Antibody-mediated Disorders Research Articles

Anti-platelet factor 4/polyanion antibodies mediate a new mechanism of autoimmunity

Antibodies recognizing complexes of the chemokine platelet factor 4 (PF4/CXCL4) and polyanions (P) opsonize PF4-coated bacteria hereby mediating bacterial host defense. A subset of these antibodies may activate platelets after binding to PF4/heparin complexes, causing the prothrombotic adverse drug reaction heparin-induced thrombocytopenia (HIT). In autoimmune-HIT, anti-PF4/P-antibodies activate platelets in the absence of heparin. Here we show that antibodies with binding forces of approximately 60–100 pN activate platelets in the presence of polyanions, while a subset of antibodies from autoimmune-HIT patients with binding forces ≥100 pN binds to PF4 alone in the absence of polyanions. These antibodies with high binding forces cluster PF4-molecules forming antigenic complexes which allow binding of polyanion-dependent anti-PF4/P-antibodies. The resulting immunocomplexes induce massive platelet activation in the absence of heparin. Antibody-mediated changes in endogenous proteins that trigger binding of otherwise non-pathogenic (or cofactor-dependent) antibodies may also be relevant in other antibody-mediated autoimmune disorders.

NMDA receptor encephalitis and other antibody-mediated disorders of the synapse: The 2016 Cotzias Lecture.

Investigations during the last 10 years have revealed a group of disorders mediated by antibodies against ion channels and synaptic receptors, which cause both neurologic and psychiatric symptoms. In this review, I discuss the process of discovery and immunologic triggers of these disorders, and use anti-NMDA receptor encephalitis to emphasize the importance of understanding the underlying physiopathologic mechanisms in those diseases. A better knowledge of these mechanisms reveals points of convergence with other disorders (e.g., schizophrenia), suggests treatment strategies beyond immunotherapy, and is helping us understand how memories are formed and retrieved.

Toward Clinical use of the IgG Specific Enzymes IdeS and EndoS against Antibody-Mediated Diseases.

The endoglycosidase EndoS and the protease IdeS from the human pathogen Streptococcus pyogenes are immunomodulating enzymes hydrolyzing human IgG. IdeS cleaves IgG in the lower hinge region, while EndoS hydrolyzes the conserved N-linked glycan in the Fc region. Both enzymes are remarkably specific for human IgG that after hydrolysis loses most of its effector functions, such as binding to leukocytes and complement activation, all contributing to bacterial evasion of adaptive immunity. However, taken out of their infectious context, we and others have shown that IdeS and EndoS can alleviate autoimmune disease in a number of animal models of antibody-mediated disorders. In this chapter, we will briefly describe the discovery and characterization of these unique enzymes, present the findings from a number of animal models of autoimmunity where the enzymes have been tested, and outline the ongoing clinical testing of IdeS. Furthermore, we will discuss the rationale for further development of IdeS and EndoS into novel pharmaceuticals against diseases where IgG antibodies contribute to the pathology, including, but not restricted to, chronic and acute autoimmunity, transplant rejection, and antidrug antibody reactions.

Biophysical tools to assess the interaction of PF4 with polyanions.

The antigen in heparin-induced thrombocytopenia (HIT) is expressed on platelet factor 4 (PF4) when PF4 complexes with polyanions. In recent years, biophysical tools (e. g. circular dichroism spectroscopy, atomic force microscopy, isothermal titration calorimetry, x-ray crystallography, electron microscopy) have gained an important role to complement immunological and functional assays for better understanding the interaction of heparin with PF4. This allowed identification of those features that make PF4 immunogenic (e. g. a certain conformational change induced by the polyanion, a threshold energy of the complexes, the existence of multimeric complexes, a certain number of bonds formed by PF4 with the polyanion) and to characterize the morphology and thermal stability of complexes formed by the protein with polyanions. These findings and methods can now be applied to test new drugs for their potential to induce the HIT-like adverse drug effect by preclinical in vitro testing. The methods and techniques applied to characterize the antigen in HIT may also be helpful to better understand the mechanisms underlying other antibody-mediated disorders in thrombosis and hemostasis (e. g. acquired hemophilia, thrombotic thrombocytopenic purpura). Furthermore, understanding the mechanisms making the endogenous protein PF4 immunogenic may help to understand the mechanisms underlying other autoimmune disorders.

Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia.

HIT is an acquired antibody-mediated disorder strongly associated with thrombosis, including microthrombosis secondary to disseminated intravascular dissemination (DIC). The clinical features of HIT are reviewed from the perspective of the 4Ts scoring system for HIT, which emphasises its characteristic timing of onset of thrombocytopenia. HIT antibodies recognize multimolecular complexes of platelet factor 4 (PF4)/heparin. However, a subset of HIT sera recognise PF4 bound to platelet chondroitin sulfate; these antibodies activate platelets in vitro and in vivo even in the absence of heparin, thus explaining: delayed-onset HIT (where HIT begins or worsens after stopping heparin); persisting HIT (where HIT takes several weeks to recover); spontaneous HIT syndrome (a disorder clinically and serologically resembling HIT but without proximate heparin exposure); and fondaparinux-associated HIT (four distinct syndromes featuring thrombocytopenia that begins or worsens during treatment with fondaparinux), with a new patient case presented with ongoing thrombocytopenia (and fatal haemorrhage) during treatment of HIT with fondaparinux, with fondaparinux-dependent platelet activation induced by patient serum ("fondaparinux cross-reactivity"). Ironically, despite existence of fondaparinux-associated HIT, this pentasaccharide anticoagulant is a frequent treatment for HIT (including one used by the author). HIT can be confused with other disorders, including those with a) timing similar to HIT (e. g. abciximab-associated thrombocytopenia of delayed-onset); b) combined thrombocytopenia/thrombosis (e. g. symmetrical peripheral gangrene secondary to acute DIC and shock liver); and c) both timing of onset and thrombosis (e. g. warfarin-associated venous limb gangrene complicating cancer-associated DIC). By understanding clinical and pathophysiological similarities and differences between HIT and non-HIT mimicking disorders, the clinician is better able to make the correct diagnosis.

Mapping autoantigen epitopes: molecular insights into autoantibody-associated disorders of the nervous system.

BackgroundOur knowledge of autoantibody-associated diseases of the central (CNS) and peripheral (PNS) nervous systems has expanded greatly over the recent years. A number of extracellular and intracellular autoantigens have been identified, and there is no doubt that this field will continue to expand as more autoantigens are discovered as a result of improved clinical awareness and methodological practice. In recent years, interest has shifted to uncover the target epitopes of these autoantibodies.Main bodyThe purpose of this review is to discuss the mapping of the epitope targets of autoantibodies in CNS and PNS antibody-mediated disorders, such as N-methyl-D-aspartate receptor (NMDAR), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), leucine-rich glioma-inactivated protein 1 (Lgi1), contactin-associated protein-like 2 (Caspr2), myelin oligodendrocyte glycoprotein (MOG), aquaporin-4 (AQP4), 65 kDa glutamic acid decarboxylase (GAD65), acetylcholine receptor (AChR), muscle-specific kinase (MuSK), voltage-gated calcium channel (VGCC), neurofascin (NF), and contactin. We also address the methods used to analyze these epitopes, the relevance of their determination, and how this knowledge can inform studies on autoantibody pathogenicity. Furthermore, we discuss triggers of autoimmunity, such as molecular mimicry, ectopic antigen expression, epitope spreading, and potential mechanisms for the rising number of double autoantibody-positive patients.ConclusionsMolecular insights into specificity and role of autoantibodies will likely improve diagnosis and treatment of CNS and PNS neuroimmune diseases.

Efficacy of Polyvalent Human Immunoglobulins in an Animal Model of Neuromyelitis Optica Evoked by Intrathecal Anti-Aquaporin 4 Antibodies.

