The Influence of SARS-CoV-2 Infection on the Development of Selected Neurological Diseases.

In 2024, over 775 million cases of COVID-19 were recorded, including approximately 7 million deaths, indicating its widespread and dangerous nature. The disease is caused by the SARS-CoV-2 virus, which can manifest a wide spectrum of symptoms, from mild infection to respiratory failure and even death. Neurological symptoms, such as headaches, confusion, and impaired consciousness, have also been reported in some COVID-19 patients. These observations suggest the potential of SARS-CoV-2 to invade the central nervous system and induce neuroinflammation during infection. This review specifically explores the relationship between SARS-CoV-2 infection and selected neurological diseases such as multiple sclerosis (MS), ischemic stroke (IS), and Alzheimer's disease (AD). It has been observed that the SARS-CoV-2 virus increases the production of cytokines whose action can cause the destruction of the myelin sheaths of nerve cells. Subsequently, the body may synthesize autoantibodies that attack nerve cells, resulting in damage to the brain's anatomical elements, potentially contributing to the onset of multiple sclerosis. Additionally, SARS-CoV-2 exacerbates inflammation, worsening the clinical condition in individuals already suffering from MS. Moreover, the secretion of pro-inflammatory cytokines may lead to an escalation in blood clot formation, which can result in thrombosis, obstructing blood flow to the brain and precipitating an ischemic stroke. AD is characterized by intense inflammation and heightened oxidative stress, both of which are exacerbated during SARS-CoV-2 infection. It has been observed that the SARS-CoV-2 demonstrates enhanced cell entry in the presence of both the ACE2 receptor, which is already elevated in AD and the ApoE ε4 allele. Consequently, the condition worsens and progresses more rapidly, increasing the mortality rate among AD patients. The above information underscores the numerous connections between SARS-CoV-2 infection and neurological diseases.

Novel model of multiple sclerosis induced by EBV-like virus generates a unique B cell population.

Epstein-Barr virus (EBV) is deemed a necessary, yet insufficient factor in the development of multiple sclerosis (MS). In this study, myelin basic protein-specific transgenic T cell receptor mice were infected with murid gammaherpesvirus 68 virus (MHV68), an EBV-like virus that infects mice, resulting in the onset neurological deficits at a significantly higher frequency than influenza or mock-infected mice. MHV68 infected mice exhibited signs including optic neuritis and ataxia which are frequently observed in MS patients but not in experimental autoimmune encephalomyelitis mice. MHV68-infected mice exhibited increased focal immune cell infiltration in the central nervous system. Single cell RNA sequencing identified the emergence of a population of B cells that express genes associated with antigen presentation and costimulation, indicating that gammaherpesvirus infection drives a distinct, pro-inflammatory transcriptional program in B cells that may promote autoreactive T cell responses in MS.

Asymptomatic herpes simplex virus brain infection elicits cellular senescence phenotypes in the central nervous system of mice suffering multiple sclerosis-like disease.

Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease affecting the central nervous system (CNS) in animals that parallels several clinical and molecular traits of multiple sclerosis in humans. Herpes simplex virus type 1 (HSV-1) infection mainly causes cold sores and eye diseases, yet eventually, it can also reach the CNS, leading to acute encephalitis. Notably, a significant proportion of healthy individuals are likely to have asymptomatic HSV-1 brain infection with chronic brain inflammation due to persistent latent infection in neurons. Because cellular senescence is suggested as a potential factor contributing to the development of various neurodegenerative disorders, including multiple sclerosis, and viral infections may induce a premature senescence state in the CNS, potentially increasing susceptibility to such disorders, here we examine the presence of senescence-related markers in the brains and spinal cords of mice with asymptomatic HSV-1 brain infection, EAE, and both conditions. Across all scenarios, we find a significant increases of senescence biomarkers in the CNS with some differences depending on the analyzed group. Notably, some senescence biomarkers are exclusively observed in mice with the combined conditions. These results indicate that asymptomatic HSV-1 brain infection and EAE associate with a significant expression of senescence biomarkers in the CNS.

Heightened Epstein-Barr virus immunity and potential cross-reactivities in multiple sclerosis.

