Regulation of myeloid cell function and major histocompatibility complex class II expression by tumor necrosis factor.
OBJECTIVE
Tumor necrosis factor (TNF)-neutralizing agents are the most successful means of ameliorating systemic autoimmune inflammation. Neutralization of TNF, however, is often associated with the development of autoantibodies, particularly to nuclear antigens, and the mechanisms of this are unknown. We undertook this study to analyze the effect of TNF and its neutralization on the expression of major histocompatibility complex class II molecules and on the function of antigen-presenting myeloid cells in rheumatoid arthritis (RA).


METHODS
Monocytes were isolated from the peripheral blood of RA patients before and after anti-TNF monoclonal antibody (mAb) treatment and from the peripheral blood of controls by negative selection, differentiated in vitro to macrophages, and analyzed by flow cytometry for HLA-DR expression. T cell responses to activation by myeloid cells were assessed in proliferation assays, and messenger RNA (mRNA) levels of the class II transactivator (CIITA) were determined by semiquantitative reverse transcriptase-polymerase chain reaction.


RESULTS
HLA-DR expression was significantly reduced on myeloid cells from RA patients with active disease, but was increased to normal levels after anti-TNF mAb treatment. Concordantly, in vitro application of TNF to monocytes from healthy individuals reduced their ability to up-regulate HLA-DR during differentiation to macrophages and, importantly, inhibited their ability to stimulate T cells in mixed lymphocyte reactions. Molecular analysis revealed that the effect of TNF on HLA-DR expression was mediated via suppression of the transcription factor CIITA.


CONCLUSIONS
The data indicate that TNF decreases HLA-DR expression by reducing CIITA mRNA levels in myeloid cells, functionally resulting in a decreased capacity of myeloid cells to stimulate T cells. Concordantly, ameliorating disease activity in chronic inflammatory diseases by neutralizing TNF restores expression of HLA-DR on myeloid cells as well as the ability of myeloid cells to stimulate T cells. Thus, anti-TNF treatment might lead to augmented T cell activation by myeloid cells, thereby promoting immune responses to (auto)antigens and the development of antinuclear antibodies that are frequently associated with anti-TNF therapy.
Mueller
Ruediger B
RB
Nikolaus Fiebiger Center for Molecular Medicine and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany.
Skapenko
Alla
A
Grunke
Mathias
M
Wendler
Jörg
J
Stuhlmuller
Bruno
B
Kalden
Joachim R
JR
Schulze-Koops
Hendrik
H
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000938:Antigen-Presenting Cells / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology*; D015870:Gene Expression; D005802:Genes, MHC Class II / Q000235:genetics*; D006801:Humans; D007959:Lymphocyte Culture Test, Mixed; D008875:Middle Aged; D022423:Myeloid Cells / Q000502:physiology*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D013601:T-Lymphocytes / Q000276:immunology; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha