Abstract Psoriasis vulgaris is a common, chronic inflammatory skin disease with a complex etiology involving genetic risk factors and environmental triggers. Here we describe the many known genetic predispositions of psoriasis with respect to immune genes and their encoded pathways in psoriasis susceptibility. These genes span an array of functions that involve antigen presentation ( HLA-Cw6 , ERAP1 , ERAP2, MICA ), the IL-23 axis ( IL12Bp40 , IL23Ap19 , IL23R, JAK2, TYK2 ), T-cell development and T-cells polarization ( RUNX1 , RUNX3 , STAT3, TAGAP, IL4, IL13 ), innate immunity ( CARD14 , c-REL , TRAF3IP2 , DDX58 , IFIH1 ), and negative regulators of immune responses ( TNIP1 , TNFAIP3 , NFKBIA , ZC3H12C , IL36RN , SOCS1 ). The contribution of some of these gene products to psoriatic disease has also been revealed in recent years through targeting of key immune components, such as the Th17/IL-23 axis which has been highly successful in disease treatment. However, many of the genetic findings involve immune genes with less clear roles in psoriasis pathogenesis. This is particularly the case for those genes involved in innate immunity and negative regulation of immune specific pathways. It is possible that risk alleles of these genes decrease the threshold for the initial activation of the innate immune response. This could then lead to the onslaught of the pathogenic adaptive immune response known to be active in psoriatic skin. However, precisely how these various genes affect immunobiology need to be determined and some are speculated upon in this review. These novel genetic findings also open opportunities to explore novel therapeutic targets and potentially the development of personalized medicine, as well as discover new biology of human skin disease.
Abstract Interleukin 17 (IL-17) includes several cytokines among which IL-17A is considered as one of the major pro-inflammatory cytokine being central to the innate and adaptive immune responses. IL-17 is produced by unconventional T cells, members of innate lymphoid cells (ILCs), mast cells, as well as typical innate immune cells, such as neutrophils and macrophages located in the epithelial barriers and characterised by a rapid response to infectious agents by recruiting neutrophils as first line of defence and inducing the production of antimicrobial peptides. Th17 responses appear pivotal in chronic and acute infections by bacteria, parasites, and fungi, as well as in autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and psoriatic arthritis. The data discussed in this review cumulatively indicate that innate-derived IL-17 constitutes a major element in the altered immune response against self antigens or the perpetuation of inflammation, particularly at mucosal sites. New drugs targeting the IL17 pathway include brodalumab, ixekizumab, and secukinumab and their use in psoriatic disease is expected to dramatically impact our approach to this systemic condition.
Abstract The role of various environmental factors in the pathogenesis of immune mediated diseases is well established. Of which, factors entailing an immune adjuvant activity such as infectious agents, silicone, aluminium salts and others were associated with defined and non-defined immune mediated diseases both in animal models and in humans. In recent years, four conditions: siliconosis, the Gulf war syndrome (GWS), the macrophagic myofasciitis syndrome (MMF) and post-vaccination phenomena were linked with previous exposure to an adjuvant. Furthermore, these four diseases share a similar complex of signs and symptoms which further support a common denominator.Thus, we review herein the current data regarding the role of adjuvants in the pathogenesis of immune mediated diseases as well as the amassed data regarding each of these four conditions. Relating to the current knowledge we would like to suggest to include these comparable conditions under a common syndrome entitled ASIA , “Autoimmune (Auto-inflammatory) Syndrome Induced by Adjuvants”.
Abstract Smoking is a central factor in many pathological conditions. Its role in neoplasm, lung and cardiovascular diseases has been well established for years. However it is less acknowledged the cigarette smoking affects both the innate and adoptive immune arms. Cigarette smoke was shown to augment the production of numerous pro-inflammatory cytokines such as TNF-α, IL-1, IL-6, IL-8 GM-CSF and to decrease the levels of anti-inflammatory cytokines such as IL-10. Tobacco smoke via multiple mechanisms leads to elevated IgE concentrations and to the subsequent development of atopic diseases and asthma. Cigarette smoke has also been shown activate in many ways macrophage and dendritic cell activity. While it is better evident how cigarette smoke evokes airway diseases more mechanisms are being revealed linking this social hazard to autoimmune disorders, for instance via the production of antibodies recognizing citrullinated proteins in rheumatoid arthritis or by the elevation of anti-dsDNA titers in systemic lupus erythematosus. The current review underlines the importance of smoking prevention and eradication not only in respiratory disorders but also in autoimmune conditions as well.
Abstract Herein we will review the role of glycans in the immune system. Specific topics covered include: the glycosylation sites of IgE, IgM, IgD, IgE, IgA, and IgG; how glycans can encode “self” identity by functioning as either danger associated molecular patterns (DAMPs) or self-associated molecular patterns (SAMPs); the role of glycans as markers of protein integrity and age; how the glycocalyx can dictate the migration pattern of immune cells; and how the combination of Fc N-glycans and Ig isotype dictate the effector function of immunoglobulins. We speculate that the latter may be responsible for the well-documented association between alterations of the serum glycome and autoimmunity. Due to technological limitations, the extent of these autoimmune-associated glycan alterations and their role in disease pathophysiology has not been fully elucidated. Thus, we also review the current technologies available for glycan analysis, placing an emphasis on Multiple Reaction Monitoring (MRM), a rapid high-throughput technology that has great potential for glycan biomarker research. Finally, we put forth The Altered Glycan Theory of Autoimmunity , which states that each autoimmune disease will have a unique glycan signature characterized by the site-specific relative abundances of individual glycan structures on immune cells and extracellular proteins, especially the site-specific glycosylation patterns of the different immunoglobulin(Ig) classes and subclasses.
Abstract The Zika virus outbreak has captivated the attention of the global audience and information has spread rapidly and wildly through the internet and other media channels. This virus was first identified in 1947, when it was isolated from a sentinel rhesus monkey placed by British scientists working at the Yellow Fever Research Laboratory located in the Zika forest area of Uganda, hence its name, and is transmitted primarily by the mosquito vector, Aedes aegypti . The fact that the rhesus macaque is an Asian species being placed in an African forest brings to mind the possibility of rapid adaptation of the virus from an African to Asian species, an issue that has not been considered. Whether such adaptation has played any role in acquiring pathogenicity due to cross species transmission remains to be identified. The first human infection was described in Nigeria in 1954, with only scattered reports of about a dozen human infections identified over a 50-year period. It was not until 2007 that Zika virus raised its ugly head with infections noted in three-quarters of the population on the tiny island of Yap located between the Philippines and Papua New Guinea in the western Pacific Ocean, followed by a major outbreak in French Polynesia in 2013. The virus remained confined to a narrow equatorial band in Africa and Asia until 2014 when it began to spread eastward, first toward Oceania and then to South America. Since then, millions of infected individuals have been identified in Brazil, Colombia, Venezuela, including 25 additional countries in the Americas. While the symptoms associated with Zika virus infection are generally mild, consisting of fever, maculopapular rash, arthralgia and conjunctivitis, there have been reports of more severe reactions that are associated with neurological complications. In pregnant women, fetal neurological complications include brain damage and microcephaly, while in adults there have been several cases of virus-associated Guillain-Barre syndrome. The virus was until recently believed to only be transmitted via mosquitoes. But when the Zika virus was isolated from the semen specimens from a patient in Texas, this provided the basis for the recent report of possible sexual transmission of the Zika virus. Due to the neurological complications, various vectors for infection as well as the rapid spread throughout the globe, it has prompted the World Health Organization to issue a global health emergency. Various governmental organizations have recommended that pregnant women do not travel to countries where the virus is epidemic, and within the countries affected by the virus, recommendations were provided for women of childbearing age to delay pregnancy. The overall public health impact of these above findings highlights the need for a rapid but specific diagnostic test for blood banks worldwide to identify those infected and for the counseling of women who are pregnant or contemplating pregnancy. As of this date, there are neither commercially licensed diagnostic tests nor a vaccine. Because cross-reactivity of the Zika virus with dengue and Chikungunya virus is common, it may pose difficulty in being able to quickly develop such tests and vaccines. So far the most effective public health measures include controlling the mosquito populations via insecticides and preventing humans from direct exposure to mosquitoes.
