Dinucleotide repeat expansion in the CTLA-4 gene leads to T cell hyper-reactivity via the CD28 pathway in myasthenia gravis.
CD28 is required to promote T cell proliferation and cytokine production, while the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) functions as a negative modulator for T cell activation. We previously reported that alleles with longer PCR products (designated as allele xx) in an (AT)n polymorphism in Ctla-4 are associated with myasthenia gravis with thymoma, while the shortest allele, 86, is negatively associated with the disease. Here, we demonstrate that serum IL-2 sRalpha increases parallel to the length of (AT)n in Ctla-4. Periphereal blood mononuclear cells (PBMC) from patients with Ctla-4 xx/xx contained higher activity of telomerase than patients bearing Ctla-4 86/86. Blockade of CTLA-4 increased the telomerase activity in PBMC stimulated by acetylcholine receptor in vitro. There was a positive correlation between the expression of CD28 and CTLA-4 on anti-CD3 activated PBMC, suggesting a balance between CD28 and CTLA-4. Cells from patients with Ctla-4 xx/xx had the highest level of T cell proliferative responses upon the addition of anti-CD28 antibodies to the anti-CD3 containing culture system while cells from patients with Ctla-4 86/xx had an intermediate and cells from patients with Ctla-4 86/86 the lowest increase. The current results point to the (AT)n in Ctla-4 as a myasthenia gravis facilitating mutation under certain permissive environments by influencing the T cell reactivity via the CD28 pathway.
Huang
D
D
The Immunological Research Unit, Center for Molecular Medicine (CMM), L8:03, and Department of Medicine, Karolinska Institutet, S-171 76, Stockholm, Sweden. huangd2@ccf.org
Giscombe
R
R
Zhou
Y
Y
Pirskanen
R
R
Lefvert
A K
AK
D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D018900:Dinucleotide Repeats; D006801:Humans; D018796:Immunoconjugates; D008213:Lymphocyte Activation; D009157:Myasthenia Gravis / Q000276:immunology*; D015375:Receptors, Interleukin-2 / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology*; D019098:Telomerase / Q000378:metabolism
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D018796:Immunoconjugates; D015375:Receptors, Interleukin-2; D000069594:Abatacept; D019098:Telomerase