BACKGROUND: Epstein-Barr virus (EBV) is a likely prerequisite for multiple sclerosis (MS) but the underlying mechanisms are unknown. We investigated antibody and T cell responses to EBV in persons with MS (pwMS), healthy EBV-seropositive controls (HC) and post-infectious mononucleosis (POST-IM) individuals up to 6 months after disease resolution. The ability of EBV-specific T cell responses to target antigens from the central nervous system (CNS) was also investigated. METHODS: Untreated persons with relapsing-remitting MS, POST-IM individuals and HC were, as far as possible, matched for gender, age and HLA-DRB1*15:01. EBV load was determined by qPCR, and IgG responses to key EBV antigens were determined by ELISA, immunofluorescence and Western blot, and tetanus toxoid antibody responses by multiplex bead array. EBV-specific T cell responses were determined ex vivo by intracellular cytokine staining (ICS) and cross-reactivity of in vitro-expanded responses probed against 9 novel Modified Vaccinia Ankara (MVA) viruses expressing candidate CNS autoantigens. RESULTS: EBV load in peripheral blood mononuclear cells (PBMC) was unchanged in pwMS compared to HC. Serologically, while tetanus toxoid responses were unchanged between groups, IgG responses to EBNA1 and virus capsid antigen (VCA) were significantly elevated (EBNA1 p = 0.0079, VCA p = 0.0298) but, importantly, IgG responses to EBNA2 and the EBNA3 family antigens were also more frequently detected in pwMS (EBNA2 p = 0.042 and EBNA3 p = 0.005). In ex vivo assays, T cell responses to autologous EBV-transformed B cells and to EBNA1 were largely unchanged numerically, but significantly increased IL-2 production was observed in response to certain stimuli in pwMS. EBV-specific polyclonal T cell lines from both MS and HC showed high levels of autoantigen recognition by ICS, and several neuronal proteins emerged as common targets including MOG, MBP, PLP and MOBP. DISCUSSION: Elevated serum EBV-specific antibody responses in the MS group were found to extend beyond EBNA1, suggesting a larger dysregulation of EBV-specific antibody responses than previously recognised. Differences in T cell responses to EBV were more difficult to discern, however stimulating EBV-expanded polyclonal T cell lines with 9 candidate CNS autoantigens revealed a high level of autoreactivity and indicate a far-reaching ability of the virus-induced T cell compartment to damage the CNS.

Endogenous retroviruses in multiple sclerosis: A network-based etiopathogenic model.

The present perspective article proposes an etiopathological model for multiple sclerosis pathogenesis and progression associated with the activation of human endogenous retroviruses. We reviewed preclinical, clinical, epidemiological, and evolutionary evidence indicating how the complex, multi-level interplay of genetic traits and environmental factors contributes to multiple sclerosis. We propose that endogenous retroviruses transactivation acts as a critical node in disease development. We also discuss the rationale for combined anti-retroviral therapy in multiple sclerosis as a disease-modifying therapeutic strategy. Finally, we propose that the immuno-pathogenic process triggered by endogenous retrovirus activation can be extended to aging and aging-related neurodegeneration. In this regard, endogenous retroviruses can be envisioned to act as epigenetic noise, favoring the proliferation of disorganized cellular subpopulations and accelerating system-specific "aging". Since inflammation and aging are two sides of the same coin (plastic dis-adaptation to external stimuli with system-specific degree of freedom), the two conditions may be epiphenomenal products of increased epigenomic entropy. Inflammation accelerates organ-specific aging, disrupting communication throughout critical systems of the body and producing symptoms. Overlapping neurological symptoms and syndromes may emerge from the activity of shared molecular networks that respond to endogenous retroviruses' reactivation.

Interactions between High Seroreactivity to Human Herpes Virus 6A and Epstein-Barr Virus in MS Development: A Presymptomatic Case-Control Study.

Synergistic interactions between human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) are hypothesized in the etiopathogenesis of multiple sclerosis (MS). This study investigated if HHV-6A and EBV seroreactivities interact regarding the risk of developing MS. Antibodies against viral antigens were analyzed in biobank samples from 670 individuals who later developed MS and matched controls. Additive interactions were analyzed. A significant interaction between HHV-6A and EBNA-1 seroreactivities was observed in study participants above the median age of 24.9 years (attributable proportion due to interaction = 0.45). This finding supports the hypothesis that HHV-6A and EBV infections interact in MS development. ANN NEUROL 2024;96:302-305.