Abstract Autoimmune myasthenia gravis (MG) is characterized by muscle weakness caused by antibodies directed against proteins of the neuromuscular junction. The main antigenic target is the acetylcholine receptor (AChR), but the muscle Specific Kinase (MuSK) and the low-density lipoprotein receptor-related protein (LRP4) are also targets. This review summarizes the clinical and biological data available for different subgroups of patients, who are classified according to antigenic target, age of onset, and observed thymic abnormalities, such as follicular hyperplasia or thymoma. Here, we analyze in detail the role of the thymus in the physiopathology of MG and propose an explanation for the development of the thymic follicular hyperplasia that is commonly observed in young female patients with anti-AChR antibodies. The influence of the pro-inflammatory environment is discussed, particularly the role of TNF-α and Th17-related cytokines, which could explain the escape of thymic T cells from regulation and the chronic inflammation in the MG thymus. Together with this immune dysregulation, active angiogenic processes and the upregulation of chemokines could promote thymic follicular hyperplasia. MG is a multifactorial disease, and we review the etiological mechanisms that could lead to its onset. Recent global genetic analyses have highlighted potential susceptibility genes. In addition, miRNAs, which play a crucial role in immune function, have been implicated in MG by recent studies. We also discuss the role of sex hormones and the influence of environmental factors, such as the viral hypothesis. This hypothesis is supported by reports that type I interferon and molecules mimicking viral infection can induce thymic changes similar to those observed in MG patients with anti-AChR antibodies.
Abstract Sex based differences in immune responses, affecting both the innate and adaptive immune responses, contribute to differences in the pathogenesis of infectious diseases in males and females, the response to viral vaccines and the prevalence of autoimmune diseases [1–5] . Indeed, females have a lower burden of bacterial, viral and parasitic infections, most evident during their reproductive years [2,6] . Conversely, females have a higher prevalence of a number of autoimmune diseases, including Sjogren’s syndrome, systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA) and multiple sclerosis (MS). These observations suggest that gonadal hormones may have a role in this sex differential. The fundamental differences in the immune systems of males and females are attributed not only to differences in sex hormones, but are related to X chromosome gene contributions and the effects of environmental factors [7,8] . A comprehensive understanding of the role that sex plays in the immune response is required for therapeutic intervention strategies against infections and the development of appropriate and effective therapies for autoimmune diseases for both males and females. This review will focus on the differences between male and female immune responses in terms of innate and adaptive immunity, and the effects of sex hormones in SLE, MS and RA.
Abstract Systemic lupus erythematosus is an autoimmune disease characterized by multi-system involvement and autoantibody production. Abnormal T cell DNA methylation and type-I interferon play an important role in the pathogenesis of lupus. We performed a genome-wide DNA methylation study in two independent sets of lupus patients and matched healthy controls to characterize the DNA methylome in naïve CD4+ T cells in lupus. DNA methylation was quantified for over 485,000 methylation sites across the genome, and differentially methylated sites between lupus patients and controls were identified and then independently replicated. Gene expression analysis was also performed from the same cells to investigate the relationship between the DNA methylation changes observed and mRNA expression levels. We identified and replicated 86 differentially methylated CG sites between patients and controls in 47 genes, with the majority being hypomethylated. We observed significant hypomethylation in interferon-regulated genes in naïve CD4+ T cells from lupus patients, including IFIT1 , IFIT3 , MX1 , STAT1 , IFI44L , USP18 , TRIM22 and BST2 , suggesting epigenetic transcriptional accessibility in these genetic loci. Indeed, the majority of the hypomethylated genes (21 out of 35 hypomethylated genes) are regulated by type I interferon. The hypomethylation in interferon-regulated genes was not related to lupus disease activity. Gene expression analysis showed overexpression of these genes in total but not naïve CD4+ T cells from lupus patients. Our data suggest epigenetic “poising” of interferon-regulated genes in lupus naïve CD4+ T cells, argue for a novel pathogenic implication for abnormal T cell DNA methylation in lupus, and suggest a mechanism for type-I interferon hyper-responsiveness in lupus T cells.
