Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression.
Introducing avidin-biotin complex ELISA for anti-DNA antibody, the mechanism of in vitro production of anti-ssDNA antibody as well as of polyclonal immunoglobulin mediated by an IL-6-IL-6R loop was studied in patients with systemic lupus erythematosus (SLE). Regardless of the presence or absence of T cells, B cells from SLE patients could produce IgG anti-ssDNA antibody as well as total IgG without any stimulation. Low density B cells obtained by Percoll gradient density centrifugation responded to rIL-6 to produce IgG and IgG anti-ssDNA antibody. rIL-2 and rIL-4 had lesser effects on the differentiation of low density B cells. In fact, IL-6R was preferentially expressed on low density B cells from active SLE patients, as detected by anti-IL-6R MoAb, MT18, which did not inhibit IL-6 binding. SLE B cells, especially high density B cells, produced greater amounts of IL-6 in culture supernatants than did T cells, regardless of whether disease was active or inactive. Normal T cells and B cells did not produce significant amounts of IL-6. Thus, endogenous IL-6 produced by high density B cells bound to the IL-6R preferentially expressed on the low density B cells, and drove them into terminal differentiation, especially in active SLE patients. Further, addition of polyclonal anti-IL-6 or anti-IL-6R MoAb (PM1), which inhibited IL-6 binding, both inhibited IgG anti-ssDNA antibody as well as total IgG production by SLE B cells in a dose-dependent manner. These results suggest that interruption of the autocrine IL-6 loop would be of therapeutic value in SLE.
Kitani
A
A
First Department of Internal Medicine, National Defence Medical College, Saitama, Japan.
Hara
M
M
Hirose
T
T
Harigai
M
M
Suzuki
K
K
Kawakami
M
M
Kawaguchi
Y
Y
Hidaka
T
T
Kawagoe
M
M
Nakamura
H
H
D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D004277:DNA, Single-Stranded / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D066298:In Vitro Techniques; D007376:Interleukin-2 / Q000494:pharmacology; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000494:pharmacology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D011971:Receptors, Immunologic / Q000032:analysis*; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D004277:DNA, Single-Stranded; D007074:Immunoglobulin G; D007376:Interleukin-2; D015850:Interleukin-6; D011971:Receptors, Immunologic; D019947:Receptors, Interleukin-6; D011994:Recombinant Proteins