Autoimmunity reviews

Publications in this journal

• Article: Prevalence and clinical significance of rare antinuclear antibody patterns.

  Pieter Vermeersch, Xavier Bossuyt
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  ABSTRACT: While some of the more frequent antinuclear (auto)antibodies (ANA) patterns such as homogenous nuclear staining have been extensively studied, the prevalence and clinical significance of rare antinuclear antibody patterns is not well understood. For the purpose of this review, we defined rare patterns as patterns occurring in less than 1% of patients that test positive on indirect immunofluorescence. The prevalence of different ANA patterns was determined in 68,128 consecutive patients who attended the outpatient clinic or were hospitalized at the University Hospitals Leuven over a 14-year period (1998-2011). To avoid bias, we only included the first sample for each patient and patients who tested positive in the period 1980-1997 were excluded. There were 9,268 patients who tested positive for ANA. With the exception of the clinical association of anti-multiple nuclear dots (at higher titers) and anti-nuclear envelope autoantibodies with autoimmune liver disease, there was no good clinical association of rare ANA patterns with the diagnosis of auto-immune disorders. The most important non-autoimmune cause of rare ANA patterns was carcinoma, particularly in patients with rare cell-cycle related ANAs.
  Autoimmunity reviews 04/2013;
• Article: Biologic therapies and systemic bone loss in Rheumatoid Arthritis.

  Theodoros Dimitroulas, Spyros N Nikas, Panagiotis Trontzas, George D Kitas
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  ABSTRACT: Chronic inflammation affects bone metabolism leading to disequilibrium in the rates of bone resorption and repair and subsequently to local and generalized bone loss. Osteoporosis represents an important co-morbidity of Rheumatoid Arthritis (RA) patients, which exhibit increased fracture risk. Osteoclasts play a pivotal role in the development and progression of bone loss, while resident synovial cells such as T cells, monocytes and synovial fibroblasts have been identified as sources of osteoclast differentiation signals in RA. This process is mainly mediated through the receptor activator of nuclear-κappa B ligand (RANKL) signalling system, which is upregulated by numerous proinflammatory cytokines involved in the pathogenesis of RA. Improved knowledge of the association between cells and cytokines of the immune system and their relationship to bone remodelling has revealed several promising targets for the treatment of inflammatory bone loss in RA. In this respect, initiation of biologic therapies targeting inflammatory cytokines and/or lymphocyte activation have modified RA therapy not only by blocking local and systemic inflammatory cascades but also by providing beneficial effects against bone and joint degradation. In this article we briefly present the modern view of the mechanisms that govern inflammatory bone loss, highlighting the role of cytokine-induced molecular pathways, and discuss in detail the effects of different biologic treatment strategies on bone mass in RA patients.
  Autoimmunity reviews 03/2013;
• Article: Is it time for biosimilars in autoimmune diseases?

  Maria-Jose Cuadrado, Savino Sciascia, Xavier Bosch, Munther A Khamashta, Manuel Ramos-Casals
  Autoimmunity reviews 03/2013;
• Article: Prognosis of vasculitis associated myelodysplasia.

  C Belizna, J F Subra, D Henrion, A Ghali, G Renier, M Royer, Y Le Corre, L Martin, J Voswinkel, N Ifrah
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  ABSTRACT: Systemic and immune manifestations have been reported in patients with MDS. The correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients remains controversial. Most of the authors agree that the median survival in myelodysplastic syndrome is not related to the presence of systemic and immune manifestations, but only with the existence of a systemic vasculitis.
  Autoimmunity reviews 03/2013;
• Article: Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality- a review of recent evidence.

  Pawel Pludowski, Michael F Holick, Stefan Pilz, Carol L Wagner, Bruce W Hollis, William B Grant, Yehuda Shoenfeld, Elisabeth Lerchbaum, David J Llewellyn, Katharina Kienreich, Maya Soni
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  ABSTRACT: BACKGROUND: Optimal vitamin D intake and its status are important not only for bone and calcium-phosphate metabolism, but for overall health and well-being. Vitamin D deficiency and insufficiency as a global health problem is likely to be a risk for wide spectrum of acute and chronic illnesses. METHODS: A review of randomized controlled trials, meta-analyses, and other evidence of vitamin D action on various health outcomes. RESULTS: Adequate vitamin D status seems to be protective against musculoskeletal disorders (muscle weakness, falls, fractures), infectious diseases, autoimmune diseases, cardiovascular disease, type 1 and type 2 diabetes mellitus, several types of cancer, neurocognitive dysfunction and mental illness, and other diseases, as well as infertility and adverse pregnancy and birth outcomes. Vitamin D deficiency/insufficiency is associated with all-cause mortality. CONCLUSIONS: Adequate vitamin D supplementation and sensible sunlight exposure to reach optimal vitamin D status are among the front line factors of prophylaxis for spectrum of disorders. Supplementation guidance and population strategies for eradication of vitamin D deficiency must be included in the priorities of physicians, medical professionals and healthcare policy-makers.
  Autoimmunity reviews 03/2013;
• Article: A literature review on optic neuritis following vaccination against virus infections.