Neuromyelitis Optica Spectrum Disorders (NMOSD) are associated with autoantibodies (ABs) targeting the astrocytic aquaporin-4 water channels (AQP4-ABs). These ABs have a direct pathogenic role by initiating a variety of immunological and inflammatory processes in the course of disease. In a recently-established animal model, chronic intrathecal passive-transfer of immunoglobulin G from NMOSD patients (NMO-IgG), or of recombinant human AQP4-ABs (rAB-AQP4), provided evidence for complementary and immune-cell independent effects of AQP4-ABs. Utilizing this animal model, we here tested the effects of systemically and intrathecally applied pooled human immunoglobulins (IVIg) using a preventive and a therapeutic paradigm. In NMO-IgG animals, prophylactic application of systemic IVIg led to a reduced median disease score of 2.4 on a 0–10 scale, in comparison to 4.1 with sham treatment. Therapeutic IVIg, applied systemically after the 10th intrathecal NMO-IgG injection, significantly reduced the disease score by 0.8. Intrathecal IVIg application induced a beneficial effect in animals with NMO-IgG (median score IVIg 1.6 vs. sham 3.7) or with rAB-AQP4 (median score IVIg 2.0 vs. sham 3.7). We here provide evidence that treatment with IVIg ameliorates disease symptoms in this passive-transfer model, in analogy to former studies investigating passive-transfer animal models of other antibody-mediated disorders.

Anti N-Methyl-D-Aspartate Receptor Encephalitis with Ovarian Teratoma: A Dilemma in Diagnosis

We report a rare case of altered mental status in a young patient with immature ovarian teratoma. A 22-year-old woman presented with seizures, hallucination, amnesia and orofacial dyskinesia. Examination and investigation revealed an ovarian massand asalphing-oophorectomy was performed. The histopathological examination result showed an immature teratoma grade 2 with thepresence of immature primitive glial tissue. Her CSF N-Methyl-D-Aspartic acid receptor (Anti-NMDAR) antibodytest was positive. N-Methyl-D-Aspartic acid receptor antibody associated limbic encephalitis is an autoimmune antibody-mediated neuropsychiatric disorder. Resection of the tumour and immunotherapy resulted in full recovery.

Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society.

Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating fatigability and weakness affecting ocular, bulbar and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4+ T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AchR) itself, or muscle-specific tyrosine-kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4) and agrin involved in clustering of AchRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in disturbance of neuromuscular transmission and thus clinical manifestation of the disease. Emphasizing evidence from clinical trials, we provide an updated overview on immunopathogenesis, and derived current and future treatment strategies for MG divided into: (a) symptomatic treatments facilitating neuromuscular transmission, (b) antibody-depleting treatments, and (c) immunotherapeutic treatment strategies.

Chapter 26 - Autoimmune neurologic disorders in children

Autoimmune neurologic diseases are of major clinical importance in children. Antibody-mediated diseases of the central nervous system are now increasingly recognized in childhood, where the antibodies bind to cell surface epitopes on neuronal or glial proteins, and the patients demonstrate either focal or more generalized clinical signs depending on the extent of brain regions targeted by the antibodies. The antibodies are directed towards ion channels, receptors, and membrane proteins; and the diseases include limbic encephalitis and N-methyl-d-aspartate receptor-antibody encephalitis, among many others. Additionally there are conditions where the wider immune system is implicated. Neurologic features like seizures, movement disorders, autonomic dysfunction, and sleep disorders, with neuroimaging and electrophysiologic features, may indicate a specific antibody-mediated or immune disorder. Often, phenotypic overlap is observed between these conditions, and phenotypic variation seen in children with the same condition. Nevertheless, many patients benefit from immunotherapy with substantial improvement, although huge efforts are still required to optimize the outcome for many patients. In many patients no antibodies have yet been identified, even though they respond to immunotherapies. Here we describe the known antibodies and associated diseases, discuss conditions that are thought to be immune-mediated but have no known immunologic biomarker, and provide guidelines for the investigation and classification of these disorders.