Abstract Systemic lupus erythematosus is a multi-organ system autoimmune disease with clinical and serological heterogeneity. The formulation of initial criteria for SLE was first proposed by the American College of Rheumatology and appeared in 1971. Although the original purpose of the criteria was to classify the disease, it became widely used as a diagnostic criteria in clinical situations. Since then the ACR criteria have undergone at least two changes (in 1982 and 1997). Clinical manifestations that can differentiate SLE patients from healthy people such as skin lesions, arthritis, renal disorder, neurologic disorder, hematologic changes and others are included in these criteria. Serum anti-nuclear antibody, anti-ds-DNA antibody and anti-Sm antibody are important biomarkers of SLE patients. In 2012, the Systemic Lupus Collaborating Clinics proposed the SLICC criteria for SLE in view of new knowledge of autoantibodies and the importance of low complement. Future biomarkers may be useful in distinguishing SLE from other diseases and in monitoring of disease activity.
Abstract Double-seronegative myasthenia gravis (dSN-MG, without detectable AChR and MuSK antibodies) presents a serious gap in MG diagnosis and understanding. Recently, autoantibodies against the low-density lipoprotein receptor-related protein 4 (LRP4) have been identified in several dSN-MG sera, but with dramatic frequency variation (∼2–50%). We have developed a cell based assay (CBA) based on human LRP4 expressing HEK293 cells, for the reliable and efficient detection of LRP4 antibodies. We have screened about 800 MG patient sera from 10 countries for LRP4 antibodies. The overall frequency of LRP4-MG in the dSN-MG group (635 patients) was 18.7% but with variations among different populations (range 7–32.7%). Interestingly, we also identified double positive sera: 8/107 anti-AChR positive and 10/67 anti-MuSK positive sera also had detectable LRP4 antibodies, predominantly originating from only two of the participating groups. No LRP4 antibodies were identified in sera from 56 healthy controls tested, while 4/110 from patients with other neuroimmune diseases were positive. The clinical data, when available, for the LRP4-MG patients were then studied. At disease onset symptoms were mild (81% had MGFA grade I or II), with some identified thymic changes (32% hyperplasia, none with thymoma). On the other hand, double positive patients (AChR/LRP4-MG and MuSK/LRP4-MG) had more severe symptoms at onset compared with any single positive MG subgroup. Contrary to MuSK-MG, 27% of ocular dSN-MG patients were LRP4 antibody positive. Similarly, contrary to MuSK antibodies, which are predominantly of the IgG4 subtype, LRP4 antibodies were predominantly of the IgG1 and IgG2 subtypes. The prevalence was higher in women than in men (female/male ratio 2.5/1), with an average disease onset at ages 33.4 for females and 41.9 for males. Overall, the response of LRP4-MG patients to treatment was similar to published responses of AChR-MG rather than to MuSK-MG patients.
Abstract Both the CTLA-4 pathway and regulatory T cells (Treg) are essential for the control of immune homeostasis. Their therapeutic relevance is highlighted by the increasing use of anti-CTLA-4 antibody in tumor therapy and the development of Treg cell transfer strategies for use in autoimmunity and transplantation settings. The CTLA-4 pathway first came to the attention of the immunological community in 1995 with the discovery that mice deficient in Ctla-4 suffered a fatal lymphoproliferative syndrome. Eight years later, mice lacking the critical Treg transcription factor Foxp3 were shown to exhibit a remarkably similar phenotype. Much of the debate since has centered on the question of whether Treg suppressive function requires CTLA-4. The finding that it does in some settings but not in others has provoked controversy and inevitable polarization of opinion. In this article, I suggest that CTLA-4 and Treg represent complementary and largely overlapping mechanisms of immune tolerance. I argue that Treg commonly use CTLA-4 to effect suppression, however CTLA-4 can also function in the non-Treg compartment while Treg can invoke CTLA-4-independent mechanisms of suppression. The notion that Foxp3 and CTLA-4 direct independent programs of immune regulation, which in practice overlap to a significant extent, will hopefully help move us towards a better appreciation of the underlying biology and therapeutic significance of these pathways.
