Membranöse Glomerulopathie-eine Autoimmunerkrankung

Membranous nephropathy is one of the most common glomerular diseases and leading causes of nephrotic syndrome in Caucasian adults. Known as a clinico-pathologic entity for over 50 years, it is defined by thickening of the glomerular capillary membrane with subepithelial immuncomplexes. Secondary forms (e. g. hepatitis B, autoimmune disease or medication-induced) are distinguished from idiopathic forms. Despite spontaneous remissions in about 30 % of cases, one third of idiopathic forms progress to end-stage renal disease after 10 years. Seminal research progress of the last decade has allowed the identification of autoantibodies directed against podocytary elements leading to secondary damage to the filtration barrier. The so-called idiopathic membranous nephropathy has thus become a prototype of autoimmune disease. The autoantibodies detectable in 70 - 80 % of cases of idiopathic membranous nephropathy are directed against the M-type phospholipase A2-receptor on the podocyte membrane and correlate with disease activity. These epochal findings influence on diagnostic and therapeutic strategies establishing a rationale for the use of B cell-directed therapy on top of optimal supportive therapy.

Is dosing of therapeutic immunoglobulins optimal? A review of a three-decade long debate in europe.

The consumption of immunoglobulins (Ig) is increasing due to better recognition of antibody deficiencies, an aging population, and new indications. This review aims to examine the various dosing regimens and research developments in the established and in some of the relevant off-label indications in Europe. The background to the current regulatory settings in Europe is provided as a backdrop for the latest developments in primary and secondary immunodeficiencies and in immunomodulatory indications. In these heterogeneous areas, clinical trials encompassing different routes of administration, varying intervals, and infusion rates are paving the way toward more individualized therapy regimens. In primary antibody deficiencies, adjustments in dosing and intervals will depend on the clinical presentation, effective IgG trough levels and IgG metabolism. Ideally, individual pharmacokinetic profiles in conjunction with the clinical phenotype could lead to highly tailored treatment. In practice, incremental dosage increases are necessary to titrate the optimal dose for more severely ill patients. Higher intravenous doses in these patients also have beneficial immunomodulatory effects beyond mere IgG replacement. Better understanding of the pharmacokinetics of Ig therapy is leading to a move away from simplistic "per kg" dosing. Defective antibody production is common in many secondary immunodeficiencies irrespective of whether the causative factor was lymphoid malignancies (established indications), certain autoimmune disorders, immunosuppressive agents, or biologics. This antibody failure, as shown by test immunization, may be amenable to treatment with replacement Ig therapy. In certain immunomodulatory settings [e.g., idiopathic thrombocytopenic purpura (ITP)], selection of patients for Ig therapy may be enhanced by relevant biomarkers in order to exclude non-responders and thus obtain higher response rates. In this review, the developments in dosing of therapeutic immunoglobulins have been limited to high and some medium priority indications such as ITP, Kawasaki' disease, Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, myasthenia gravis, multifocal motor neuropathy, fetal alloimmune thrombocytopenia, fetal hemolytic anemia, and dermatological diseases.

A highly conserved interspecies V(H) in the human genome.

Idiotype conservation between human and mouse antibodies has been observed in association with various infectious and autoimmune diseases. We have isolated a human anti-idiotypic antibody to a mouse monoclonal anti-IgE antibody (BSW17) suggesting a conserved interspecies idiotype associated with an anti-IgE response. To find the homologue of BSW17 in the human genome we applied the guided selection strategy. Combining V(H) of BSW17 with a human V(L) repertoire resulted in three light chains. The three V(L) chains were then combined with a human V(H) repertoire resulting in three clones specific for human IgE. Surprisingly, one clone, Hu41, had the same epitope specificity and functional in vitro activity as BSW17 and V(H) complementarity-determining regions identical with that of BSW17. Real-time PCR analysis confirmed the presence of the Hu41 V(H) sequence in the human genome. These data document the first example of the isolation of a human antibody where high sequence similarity to the original murine V(H) sequence is associated with common antigen and epitope specificity.

A high-affinity natural autoantibody from human cord blood defines a physiologically relevant epitope on the FcepsilonRIalpha.

Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the alpha domain of the high-affinity IgE receptor (FcepsilonRIalpha) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-FcepsilonRIalpha Abs are present in the germline repertoire, we constructed a phage Fab display library from human cord blood, which represents the naive immune repertoire before exposure to exogenous Ags. All isolated clones specific to the FcepsilonRIalpha had the same sequence. This single IgM Ab, named CBMalpha8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the FcepsilonRIalpha recognized by both CBMalpha8 and the previously isolated anti-FcepsilonRIalpha Abs from autoimmune and healthy donors. This common epitope on FcepsilonRIalpha coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBMalpha8-like specificity, but with a significantly lower affinity in i.v. Ig, a therapeutic multidonor IgG preparation. We propose a hypothesis of escape mutants, whereby the resulting lower affinity IgG anti-FcepsilonRIalpha Abs are rendered less likely to compete with IgE for binding to FcepsilonRIalpha.

EAACI IG Biologicals task force paper on the use of biologic agents in allergic disorders.

Biologic agents (also termed biologicals or biologics) are therapeutics that are synthesized by living organisms and directed against a specific determinant, for example, a cytokine or receptor. In inflammatory and autoimmune diseases, biologicals have revolutionized the treatment of several immune-mediated disorders. Biologicals have also been tested in allergic disorders. These include agents targeting IgE; T helper 2 (Th2)-type and Th2-promoting cytokines, including interleukin-4 (IL-4), IL-5, IL-9, IL-13, IL-31, and thymic stromal lymphopoietin (TSLP); pro-inflammatory cytokines, such as IL-1β, IL-12, IL-17A, IL-17F, IL-23, and tumor necrosis factor (TNF); chemokine receptor CCR4; and lymphocyte surface and adhesion molecules, including CD2, CD11a, CD20, CD25, CD52, and OX40 ligand. In this task force paper of the Interest Group on Biologicals of the European Academy of Allergy and Clinical Immunology, we review biologicals that are currently available or tested for the use in various allergic and urticarial pathologies, by providing an overview on their state of development, area of use, adverse events, and future research directions.

Eosinophilia in Dermatologic Disorders

Eosinophil infiltration can be observed in skin disorders, such as allergic/immunologic, autoimmune, infectious, and neoplastic diseases. Clinical presentations are variable and include eczematous, papular, urticarial, bullous, nodular, and fibrotic lesions; pruritus is a common symptom in all. In this review, we present representative eosinophilic skin diseases according to their clinical pattern, together with histologic findings and diagnostic procedures. We also discuss the potential roles of eosinophils in the pathogenesis of dermatologic disorder. Current pathogenesis-based diagnostic and therapeutic approaches are outlined.

Myositides : What is the current situation?

This article gives a review of the classification, diagnostic procedures and treatment of idiopathic inflammatory myopathies from a neurological point of view. The myositis syndromes can be subdivided into four groups, polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM) and necrotizing myopathy (NM), which substantially differ clinically and pathophysiologically. Myositis may also occur in association with cancer or autoimmune systemic diseases (overlap syndrome). Diagnosis of inflammatory myopathies is based on clinical symptoms, determination of creatine phosphokinase and acute phase parameters in blood (e.g. C-reactive protein and erythrocyte sedimentation rate), electromyography results and findings of magnetic resonance imaging (MRI) in muscle. A muscle biopsy is mandatory to confirm the diagnosis. High quality randomized controlled trials of treatment regimens for inflammatory myopathies are sparse; however, empirical experience indicates a clear effectiveness of immunosuppressive treatment of PM, DM and NM.

PreImplantation Factor bolsters neuroprotection via modulating Protein Kinase A and Protein Kinase C signaling

A synthetic peptide (sPIF) analogous to the mammalian embryo-derived PreImplantation Factor (PIF) enables neuroprotection in rodent models of experimental autoimmune encephalomyelitis and perinatal brain injury. The protective effects have been attributed, in part, to sPIF's ability to inhibit the biogenesis of microRNA let-7, which is released from injured cells during central nervous system (CNS) damage and induces neuronal death. Here, we uncover another novel mechanism of sPIF-mediated neuroprotection. Using a clinically relevant rat newborn brain injury model, we demonstrate that sPIF, when subcutaneously administrated, is able to reduce cell death, reverse neuronal loss and restore proper cortical architecture. We show, both in vivo and in vitro, that sPIF activates cyclic AMP dependent protein kinase (PKA) and calcium-dependent protein kinase (PKC) signaling, leading to increased phosphorylation of major neuroprotective substrates GAP-43, BAD and CREB. Phosphorylated CREB in turn facilitates expression of Gap43, Bdnf and Bcl2 known to have important roles in regulating neuronal growth, survival and remodeling. As is the case in sPIF-mediated let-7 repression, we provide evidence that sPIF-mediated PKA/PKC activation is dependent on TLR4 expression. Thus, we propose that sPIF imparts neuroprotection via multiple mechanisms at multiple levels downstream of TLR4. Given the recent FDA fast-track approval of sPIF for clinical trials, its potential clinical application for treating other CNS diseases can be envisioned.

