Work

The soluble CD40 ligand sCD154 in systemic lupus erythematosus

Year: 1999

Type: article

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by prominent lymphocyte activation, resulting in production of pathogenic IgG autoantibodies such as anti-double-stranded DNA antibody (anti-dsDNA Ab).Such autoantibodies may play a critical role in the progression of lupus nephritis (1).Whereas low amounts of low-affinity anti-dsDNA Ab also can be detected in the sera of healthy adults, high serum titers of anti-dsDNA Ab's of the IgG isotype are found nearly exclusively in patients with SLE.Moreover, the levels of such IgG anti-dsDNA Ab's appear related to disease activity.Aberrant expression of immune costimulatory molecules may contribute to this pathophysiology.Studies indicate that the blood lymphocytes of SLE patients often express higher levels of immune accessory molecules, such as CD54, CD80, CD86, and CD95, than the blood lymphocytes of normal adults (2-5).High-level expression of CD80 or CD86 may contribute to pathologic presentation of self antigens to T cells and/or the production of pathologic anti-DNA autoantibodies.Consistent with this notion, the production of pathologic autoantibodies by lupusprone New Zealand black (NZB) and New Zealand white (NZW) F 1 mice can be ameliorated by CTLA4-Ig (6, 7), a recombinant protein that can block CD80/CD86↔CD28 interactions (8).This has led to speculation that aberrant expression of these costimulatory molecules may contribute to the T-cell activation seen in patients with this disease.Normal B cells can be induced to express immune costimulatory molecules by activated T cells.Activated CD4 T cells can express CD40 ligand (CD154), a molecule that can engage CD40 on the B-cell surface (9).This triggers a cascade of events that ultimately results in expression of a variety of heretofore nonexpressed stimulatory surface accessory molecules, such as CD80 (B7-1) (10-15).High-level expression of CD154 has also been detected on T cells from patients with active SLE, indicating that such cells may have exaggerated expression of this stimulatory molecule (16,17).Conceivably, the exaggerated expression of CD154 could account for the high-level expression of immune accessory molecules on B cells of patients with active disease.Moreover, high-level expression of CD154 may be required for disease activity, which appears to be the case in animal models of SLE.Early et al., for example, reported that the anti-dsDNA Ab production in NZB/NZW F1 mice could be suppressed by treatment with anti-mouse CD154 antibody in vivo (18).Also, lpr/lpr mice made genetically defective in their ability to express CD154 did not develop IgG rheumatoid factor or anti-dsDNA (19).

Source: Journal of Clinical Investigation

DOI: 10.1172/jci7014