Elsevier

Journal of Neuroimmunology

Volumes 201–202, 15 September 2008, Pages 21-27
Journal of Neuroimmunology

Review article
Reflections on the “intrathymic pathogenesis” of myasthenia gravis

https://doi.org/10.1016/j.jneuroim.2008.05.020Get rights and content

Abstract

The beneficial effects of thymectomy argue for a causal role of the thymus in myasthenia gravis (MG). The MG thymus contains acetylcholine receptor (AChR), which is expressed by myoid cells (whole AChR), and by medullary thymic epithelial cells (AChR subunits). The myoid cells are closely associated with antigen-presenting dendritic cells, helper T cells, and antibody-producing B cells in lymphoid follicles (“lymphofollicular hyperplasia”). Thus, all the cellular components required to initiate and maintain an autoimmune response to AChR are present in the MG thymus. It is unlikely that the cellular alterations in the thymus are secondary to an ongoing peripheral immune response, because they are absent in experimental autoimmune myasthenia gravis.

Introduction

The earliest paper we retrieved when searching PubMed for Newsom-Davis J AND Myasthenia gravis is a “preliminary communication” published in the Lancet in 1978. In that paper, Angela Vincent, Glenis K. Scadding, H.C. Thomas, and J. Newsom-Davis showed that cultured human thymic lymphocytes produce anti-acetylcholine receptor (AChR) antibodies in vitro (Vincent et al., 1978).

Ever since, John and his colleagues have remained curious about the enigmatic role of the thymus in MG. Together with observations from other groups, their findings provided early support for the idea that the pathogenesis of early-onset myasthenia gravis takes its origin in the thymus. Indeed, that seems much likelier than in muscle (Nakano and Engel, 1993). Specifically, intrathymic antibody production and T cell sensitization could plausibly explain why patients benefit from thymectomy, a therapy that is widely applied on a purely empirical basis. Thus, John devoted the last years of his life in designing and organizing the first-ever controlled trial of thymectomy in MG, which will become one of his many legacies. Here we briefly review the concept of intrathymic pathogenesis of MG, and consider how it fits into contemporary knowledge of thymic function.

Section snippets

Thymic autoantibody production

Alterations of cell populations in the MG thymus, including increased numbers of B cells, were described in the 1970s (Abdou et al., 1974) — about 15years after the fundamental “immunological significance of the thymus” had been discovered (Miller, 1961). In 1976 Mittag et al. reported that serum and thymus from MG patients contained “anti-acetylcholine receptor factors” (Mittag et al., 1976), and around the same time, Toyka et al. unequivocally identified the “inhibitory activity” as anti-AChR

Key tenets of “intrathymic pathogenesis”

If the pathogenesis of MG begins in the thymus, then it must contain the cellular and molecular machinery for activating autoimmune T cells and B cells. This means that the MG thymus must contain the autoantigen, the nicotinic AChR, antigen-presenting cells that can efficiently present autoimmunogenic epitopes, and autoreactive T cells recognizing these epitopes. Over the years evidence has accumulated in support of all of these predictions.

Intrathymic myoid cells and AChR

The concept of intrathymic pathogenesis of MG was initially suggested by several different lines of evidence (Wekerle and Ketelsen, 1977, Straus, 1977). The thymus of young mice harbors myogenic progenitor cells, the progeny of which expresses abundant AChR (Wekerle et al., 1975, Wekerle and Ketelsen, 1977). This finding harmonized with the observation by other investigators that a protein fraction of the calf thymus immunologically cross-reacts with AChR isolated from the electric organ of

Intrathymic antigen presentation

Because myoid cells in the MG thymus remain negative for MHC class II, they are probably unable to directly present antigen to CD4+ T cells. But other more professional antigen-presenting cells, e.g., dendritic cells, can take up AChR released from myoid cells and efficiently present it to AChR-reactive helper T cells. Indeed, clusters of myoid cells surrounded by antigen-presenting dendritic cells are frequently observed in MG thymus (Kirchner et al., 1986). This old observation fits well with

Intrathymic germinal centers and B cells

One of the most conspicuous features of the “hyperplastic” thymus in MG is the presence of intrathymic germinal centers. In fact, about 40% of MG patients have a thymus with histological changes of “lymphoid follicular hyperplasia” (reviewed in Marx et al., 1997). This is accompanied by profound structural changes. The perivascular spaces are expanded by B cells forming lymphoid follicles and germinal centers. Nearby, moreover, there is disruption of the basal membrane separating the

