile ducts. Epidemiological studies have suggested that infections agents can trigger or even exacerbate the disease. Among other gram negative bacteria, Escherichia Coli, and Nosphingobium aromaticivorans are the most associated agents reported hitherto. Epidemiological and molecular evidence points towards molecular mimicry between some components of these microorganisms and specific amino-acid sequences that are present in proteins on normal cells of the biliary tract. In this review, we revisit all reports suggesting that infectious agents might be associated with the autoimmune pathogenesis of PBC. We also retrieve the immune molecular mimicry mechanisms that are likely involved with the autoimmune process in PBC.

Autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen class II alleles in chronic fatigue syndrome: are they associated with age at onset and specific symptoms?

This study aimed to determine the influence of autoantibodies, polymorphisms in the serotonin pathway, and human leukocyte antigen (HLA) class II genes on age at chronic fatigue syndrome (CFS) onset and symptoms. Eighty-one CFS patients were enrolled, and clinical data were recorded. Autoantibodies to different components of the central nervous system were tested. Polymorphisms in the promoter of the serotonin transporter gene (l/s) and a single nucleotide polymorphism in the serotonin receptor-2A gene (A/G) as well as HLA class II alleles were determined. Multivariate logistic-regression analyses were carried out. The mean age at CFS onset +/- SD was 33.5 +/- 12.5 years. An age at CFS onset (ACFSO) during the third decade of life was associated with the serotonin receptor AA genotype and the HLA-DRB1*03 allele. An ACFSO during the fourth decade of life was associated with the HLA-DRB1*07 allele, whereas an ACFSO > or = 43 years was associated with having at least one copy of the serotonin G allele. Concerning CFS symptoms, the serotonin AG genotype was protective against depressive symptoms. Although having at least one copy of the serotonin A allele and being female were associated with risk for arthralgia, the presence of antineuronal cell antibodies was protective against this. Episodes of unexplained fever were associated with the HLA-DRB1*11 allele. None of the genetic or serological features was associated with myalgia. None of the antibodies determined correlated with any ACFSO or other symptoms. Our results reveal that in CFS, like other autoimmune diseases, different genetic features are related to age at CFS onset and symptoms.

Infection, vaccination, and autoantibodies in chronic fatigue syndrome, cause or coincidence?

Chronic fatigue syndrome (CFS) is a heterogeneous syndrome of unknown etiology and physiopathology. CFS patients complain about disabling fatigue, depression, difficulty with memory, and concomitant skeletal and muscular pain. Interestingly enough, there is certain overlap between CFS symptoms, autoimmune rheumatic disease, and infectious diseases. Certain neuroendocrine-immune abnormalities have also been described, and autoantibodies commonly described in some autoimmune diseases have been found in CFS patients as well. An increasing number of autoantibodies, mainly directed against other nuclear cell components, have been illustrated. Likewise, an association between some infectious agents, antibody production, and later CFS onset has been reported. Similarly, vaccination is depicted as playing an important role in CFS onset. Recently, a case report pointed toward a causal association between silicone breast linkage, hepatitis B virus vaccination, and CFS onset in a previous healthy woman. Such findings suggest that there is a likely deregulation of the immune system influenced by specific agents (infections, vaccination, and products, such as silicone). Evidence suggests that CFS is a complex disease in which several risk factors might interact to cause its full expression. Thus, although different alterations have been found in CFS patients, undoubtedly the main feature is central nervous system involvement with immunological alterations. Therefore, a new term neuro-psycho-immunology must be quoted. New studies based on this concept are needed in order to investigate syndromes, such as CFS, in which immunological alterations are thought to be associated with concomitant psychological and health disturbances.

Cardiovascular disease is associated with extra-articular manifestations in patients with rheumatoid arthritis.