Multiple sclerosis patient-derived spontaneous B cells have distinct EBV and host gene expression profiles in active disease.

Epstein-Barr virus (EBV) is an aetiologic risk factor for the development of multiple sclerosis (MS). However, the role of EBV-infected B cells in the immunopathology of MS is not well understood. Here we characterized spontaneous lymphoblastoid cell lines (SLCLs) isolated from MS patients and healthy controls (HC) ex vivo to study EBV and host gene expression in the context of an individual's endogenous EBV. SLCLs derived from MS patient B cells during active disease had higher EBV lytic gene expression than SLCLs from MS patients with stable disease or HCs. Host gene expression analysis revealed activation of pathways associated with hypercytokinemia and interferon signalling in MS SLCLs and upregulation of forkhead box protein 1 (FOXP1), which contributes to EBV lytic gene expression. We demonstrate that antiviral approaches targeting EBV replication decreased cytokine production and autologous CD4+ T cell responses in this ex vivo model. These data suggest that dysregulation of intrinsic B cell control of EBV gene expression drives a pro-inflammatory, pathogenic B cell phenotype that can be attenuated by suppressing EBV lytic gene expression.

Lactate Dehydrogenase-Elevating Virus Infection Inhibits MOG Peptide Presentation by CD11b+CD11c+ Dendritic Cells in a Mouse Model of Multiple Sclerosis.

Infections may affect the course of autoimmune inflammatory diseases of the central nervous system (CNS), such as multiple sclerosis (MS). Infections with lactate dehydrogenase-elevating virus (LDV) protected mice from developing experimental autoimmune encephalomyelitis (EAE), a mouse counterpart of MS. Uninfected C57BL/6 mice immunized with the myelin oligodendrocyte glycoprotein peptide (MOG35-55) experienced paralysis and lost weight at a greater rate than mice who had previously been infected with LDV. LDV infection decreased the presentation of the MOG peptide by CD11b+CD11c+ dendritic cells (DC) to pathogenic T lymphocytes. When comparing non-infected mice to infected mice, the histopathological examination of the CNS showed more areas of demyelination and CD45+ and CD3+, but not Iba1+ cell infiltration. These results suggest that the protective effect of LDV infection against EAE development is mediated by a suppression of myelin antigen presentation by a specific DC subset to autoreactive T lymphocytes. Such a mechanism might contribute to the general suppressive effect of infections on autoimmune diseases known as the hygiene hypothesis.

Absence of JC polyomavirus in stool samples of patients with multiple sclerosis despite high anti-JCV antibodies in serum.

BACKGROUND: Natalizumab is an effective treatment for relapsing multiple sclerosis (MS). During therapy, individuals are at increased risk of developing progressive multifocal leukoencephalopathy (PML). So far, the relevant reservoir for PML-type JC polyomavirus (JCV) remains elusive. We here tested if the detection of JCV-DNA in stool of persons with MS treated with natalizumab could be a future tool for PML risk assessment. METHODS: The presence of JCV-DNA in stool, urine, and whole blood of MS patients treated with natalizumab and known serum anti-JCV antibodies index values (IV) was studied. Different DNA extraction methods, real-time (RT) and droplet digital (dd) PCR techniques were compared. JCV isolates were screened for PML-associated variants by sequencing. RESULTS: Thirty MS patients treated with natalizumab were screened. For 21 patients, blood, stool, and urine samples were available. These patients were stratified according to their serum anti-JCV antibody IV (high (>1.5, n = 12); medium (1.5-0.9, n = 2); low (<0.9, n = 1); negative (n = 6)). JCV-DNA could not be detected in the whole blood or stool samples. Four urine samples had measurable JCV-DNA, ranging from 1.71×104-1.07×108 international units (IU)/mL detected by RT-PCR, corresponding to 4.62×104-9.85×106 copies/mL measured by ddPCR. All JCV variants were wild-type and derived from patients with high antibody IV. CONCLUSION: Stool-specific DNA extraction methods provided the highest quality of DNA, while the sensitivity of ddPCR and RT- PCR was comparable. Our findings do not support assessing stool samples for PML risk stratification in persons with MS. Further studies are needed to explore where PML-associated viral variants arise.

Ocrelizumab B cell depletion has no effect on HERV RNA expression in PBMC in MS patients.