Membrane Remodeling By Pathogenic Antibodies Underlies Monocyte Activation in Heparin-Induced Thrombocytopenia

Heparin induced thrombocytopenia (HIT) is an iatrogenic antibody-mediated disorder with a paradoxically high propensity for thrombosis. We have shown previously that human HIT IgGs and the HIT-like monoclonal antibody (MAb) KKO bind to platelet factor 4 (PF4) complexed with glycosaminoglycans (GAGs) on the surface of platelets and monocytes, initiating cell activation in vitro, thrombocytopenia in a transgenic mouse model, and thrombus formation in a laser microvascular injury model in vivo even in the absence of exogenous heparin. Monocytes bind PF4 and HIT Ab more readily than platelets because they express higher affinity GAGs, heparan sulfate and dermatan sulfate, in addition to chondroitin sulfate found on both cell types. To study changes in the structure of the monocytes that accompany HIT, we used scanning electron microscopy, confocal microscopy and flow cytometry to characterize the morphology and function of isolated human monocytes and mouse transgenic Fcg receptor IIA positive (FcγRIIA+) or wt (FcγRIIA-) monocytes in the absence or presence of platelets. We show by scanning electron microscopy that upon binding of pathogenic HIT Abs to PF4/GAG complexes on FcgRIIA expressing monocytes, they initiate profound remodeling of the cell membrane. Addition of 100 μg/ml recombinant human PF4 in the absence of HIT Abs initiates the activation process with the appearance of 177 ± 53 nm "knobs" on the surface of 70% of monocytes. Subsequent addition of the HIT-like monoclonal antibody KKO at 50 μg/ml dramatically alters the cellular surface with the appearance of large 701 ± 208 nm membrane "blebs" that were not seen on FcγRIIA-mouse monocytes. These large, membrane-associated structures likely engage FcγRIIA, clustering them in proximity to cell-bound immune complexes, which promotes cell activation that leads to thrombosis. These blebs increase in size over time and are then shed from the cells as monocyte-derived microparticles, which self-aggregate. As a result of shedding of these blebs, the monocytes lose much of their typical ruffled surface (only 67% of monocytes maintain ruffles in the presence of PF4 plus KKO, compared to 97% of control monocytes) and appear smoother, sometimes with pores indicating degranulation. In the presence of platelets, monocytes exposed to PF4 and KKO formed heterocellular aggregates in addition to these subcellular changes. In contrast to KKO, addition of the non-pathogenic MAb RTO not only did not induce blebbing, but largely inhibited PF4-induced changes in the monocyte surface. This suggests that RTO might prevent monocyte activation by interfering with PF4 tetramerization. Structural analysis of the shed microparticles by microscopy revealed that they had an average diameter of 356 ± 307 nm, with many larger particles and aggregates. Flow cytometry confirmed that the shed particles contain cell membrane lipids and receptors. Confocal microscopy showed uniform binding of labeled PF4 to the monocyte cell membrane followed by rapid clustering into large complexes after the addition of KKO, but not RTO. These studies affirm the centrality of cell surface PF4/GAG complexes in the pathogenesis of HIT and provide quantitative morphometric characteristics of the changes in the monocyte membrane structure. We propose that PF4 released from activated platelets binds to the surface of GAG-expressing monocytes in vivo, forming clusters of PF4/GAG complexes that likely promote antibody binding and cause monocyte activation through FcγRIIA along with large-scale remodeling of the cell membrane and shedding of procoagulant microparticles. DisclosuresNo relevant conflicts of interest to declare.