The objective of this study was to examine the clinical and genetic variables associated with extra-articular rheumatoid arthritis (ExRA). This was a cross-sectional study in which 538 Northwestern Colombian patients with rheumatoid arthritis (RA) were included. Information about demographics and clinical characteristics including disease activity, inflammatory markers, co-morbidities, cardiovascular (CV) risk factors, history of familial autoimmunity and therapy was recorded. The presence of HLA "shared epitope" (SE) alleles and TNF gene polymorphism was assessed. A multivariate statistical analysis was performed. ExRA was found in 32% of the patients, of which nodulosis, Sjögren's syndrome, and lung involvement were registered in 21%, 9%, and 4% of patients, respectively. Patients with ExRA were older than patients without it and they presented longer disease duration as well. Thus, an association between disease duration and ExRA manifestations was also observed. Patients with ExRA presented significant higher titers of anti-CCP antibodies as compared to patients without ExRA. Hypertension and thrombosis were significantly associated with ExRA. Never having smoked constituted a protective factor against ExRA onset. Associations between ExRA and the presence of traditional CV risk factors were also found. Our results show that duration of RA, CV disease and high titers of anti-CCP antibodies are associated with ExRA in Colombian patients with RA, and highlight the importance of preventing smoking in those who are prone to develop autoimmune diseases including RA.

Olfaction, psychiatric disorders and autoimmunity: is there a common genetic association?

Psychiatric diseases are often associated with mild alterations in immune functions (e.g., schizophrenia) as well as autoimmune features. Recent evidence suggests that autoimmune diseases (AD) demonstrate a higher prevalence of psychiatric disorders, such as depression and psychosis, than in the normal population. Patients with AD often have an olfactory impairment as well, based on smell studies, accompanied by olfactory regional alterations in neuroimaging. Some evidence suggests that olfactory gene receptors have additional functions in the brain, related to their direct anatomical connection to the limbic system. For example, odor sensing may explain HLA-dissimilar mate selection in humans and animals. Recently, a large cluster of the olfactory receptor (OR) genes was mapped in proximity to the HLA locus on chromosome 6. The HLA and linked OR genes are clustered in haplotypes and are highly polymorphic. This finding may constitute an association among autoimmunity, psychiatric disorders and smell impairment. In this review, we examine the anatomic, genetic and clinical clues that may support an association among these conditions.

The long pentraxin 3 and its role in autoimmunity.

OBJECTIVES: To review the physiological and physiopathological roles of pentraxin 3 (PTX3), focusing on autoimmunity and vascular pathology. METHODS: A systematic literature review using the keywords "pentraxin 3," "innate immunity," "apoptosis," "autoimmunity," and "endothelial dysfunction" from 1990 to 2007 was performed. All relevant articles and pertinent secondary references in English were reviewed. RESULTS: PTX3 has a large number of multiple functions in different contexts. PTX3 plays an important role in innate immunity, inflammation, vascular integrity, fertility, pregnancy, and also in the central nervous system. In innate immunity, its normal function is to increase the immune response to selected pathogens while also exerting control over potential autoimmune reactions. It maintains a tightly homeostatic equilibrium in the local immune microenvironment by avoiding an exaggerated immune response and controlling peripheral tolerance to self-antigens. In contrast, in some autoimmune diseases, PTX3 appears to be involved in the development of autoimmune phenomena. A possible explanation for these apparent paradoxical functions may be related to the highly polymorphic PTX3 gene. CONCLUSION: PTX3 is physiologically a protective molecule. However, in several autoimmune diseases PTX3 appears to facilitate the development of autoimmunity. The PTX3 gene could influence the development of autoimmune reactions and vascular involvement in human pathology.

The physiopathology of the catastrophic antiphospholipid (Asherson's) syndrome: compelling evidence.

Catastrophic antiphospholipid (Asherson's) syndrome (cAPS) was described in the past as a severe variant of the antiphospholipid syndrome (APS). Currently growing evidence suggests it is a unique condition. This statement is based on several clinical and physiopathological features that although not well understood define cAPS by itself. The remarkable features of cAPS are the presence of antiphospholipid antibodies (aPLAs) and microthromboses. Additional physiopathological features are the presence of anemia and thrombocytopenia, which are also often described in similar autoimmune conditions. A strong association with concomitant infection is thought to act as the main trigger of microthromboses in cAPS. Several theories have been proposed to explain these physiopathological features. Some of them suggest the possibility of molecular mimicry between components of infectious microorganisms and natural anticoagulants, which might be involved in the production of cross-reacting aPLAs in cAPS. Some genetic risk factors have also been suggested to be implicated in the onset of cAPS, however they have not been defined yet. Herein, we review the remarkable physiopathological features commonly described in cAPS hitherto. We concluded that although they are not completely understood, it is possible to differentiate them from similar conditions. Nevertheless further studies on these physiopathological mechanisms of the disease are needed.

