Muscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disorder caused by predominantly IgG4 antibodies targeting the MuSK protein. IgG4 has the unique ability to... Show moreMuscle-specific kinase (MuSK) myasthenia gravis (MG) is a neuromuscular autoimmune disorder caused by predominantly IgG4 antibodies targeting the MuSK protein. IgG4 has the unique ability to exchange half-molecules with other IgG4s, resulting in monovalent binding to their antigen. To investigate if MuSK-antibody valency influences its pathogenicity, recombinant bivalent and functionally monovalent MuSK antibodies were generated from B-cell receptor sequences isolated from MuSK MG patients. Passive transfer studies revealed that monovalency amplifies MuSK antibody pathogenicity in vivo. This may be because monovalent MuSK antibodies inhibit MuSK signaling (antagonist), while bivalent MuSK antibodies activate MuSK signaling (agonist) in vitro. The binding epitope on MuSK further influences the consequences and pathogenicity of MuSK antibodies. Collectively, these results suggest that the pathophysiology in individual patients depends on their unique antibody composition and that class-switching to IgG4 is a critical step in developing MuSK MG. Furthermore, the IgG4 response against MuSK does not appear to result from a global increase in IgG4 responses, as MuSK MG patients only had mildly elevated serum IgG4. Instead, it is thought to be driven by the antigen itself. Importantly, MUSK and other MG associated genes are also expressed outside skeletal muscle. These locations are at risk for non-motor symptoms caused by autoantibodies or mutations, or for side-effects of targeted therapeutic strategies. Show less
This work is the first comprehensive description of Makalero, a language spoken by approximately 6,500 speakers in the Iliomar subdistrict, in the south-east of the Republic of East Timor. Makalero... Show moreThis work is the first comprehensive description of Makalero, a language spoken by approximately 6,500 speakers in the Iliomar subdistrict, in the south-east of the Republic of East Timor. Makalero has been classified as belonging to the Trans-New Guinea family, making it one of the westernmost Papuan languages. While it retains scattered derivational and inflectional processes, it is largely isolating in structure. Underlying the organisation of discourse at a very basic level is the rigid structure of the Makalero clause, which allows for the expression of two verbal arguments at most. A characteristic feature of this clause structure is the presence of two distinct, mutually exclusive argument positions within the verb phrase, the first of which is reserved for undergoers, while the second may express either undergoers, or location and manner information. The description brought forward in this dissertation is not couched in a particular theoretical framework, although insights from several linguistic theories are adduced to support the analysis. The appendices provide transcripts of several Makalero texts as well as a Makalero-English and an English-Makalero word list. Show less