  Joerg-Patrick Stübgen
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  ABSTRACT: Optic neuritis (ON) is a primary inflammation of the optic nerve. ON is mostly idiopathic, and infrequently occurs on the background of systemic autoimmune disease, recent infectious disease or inoculation with mostly adjuvanted vaccines. Published case histories, retrospective reviews and analyses of epidemiological data report on the onset of immune-mediated ON (and other autoimmune disorders) within a defined period (days to weeks) after immunization of patients with probable genetic predisposition. After vaccination, there exists no long-term increased risk to develop ON. The risk for these vaccine-induced adverse events may be enhanced by adjuvants. Patient age distribution reflected immunization schedules and advisories, or patient age groups studied. Vaccination is one of the most important prevention tools in modern medicine, and a discussion on risk-benefit or cost-benefit analysis, and advisory on individual vaccines or vaccination programs falls outside the scope of this review. Despite a great deal of scientific uncertainty, the existence of a possible causal link between vaccines and acute ON should not be totally disregarded.
  Autoimmunity reviews 03/2013;
• Article: Assessment of intracellular cytokines and regulatory cells in patients with autoimmune diseases and primary immunodeficiencies-novel tool for diagnostics and patient follow-up.

  Liv T Osnes, Britt Nakken, Edit Bodolay, Peter Szodoray
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  ABSTRACT: Serum and intracytoplasmic cytokines are mandatory in host defense against microbes, but also play a pivotal role in the pathogenesis of autoimmune diseases by initiating and perpetuating various cellular and humoral autoimmune processes. The intricate interplay and fine balance of pro- and anti-inflammatory processes drive, whether inflammation and eventually organ damage will occur, or the inflammatory cascade quenches. In the early and late, as well as inactive and active stages of autoimmune diseases, different cellular and molecular patterns can dominate in these patients. However, the simultaneous assessment of pro- and anti-inflammatory biomarkers aids to define the immunological state of a patient. A group of the most useful inflammatory biomarkers are cytokines, and with increasing knowledge during the last decade their role have been well-defined in patients with autoimmune diseases and immunodeficiencies. Multiple pathological processes drive the development of autoimmunity and immunodeficiencies, most of which involve quantitative and qualitative disturbances in regulatory cells, cytokine synthesis and signaling pathways. The assessment of these biomarkers does not aid only in the mechanistic description of autoimmune diseases and immunodeficiencies, but further helps to subcategorize diseases and to evaluate therapy responses. Here, we provide an overview, how monitoring of cytokines and regulatory cells aid in the diagnosis and follow-up of patients with autoimmune diseases and immunodeficiencies furthermore, we pinpoint novel cellular and molecular diagnostic possibilities in these diseases.
  Autoimmunity reviews 03/2013;
• Article: Cardiovascular disease in autoimmune rheumatic diseases.

  Ivana Hollan, Pier Luigi Meroni, Joseph M Ahearn, J W Cohen Tervaert, Sam Curran, Carl S Goodyear, Knut A Hestad, Bashar Kahaleh, Marcello Riggio, Kelly Shields, Mary C Wasko
  Autoimmunity reviews 03/2013;
• Article: Mechanisms associated with the pathogenicity ofantibodies against muscle-specific kinase in myasthenia gravis.

  Suuichi Mori, Kazuhiro Shigemoto
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  ABSTRACT: The presence of autoantibodies against muscle-specific kinase (MuSK) at the neuromuscular junction (NMJ) results in myasthenia gravis (MG). MuSK antibody-associated MG (MuSK MG) patients often have severe symptoms, including bulbar dysfunction, respiratory insufficiency and atrophy of the facial and tongue muscles. MuSK antibodies in MG patients predominantly belong to the IgG4 subclass, and the unique properties of IgG4 antibodies are directly associated with the pathogenic mechanisms of MuSK MG. Histopathological studies inanimal models of MuSK MGhave revealedthat anti-MuSK antibodies cause contraction of motor terminals,significant loss of acetylcholine receptor (AChR) expression, and a reduction in synaptic folds at the postsynaptic membrane in the absence of complement involvement. Failure of neuromuscular transmission at pre- and postsynaptic membranes of the NMJs has been observedin both patients and animal models of MuSK MG. A murine model of MuSK-MG revealed the mechanisms underlying cholinergic hypersensitivity after administration of acetylcholinesterase inhibitors, which has also been observed in MuSK-MG patients. Further studies of this model have provided evidence suggesting that 3,4-diaminopyridine may be effective as a symptomatic therapy for MuSK MG.
  Autoimmunity reviews 03/2013;
• Article: Ectopic germinal centers, BAFF and anti-B cell therapy in Myasthenia Gravis.

