The unique properties of IgG4 and its roles in health and disease

IgG4 has unique functional characteristics that are increasingly recognized to have a pathogenic role in autoimmunity, tumour immunology, IgG4-related diseases and anti-biologic responses, as well as a beneficial role in allergy and parasitic infections.IgG4 is the least abundant subclass of IgG in human serum and has unique functional features. IgG4 is largely unable to activate antibody-dependent immune effector responses and, furthermore, undergoes Fab (fragment antigen binding)-arm exchange, rendering it bispecific for antigen binding and functionally monovalent. These properties of IgG4 have a blocking effect, either on the immune response or on the target protein of IgG4. In this Review, we discuss the unique structural characteristics of IgG4 and how these contribute to its roles in health and disease. We highlight how, depending on the setting, IgG4 responses can be beneficial (for example, in responses to allergens or parasites) or detrimental (for example, in autoimmune diseases, in antitumour responses and in anti-biologic responses). The development of novel models for studying IgG4 (patho)physiology and understanding how IgG4 responses are regulated could offer insights into novel treatment strategies for these IgG4-associated disease settings.Functional Genomics of Muscle, Nerve and Brain Disorder

Fundamental Molecules and Mechanisms for Forming and Maintaining Neuromuscular Synapses

Neurological Motor Disorder

Trials, Truth-telling and the Performing Body

In this thesis, I examine the role performance plays in the adversarial criminal jury trial. The initial motivation behind this inquiry was the pervasiveness of a metaphor: why is the courtroom so frequently compared to a theatre? Most writings on this topic see the courtroom as bearing what might be termed a cosmetic resemblance to a theatre, making comparisons, for instance, between elements of costume and staging. I pursue a different line of argument. I argue that performance is not simply an embellishment of the trial process but rather a constitutive feature of the criminal jury trial. It is by means of what I call the performance of tradition that the trial acquires its social significance as a (supposedly) timeless bulwark of authority and impartiality. In the first three chapters I show that popular usage of the term ‘theatrical’ (whether it be to describe the practice of a flamboyant lawyer, or a misbehaving defendant) is frequently laden with pejorative connotations and invariably (though usually only implicitly) invokes comparison to a presupposed authentic or natural way of behaviour (‘not-performing’). Drawing on the work of Michel Foucault and Pierre Bourdieu I argue that, whatever legal agents see as appropriate trial conduct (behaviour that is ‘not-performing’), they are misrecognising the performative accomplishments and demands required of both legal agents and laypersons in the trial. This performance constructs and maintains a gap between legal practitioners and laypersons which is essential to maintaining the status of the legal profession, and which continually positions the trial in legal and popular belief. I then look at specific moments of ‘anxiety’ where alterations to traditional procedure provoke debate as to the otherwise unnoticed or unarticulated value of live performance. In Chapter 4, I examine the growth of the private advocacy training industry that frequently positions lawyers as actors. Resistance to the idea of acting demonstrates the tainted status of performance terminology as well as legal agents’ belief that lawyers are acting naturally. I argue instead that lawyers have always been trained in acting: an habituated performance style I term legal naturalism. In Chapter 5, I examine the television broadcasting of trials. Some legal agents argue that broadcasting risks ‘theatricalising’ the trial—causing participants to ‘act up’. However, this overlooks the fact that the court has a long history as a source of popular entertainment. I argue that resistance to broadcasting also stems from a reluctance to remit control of the trial to external producers. Broadcasting invites greater scrutiny into a process that if not always fair, needs to be believed in as fair and has historically been tightly self-regulated by the legal field, through its reliance on live performance’s ‘essential’ quality—its inability to be captured and subsequent disappearance. In Chapter 6, I examine the debates around CCTV testimony, which demonstrate a consistency of belief in live or ‘face-to-face’ confrontation to produce juridical ‘Truth’ that can be traced back over 800 years. The final chapter of this thesis examines sexual assault trials. This chapter brings together all of these sources of anxiety. Although often termed ‘exceptional’, sexual assault trials highlight how essential live performance is to manufacturing the authority of ‘The Law’ through the weight given to demeanour assessment, and because these trials make visible the sustained symbolic violence characteristic of adversarial criminal trials that is particularly traumatic for sexual assault complainants. Examination of sexual assault trials also reveals the double-edged position of performance in the trial. The exploitation of the symbolic value of live performance is the source of much trauma, yet the performance of tradition is also essential to maintaining popular belief in the adversarial criminal jury trial

IgG4-mediated autoimmune diseases: a niche of antibody-mediated disorders

Paroxysmal Cerebral DisordersNeurological Motor Disorder

Functional monovalency amplifies the pathogenicity of anti-MuSK IgG4 in myasthenia gravis

