The transmembrane form of TNF-alpha drives autoantibody production in the absence of CD154: studies using MRL/Mp-Fas(lpr) mice.
It is generally accepted that the interaction between CD40 and its ligand (CD154) plays a decisive role in contact-dependent help for T and B cells. In CD154-deficient MRL/Mp-Fas(lpr) (MRL/lpr) mice, however, high titres of IgG2a-type autoantibodies against small nuclear ribonucleoproteins (snRNPs) are observed. We successfully isolated two CD154-deficient MRL/lpr Th1 lines, which could provide B cell help for anti-snRNP antibody production. The proliferative responses of the Th1 cell lines were MHC class II (I-Ek)-restricted. Although syngeneic B cell proliferation was induced by Th1 lines in both a contact-dependent and -independent manner, the soluble form of TNF-alpha (sTNF-alpha) was not involved in contact-independent B cell proliferation. On the other hand, both anti-TNF-alpha and TNF-receptor 2 (TNF-R2, p75) monoclonal antibody (MoAb) blocked contact-dependent B cell proliferation, suggesting that the transmembrane form of TNF-alpha (mTNF-alpha)-TNF-R2 co-stimulation participates in B cell activation. Similarly, anti-TNF-alpha and TNF-R2 MoAb inhibited anti-snRNP antibody production in vitro, but anti-CD154 or TNF-R1 MoAb did not. These results indicate that the interaction of mTNF-alpha on activated Th1 cells with TNF-R2 on B cells may be involved in the autoimmunity seen in MRL mice, and that the blockade of CD40-CD154 co-stimulation may not always be able to suppress some Th1-related manifestations of lupus.
Fujii
T
T
Section of Rheumatology, Department of Internal Medicine, Yale School of Medicine, USA. takfujii@kuhp.kyoto-u.ac.jp
Okada
M
M
Mimori
T
T
Craft
J
J
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D017411:Ribonucleoproteins, Small Nuclear / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry / Q000502:physiology*
D000974:Antibodies, Antinuclear; D008565:Membrane Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018124:Receptors, Tumor Necrosis Factor; D017411:Ribonucleoproteins, Small Nuclear; D014409:Tumor Necrosis Factor-alpha; D023201:CD40 Ligand