Abstract Rheumatoid arthritis is an autoimmune disease characterized by the production of two known antibodies – rheumatoid factor and anti-citrullinated peptide antibody (ACPA) – against common autoantigens that are widely expressed within and outside the joints. The interactions between genes and environment are crucial in all stages of the disease, involving namely genes from major histocompatibility complex locus, and antigens such as tobacco or microbes (e.g. Porphyromonas gingivalis ). T and B cells are activated as soon as the earliest phases of the disease, rheumatoid arthritis appearing as a Th1 and Th17 disease. Inflammatory cytokines have a considerable importance in the hierarchy of the processes involved in RA. The joint destruction seen in RA is caused not only by cytokine imbalances, but also by specific effects of the Wnt system and osteoprotegerin on osteoclasts and by matrix production dysregulation responsible for cartilage damage. Both innate and adaptative immunity demonstrated their respective cornerstone position in rheumatoid arthritis, since targeted treatments has been efficiently developed against TNF-α, IL-6 receptor, IL-1β, CD20 B cells and T-cell/Dendritic cell interactions.
Abstract Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and common cause of non-traumatic neurological disability in young adults. The likelihood for an individual to develop MS is strongly influenced by her or his ethnic background and family history of disease, suggesting that genetic susceptibility is a key determinant of risk. Over 100 loci have been firmly associated with susceptibility, whereas the main signal genome-wide maps to the class II region of the human leukocyte antigen ( HLA ) gene cluster and explains up to 10.5% of the genetic variance underlying risk. HLA - DRB1*15:01 has the strongest effect with an average odds ratio of 3.08. However, complex allelic hierarchical lineages, cis/trans haplotypic effects, and independent protective signals in the class I region of the locus have been described as well. Despite the remarkable molecular dissection of the HLA region in MS, further studies are needed to generate unifying models to account for the role of the MHC in disease pathogenesis. Driven by the discovery of combinatorial associations of Killer-cell Immunoglobulin-like Receptor (KIR) and HLA alleles with infectious, autoimmune diseases, transplantation outcome and pregnancy, multi-locus immunogenomic research is now thriving. Central to immunity and critically important for human health, KIR molecules and their HLA ligands are encoded by complex genetic systems with extraordinarily high levels of sequence and structural variation and complex expression patterns. However, studies to-date of KIR in MS have been few and limited to very low resolution genotyping. Application of modern sequencing methodologies coupled with state of the art bioinformatics and analytical approaches will permit us to fully appreciate the impact of HLA and KIR variation in MS.
Abstract The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses, often multiple, and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL). Some estimates indicate that the incidence of the APS is around 5 new cases per 100,000 persons per year and the prevalence around 40–50 cases per 100,000 persons. The aPL are positive in approximately 13% of patients with stroke, 11% with myocardial infarction, 9.5% of patients with deep vein thrombosis and 6% of patients with pregnancy morbidity. The original classification criteria for the APS were formulated at a workshop in Sapporo, Japan, in 1998, during the 8th International Congress on aPL. The Sapporo criteria, as they are often called, were revised at another workshop in Sydney, Australia, in 2004, during the 11th International Congress on aPL. At least one clinical (vascular thrombosis or pregnancy morbidity) and one laboratory (anticardiolipin antibodies, lupus anticoagulant or anti-β2 -glycoprotein I antibodies) criterion had to be met for the classification of APS.
Rationale: The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic. Objectives: We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NM) cells from circulating counterparts. Findings: Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56(bright) lr-NK cells that localize within hepatic sinusoids. CD56(bright) lr-NM cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. Here, we also show that hepatic sinusoids express CCL3(pos) Kupffer cells, CXCL16(pos) endothelial cells and CCL5(pos) T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56(bright) NK cells that constitutively express CCR5 and CXCR6. CD56(bright) lr-NK cells co-exist with CD56(dim) conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56(dim) c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX(3)CR1. Conclusion: Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56(bright) lr-NK cells will require modification of hepatic CCR5 and CXCR6. (C) 2015 Elsevier Ltd. All rights reserved.
