Overexpression of select T cell receptor V beta gene families within CD4+ and CD8+ T cell subsets of myasthenia gravis patients: a role for superantigen(s)?
BACKGROUND
The principal symptoms of myasthenia gravis (MG), muscle weakness and fatigue due to impaired neuromuscular transmission, are caused by autoantibodies to the muscle nicotinic acetylcholine receptor (AChR). The mechanisms underlying the autoimmune response, however, appear to be initiated by activation of specific HLA class II-restricted CD4+ T lymphocytes. Thus, central to elucidating the causation of MG is determining how T cells are recruited to contribute to misguided immunological assaults on the major autoantigenic target, AChR.


METHODS
By combining a polymerase chain reaction (PCR)-based strategy and Southern blot technique, we have analyzed the frequency of expression of 22 individual T cell receptor (TCR) V beta gene subfamilies in CD4+ and CD8+ peripheral blood T cell subsets derived from eight MG patients and seven healthy controls. The quantification of relative usage of individual TCR J beta gene segments was performed by hybridization of PCR-amplified products (specifically V beta 1-C beta) with a complete panel of 32P-5'-end-labeled J beta-specific oligonucleotide probes, followed by scanning analysis of autoradiographs.


RESULTS
Comparisons of data obtained from V beta analyses of T cells from MG patients with those from healthy individuals established that MG patients significantly overexpressed V beta 1, V beta 13.2, V beta 17, and V beta 20 gene family members within both CD4+ and CD8+ T cell subpopulations. Moreover, analysis of the relative utilization of individual TCR J beta gene segments in V beta 1+/CD4+ and V beta 1+/CD8+ T lymphocytes revealed distribution patterns in patients indistinguishable from those recorded in the corresponding cell subsets derived from controls.


CONCLUSIONS
T lymphocytes from MG patients displayed a biased overexpression of four TCR V beta gene segments: V beta 1, V beta 13.2, V beta 17, and V beta 20. The relative frequencies of association of individual V beta 1 (D beta) J beta combinations revealed that J beta gene usage in the V beta 1-over-represented T cell subsets had normal distribution patterns. It can thus be deduced that J beta gene segment products appear not to have a selective effect on the process leading to overexpression of V beta 1 exons in MG patients. Hence, our observations suggest a possible role for superantigen(s) in the T cell activation in MG patients.
Gigliotti
D
D
Microbiology and Tumorbiology Center (MTC), Karolinska Institute, Stockholm, Sweden.
Lefvert
A K
AK
Jeddi-Tehrani
M
M
Esin
S
S
Hodara
V
V
Pirskanen
R
R
Wigzell
H
H
Andersson
R
R
D000328:Adult; D000368:Aged; D015139:Blotting, Southern; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D009157:Myasthenia Gravis / Q000097:blood / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D018089:Superantigens / Q000502:physiology*
D011948:Receptors, Antigen, T-Cell; D018089:Superantigens