Type I Interferon Blockade in Systemic Lupus Erythematosus
Type I Interferon Blockade in Systemic Lupus Erythematosus
Blanco et al. demonstrated that SLE, as opposed to control sera, have the ability to induce the in vitro differentiation of monocytes into dendritic cells with high antigen-presenting properties that induce the proliferation of autologous CD4 T cells. This effect can be blocked by the addition of an anti-IFN-α antibody, thereby illustrating one of the probable mechanisms by which type I IFNs promote pathogenesis of the disease.
The priming effect of type I IFNs on antigen-presenting cell function was also recently illustrated in vivo in SLE patients treated with IFN-α kinoid (IFN-K). IFN-K is a synthetic compound made of IFN-α2b molecules linked to a strong immunogenic carrier (see below) that induces the production of anti-IFN-α autoantibodies. Strikingly, we observed that the anti-IFN-α antibody response is about 10-fold higher in SLE patients with a positive IFN signature at the time of immunization compared with patients without such a signature, thereby confirming that the overexpression of IFN-induced genes is associated in vivo with improved T cell–mediated responses to (auto)antigens.
Type I IFNs also affect B cell functions. B cell exposure to type I IFNs induces a switch toward and a strong increase in IgG production. Type I IFNs also potentiate B cell responses to several stimuli, including TLR activation. Interestingly, Uccellini et al. found that IFN-α stimulation also potentiates signalling through the B cell receptor (BCR). It can thereby lower the activation threshold of RF-producing B cells in response to immune complexes made of anti-DNA antibodies and poorly stimulating mammalian DNA. Finally, type I IFNs also exert indirect effects on B cell survival and activation through increased production of BLyS by monocytes.
The observations described here show how dysregulation of type I IFN production is potentially involved in the pathogenesis of SLE (Fig. 2). In a first step, endogenous apoptotic material released after exposure to ultraviolet (UV) irradiation or a viral infection is made available to antigen-presenting cells. It is important to stress that apoptotic material is usually eliminated by macrophages/monocytes, a process that does not result in any inflammatory response. In SLE patients, however, it was shown that the removal of apoptotic debris by monocytes/macrophages is impaired, resulting in the availability of nucleic acid–containing material to dendritic cells. In a second step, the apoptotic material is processed by antigen-presenting cells. In the endosomal compartment of these cells, the endogenous nucleic acids bind specific TLRs, resulting in the production of type I IFN and IFN-induced genes. In parallel, peptides originating from ribonucleoproteins or histones are loaded onto class II molecules and presented to autoreactive CD4 T cells. This phenomenon can be facilitated by the presence of low-affinity natural antibodies directed against nucleic acids that enhance the capture of immune complexes containing apoptotic material. However, their presence is not required at this point. Because of the low affinity of the T cell receptors of autoreactive T cells, presentation of self-peptides does not usually lead to lower tolerance, or only causes a transient, self-contained activation resulting in the production of low-affinity antinuclear antibodies.
(Enlarge Image)
Figure 2.
SLE pathogenesis at a glance
Apoptotic material (released after UV irradiation or bacterial or viral infections and not adequately removed by macrophages) is processed by antigen-presenting cells. In the endosomal compartment, self-peptides are loaded onto HLA II molecules. In parallel, endogenous nucleic acids bind to TLRs, resulting in the production of type I IFNs. Type I IFNs increase the maturation of antigen-presenting cells and their ability to reduce the tolerance of autoreactive T cells to self-peptides. Autoreactive T cells provide help to antinuclear antibody B cells. Finally, immune complexes, made of antinuclear antibodies and nuclear antigens are captured by antigen-presenting cells, and dual signalling through Fc-γ receptors and TLRs increases type I IFN production.
In contrast, in individuals with a genetic susceptibility, signalling through endosomal TLRs leads to greater production of type I IFNs and IFN-induced genes. This leads to increased maturation of dendritic cells and more efficient presentation of self-peptides to autoreactive T cells. Activated T cells in turn stimulate the maturation and production of immunoglobulins by autoantibody-producing B cells, resulting in the secretion of pathogenic antibodies directed against chromatin constituents. Finally, an amplification loop is initiated, fed by the presence of immune complexes, the components of which synergistically induce the production of type I IFNs by antigen-presenting cells.
Pathogenic Role of Type I IFNs in SLE
Blanco et al. demonstrated that SLE, as opposed to control sera, have the ability to induce the in vitro differentiation of monocytes into dendritic cells with high antigen-presenting properties that induce the proliferation of autologous CD4 T cells. This effect can be blocked by the addition of an anti-IFN-α antibody, thereby illustrating one of the probable mechanisms by which type I IFNs promote pathogenesis of the disease.
The priming effect of type I IFNs on antigen-presenting cell function was also recently illustrated in vivo in SLE patients treated with IFN-α kinoid (IFN-K). IFN-K is a synthetic compound made of IFN-α2b molecules linked to a strong immunogenic carrier (see below) that induces the production of anti-IFN-α autoantibodies. Strikingly, we observed that the anti-IFN-α antibody response is about 10-fold higher in SLE patients with a positive IFN signature at the time of immunization compared with patients without such a signature, thereby confirming that the overexpression of IFN-induced genes is associated in vivo with improved T cell–mediated responses to (auto)antigens.
Type I IFNs also affect B cell functions. B cell exposure to type I IFNs induces a switch toward and a strong increase in IgG production. Type I IFNs also potentiate B cell responses to several stimuli, including TLR activation. Interestingly, Uccellini et al. found that IFN-α stimulation also potentiates signalling through the B cell receptor (BCR). It can thereby lower the activation threshold of RF-producing B cells in response to immune complexes made of anti-DNA antibodies and poorly stimulating mammalian DNA. Finally, type I IFNs also exert indirect effects on B cell survival and activation through increased production of BLyS by monocytes.
The observations described here show how dysregulation of type I IFN production is potentially involved in the pathogenesis of SLE (Fig. 2). In a first step, endogenous apoptotic material released after exposure to ultraviolet (UV) irradiation or a viral infection is made available to antigen-presenting cells. It is important to stress that apoptotic material is usually eliminated by macrophages/monocytes, a process that does not result in any inflammatory response. In SLE patients, however, it was shown that the removal of apoptotic debris by monocytes/macrophages is impaired, resulting in the availability of nucleic acid–containing material to dendritic cells. In a second step, the apoptotic material is processed by antigen-presenting cells. In the endosomal compartment of these cells, the endogenous nucleic acids bind specific TLRs, resulting in the production of type I IFN and IFN-induced genes. In parallel, peptides originating from ribonucleoproteins or histones are loaded onto class II molecules and presented to autoreactive CD4 T cells. This phenomenon can be facilitated by the presence of low-affinity natural antibodies directed against nucleic acids that enhance the capture of immune complexes containing apoptotic material. However, their presence is not required at this point. Because of the low affinity of the T cell receptors of autoreactive T cells, presentation of self-peptides does not usually lead to lower tolerance, or only causes a transient, self-contained activation resulting in the production of low-affinity antinuclear antibodies.
(Enlarge Image)
Figure 2.
SLE pathogenesis at a glance
Apoptotic material (released after UV irradiation or bacterial or viral infections and not adequately removed by macrophages) is processed by antigen-presenting cells. In the endosomal compartment, self-peptides are loaded onto HLA II molecules. In parallel, endogenous nucleic acids bind to TLRs, resulting in the production of type I IFNs. Type I IFNs increase the maturation of antigen-presenting cells and their ability to reduce the tolerance of autoreactive T cells to self-peptides. Autoreactive T cells provide help to antinuclear antibody B cells. Finally, immune complexes, made of antinuclear antibodies and nuclear antigens are captured by antigen-presenting cells, and dual signalling through Fc-γ receptors and TLRs increases type I IFN production.
In contrast, in individuals with a genetic susceptibility, signalling through endosomal TLRs leads to greater production of type I IFNs and IFN-induced genes. This leads to increased maturation of dendritic cells and more efficient presentation of self-peptides to autoreactive T cells. Activated T cells in turn stimulate the maturation and production of immunoglobulins by autoantibody-producing B cells, resulting in the secretion of pathogenic antibodies directed against chromatin constituents. Finally, an amplification loop is initiated, fed by the presence of immune complexes, the components of which synergistically induce the production of type I IFNs by antigen-presenting cells.