Predicción de las enfermedades autoinmunes: mito, realidad y riesgo / Predição das doenças autoinmunes: mito, realidade e risco / Prediction of autoimmuneity diseases: mith, reality and risk

Las enfermedades autoinmunes comprenden un conjunto de desórdenes crónicos multisistémicos y complejos de etiología desconocida, asociados a factores genéticos, hormonales y ambientales. La susceptibilidad a padecerlas incluye la presencia de ciertos genes, algunos de ellos del complejo mayor de histocompatibilidad (CMH), combinados con determinados autoanticuerpos. Clínicamente definida, la enfermedad autoinmune es precedida por un largo período de tiempo, en el que ciertos tipos de autoanticuerpos se pueden identificar en el suero. En conjunto, los autoanticuerpos y la identificación de alelos de susceptibilidad se pueden usar como predictores del inicio de la enfermedad e, inclusive, de ciertas manifestaciones clínicas y desenlaces. A continuación revisamos los principales factores de riesgo usados como predictores de enfermedades autoinmunes, al igual que las potenciales implicaciones clínicas y éticas...

Autoimmune diseases are chronic complex multisystem disorders. Their etiology is unknown but genetic, horonal and environmental factors have been associated. The susceptibility to autoimmune diseases includes the presence of major histocompatibility complex (MHC) genes and others non-related, combined with autoantibodies. The clinical autoimmune disease is preceded by the presence of autoantibodies in serum a long period of time before the onset of clinical manifestations. Together, the presence of autoantibodies as well as the identification of susceptible alleles could be used as predictors of disease onset and clinical outcomes in these patients. Herein, we review the major risk factors that can be used as predictors for autoimmune diseases and their potential clinical and ethical implications as well...

As doenças autoinmunes compreendem um conjunto de desordens crônicas multisistémicos e complexos de etiología desconhecida, associado a fatores genéticos, hormonais e ambientais. A susceptibilidade a padecê-las inclui a presença de certos genes, alguns deles do complexo principal de histocompatibilidade (CMH), combinados com determinados auto-anticorpos. Clinicamente definida, a doença autoinmune é precedida por um longo período de tempo no que certos tipos de auto anticuerpos se podem identificar no soro. Em conjunto, os auto-anticorpos e a identificação de alelos de susceptibilidade se podem usar como previsões do início da doença e, inclusive, de certas manifestações clínicas e desenlaces. A seguir revisamos os principais fatores de risco usados como predictores de doenças autoinmunes, ao igual que os potenciais envolvimentos clínicos e éticos...

Risk factors associated with different stages of atherosclerosis in Colombian patients with rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is associated with an increased prevalence of cardiovascular disease (CVD). Since atherosclerosis development is a gradual process of damage inside the artery wall, and the phenotype-genotype correlation of complex diseases may vary depending on ethnicity, we sought to investigate the influence of clinical features, routine inflammatory markers, and the genetic component of RA on different stages of atherosclerosis in northwestern Colombian patients with RA. METHODS: A group of 140 patients with RA were enrolled in this study. All patients underwent a noninvasive evaluation of endothelial function by flow-mediated vasodilation (FMV) and an assessment of carotid intima-media thickness (IMT) by high-resolution B-mode ultrasonography. The patients were classified into 3 categories: endothelial dysfunction (FMV <5%), increased IMT (0.91-1.29 mm), and plaque (IMT >1.30 mm). The risk of being in each category was assessed by investigating traditional and nontraditional cardiovascular risk factors. For each stage of atherosclerosis development, we searched for nontraditional risk factors that were significantly associated with the stage after adjusting for traditional risk factors and current age. RESULTS: Rheumatoid factor seropositivity was significantly associated with endothelial dysfunction (adjusted odds ratio, AOR = 3.0). A duration of RA >10 years (AOR = 29.0) and being a carrier of an HLA-DRB1 shared epitope allele (AOR = 4.8) were associated with atherosclerotic plaque. No association of extra-articular manifestations, anticyclic citrullinated peptide (anti-CCP3) antibodies, and tumor necrosis factor -308 polymorphism with CVD was found. CONCLUSIONS: Our results reveal the presence of RA-related risk factors for CVD which act independently of traditional risk factors. These factors can be used by clinicians to predict CVD in RA patients, and this data should assist in the development of public health policies in our population for the improvement of patient outcomes.