T cells and costimulatory factors in myasthenia gravis

The autoimmune disease myasthenia gravis (MG) is characterized by muscle weakness due to a loss of acetylcholine receptors (AChR) at the neuromuscular end plate. Most MG patients have pathogenic antibodies directed against the receptor. We provide further evidence that T cells are important for establishment and continuation of the disease. We have detected pathogenic antibodies capable of transferring disease to mice in healthy twin sisters as well as in their MG affected sisters in two monozygotic twin pairs discordant for MG. However, the healthy twin sisters did not demonstrate T cell responses against the AChR.

A further support to the importance of T cells in maintaining the disease is shown in a successful treatment of an MG patient with antibodies targeting CD25. This molecule is expressed on activated cells. The levels of activated T cells, serum levels of IL-10 as well as the soluble costimulatory molecules sCD28, sCD80, sCD86 and sCD152 decreased, suggesting a normalization of an abnormally activated immune system.

Costimulatory molecules are important in the activation and inhibition of an immune response. We demonstrated reduced expression of the costimulatory molecule CD152 (cytotoxic T lymphocyte associated antigen 4, CTLA-4) in T cells from MG patients. CD152 is essential to inhibit an immune response, therefore the patients might have a reduced potential to down-regulate an ongoing immune reaction. We observed that the G allele at position +49 in coding sequence 1 of the CD152 gene was associated to increased immune activity, manifested as increased levels of IL-1beta and CD3+CD28+ cells. MG patients with thymoma more frequently had the G/G genotype or the G allele, which could explain a more active immune response in patients with this genotype.

The costimulatory factors CD28, CD80, CD86 and CD152 also exist in soluble forms. The concentrations of sCD28, sCD80, sCD86 and sCD152, all of which recently have been shown to be increased in different diseases, were not increased in MG patients. However, in one of our studies we detected elevated levels of sCD152 in MG patients. The concentrations of sCD28, sCD80, sCD86 and sCD152 correlated to each other and to IL-6, IL-10 and IFN-gamma. All four soluble costimulatory molecules correlated to sCD25 in healthy persons, while only sCD80 and sCD86 correlated to sCD25 in MG patients. In addition, we confirmed results by others demonstrating increased serum levels of sCD25 and sICAM-1.

We produced a recombinant form of the naturally occurring soluble costimulatory factor CD80. Recombinant sCD80 demonstrated capacity to interact with its natural ligands CD28 and CD152. It preferentially bound to activated cells. In addition, it displayed immunosuppressive properties, demonstrated by inhibition of T cell activation, inhibition of the mixed lymphocyte reaction and the ability to alter the cytokine secretion balance in vitro. The effect of sCD80 in vivo has to be clarified, but it is tempting to speculate about a potential future use of the soluble protein in treatment of diseases like MG. In summary, we have provided further evidence that T cells are important in the initiation and maintenance of MG, and that the costimulatory factors could be involved in disease progression.

List of scientific papers

I. Kakoulidou M, Ahlberg R, Yi Q, Giscombe R, Pirskanen R, Lefvert AK (2004). The autoimmune T and B cell repertoires in monozygotic twins discordant for myasthenia gravis. J Neuroimmunol. 148(1-2): 183-91.
https://pubmed.ncbi.nlm.nih.gov/14975600

II. Wang XB, Kakoulidou M, Qiu Q, Giscombe R, Huang D, Pirskanen R, Lefvert AK (2002). CDS1 and promoter single nucleotide polymorphisms of the CTLA-4 gene in human myasthenia gravis. Genes Immun. 3(1): 46-9.
https://pubmed.ncbi.nlm.nih.gov/11857062

III. Wang XB, Kakoulidou M, Giscombe R, Qiu Q, Huang D, Pirskanen R, Lefvert AK (2002). Abnormal expression of CTLA-4 by T cells from patients with myasthenia gravis: effect of an AT-rich gene sequence. J Neuroimmunol. 130(1-2): 224-32.
https://pubmed.ncbi.nlm.nih.gov/12225905

IV. Kakoulidou M, Wang XB, Zhao X, Pirskanen R, Lefvert AK (2005). Soluble costimulatory factors in relation to other markers of immune activation in patients with myasthenia gravis. [Manuscript]

V. Kakoulidou M, Giscombe R, Zhao X, Lefvert AK, Wang XB (2005). Human soluble CD80 is generated by alternative splicing. Recombinant soluble CD80 binds to CD28 and CD152 and inhibits T cell activation. [Submitted]

VI. Kakoulidou M, Pirskanen R, Lefvert AK (2005). Treatment of a patient with myasthenia gravis using antibodies against CD25. [Manuscript]