Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings.
OBJECTIVE
To analyze whether patients with rheumatoid arthritis (RA) have an intrinsic defect in T cell proliferation and survival, possibly contributing to the infiltration of the synovial membrane with CD4+ T cells.


METHODS
Fifteen patients with seropositive RA, 11 patients with psoriatic arthritis, 20 normal controls, and 9 affected and 13 unaffected siblings from 7 multiplex families with RA were analyzed for clonal proliferation. To investigate this clonal T cell proliferation, CD4+ T cells were purified from peripheral blood and synovial fluid by magnetic bead separation. T cell receptor (TCR) beta-chain sequences were amplified by reverse transcriptase-polymerase chain reaction, using TCR BV and BJ gene segment-specific primer sets. Clonally expanded T cell specificities were identified by size fractionation and sequencing of the amplified product.


RESULTS
All RA patients carried clonally expanded CD4+ T cells in the peripheral blood compartment. Such expanded CD4+ T cell clonotypes were only infrequently observed both in normal individuals (P < 0.0001) and in patients with psoriatic arthritis (P = 0.004). Lymphoproliferation of selected CD4+ T cells was shared by affected and unaffected siblings from RA multiplex families (P = 0.005 and P = 0.0003, respectively, compared with normal controls). Expanded clonotypes persisted for several years and contributed to the T cell infiltrate in the joint. Clonal T cell proliferation involved a diverse spectrum of TCR molecules.


CONCLUSIONS
RA patients have an abnormality in the homeostasis of CD4+ T cells, characterized by the emergence of clonally proliferating populations. The presence of clonal outgrowth of selected CD4+ T cells specificities in unaffected siblings of RA patients suggests that oligoclonality of CD4+ T cells is inherited and is a risk factor for, rather than a result of, synovial inflammation.
Waase
I
I
Mayo Clinic, Rochester, MN 55905, USA.
Kayser
C
C
Carlson
P J
PJ
Goronzy
J J
JJ
Weyand
C M
CM
D000328:Adult; D000368:Aged; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001483:Base Sequence; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology* / Q000473:pathology; D002455:Cell Division / Q000235:genetics; D048429:Cell Size; D002999:Clone Cells / Q000737:chemistry / Q000276:immunology / Q000473:pathology; D005190:Family; D006801:Humans; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008875:Middle Aged; D008969:Molecular Sequence Data; D010641:Phenotype; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology* / Q000473:pathology
D011948:Receptors, Antigen, T-Cell