Immune response in pemphigus and beyond: progresses and emerging concepts

Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two severe autoimmune bullous diseases of the mucosae and/or skin associated with autoantibodies directed against desmoglein (Dsg) 3 and/or Dsg1. These two desmosomal cadherins, typifying stratified epithelia, are components of cell adhesion complexes called desmosomes and represent extra-desmosomal adhesion receptors. We herein review the advances in our understanding of the immune response underlying pemphigus, including human leucocyte antigen (HLA) class II-associated genetic susceptibility, characteristics of pathogenic anti-Dsg antibodies, antigenic mapping studies as well as findings about Dsg-specific B and T cells. The pathogenicity of anti-Dsg autoantibodies has been convincingly demonstrated. Disease activity and clinical phenotype correlate with anti-Dsg antibody titers and profile while passive transfer of anti-Dsg IgG from pemphigus patients' results in pemphigus-like lesions in neonatal and adult mice. Finally, adoptive transfer of splenocytes from Dsg3-knockout mice immunized with murine Dsg3 into immunodeficient mice phenotypically recapitulates PV. Although the exact pathogenic mechanisms leading to blister formation have not been fully elucidated, intracellular signaling following antibody binding has been found to be necessary for inducing cell-cell dissociation, at least for PV. These new insights not only highlight the key role of Dsgs in maintenance of tissue homeostasis but are expected to progressively change pemphigus management, paving the way for novel targeted immunologic and pharmacologic therapies.

Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology

Bullous pemphigoid is the most common autoimmune subepidermal blistering disease of the skin and mucous membranes. This disease typically affects the elderly and presents with itch and localized or generalized bullous lesions. In up to 20% of affected patients, bullae may be completely absent, and only excoriations, prurigo-like lesions, eczematous lesions, urticated lesions and/or infiltrated plaques are observed. The disease is significantly associated with neurological disorders. The morbidity of bullous pemphigoid and its impact on quality of life are significant. So far, a limited number of national treatment guidelines have been proposed, but no common European consensus has emerged. Our consensus for the treatment of bullous pemphigoid has been developed under the guidance of the European Dermatology Forum in collaboration with the European Academy of Dermatology and Venereology. It summarizes evidence-based and expert-based recommendations.

Definitions and outcome measures for mucous membrane pemphigoid: recommendations of an international panel of experts

Mucous membrane pemphigoid encompasses a group of autoimmune bullous diseases with a similar phenotype characterized by subepithelial blisters, erosions, and scarring of mucous membranes, skin, or both. Although knowledge about autoimmune bullous disease is increasing, there is often a lack of clear definitions of disease, outcome measures, and therapeutic end points. With clearer definitions and outcome measures, it is possible to directly compare the results and data from various studies using meta-analyses. This consensus statement provides accurate and reproducible definitions for disease extent, activity, outcome measures, end points, and therapeutic response for mucous membrane pemphigoid and proposes a disease extent score, the Mucous Membrane Pemphigoid Disease Area Index.

Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV)

BACKGROUND Pemphigus encompasses a group of life-threatening autoimmune bullous diseases characterized by blisters and erosions of the mucous membranes and skin. Before the era of immunosuppressive treatment, the prognosis of pemphigus was almost fatal. Due to its rarity, only few prospective controlled therapeutic trials are available. OBJECTIVES For this reason, a group of European dermatologists with a long-standing interest and expertise in basic and clinical pemphigus research has sought to define diagnostic and therapeutic guidelines for the management of patients with pemphigus. RESULTS This group identified the statements of major agreement or disagreement regarding the diagnostic and therapeutic management of pemphigus. The revised final version of the pemphigus guideline was finally passed on to the European Dermatology Forum (EDF) for a final consensus with the European Academy of Dermatology and Venereology (EADV) and the European Union of Medical Specialists (UEMS).

The expanding role of immunopharmacology: IUPHAR Review 16

Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research have made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar (http://iuphar.us/index.php/sections-subcoms/immunopharmacology) is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR, http://iuphar.us/). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.

Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

OBJECTIVE Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. DESIGN HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. RESULTS HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10-4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10-3), and B*35:01 (OR=1.46 [1.13-1.89] P = 3.64*10-3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10-5) and HLA-C-Ser11 (OR=1.34 [1.15-1.57] P = 2.43*10-4). CONCLUSIONS Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons.