**7. Acknowledgements**

We wish to thank Professors Nick Willcox and Angela Vincent, F.R.S. (Institute for Molecular Medicine, University of Oxford, U.K.), Paul Garside and Iain McInnes (Institute of Infection, Immunity & Inflammation, University of Glasgow, U.K.) for critically reading the manuscript and their helpful suggestions. We also wish to thank all the people who have worked in D.I. Stott's research group and those of his collaborators whose work contributed to the results described here, especially Gary Sims, Michael Matthews, Sazini Nzula and Anne-Sophie Rouziere, whose data on myasthenia gravis and ductal carcinoma are presented in this chapter. Any errors and oversights are entirely our own.

The original research described in this chapter was funded by The Wellcome Trust, the Scottish Executive Health Dept. Chief Scientist Office, Cancer Research UK, the Dr. Robert Mairs Trust and the Medical Research Council.

## **8. References**

Adams, C. L., MacLeod, M. K. L., Milner-White, E. J., Aitken, R., Garside, P., & Stott, D. I. 2003, "Complete analysis of the B-cell response to a protein antigen, from *in vivo* germinal centre formation to 3-D modelling of affinity maturation", *Immunology*, vol. 108, pp. 274-287.

In several cases it has been shown that the autoantibodies generated in ectopic g.c.s have similar specificities to the autoantibodies found in the blood, notably in Hashimoto's thyroiditis, Sjögren's syndrome and rheumatoid arthritis, suggesting that the g.c.s contribute to pathological mechanisms, although whether they are critical in the early stages of development of the disease, or only contribute to its maintenance once the initial tissue damage has commenced, has yet to be established. Production of cytokines and chemokines at sites of damage that attract lymphocytes and contribute to lymphoid neogenesis suggests that the latter may be the more likely scenario. Nevertheless, a detailed understanding of the mechanisms involved in generation of ectopic g.c. structures and maintenance of production of plasma cells and memory B-cells producing potentially pathogenic antibodies is essential for a full understanding of the pathology of autoimmune disease and holds promise for developing new methods of therapy, based on controlling this response or inducing

Even more work needs to be done to determine the role of ectopic g.c.s in other diseases, including sterile and infectious chronic inflammatory diseases and cancer. What other types of cancer, in addition to breast cancer and lymphoma, induce germinal centre reactions within the tumour and the nature of their response in elimination of cancer cells have yet to be determined. The identification of intra-tumour g.c.s producing antibodies and memory Bcells with specificity for members of the epidermal growth factor receptor family holds out hope that therapeutic vaccines can be developed to boost this response for therapy of breast cancer and, potentially other neoplasias, such as ovarian cancer, in which these molecules are overexpressed. Experimental approaches using mouse models of breast cancer support this optimism (Renard *et al.*, 2003; Renard & Leach, 2007; Mukhopadhyay, MS in preparation). Cloning of antibodies against tumour-associated antigens from intra-tumour g.c.s is also a novel way of producing fully human antibodies for passive immunotherapy.

We wish to thank Professors Nick Willcox and Angela Vincent, F.R.S. (Institute for Molecular Medicine, University of Oxford, U.K.), Paul Garside and Iain McInnes (Institute of Infection, Immunity & Inflammation, University of Glasgow, U.K.) for critically reading the manuscript and their helpful suggestions. We also wish to thank all the people who have worked in D.I. Stott's research group and those of his collaborators whose work contributed to the results described here, especially Gary Sims, Michael Matthews, Sazini Nzula and Anne-Sophie Rouziere, whose data on myasthenia gravis and ductal carcinoma are

The original research described in this chapter was funded by The Wellcome Trust, the Scottish Executive Health Dept. Chief Scientist Office, Cancer Research UK, the Dr. Robert

Adams, C. L., MacLeod, M. K. L., Milner-White, E. J., Aitken, R., Garside, P., & Stott, D. I.

2003, "Complete analysis of the B-cell response to a protein antigen, from *in vivo* germinal centre formation to 3-D modelling of affinity maturation", *Immunology*,

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Mairs Trust and the Medical Research Council.

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**22** 

*Sweden* 

Anna Rostedt Punga

**Myasthenia Gravis: New Insights into** 

Myasthenia Gravis (MG) is an autoimmune neuromuscular disorder in which autoantibodies are directed against muscle receptors. MG causes fluctuating muscle weakness, which often involves droopy eyelids, swallowing difficulties and generalized muscle fatigue in the neck and proximal muscles of the legs and arms. The prevalence of MG is two times higher in women than in men. Age is also a prevailing factor, affecting women whom are 20-30 years of age, whereas men are 60-80 years old (Osserman and Genkins 1971). The annual incidence of MG has been reported to be about 3-4 cases per million and the overall prevalence about 60 cases per million; however, higher rates have recently been suggested, indicating a potential prevalence as high as 20 per 100 000 persons. (Kalb, Matell et al. 2002; Phillips 2003). The most common form of MG is associated with antibodies against the nicotinic acetylcholine receptor (AChR), present in about 85% of patients with generalised MG (Vincent and Newsom Davis 1980). In 2001 antibodies against the muscle specific tyrosine kinase (MuSK) were identified in about 40-70% of patients without detectable AChR antibodies (Hoch, McConville et al. 2001). Furthermore, in approximately 5-10% of patients with the generalized disease no antibodies are present in the serum, but these cases all have the features of an autoimmune course. This chapter deals with the clinical phenotype, neurophysiology and consequences at the neuromuscular junction of the autoimmune attack associated with MG as well as treatment options. The focus will be on MuSK antibody seropositive (MuSK+) MG in human patients and the

**1. Introduction** 

experimental murine model of MuSK+ MG.

**autoimmune attack** 

**2. Myasthenia gravis: Targets, consequences and treatment of the** 

In 1960, the Scottish neurologist Simpson suggested that MG might be caused by an autoimmune mechanism based on the relatively high incidence of concomitant autoimmune diseases, e.g. rheumatoid arthritis and systemic lupus erytematosus, among the MG patients (Simpson 1960). Abnormalities of the thymus gland were discovered, as well as the presence of lymphorrages in muscles, which further supported Simpson´s hypothesis (Miller 1961). A

**the Effect of MuSK Antibodies and** 

 **Acetylcholinesterase Inhibitors** 

*Uppsala University Hospital, Institute of Neuroscience,* 

*Department of Clinical Neurophysiology* 