Autoimmune autonomic ganglionopathy: Bench to Bedside

Autoimmune autonomic ganglionopathy (AAG) presents as severe generalized sympathetic and parasympathetic autonomic failure. This disorder is also known as acute pandysautonomia or idiopathic subacute autonomic neuropathy. Themost disablingmanifestations are orthostatic hypotension (OH) and gastrointestinal dysmotility. An autoimmune pathogenesis was suggested by the subacute onset, frequent associationwith antecedent viral illness, occasional association with cancer or other autoimmune disorders, and spontaneous recovery in some patients. Many cases have a rapid onset, but others have a chronic progressive course. Clinical and experimental observations demonstrate that AAG is an antibody-mediated disorder. (1) AAG patients have high levels of serum antibodies specific for the neuronal AChR in autonomic ganglia. This ganglionic AChR mediates fast synaptic transmission in all autonomic ganglia. Ganglionic AChR antibodies found in AAG patients are distinct from muscle AChR antibodies found in patients with MG. (2) Ganglionic AChR antibody levels correlate with severity of autonomic deficits. Patients with high antibody levels have a combination of OH, dry eyes and dry mouth, Adies pupil, gastroparesis, and neurogenic bladder. (3) Induction of ganglionic AChR antibodies in rabbits by immunization leads to experimental AAG which reproduces many of the cardinal features of the human disease. (4) Passive transfer of ganglionic AChR antibodies tomice causes transient autonomic failure. In electrophysiological studies, ganglionic AChR antibodies produce a reduction in ganglionic AChR current in cultured neuroblastoma cells and inhibit synaptic transmission in isolated autonomic ganglia. AAG is an antibody-mediated channelopathy that produces a severe, but treatable, form of autonomic failure.

Neuroinflammation: Ways in Which the Immune System Affects the Brain.

Neuroinflammation is the response of the central nervous system (CNS) to disturbed homeostasis and typifies all neurological diseases. The main reactive components of the CNS include microglial cells and infiltrating myeloid cells, astrocytes, oligodendrocytes, and the blood-brain barrier, cytokines, and cytokine signaling. Neuroinflammatory responses may be helpful or harmful, as mechanisms associated with neuroinflammation are involved in normal brain development, as well as in neuropathological processes. This review examines the roles of various cell types that contribute to the immune dysregulation associated with neuroinflammation. Microglia enter the CNS very early in embryonic development and, as such, play an essential role in both the healthy and diseased brain. B-cell diversity contributes to CNS disease through both antibody-dependent and antibody-independent mechanisms. The influences of these B-cell mechanisms on other cell types, including myeloid cells and T cells, are reviewed in relationship to antibody-mediated CNS disorders, paraneoplastic neurological diseases, and multiple sclerosis. New insights into neuroinflammation offer exciting opportunities to investigate potential therapeutic targets for debilitating CNS diseases.

OP43 – 2438: Generalized juvenile myasthenia gravis: Long-term outcome

Juvenile myasthenia gravis (JMG) is an antibody-mediated autoimmune disorder of the neuromuscular junction, with the first symptoms under 18. Objective To evaluate the course of generalized JMG in patients who have the disease for more than 5 years. Methods 44 patients were examined. Results The average age of JMG onset was 14±2.6 years; 16% of men and 84% of women. The average duration of the disease was 14.5 years (from 5 to 43). According to the MGFA clinical classification maximum severity of the disease during the entire period was the following: 12 (27.3%) patients had 2a and 2b, 18 (40.9%) – 3a and 3b, 8 (18.2%) – 4a and 4b, 6 (13.6%) of them had myasthenic crisis. In 41 (93.2%) cases, the maximum severity of the disease was already observed in the first 3 years after onset. The treatment was the following: 31 (70.5%) patients were treated with glucocorticoids, 12 (27.3%) – with cytostatics (azathioprine, cyclosporine), 24 (54.6%) – repeated courses of plasmapheresis and 4 (9%) with VVIG. Thymectomy was performed in 32 (72.7%) cases (in 11cases under 18, in 21 – after 18). The postintervention status (at the present time): 8 (18.2%) patients have a complete stable remission, 2 (4.5%) – pharmacologic remission, 30 patients were improved, but continued to take some medications (19 (43.2%)- immunosupression drug and pyridostigmine, 11 (25%) – only pyridostigmine). In 4 (9%) cases, there was no improvement: all of them were female; they had early onset (from 8 to 12 years old), class 4 and 5 of the severity at the beginning and had antibodies to AchR above 20 nmol/l. 10 (27.0%) out of the 37 women were pregnant, gave birth to 12 children. 1 (8.3%) child had transient neonatal myasthenia. Conclusion Early age onset, female gender, severe course at the beginning of the disease are the predictors to treatment-resistant myasthenia.