BACKGROUND: Epstein barr virus (EBV) infection of B cells is now understood to be one of the triggering events for the development of Multiple Sclerosis (MS), a progressive immune-mediated disease of the central nervous system. EBV infection is also linked to expression of human endogenous retroviruses (HERVs) of the HERV-W group, a further risk factor for the development of MS. Ocrelizumab is a high-potency disease-modifying treatment (DMT) for MS, which depletes B cells by targeting CD20. OBJECTIVES: We studied the effects of ocrelizumab on gene expression in peripheral blood mononuclear cells (PBMC) from paired samples from 20 patients taken prior to and 6 months after beginning ocrelizumab therapy. We hypothesised that EBV and HERV-W loads would be lower in post-treatment samples. METHODS: Samples were collected in Paxgene tubes, subject to RNA extraction and Illumina paired end short read mRNA sequencing with mapping of sequence reads to the human genome using Salmon and differential gene expression compared with DeSeq2. Mapping was also performed separately to the HERV-D database of HERV sequences and the EBV reference sequence. RESULTS: Patient samples were more strongly clustered by individual rather than disease type (relapsing/remitting or primary progressive), treatment (pre and post), age, or sex. Fourteen genes, all clearly linked to B cell function were significantly down regulated in the post treatment samples. Interestingly only one pre-treatment sample had detectable EBV RNA and there were no significant differences in HERV expression (of any group) between pre- and post-treatment samples. CONCLUSIONS: While EBV and HERV expression are clearly linked to triggering MS pathogenesis, it does not appear that high level expression of these viruses is a part of the ongoing disease process or that changes in virus load are associated with ocrelizumab treatment.

Altered EBV specific immune control in multiple sclerosis.

Since the 1980s it is known that immune responses to the Epstein-Barr virus (EBV) are elevated in multiple sclerosis (MS) patients. Recent seroepidemiologial data have shown that this alteration after primary EBV infection identifies individuals with a more than 30-fold increased risk to develop MS. The mechanisms by which EBV infection might erode tolerance for the central nervous system (CNS) in these individuals, years prior to clinical MS onset, remain unclear. In this review I will discuss altered frequencies of EBV life cycle stages and their tissue distribution, EBV with CNS autoantigen cross-reactive immune responses and loss of immune control for autoreactive B and T cells as possible mechanisms. This discussion is intended to stimulate future studies into these mechanisms with the aim to identify candidates for interventions that might correct EBV specific immune control and/or resulting cross-reactivities with CNS autoantigens in MS patients and thereby ameliorate disease activity.

How to and should we target EBV in MS?

INTRODUCTION: The etiology of multiple sclerosis (MS) remains unknown. Pathogenesis likely relies on a complex interaction between multiple environmental, genetic, and behavioral risk factors. However, a growing body of literature supports the role of a preceding Epstein-Barr virus (EBV) infection in the majority of cases. AREAS COVERED: In this narrative review, we summarize the latest findings regarding the potential role of EBV as a predisposing event inducing new onset of MS. EBV interactions with the genetic background and other infectious agents such as human endogenous retrovirus are explored. Additional data regarding the role of EBV regarding the rate of mid- and long-term disease progression is also discussed. Lastly, the effect of currently approved disease-modifying therapies (DMT) for MS treatment on the EBV-based molecular mechanisms and the development of new EBV-specific therapies are further reviewed. EXPERT OPINION: Recent strong epidemiological findings support that EBV may be the primary inducing event in certain individuals that shortly thereafter develop MS. More studies are needed in order to better understand the significant variability in susceptibility based on environmental factors such as EBV exposure. Future investigations should focus on determining the specific EBV-related risk antigen(s) and phenotyping people with likely EBV-induced MS. Targeting EBV via several different avenues, including development of an EBV vaccine, may become the mainstay of MS treatment in the future.

Disease-Modifying Treatments for Multiple Sclerosis Affect Measures of Cellular Immune Responses to EBNA-1 Peptides.

BACKGROUND AND OBJECTIVES: Epstein-Barr virus (EBV) has been strongly implicated in the pathogenesis of multiple sclerosis (MS). Despite this, there are no routinely used tests to measure cellular response to EBV. In this study, we analyzed the cellular response to EBV nuclear antigen-1 (EBNA-1) in people with MS (pwMS) using a whole blood assay. METHODS: This cross-sectional study took place in a dedicated MS clinic in a university hospital. We recruited healthy controls, people with epilepsy (PWE), and pwMS taking a range of disease-modifying treatments (DMTs) including natalizumab, anti-CD20 monoclonal antibodies (mAbs), dimethyl fumarate (DMF), and also treatment naïve. Whole blood samples were stimulated with commercially available PepTivator EBNA1 peptides and a control virus-cytomegalovirus (CMV) peptide. We recorded the cellular response to stimulation with both interferon gamma (IFN-γ) and interleukin-2 (IL-2). We also compared the cellular responses to EBNA1 with IgG responses to EBNA1, viral capsid antigen (VCA), and EBV viral load. RESULTS: We recruited 86 pwMS, with relapsing remitting MS, in this group, and we observed a higher level of cellular response recorded with IFN-γ (0.79 IU/mL ± 1.36) vs healthy controls (0.29 IU/mL ± 0.90, p = 0.0048) and PWE (0.17 IU/mL ± 0.33, p = 0.0088). Treatment with either anti-CD20 mAbs (0.28 IU/mL ± 0.57) or DMF (0.07 IU/mL ± 0.15) resulted in a cellular response equivalent to control levels or in PWE (p = 0.26). The results of recording IL-2 response were concordant with IFN-γ: with suppression also seen with anti-CD20 mAbs and DMF. By contrast, we did not record any differential effect of DMTs on the levels of IgG to either EBNA-1 or VCA. Nor did we observe differences in cellular response to cytomegalovirus between groups. DISCUSSION: This study demonstrates how testing and recording the cellular response to EBNA-1 in pwMS may be beneficial. EBNA-1 stimulation of whole blood samples produced higher levels of IFN-γ and IL-2 in pwMS compared with controls and PWE. In addition, we show a differential effect of currently available DMTs on this response. The functional assay deployed uses whole blood samples with minimal preprocessing suggesting that employment as a treatment response measure in clinical trials targeting EBV may be possible.

EBV infected cells in the multiple sclerosis brain express PD-L1: How the virus and its niche may escape immune surveillance.

The presence of EBV infected B cells in postmortem multiple sclerosis (MS) brain tissue suggests immune evasion strategies. Using immunohistochemical techniques we analysed the expression of the immune checkpoint molecule PD-L1 and its receptor PD-1 in MS brains containing B cell-enriched perivascular infiltrates and meningeal follicles, a major EBV reservoir. PD-1 and PD-L1 immunoreactivities were restricted to CNS-infiltrating immune cells. PD-L1 was expressed on B cells, including EBV infected B cells, while PD-1 was expressed on many CD8+ T cells, including EBV-specific CD8+ T-cells, and fewer CD4+ T cells. PD-L1+ cells and EBV infected cells were in close contact with PD-1+ T cells. PD-L1 expressed by EBV infected B cells could favour local immune evasion leading to EBV persistence and immunopathology in the MS brain.

Understanding the link between neurotropic viruses, BBB permeability, and MS pathogenesis.

Neurotropic viruses can infiltrate the CNS by crossing the blood-brain barrier (BBB) through various mechanisms including paracellular, transcellular, and "Trojan horse" mechanisms during leukocyte diapedesis. These viruses belong to several families, including retroviruses; human immunodeficiency virus type 1 (HIV-1), flaviviruses; Japanese encephalitis (JEV); and herpesviruses; herpes simplex virus type 1 (HSV-1), Epstein-Barr virus (EBV), and mouse adenovirus 1 (MAV-1). For entering the brain, viral proteins act upon the tight junctions (TJs) between the brain microvascular endothelial cells (BMECs). For instance, HIV-1 proteins, such as glycoprotein 120, Nef, Vpr, and Tat, disrupt the BBB and generate a neurotoxic effect. Recombinant-Tat triggers amendments in the BBB by decreasing expression of the TJ proteins such as claudin-1, claudin-5, and zona occludens-1 (ZO-1). Thus, the breaching of BBB has been reported in myriad of neurological diseases including multiple sclerosis (MS). Neurotropic viruses also exhibit molecular mimicry with several myelin sheath proteins, i.e., antibodies against EBV nuclear antigen 1 (EBNA1) aa411-426 cross-react with MBP and EBNA1 aa385-420 was found to be associated with MS risk haplotype HLA-DRB1*150. Notably, myelin protein epitopes (PLP139-151, MOG35-55, and MBP87-99) are being used to generate model systems for MS such as experimental autoimmune encephalomyelitis (EAE) to understand the disease mechanism and therapeutics. Viruses like Theiler's murine encephalomyelitis virus (TMEV) are also commonly used to generate EAE. Altogether, this review provide insights into the viruses' association with BBB leakiness and MS along with possible mechanistic details which could potentially use for therapeutics.

