SLE is rarely a single-gene disorder. Although genetic risk factors clearly contribute to lupus, a significant portion of patients do not display any known mutations in their genomes [128
]. On the other hand, stochastic stimuli and environmental factors (e.g.
infections, chemical compounds, somatic mutations, drugs, and aging [129
]) play roles that exacerbate autoimmune susceptibility and, at times, stimulate immune responses that lead to systemic autoimmunity. An immunocompetent host employs a multitude of regulatory mechanisms (e.g.
negative selection, anergy, receptor editing, and suppressor cells) to minimize autoreactivity that would cause damage and harm to itself. Understanding the mechanism by which immune tolerance is breached by an exogenous trigger is crucial for identifying the essential pathways responsible for the establishment of autoimmunity.
It is well known that significant fraction of newly generated and mature B cells shows some degree of autoreactivity [134
]. Even so, humoral immune tolerance is largely maintained even after challenges with autoantigens. In one study, immunization of bacterial DNA in the presence of a carrier protein in non-autoimmune mice induced the production of anti-bacterial DNA antibody lacking reactivity to mammalian DNA [136
]. In another study, wild-type mice that received an injection of a large number of apoptotic human cells developed modest and transient autoantibody production without exhibiting clinical changes [137
]. HMGB1-nucleosome complexes constitute the major nuclear component recognized by SLE autoantibodies. However, after inoculation into non-autoimmune mice, these complexes induced a limited antibody response against the immunized components without overt lupus-like disease [138
The innate immune response instructs the corresponding adaptive immune response. For effective antibody induction, various adjuvants with strong innate stimulatory activities have been used to boost the B cell response and generate high titers of immunogen-specific antibodies in experimental settings and effective vaccines. The role played by innate immune activation in initiating the autoreactive humoral response has not been extensively studied. Hydrocarbon oil pristine triggers profound inflammation and IFN production; the latter is essential to the development of autoantibodies and glomerulonephritis in non-autoimmune mice [139
]. This finding thus highlights an equally critical role of type I IFN in the induced and spontaneous systemic autoimmunity.
Amyloid is formed from a native protein after a process of aberrant aggregation and misfolding [141
]. Amyloid fibrils contain extensive β sheet structures and can be found extracellularly or intracellularly. Amyloid depositions in vivo
are often heterogeneous and contain non-proteinaceous cofactors [141
], which may be explained by the fact that amyloid precursor proteins display an intrinsic affinity towards nucleic acids and glycosaminoglycans, an interaction that promotes the rapid formation of amyloid [144
]. We examined the innate immune properties of amyloid fibrils containing nucleic acids and found that these complexes are potent inducers of type I IFN from human pDCs [145
] (Figure 1). Regardless of their source or type, nucleic acids incorporated into amyloid fibrils could be efficiently internalized by human pDCs into an endosomal compartment to trigger TLR activation and strongly induce IFN production. Because amyloid proteins use a variety of mechanisms to penetrate cells, amyloid fibrils containing nucleic acids trigger IFN production independently of FcγRIIα [145
When inoculated into the peritoneal cavity, DNA-containing amyloid fibrils induced selective pDC infiltration, which was associated with a predominant type I IFN response. After immunization with DNA-containing amyloid fibrils, non-autoimmune mice developed stable anti-nuclear autoantibodies and abroad autoreactive humoral response against DNA, RNA, Sm/RNP, and histone [145
]. Proteinuria and antibody depositions in the glomeruli of the kidneys were also detected, suggesting the development of a lupus-like syndrome. In amyloid-immunized mice, the establishment of anti-nuclear serology requires the signaling of IFNα/β receptors. We found that pDCs were indispensable for not only the acute IFN response but also the subsequent autoantibody development [145
]. By contrast, pDCs were not involved in the induction of antibodies against the amyloid protein per se
, and pDC depletion did not affect the development of proteinuria. Therefore, IFN-producing pDCs play an essential and selective role in instigating the humoral autoimmune response following a strong innate immune activation (Figure 2).
Whereas pDCs and IFN appears to influence B cell differentiation in vitro
(see earlier section), our data suggests that pDCs are largely dispensable for the immunogen-specific IgG response in vivo
. Consistent with this observation, Baccala et al. reported that feeble
mice elicited normal T cell–dependent and –independent IgG responses that were indistinguishable from those of wild-type mice [113
]. In addition, it has been shown that neither pDCs or IFN was required to elicit a protective antibody response after inoculation with live attenuated flu vaccine [146
]. By contrast, pDCs and IFN were critical for the generation of primary IgG and IgA response after immunization of inactivated whole virus flu vaccine [146
]. On the other hand, pDCs are suggested to have a role in IgA production under steady-state conditions, based on the observation that, when co-cultured with mucosal B cells, pDCs from mesenteric lymph nodes and Peyer's patches can facilitate T cell–independent IgA secretion via production of APRIL and BAFF [147
]. Remarkably, during intestinal rotavirus infection, pDC-derived type I IFN was required for optimal B cell activation and virus-specific IgA antibody secretion for effective protection [148
]. Therefore, pDCs seem to have multifarious effects on humoral responses. Further investigation on how pDC-IFN pathway selectively instructs autoreactive B cell selection and expansion would shed light on the key processes involved in the breakdown of immune tolerance.
The fact that nucleic acid-containing ICs and autoantibody-induced NET potently trigger IFN production from pDCs implies a role of type I IFN at late stage of lupus pathogenesis after the establishment of humoral autoimmunity. However, our results demonstrate that IFN also function as a critical mediator in the early stage of autoimmune development, a conclusion further supported by the finding that IFNα/β receptor blockade was effective in BXSB mice only when administrated to young mice at a preclinical phase [112
]. These studies indeed suggest a therapeutic window of IFN blockade, which may be more effective at the onset of autoimmune response.
For a long time, the presence of amyloid was exclusively associated with about two dozen human pathologies with Alzheimer's disease as the best known example [149
]. However, an increasing number of so-called functional amyloids have been shown to participate in diverse normal cellular functions, suggesting a prevalence of this peculiar form of protein post-translational modification [151
]. Amyloid fibrils also represent a type of DAMP that is capable of activating inflammasome thus contributes to autoinflammatory responses [159
]. Therefore, it would be important to examine the direct involvement of amyloid in disease pathogenesis among SLE patients.