Human immunoglobulin (Ig) G4 usually displays antiinflammatory activity, and observations of IgG4 autoantibodies causing severe autoimmune disorders are therefore poorly understood. In blood, IgG4 naturally engages in a stochastic process termed "Fab-arm exchange" in which unrelated IgG4s exchange half-molecules continuously. The resulting IgG4 antibodies are composed of two different binding sites, thereby acquiring monovalent binding and inability to cross-link for each antigen recognized. Here, we demonstrate that this process amplifies autoantibody pathogenicity in a classic IgG4-mediated autoimmune disease: muscle-specific kinase (MuSK) myasthenia gravis. In mice, monovalent anti-MuSK IgG4s caused rapid and severemyasthenicmuscleweakness, whereas the same antibodies in their parental bivalent form were less potent or did not induce a phenotype. Mechanistically this could be explained by opposing effects onMuSK signaling. Isotype switching to IgG4 in an autoimmune response thereby may be a critical step in the development of disease. Our study establishes functional monovalency as a pathogenic mechanism in IgG4-mediated autoimmune disease and potentially other disorders.Neurological Motor Disorder

Autoantibody subclass predominance is not driven by aberrant class switching or impaired B cell development

A subset of autoimmune diseases is characterized by predominant pathogenic IgG4 autoantibodies (IgG4-AID). Why IgG4 predominates in these disorders is unknown. We hypothesized that dysregulated B cell maturation or aberrant class switching causes overrepresentation of IgG4+ B cells and plasma cells. Therefore, we compared the B cell compartment of patients from four different IgG4-AID with two IgG1-3-AID and healthy donors, using flow cytometry. Relative subset abundance at all maturation stages was normal, except for a, possibly treatment-related, reduction in immature and naïve CD5+ cells. IgG4+ B cell and plasma cell numbers were normal in IgG4-AID patients, however they had a (sub)class-independent 8-fold increase in circulating CD20-CD138+ cells. No autoreactivity was found in this subset. These results argue against aberrant B cell development and rather suggest the autoantibody subclass predominance to be antigen-driven. The similarities between IgG4-AID suggest that, despite displaying variable clinical phenotypes, they share a similar underlying immune profile.Neurological Motor Disorder

Treating muscle-specific kinase myasthenia gravis from the inside out

Myasthenia gravis (MG) with antibodies to muscle-specific kinase (MuSK) is an autoimmune disease of the neuromuscular junction with some remarkable characteristics. Although MuSK is expressed in all skeletal muscles, patients with this disease present with particularly cranial, bulbar, and respiratory muscle weakness, leading to a relatively high frequency of respiratory crises.(1) Despite several available immunosuppressive or immunomodulatory treatments, patients with MuSK MG often retain residual muscle weakness and experience more often severe muscle atrophy than patients with the more frequent MG with acetylcholine receptor (AChR) antibodies.(2) Symptomatic treatment with acetylcholinesterase inhibitors is usually ineffective or even detrimental in MuSK MG,(1) although 3,4-diaminopyridine might be effective in some patients.(3) Therefore, treatment of MuSK MG today still mostly relies on immunosuppressive treatment.(1</SUP)Functional Genomics of Muscle, Nerve and Brain Disorder

Antibiotic neuromuscular junction myasthenic mimetics Reply

Functional Genomics of Muscle, Nerve and Brain Disorder

MuSK antibodies, lessons learned from poly- and monoclonality

Muscle-specific kinase (MuSK) plays a critical role in establishing and maintaining neuromuscular synapses. Antibodies derived from immunizing animals with MuSK were important tools to help detect MuSK and its activity. The role of antibodies in MuSK-related research got an extra dimension when autoantibodies to MuSK were found to cause myasthenia gravis (MG) in 2001. Active immunization with MuSK or passive transfer of polyclonal purified IgG(4) fractions from patients reproduced myasthenic muscle weakness in a range of animal models. Polyclonal patient-purified autoantibodies were furthermore found to block agrin-Lrp4-MuSK signaling, explaining the synaptic disassembly, failure of neuromuscular transmission and ultimately muscle fatigue observed in vivo. MuSK autoantibodies are predominantly of the IgG4 subclass. Low levels of other subclass MuSK antibodies coexist, but their role in the pathogenesis is unclear. Patient-derived monoclonal antibodies revealed that MuSK antibody subclass and valency alters their functional effects and possibly their pathogenicity. Interestingly, recombinant functional bivalent MuSK antibodies might even have therapeutic potential for a variety of neuromuscular disorders, due to their agonistic nature on the MuSK signaling cascade. Thus, MuSK antibodies have proven to be helpful tools to study neuromuscular junction physiology, contributed to our understanding of the pathophysiology of MuSK MG and might be used to treat neuromuscular disorders. The source of MuSK antibodies and consequently their (mixed) polyclonal or monoclonal nature were important confounding factors in these experiments. Here we review the variety of MuSK antibodies described thus far, the insights they have given us and their potential for the future.Functional Genomics of Muscle, Nerve and Brain Disorder

Advances in the understanding of disease mechanisms of autoimmune neuromuscular junction disorders

Muscle weakness and fatigue are the hallmarks of autoimmune neuromuscular junction disorders. Although a plethora of immunosuppressive treatments exist, no cure is available to date and many patients are left with debilitating muscle weakness. Recent advances in the understanding of the structure and function of the neuromuscular junction, and the development of novel in vitro and in vivo models, have been instrumental in unravelling the pathophysiology of these autoimmune diseases. These advances are providing the rationale for the development of new therapeutic strategies. Restoration of the immune imbalance in these diseases, in parallel with symptomatic therapeutic approaches at the neuromuscular junction, will be crucial to obtain long-term remission or even cure.Functional Genomics of Muscle, Nerve and Brain Disorder