Clonal expansions of CD4+ B helper T cells in autoimmune myasthenia gravis.
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) Vbeta usage/expansions in blood from 118 MG patients. We found major expansions (>or= five standard deviations above the mean of 118 healthy, individually age- and sex-matched controls) in diverse Vbeta 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 >or=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 Vbeta 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.
Tackenberg
Björn
B
Clinical Neuroimmunology Group, Department of Neurology, Philipps-University, Marburg, Germany.
Kruth
Jens
J
Bartholomaeus
Johanna E
JE
Schlegel
Kerstin
K
Oertel
Wolfgang H
WH
Willcox
Nicholas
N
Hemmer
Bernhard
B
Sommer
Norbert
N
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D049109:Cell Proliferation; D002999:Clone Cells; D005260:Female; D019674:Genes, T-Cell Receptor beta; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000096:biosynthesis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*
D007135:Immunoglobulin Variable Region