The antigen responsible for autoimmunization in systemic lupus erythematosus is unknown. In spite of this obstacle, we show that T helper (Th) cell lines that are functionally relevant to this disease can be established in vitro. We derived a total of 396 interleukin 2-dependent T-cell lines from the in vivo activated T cells of five patients with lupus nephritis. Only 59 (-15%) of these lines had the ability to selectively augment the production of pathogenic anti-DNA autoantibodies that were IgG in class, cationic in charge, specific for native DNA, and clonally restricted in spectrotype.Forty-nine of these autoantibody-inducing Th lines were CD4+ and expressed the qri T-cell receptor (TCR). The other 10 were CD4-8-(double negative), 3 expressing the afi TCR and 7 expressing the yb TCR. All of the autoantibody-inducing Th lines responded to some endogenous antigen presented by autologous B cells. The autoreactive responses of the CD4+ Th lines were restricted to HLA class II antigens, whereas those of the double-negative cells were not. Endogenous heat shock or stress proteins of the HSP60 family that were expressed by the lupus patients' B cells were involved in stimulating an autoreactive proliferation of the y8 Th cells. These studies demonstrate a novel helper activity of certain y6 T cells in a spontaneous autoimmune response.
In the (SWR x NZB)F1 (SNF1) model of lupus nephritis, pathogenic variety of IgG anti-DNA autoantibodies are induced by certain T helper (Th) cells that are either CD4+ or CD4-CD8- (double negative; DN) in phenotype. From the spleens of eight SNF1 mice with lupus nephritis, 149 T cell lines were derived and out of these only 25 lines (approximately 17%) were capable of augmenting the production of pathogenic anti-DNA autoantibodies. Herein, we analyzed the T cell receptor (TcR) V beta genes used by 16 such pathogenic autoantibody-inducing Th cell lines. Twelve of the Th lines were CD4+ and among these five lines expressed V beta 8 (8.2 or 8.3). The V beta 8 gene family is contributed by the NZB parent to the SNF1 mice, since it is absent in the SWR parental strain. Three other CD4+ Th lines expressed V beta 4, another was V beta 2+ and one line with poor autoantibody-inducing capability expressed V beta 1. Four autoantibody-inducing Th lines from the SNF1 mice had a DN phenotype and these lines were also autoreactive, proliferating in response to syngeneic spleen cells. Among these DN Th lines, two expressed V beta 6 and one expressed V beta 8.1 TcR. Both of these are forbidden TcR directed against Mls-1a (Mlsa) autoantigens expressed by the SNF1 mice and such autoreactive T cells should have been deleted during thymic ontogeny. Thus, the DN Th cells of non-lpr SNF1 mice are different from the DN cells or MRL-lpr which lack helper activity and do not express forbidden TcR. The spleens of 6 out of 19 nephritic SNF1 animals tested also showed an expansion of forbidden autoreactive TcR+ cells that were mainly DN. Two of these animals expressed high levels of V beta 6 (anti-Mlsa) and V beta 11 (anti-I-E) TcR+ cells, three others had high levels of V beta 11+ cells alone and one animal had an expanded population of V beta 17a+ (anti-I-E) cells. The I-E-reactive TcR again should have been eliminated in the SNF1 thymus, since they express I-E molecules contributed by the NZB parent. The SWR parents of SNF1, are I-E-; moreover, they lack the V beta 11 gene but they express V beta 17a in peripheral T cells. Whereas the NZB parents are I-E+, they lack a functional V beta 17a gene and they delete mature V beta 11+ T cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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