Transplantation of Myasthenia Gravis Thymus to SCID Micea

S, Schönbeck; Padberg, Frank; Marx, Alexander; Hohlfeld, Reinhard; Wekerle, Hartmut

doi:10.1111/j.1749-6632.1993.tb22870.x

Cited by 16 publications

(6 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In thymic hyperplasia all the elements required for the autoimmune response to AChR are present: both T and B lymphocytes, myoid cells expressing AChR and antigen-presenting interdigitating cells (Wekerle, 1993). Furthermore, lymphocytes from MG hyperplastic thymuses spontaneously produce anti-AChR antibodies in vitro (Newsom-Davis et al, 1991) and transplantation of small pieces of hyperplastic thymus in SCID mice induces long-lasting production of these antibodies (Schonbeck et al, 1992;Schonbeck et al, 1993). On the other hand, the presence of AChR in MG thymoma has never been demonstrated and thymoma transplants in SCID mice never produced autoantibodies unless hyperplastic extrathymomal tissue is also transplanted (Spuler et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor β gene polymorphisms in myasthenia gravis

Zelano¹,

Lino²,

Evoli³

et al. 1998

European Journal of Immunogenetics

View full text Add to dashboard Cite

Genetic analyses indicate that genes within the major histocompatibility complex (MHC) can be involved in susceptibility to autoimmune disease. To investigate the role of the tumour necrosis factor beta (TNFB) gene in myasthenia gravis (MG) susceptibility, we analysed an NcoI polymorphism within the TNFB gene in 63 MG patients and 93 healthy individuals. When patients were subdivided according to thymic pathology, we found differences between MG patients with thymic hyperplasia and thymoma versus controls. In MG patients with thymic hyperplasia we found a positive association with the TNFB*1 allele [Relative risk (RR): 2.6; P < 0.001] and phenotype (RR: 1.8; P < 0.005) and a negative association with the TNFB*2/2 genotype (RR: 0.2; P < 0.001) when compared to the controls. On the other hand, in MG patients with thymoma we found a positive association with the TNFB*2/2 genotype (RR: 5.6; P < 0.01) and a negative association with the TNFB*1 allele (RR: 0.3; P < 0.05) and *1/2 genotype (RR: 0.2; P < 0.01). These data suggest that the two different forms of MG can have different pathogenesis and that the TNFB gene could influence susceptibility to MG.

show abstract

Section: Discussionmentioning

confidence: 99%

Tumour necrosis factor β gene polymorphisms in myasthenia gravis

Zelano¹,

Lino²,

Evoli³

et al. 1998

European Journal of Immunogenetics

View full text Add to dashboard Cite

show abstract

“…Whether such an antibody-mediated or a cytotoxic mechanism is the basis of the increased apoptosis of thymic myoid cells in MG [9] has yet to be investigated. As elegantly shown by the transplantation of thymitis specimens into mice with severe combined immunodeficiency (resulting in the prolonged production of human anti-AChR autoantibodies in these immunodeficient mice), such thymuses contain all the necessary constituents of a complete and self-sustaining autoimmune reaction [90,91,104]. The "intrathymic pathogenesis model" is shown schematically in Fig.…”

Section: Pathogenesis Of Mg In Lympho-folicular Thymitismentioning

confidence: 99%

Pathogenesis of myasthenia gravis

et al. 1997

View full text Add to dashboard Cite

Various studies over the last 25 years in Man and animal models have revealed many steps in the pathogenesis of myasthenia gravis (MG) which is now considered the classical organ specific, autoantibody mediated and T cell dependent human autoimmune disease. Though not a disease entity, MG is associated with pathological alterations of the thymus in about 80% of cases. These are described here with reference to distinct models of autoimmunization against the acetylcholine receptor (AChR). In MG with thymitis, intrathymic production of AChR-specific autoantibodies is the result of a classical antigen-driven immune reaction that occurs completely inside the thymus and probably involves AChR on myoid cells as the triggering (myasthenogenic) antigen. Genetic factors contribute essentially to the pathogenesis of this form of MG. In thymoma-associated MG genetic factors are probably of marginal significance. Neither intratumour autoantibody production nor T cell activation seem to occur and the AChR is not the myasthenogenic antigen. Instead, abnormal neurofilaments that share epitopes with the AChR and other autoantigen targets in paraneoplastic MG are expressed in thymomas and may trigger autoantigen-specific, non-tolerogenic T cell selection by molecular mimicry. These data support the hypothesis that initial steps in the pathogenesis of most MG cases take place within abnormal thymic microenvironments, be they inflammatory or neoplastic. Where these initial steps occur in MG cases without thymic pathology is not known. Likewise, the factors involved in the initial triggering of MG remain enigmatic in all MG subtypes.& k w d : Key words Autoimmunity · Thymus · Thymoma · Acetylcholine receptor · Aetiology& b d y :Myasthenia gravis as a prototypic model autoimmune diseaseThe triggering of a autoimmune disease is incompletely understood. In experimental models molecular alterations of autoantigens in an otherwise intact immune system may elicit autoimmunity [27], however, defects of the immune system facing an intact antigen repertoire may also lead to autoimmunity [75]. In addition, microenvironmental factors such as abnormal interleukin levels may change the interaction between a normal T cell repertoire and normal autoantigens [including the acetylcholine receptor (AChR)] as shown in mice [30,77]. In mice, the loss of an established tolerance [65,92,93] or the recruitment of ignorant T cells [32,76] have been described as mechanisms in the induction of autoimmunity but whether or not these mechanisms are involved in human autoimmune diseases has not been resolved.In fact, myasthenia gravis (MG) may be an ideal model to investigate the role of T cell tolerance in humans. The target autoantigens in MG (the AChR and striational autoantigens) are well characterized [52] as are the autoreactive T cells that play a pivotal role in MG by providing B cell help [36,61,62,82,111]. Since the late steps in the pathogenesis are well defined, MG should be an ideal disease in which to investigate those early steps in pathogenesis t...

show abstract

“…Extrathymic immunization with AChR can induce experimental autoimmune MG (EAMG), but does not elicit TFH 29. By contrast, transplantation of TFH‐affected thymus into SCID mice results in prolonged production of anti‐AChR autoantibodies, showing that TFH contains all constituents of a self‐sustaining autoimmune reaction 30–32. Since myoid cells remain largely negative for MHC class II in MG, they are probably unable to prime AChR‐reactive CD4+ T cells 33.…”

Section: Pathogenic Concepts In Seropositive Mgmentioning

confidence: 99%