The transfusion‐related acute lung injury controversy: lessons from heparin‐induced thrombocytopenia

The transfusion‐related acute lung injury controversy: lessons from heparin‐induced thrombocytopenia

Critical Role of T Cells in PF4/Heparin Antibody Production

Heparin-induced thrombocytopenia (HIT) is an antibody-mediated disorder that can cause arterial or venous thrombosis/thromboembolism, and platelet factor 4 (PF4)/ heparin-reactive antibodies are essential to the pathogenesis of HIT. Our recent studies have demonstrated that marginal zone (MZ) B cells play a major role in production of PF4/heparin-specific antibodies. However, the role of T cells in production of these pathogenic antibodies is not clear. Here we showed that PF4/heparin complex-induced production of PF4/heparin-specific antibodies was markedly impaired in mice, in which CD4 T cells were depleted by administration of GK1.5 anti-CD4 monoclonal antibody. As expected, the CD4 T cell-depleted mice responded normally to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, in agreement with the lack of CD4 T cells in these GK1.5-treated mice. Further, following adoptive transfer of a mixture of wild-type splenic B cells and splenocytes from B cell-deficient μMT mice, T and B cell-deficient Rag1 knockout mice responded to PF4/heparin complex challenge to produce PF4/heparin-specific antibodies. In contrast, Rag1-deficient mice that received a mixture of wild-type splenic B cells and splenocytes from Rag1-deficient mice barely produced PF4/heparin-specific antibodies upon PF4/heparin complex challenge. These data suggest that T cells are required for production of PF4/heparin-specific antibodies. Consistent with this concept, mice with B cells lacking CD40 molecule, a B cell costimulatory molecule that helps T cell-dependent B cell responses, displayed a marked reduction of PF4/heparin-specific antibody production following PF4/heparin complex challenge. Also as expected, mice with CD40-deficient B cells were able to respond to T cell-independent antigen TNP-Ficoll but not T cell-dependent antigen NP-CGG, consistent with the lack of T-cell help in these mice. Taken together, these findings demonstrate that T cells play an essential role in production of PF4/heparin-specific antibodies by MZ B cells. DisclosuresNo relevant conflicts of interest to declare.

Regulation of germinal center, B-cell memory, and plasma cell formation by histone modifiers.

Understanding the regulation of antibody production and B-cell memory formation and function is core to finding new treatments for B-cell-derived cancers, antibody-mediated autoimmune disorders, and immunodeficiencies. Progression from a small number of antigen-specific B-cells to the production of a large number of antibody-secreting cells is tightly regulated. Although much progress has been made in revealing the transcriptional regulation of B-cell differentiation that occurs during humoral immune responses, there are still many questions that remain unanswered. Recent work on the expression and roles of histone modifiers in lymphocytes has begun to shed light on this additional level of regulation. This review will discuss the recent advancements in understanding how humoral immune responses, in particular germinal centers and memory cells, are modulated by histone modifiers.

Paraneoplastische neurologische Syndrome und Autoimmunenzephalitiden

Paraneoplastic neurological syndromes (PNS) are defined as remote effects on the central and peripheral nervous system that are not caused directly by the tumor, its metastases and treatment, or metabolic disorders. The most probable cause is a falsely initiated immune reaction. Well-defined classical PNSs are associated with distinct tumors and occur with onconeural antibodies directed against intracellular neuronal antigens. However, response to therapy is limited. Recently, new antibodies directed against neuronal surface antigens were described in encephalitic syndromes of autoimmune origin. These probably antibody-mediated disorders are more frequent than classical PNS, occur with or without tumor association and often show a good response to immunosuppressive treatment.