The CD40/CD40 ligand dyad and its downstream effector molecule ISG54 in relating acute neuroinflammation with persistent, progressive demyelination.

Although Multiple Sclerosis (MS) is primarily thought to be an autoimmune condition, its possible viral etiology must be taken into consideration. When mice are administered neurotropic viruses like mouse hepatitis virus MHV-A59, a murine coronavirus, or its isogenic recombinant strain RSA59, neuroinflammation along with demyelination are observed, which are some of the significant manifestations of MS. MHV-A59/RSA59 induced neuroinflammation is one of the best-studied experimental animal models to understand the viral-induced demyelination concurrent with axonal loss. In this experimental animal model, one of the major immune checkpoint regulators is the CD40-CD40L dyad, which helps in mediating both acute-innate, innate-adaptive, and chronic-adaptive immune responses. Hence, they are essential in reducing acute neuroinflammation and chronic progressive adaptive demyelination. While CD40 is expressed on antigen-presenting cells and endothelial cells, CD40L is expressed primarily on activated T cells and during severe inflammation on NK cells and mast cells. Experimental evidences revealed that genetic deficiency of both these proteins can lead to deleterious effects in an individual. On the other hand, interferon-stimulated genes (ISGs) possess potent antiviral properties and directly or indirectly alter acute neuroinflammation. In this review, we will discuss the role of an ISG, ISG54, and its tetratricopeptide repeat protein Ifit2; the genetic and experimental studies on the role of CD40 and CD40L in a virus-induced neuroinflammatory demyelination model.

Virus de Epstein-Barr: más que una mononucleosis infecciosa / Epstein-Barr virus: more than infectious mononucleosis

El virus de Epstein-Barr (VEB) fue el primer virus asociado a neoplasias en humanos. Infecta el 95 % de la población mundial, y aunque usualmente es asintomático, puede causar mononucleosis infecciosa y se relaciona con más de 200.000 casos de neoplasias al año. De igual forma, se asocia con esclerosis múltiple y otras enfermedades autoinmunes. A pesar de ser catalogado como un virus oncogénico, solo un pequeño porcentaje de los individuos infectados desarrollan neoplasias asociadas a VEB. Su persistencia involucra la capacidad de alternar entre una serie de programas de latencia, y de reactivarse cuando tiene la necesidad de colonizar nuevas células B de memoria, con el fin de sostener una infección de por vida y poder transmitirse a nuevos hospederos. En esta revisión se presentan las generalidades del VEB, además de su asociación con varios tipos de neoplasias, como son el carcinoma nasofaríngeo, el carcinoma gástrico, el linfoma de Hodgkin y el linfoma de Burkitt, y la esclerosis múltiple. Adicionalmente, se describen los mecanismos fisiopatológicos de las diferentes entidades, algunos de ellos no completamente dilucidados

Epstein-Barr virus (EBV) was the first virus associated with human cancer. It infects 95% of the world's population, and although it is usually asymptomatic, it causes infectious mononucleosis. It is related to more than 200,000 cases of cancer per year, and is also associated with multiple sclerosis and other autoimmune diseases. Despite being classified as an oncogenic virus, only a small percentage of infected individuals develop EBV-associated cancer. Its persistence involves the ability to alternate between a series of latency programs, and the ability to reactivate itself when it needs to colonize new memory B cells, in order to sustain a lifelong infection and be able to transmit to new hosts. In this review, the general characteristics of EBV are presented, in addition to its association with various types of cancers, such as nasopharyngeal carcinoma, gastric carcinoma, Hodgkin's lymphoma and Burkitt's lymphoma, and multiple sclerosis. Additionally, the pathophysiological mechanisms of the different entities are described, some of them not completely elucidated yet