TY - JOUR
T1 - Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis
AU - Tackenberg, Björn
AU - Kruth, Jens
AU - Bartholomaeus, Johanna E.
AU - Schlegel, Kerstin
AU - Oertel, Wolfgang H.
AU - Willcox, Nicholas
AU - Hemmer, Bernhard
AU - Sommer, Norbert
PY - 2007/3
Y1 - 2007/3
N2 - The weakness in myasthenia gravis (MG) is mediated by T helper cell (Th)-dependent autoantibodies against neuromuscular epitopes. So far, analyzing Th phenotypes or antigen specificities has yielded very few clues to pathogenesis. Here we adopt an alternative antigen-independent approach, analyzing T cell receptor (TCR) Vβ usage/expansions in blood from 118 MG patients. We found major expansions (≥ five standard deviations above the mean of 118 healthy, individually age- and sex-matched controls) in diverse Vβ in 21 patients (17.6%, p<0.001) among CD4+ T cells, and in 45 patients (38.1%, p<0.001) among CD8+ T cells. In informative probands, the expanded CD4+ cells consistently showed a Th cell phenotype (CD57+ CXCR5+) and expressed Th1 cytokines. Furthermore, their expression of markers for activation, lymphocyte trafficking and B cell-activating ability persisted for ≥3 years. Surprisingly, we noted a selective decline in the expansions/their CD57 positivity while the probands' MG was improving. CDR3 spectratyping suggested mono- or oligoclonal origins, which were confirmed by the prevalent TCR Vβ CDR3 sequences of Th cells cloned from repeat bleeds. Thus, our data provide evidence for persistent clonally expanded CD4+ B helper T cell populations in the blood of MG patients. These unexpected CD4+ expansions might hold valuable clues to MG immunopathogenesis.
AB - The weakness in myasthenia gravis (MG) is mediated by T helper cell (Th)-dependent autoantibodies against neuromuscular epitopes. So far, analyzing Th phenotypes or antigen specificities has yielded very few clues to pathogenesis. Here we adopt an alternative antigen-independent approach, analyzing T cell receptor (TCR) Vβ usage/expansions in blood from 118 MG patients. We found major expansions (≥ five standard deviations above the mean of 118 healthy, individually age- and sex-matched controls) in diverse Vβ in 21 patients (17.6%, p<0.001) among CD4+ T cells, and in 45 patients (38.1%, p<0.001) among CD8+ T cells. In informative probands, the expanded CD4+ cells consistently showed a Th cell phenotype (CD57+ CXCR5+) and expressed Th1 cytokines. Furthermore, their expression of markers for activation, lymphocyte trafficking and B cell-activating ability persisted for ≥3 years. Surprisingly, we noted a selective decline in the expansions/their CD57 positivity while the probands' MG was improving. CDR3 spectratyping suggested mono- or oligoclonal origins, which were confirmed by the prevalent TCR Vβ CDR3 sequences of Th cells cloned from repeat bleeds. Thus, our data provide evidence for persistent clonally expanded CD4+ B helper T cell populations in the blood of MG patients. These unexpected CD4+ expansions might hold valuable clues to MG immunopathogenesis.
KW - Autoimmunity
KW - Myasthenia gravis
KW - Oligoclonal
KW - T cell receptor
UR - http://www.scopus.com/inward/record.url?scp=34147103812&partnerID=8YFLogxK
U2 - 10.1002/eji.200636449
DO - 10.1002/eji.200636449
M3 - Article
C2 - 17323412
AN - SCOPUS:34147103812
SN - 0014-2980
VL - 37
SP - 849
EP - 863
JO - European Journal of Immunology
JF - European Journal of Immunology
IS - 3
ER -