Human MG thymus grafted into SCID mice

After publication of the first paper demonstrating that cultured thymocytes produce anti-AChR autoantibodies (Vincent et al., 1978), several subsequent studies tried to assess the contribution of different subsets of thymocytes, and especially, to demonstrate the predicted functional effects of thymic helper T cells. However, it turned out to be very difficult to demonstrate any AChR-specific helper T cell effects. The problem was that whereas in MG, B and T cells interact in highly structured

Absence of thymic autoantibody production in thymoma

About 15% of MG patients have a thymic epithelial tumor (thymoma). It is assumed that the pathogenesis of paraneoplastic MG differs from that of MG associated with thymic hyperplasia, though similar changes are seen in the adjacent thymic remnant in MG patients (reviewed by Marx et al., 1997). Although the mechanisms of autosensitization are unknown, the following observations should be relevant. a) In contrast to hyperplastic thymus, thymoma tissue does not produce anti-AChR antibodies (

The thymus in “seronegative” myasthenia

About 15% of patients with generalized myasthenia gravis do not have detectable serum anti-AChR antibody, as measured by radio-immunoprecipitation assay. It is thought that “seronegative myasthenia gravis” itself is heterogeneous. In a proportion of seronegative patients, anti-AChR antibodies may be present but undetectable with the conventional assay for various reasons. Other patients with AChR antibody-negative myasthenia produce IgG4 autoantibodies to muscle-specific kinase (MuSK) (Hoch et

Heterogeneity of anti-AChR antibodies and evidence for T cell help

It is important to remember that the anti-AChR autoantibodies in human MG are heterogeneous with respect to isotype, effector mechanism, and epitope recognition. This implies that the antibodies are produced by different clones of AChR-specific B cells (Sims et al., 2001), ruling out the possibility that MG is caused by the expansion of a single “forbidden” clone of B cells. (The concept of forbidden clones, i.e., lymphocytes that escaped immunological censorship, was proposed by F.M. Burnet in

AChR-specific T cells

Systematic investigation of the T cell response against the AChR became feasible in the late 1970s and early 1980s when methods were devised to purify antigen-specific T cells and to maintain T cell lines in long-term cultures. Before this technical breakthrough, T cell reactivity was usually measured by the proliferative response of a mixed population of cultured lymphocytes stimulated by antigen. The first AChR-specific T cell lines were generated in rats (Hohlfeld et al., 1981). These

Antigenic epitopes recognized by AChR-specific T cells

Immunogenic T cell epitopes of AChR have been studied by different groups of investigators using different techniques in different animal species and in different MG patients. The overall picture created by these results is incomplete, and the major pathogenic T cell epitopes of human AChR remain to be confirmed (reviewed by Protti et al., 1993, Hawke et al., 1996). Three principles, however, have been firmly established:

(a) The T cell response, like the B cell response against AChR, is

A two-step model of intrathymic autosensitization

The concept of intrathymic pathogenesis initially focused on thymic myoid cells as the most relevant source of intrathymic AChR. Indeed, myoid cells are the only cells outside the muscle known to express whole AChR. More recent evidence indicates that medullary thymic epithelial cells (mTEC) are another source of thymic AChR. However, in contrast to myoid cells, mTEC produce only subunits or fragments of AChR (Wakkach et al., 1996, MacLennan et al., 1998). Nick Willcox et al. proposed a version

“Promiscuous” expression of autoantigens by medullary thymic epithelial cells

Medullary thymic epithelial (mTECs) cells are now known to play an important role not only in MG, but also in “central” (thymic) tolerance and in autoimmunity in general. They express a wide array of self-antigens, representing virtually all parenchymal organs. This property of mTECs has been called “promiscuous gene expression”. It is regulated at multiple levels, including the autoimmune regulator gene aire (see below). Expression of tissue-restricted antigens in mTECs contributes to negative

Conclusion

The concept of “intrathymic pathogenesis” of MG has proved remarkably robust. First proposed almost 30years ago, not only has it stood the test of time, but surprisingly, it remains consistent with even the most recent theories of thymic function. It continues to guide our understanding of MG pathogenesis, and provides a conceptual basis for thymectomy. This does not imply that all mysteries of MG pathogenesis have been solved. For example, the initiation of the various changes is still a major

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      Approximately 70% of MG patients have thymic follicular hyperplasia, 15% have thymomas, and the remainder have a histologically normal thymus for their age. The myasthenic thymus is implicated in initiating or perpetuating the disease process (Hohlfeld and Wekerle, 2008; Le Panse et al., 2010). It is thought that the thymic germinal center environment is providing signals that promote autoreactive B-cell survival, activation, and maturation.

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    Dedicated to the memory of John Newsom-Davis.

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