Techniques and applications of perioperative therapeutic plasma exchange

Therapeutic plasma exchange (TPE) is a useful adjunct in the management of antibody-mediated disorders. The indications for TPE now include the perioperative setting. This review updates the anesthesiologist on the relevant clinical indications and precautions of plasma exchange. Although still considered experimental, TPE for heparin-induced thrombocytopenia for urgent cardiac surgery is the most promising recent advance. Plasmapheresis, or TPE, removes monoclonal antibodies, immune complexes and paraproteins. The utility of TPE in the perioperative period has recently become more apparent. Antibody-mediated disorders are associated with postoperative morbidity and mortality and are treated with TPE. Indications for TPE for cardiac surgery include heparin-induced thrombocytopenia, thrombotic thrombocytopenia purpura and antiphospholipid syndrome. Other indications for perioperative TPE are typically related to immunomodulation during solid-organ transplant. Immunomodulation, primarily with immunosuppressive medications and TPE, of a previously allosensitized recipient pretransplant increases the likelihood of a successful match. TPE is also useful in the management of intentional and inadvertent ABO incompatible recipients and is essential in the treatment of hyperacute rejection. TPE will likely be more utilized in the future and understanding the essentials of the procedure will facilitate the perioperative management of antibody-mediated disorders.

Advances in Neuroimmunology: From Bench to Bedside

The understanding of the interactions between the immune and the nervous systems and the resultant therapeutic implications has expanded significantly in the last decade [1]. There have been significant developments in the field of neuroimmunology as new antibody-mediated disorders have been described and involvement of the immune system in the pathogenesis of neurodegenerative diseases has been established [2, 3]. These discoveries have led to novel and effective treatments, which have broadened our therapeutic options regarding neuroimmune disorders [4, 5]. The goal of this special issue was to address the translational aspects of neuroimmunology, “from bench to bedside,” in order to update clinicians on basic research discoveries that will have therapeutic clinical efficacy. Moreover, there was an emphasis on conditions that have undergone a systematic nosographic characterization which have resulted in therapeutic approaches with greater specificity. In this context, the paper entitled “Immunotherapy of neuromyelitis optica” provides a framework for understanding an antibody-mediated central nervous system demyelinating disease that has a different pathophysiology than multiple sclerosis (MS). This distinction is important as NMO responds to different immunomodulating agents than does MS. The spectrum of pediatric MS has also been the focus of extensive nosographic revision in recent years, and diagnostic criteria have been recently revised by the International Pediatric Multiple Sclerosis Study Group (IPMSSG) [6]. The paper “Pediatric multiple sclerosis: current concepts and consensus definitions” offers a careful update on risk factors, clinical manifestations, diagnostic procedures, prognostic implications, and treatment of this increasingly frequent form of MS. MS is a salient neuroimmunological disease for which the “bench to bedside approach” has provided the greatest therapeutic advances. Although there are more treatments for MS, the study of novel and less explored molecular pathways ought to provide relevant alternative targets. This concept is well expressed in the paper entitled “Current understanding on the role of standard- and immuno-proteasomes in inflammatory/immunological pathways of Multiple Sclerosis,” in which the authors describe the current knowledge on the potential role of proteasomes in MS and discuss the pro et contra of possible therapies for MS targeting proteasome isoforms. Immune mediated diseases of the peripheral nervous system (PNS) are less studied than their “central” counterparts [7]. Nonetheless, important advances in both pathogenesis and treatment of inflammatory demyelinating neuropathies have been extensively evaluated in the articles authored by J. B. Weiner and P. Ripellino et al. The first publication entitled “An update in Guillain-Barre Syndrome” provides a comprehensive discussion of the current state of knowledge on acute inflammatory neuropathies from diagnosis to treatment. The second article, entitled “Treatment of chronic inflammatory demyelinating polyneuropathy: from molecular bases to practical considerations,” bridges the biological rationale of immunotherapy to clinical practice also in the context of pharmacoeconomics. Finally, the paper entitled “An update in the use of antibodies to treat glioblastoma multiforme” reviews the current knowledge on an expanding field immunotherapy, which is expected to have a significant impact on the progression of these high grade gliomas. The editors believe that you will agree that this special issue will prove to be highly valuable to basic scientists and clinicians alike. Cristoforo Comi Umberto Dianzani Filippo Martinelli Boneschi Daniel Menkes