Abstract Rationale The liver-specific natural killer (NK) cell population is critical for local innate immune responses, but the mechanisms that lead to their selective homing and the definition of their functionally relevance remain enigmatic. Objectives We took advantage of the availability of healthy human liver to rigorously define the mechanisms regulating the homing of NK cells to liver and the repertoire of receptors that distinguish liver-resident NK (lr-NK) cells from circulating counterparts. Findings Nearly 50% of the entire liver NK cell population is composed of functionally relevant CD56bright lr-NK cells that localize within hepatic sinusoids. CD56bright lr-NK cells express CD69, CCR5 and CXCR6 and this unique repertoire of chemokine receptors is functionally critical as it determines selective migration in response to the chemotactic stimuli exerted by CCL3, CCL5 and CXCL16. Here, we also show that hepatic sinusoids express CCL3pos Kupffer cells, CXCL16pos endothelial cells and CCL5pos T and NK lymphocytes. The selective presence of these chemokines in sinusoidal spaces creates a unique tissue niche for lr-CD56bright NK cells that constitutively express CCR5 and CXCR6. CD56bright lr-NK cells co-exist with CD56dim conventional NK (c-NK) cells that are, interestingly, transcriptionally and phenotypically similar to their peripheral circulating counterparts. Indeed, CD56dim c-NK cells lack expression of CD69, CCR5, and CXCR6 but express selectins, integrins and CX3 CR1. Conclusion Our findings disclosing the phenotypic and functional differences between lr-Nk cells and c-NK cells are critical to distinguish liver-specific innate immune responses. Hence, any therapeutic attempts at modifying the large population of CD56bright lr-NK cells will require modification of hepatic CCR5 and CXCR6.
Abstract Psoriasis and Psoriatic Arthritis (PsA) are chronic inflammatory diseases that have a major impact on health. The prevalence and incidence estimates of these two closely related diseases show ethnic and geographic variations, being generally more common in the colder north than in the tropics. In Europe the prevalence of psoriasis varies anywhere from 0.6 to 6.5%. In the USA, the estimated prevalence of diagnosed psoriasis is 3.15%. The prevalence in Africa varies depending on geographic location, being lowest in West Africa. Psoriasis is less prevalent in China and Japan than in Europe, and is entirely absent in natives of the Andean region of South America. There are fewer reports on the incidence of psoriasis, but a recent study from Rochester, USA showed an increasing trend over the last 2 decades. The prevalence of PsA also shows similar variation, being highest in people of European descent and lowest in the Japanese. Although, study methodology and case definition may explain some of the variations, genetic and environmental factors are important. Genetic epidemiologic studies have shown that both diseases have a strong genetic component. The strongest association is with HLA-Cw*06. Associations with a number of genes including IL12B and IL23R have recently been confirmed. Environmental risk factors including streptococcal pharyngitis, stressful life events, low humidity, drugs, HIV infection, trauma, smoking and obesity have been associated with psoriasis and PsA. Here we have reviewed the current literature on the epidemiology and genetics of psoriasis and PsA.
Abstract Myasthenia gravis is characterized by muscle weakness and abnormal fatigability. It is an autoimmune disease caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction. In most cases, the autoantibodies are against the acetylcholine receptor (AChR). Recently, other targets have been described such as the MuSK protein (muscle-specific kinase) or the LRP4 (lipoprotein related protein 4). Myasthenia gravis can be classified according to the profile of the autoantibodies, the location of the affected muscles (ocular versus generalized), the age of onset of symptoms and thymic abnormalities. The disease generally begins with ocular symptoms (ptosis and/or diplopia) and extends to other muscles in 80% of cases. Other features that characterize MG include the following: variability, effort induced worsening, successive periods of exacerbation during the course of the disease, severity dependent on respiratory and swallowing impairment (if rapid worsening occurs, a myasthenic crisis is suspected), and an association with thymoma in 20% of patients and with other autoimmune diseases such as hyperthyroidism and Hashimoto's disease. The diagnosis is based on the clinical features, the benefit of the cholinesterase inhibitors, the detection of specific autoantibodies (anti-AChR, anti-MuSK or anti-LRP4), and significant decrement evidenced by electrophysiological tests. In this review, we briefly describe the history and epidemiology of the disease and the diagnostic and clinical classification. The neonatal form of myasthenia is explained, and finally we discuss the main difficulties of diagnosis.