The NIPCs/PDCs express molecules that can detect danger signals and foreign antigens. As mentioned, they express the pattern recognition molecule TLR9, which interacts with and mediates responses to unmethylated CpG-DNA [31
]. The induction of IFN-α might also require TLR9, because a new highly efficient IFN-α-inducing ODN required unmethylated CpG [53
]. Furthermore, the poor IFN-inducing ability of other potent immunostimulatory ODNs was strongly increased when PDCs were co-stimulated by CD40L [54
]. Consequently, several different signals via cell-membrane molecules might be required to initiate IFN-α gene expression. It is here relevant that NIPCs/PDCs express FcγRIIa ([51
]; U Båve, M Magnusson, M-L Eloranta, A Perers, GV Alm and L Rönnblom, unpublished work) and that the antibodies in SLE-IIF are essential for IFN-α production [48
]. The direct involvement of FcRγII in the stimulation of NIPCs/PDCs by SLE-IIF [55
], or by the combination of apoptotic cells and SLE autoantibodies (U Båve, M Magnusson, M-L Eloranta, A Perers, GV Alm and L Rönnblom, unpublished work), was shown by means of blocking anti-FcRγII antibodies.
It is known that FcγRII can provide intracellular signals and internalize ICs [56
] and such material might be targeted to cytoplasmic compartments [58
]. Thus, internalization of the IFN-α inducer could be an essential step and there might exist intracellular recognition structures for nucleic acid (DNA and RNA) motifs. The exact recognition and activation mechanisms for the different IFN-α inducers in SLE patients are unclear at present, and other TLRs than TLR9 might be involved. Thus, NIPCs/PDCs also express TLR1, 6, 7, and 10 but not the dsRNA-binding receptor TLR3 [30
], and ligation of TLR7 by the drug imiquimod can elicit IFN-α production [59
]. Several intracellular pathways might therefore lead to IFN-α gene expression.
IFN-α/β gene transcription in NIPCs/PDCs were, early on, shown to be dependent on de novo
protein synthesis [60
], and the presence of cytokines such as type I IFN, IFN-γ, IL-3, and GM-CSF increased the IFN-α production caused by viral inducers [61
]. In addition, the induction of IFN-α production triggered by SLE-IIF, or the combination of apoptotic cells and autoantibodies, was markedly dependent on priming with especially IFN-α/β [48
]. Such priming is important for the viral induction of many IFN-α genes and might involve an initial activation of some IFN-α or IFN-β gene expression because of activation of pre-existing transcription factors [63
]. This IFN then causes the synthesis of further transcription factors, such as interferon regulatory factor-5 (IRF-5) and IRF-7, that become activated and promote the expression of a wider spectrum of IFN-α genes. It is not known whether a similar mechanism is necessary for the activation of IFN-α gene expression in NIPCs/PDCs by the endogenous SLE-related IFN-α inducers.
Certain cytokines have a negative impact on NIPCs/PDCs, and IL-10 has been shown to be a potent inhibitor of IFN-α production caused by different IFN-α inducers, such as virus, SLE-IIF and the combination of apoptotic cells with antibodies [48
]. In addition, TNF-α inhibited the action of these inducers [62
]; this observation is interesting because it can explain why a blockade of TNF-α by anti-TNF-α antibodies or soluble TNF-α receptors in human patients can result in autoimmune side effects, including SLE [65
]. We therefore propose that such side effects are due to an increased activity of NIPCs/PDCs, which promotes the development of autoimmunity.