  Sonia Berrih-Aknin, Samia Ragheb, Rozen le Panse, Robert P Lisak
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  ABSTRACT: Myasthenia Gravis (MG) is an autoimmune disease mediated by antibodies directed to molecules of the endplate of the neuromuscular junction. B cells play a major role in MG disease since they produce the pathogenic antibodies and therapies targeting B cells are effective. The aim of this article is to review the role of B cells in Myasthenia Gravis. We will first describe what we know about B cells in this disease and examine the involvement of the B cells in the thymus of MG patients. We will detail the role of factors associated with B cell function such as BAFF. Finally we will discuss the effects of therapy targeting B cells.
  Autoimmunity reviews 03/2013;
• Article: Complement Associated Pathogenic Mechanisms in Myasthenia Gravis.

  Erdem Tüzün, Premkumar Christadoss
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  ABSTRACT: The complement system is profoundly involved in the pathogenesis of acetylcholine receptor (AChR) antibody (Ab) related myasthenia gravis (MG) and its animal model experimental autoimmune myasthenia gravis (EAMG). The most characteristic finding of muscle pathology in both MG and EAMG is the abundance of IgG and complement deposits at the nerve-muscle junction (NMJ), suggesting that AChR-Ab induces muscle weakness by complement pathway activation and consequent membrane attack complex (MAC) formation. This assumption has been supported with EAMG resistance of complement factor C3 knockout (KO), C4 KO and C5 deficient mice and amelioration of EAMG symptoms following treatment with complement inhibitors such as cobra venom factor, soluble complement receptor 1, anti-C1q, anti-C5 and anti-C6 Abs. Moreover, the complement inhibitor decay accelerating factor (DAF) KO mice exhibit increased susceptibility to EAMG. These findings have brought forward improvisation of novel therapy methods based on inhibition of classical and common complement pathways in MG treatment.
  Autoimmunity reviews 03/2013;
• Article: Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens.

  Paraskevi Zisimopoulou, Talma Brenner, Nikolaos Trakas, Socrates J Tzartos
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  ABSTRACT: Myasthenia gravis (MG) is the most common immune-mediated disorder of the neuromuscular junction with a prevalence of 200-300/million population and its study has established paradigms for exploring other antibody-mediated diseases. Most MG patients (~85%) have autoantibodies against the muscle acetylcholine receptor (AChR-MG), whereas about 6% of MG patients have autoantibodies against the muscle specific kinase (MuSK-MG). Until recently no autoantibodies could be detected in the remaining patients (seronegative MG). Probably, the most sensitive assays for the detection of the autoantibodies in MG sera have been the radioimmunoprecipitation assays (RIPA) for both types of MG. However, with recent novel methods, not yet used routinely, it has been shown that the "seronegative" MG group includes patients with low levels of autoantibodies or of low affinity, against the known autoantigens, or even with antibodies to recently identified autoantigens. Since MG is heterogeneous in terms of pathophysiology, depending on the autoantigen targeted and on other factors (e.g. presence of thymoma), the serological tests are crucial in verifying the initial clinical diagnosis, whereas frequent measurement of autoantibody levels is important in monitoring the course of the disease and the efficacy of treatment. In addition, in AChR-MG, autoantibodies against the muscle proteins titin and ryanodin receptor have been identified; these antibodies are useful for the classification of MG, indicating the concomitant presence of thymoma, and as prognostic markers.
  Autoimmunity reviews 03/2013;
• Article: Effect of stress on brain inflammation and multiple sclerosis.

  Anna Karagkouni, Michail Alevizos, Theoharis C Theoharides
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  ABSTRACT: Substantial evidence indicates that stress can precipitate or worsen symptoms of inflammation in general and more specifically in multiple sclerosis (MS), a demyelinating, autoimmune disease characterized by inflammation of the central nervous system (CNS). However, the mechanism of how stress affects MS is not well understood. We reviewed publications in PubMed since 1995 and propose that neuropeptides secreted under stress, such as corticotropin releasing hormone (CRH) and neurotensin (NT), activate microglia and mast cells to release inflammatory molecules. These lead to maturation and activation of T17 autoimmune cells, disruption of the blood-brain barrier (BBB) and T cell entry into the CNS, thus promoting brain inflammation and contributing to MS pathology. Reduction of stress and inhibition of these processes by select flavonoids could provide novel therapeutic approaches.
  Autoimmunity reviews 03/2013;
• Article: Novel future therapeutic options in Myasthenia Gravis.

  Marinos C Dalakas
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  ABSTRACT: BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease caused by complement-fixing antibodies against the acetylcholine receptors (AChR). Antigen-specific CD4+ T cells, Tregs and Th17+ are also necessary. Consequently, antibodies, B cells, molecules associated with signalling pathways on T helper cells, cytokines and complement are targets for more specific treatment options. OBJECTIVES: Because available therapies (like immunosuppressors) cause unacceptable side effects after long-term use or are not always effective in inducing remission, novel biological agents directed against the following targets might be options for future therapies in MG: 1) T cell Intracellular Signaling Pathways associated with T cell activation, such as monoclonal antibodies against CD52, Interleukin 2-receptor (IL-2 R), co-stimulatory molecules or compounds inhibiting Janus tyrosine Kinases JAK1, JAK3; 2) B cells, against key B cell-surface molecules or trophic factors B cell activation factor (BAFF) and a proliferating inducing ligand (APRIL); 3) Complement, against C3 or C5 that intercept Membranolytic attack complex formation; 4) Cytokines and cytokine receptors, including IL-6, IL-17, the p40 subunit of IL12/1L-23, and GM-CSF; and 5) Lymphocyte migration molecules. Construction of recombinant AChR antibodies that block the binding of the pathogenic antibodies, are future molecular tools. CONCLUSION: New biological agents are in the offing for future therapies in MG. Their efficacy needs to be secured with vigorously controlled clinical trials and weighted against excessive cost and rare complications.
  Autoimmunity reviews 03/2013;
• Article: Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase.

  Amelia Evoli, Luca Padua
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  ABSTRACT: Myasthenia gravis (MG) with antibodies to the muscle-specific receptor tyrosine kinase (MuSK-MG) is a rare disease which covers 5-8% of all MG patients. Symptoms are nearly always generalized, though more focal than in MG with anti-acetylcholine receptor antibodies, with predominant involvement of cranial, bulbar and axial muscles; early respiratory crises are frequent. Focal atrophy, mostly of facial, masseter and tongue muscles, occurs in a proportion of patients. Diagnosis is often challenging on account of atypical presentation with little or no symptom fluctuations, lack of response to acetylcholinesterase inhibitors in a high proportion of patients and negative results of electrodiagnostic studies when performed on limb muscles. Immunosuppression is the mainstay of treatment, since the response to acetyl-cholinesterase inhibitors is generally unsatisfactory and thymectomy does not appear to improve the course of the disease. Although corticosteroids result in marked improvement, disease flares are frequent during prednisone dosage tapering and most patients remain dependent on treatment. Since treatment with rituximab, in uncontrolled studies, induced sustained benefit in patients with refractory disease, B cell depletion is an attractive option for MuSK-MG patients unresponsive to conventional immunosuppressants.
  Autoimmunity reviews 03/2013;
• Article: Myasthenia Gravis: Special issue.

  Sonia Berrih-Aknin, Miriam C Souroujon
  Autoimmunity reviews 03/2013;
• Article: The Different Roles of the Thymus in the Pathogenesis of the various Myasthenia Gravis Subtypes.

  Alexander Marx, Frederick Pfister, Berthold Schalke, Güher Saruhan-Direskeneli, Arthur Melms, Philipp Ströbel
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  ABSTRACT: The thymus plays distinct roles in the pathogenesis of the different Myasthenia gravis (MG) subtypes. Inflammatory, neoplastic and age-related alterations of the thymus are of pivotal relevance for the initiation of anti-acetylcholine receptor (AChR)autoimmunity in early onset MG, thymoma-associated MG and, likely, late onset MG, respectively. By contrast, the thymus is presumably not related to MG that is due to autoantibodies to the muscle specific kinase, MuSK. Finally, the role of the thymus is still obscure in MG defined by antibodies against the agrin receptor LRP4 and in MG without all of the above autoantibdies (triple sero-negative MG) since these MG subtypes have been described only recently and thymectomy has not been their standard treatment. This review aims to give an update on intrathymic mechanisms of tolerance breakdown in MG, including abnormal T cell selection and activation, the role of thymic myoid cells, the autoimmune regulator (AIRE) and regulatory T cells.
  Autoimmunity reviews 03/2013;
• Article: Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4.

  Jan J G M Verschuuren, Maartje G Huijbers, Jaap J Plomp, Erik H Niks, Peter C Molenaar, Pilar Martinez Martinez, Alejandro M Gomez, Marc H De Baets, Mario Losen
  Autoimmunity reviews 03/2013;