State of the Art REVIEW
The role of immune complexes in human systemic lupus erythematosus is less clear. Immune complexes are present in kidney biopsies from patients with nephritis, 83 but both affected and unaffected skin in systemic lupus erythematosus are characterized by immune complex deposition 84 85 ; the basis of the classical “lupus band test”. The question of why and how immune complexes can be constantly present in skin without causing inflammation has not been answered but indicates that other cofactors must be required to drive clinical inflammation. This conclusion raises the question about how critical immune complex deposition is in the pathogenesis of nephritis, despite the subendothelial location of immune complex deposition corresponding to the severity of nephritis. 86 While the exact role of autoantibodies in pathogenesis remains to be elucidated, developments in treatment (see below) support humoral autoimmunity as an ongoing driver of disease in lupus, even though additional functions of B cells outside antibody production include antigen presentation, cytokine production, and cell- cell interactions. Innate immunity Another important early event in the pathogenesis of systemic lupus erythematosus is activation of the innate immune system. This activation is believed to occur in response to stimulation by cellular or nuclear debris, or both, with several possible sources ( fig 1 ). The activation is associated with modification and exposure of normally intracellular antigens, which could lead to a loss of immune self-tolerance depending on the individual’s genetic and epigenetic background. Supporting this idea, functional impairment of DNASE1L3, an extracellular enzyme capable of digesting chromatin released by apoptotic cells, can lead to a clinical phenotype of systemic lupus erythematosus in humans and mice. 87-89 An alternative mechanism of externalization of intracellular products is the release of neutrophil extracellular traps (NETs). NETosis describes the release of net-like structures containing chromatin and antimicrobial peptides after cell death or non-lytic extrusion. 90 Low density granulocytes represent a distinct subset of neutrophils in systemic lupus erythematosus, with enhanced ability to release NETs, stimulate inflammatory responses, and generate tissue damage, including vascular injury and accelerated atherosclerosis. 91-93 Dysregulation in the complement system also contributes to systemic lupus erythematosus pathogenesis via this pathway, as early components of the classical complement pathway facilitate the removal of apoptotic and damaged cells. 94 95 Exposure of systemic lupus erythematosus neutrophils to immune complexes also induces NETosis, which can further contribute to self-chromatin exposure. 96 Similarly, dysfunctional macrophages can also contribute to impaired phagocytosis of apoptotic bodies in systemic lupus erythematosus. 97
Exposed intracellular autoantigens, either by themselves or bound to autoantibodies in the form of immune complexes, are engulfed, processed, and presented to T cells by dendritic cells, macrophages, and other antigen presenting cells, leading to the adaptive immune responses to intracellular self- antigens. In addition, nucleic acids are potent inducers of inflammatory responses in their own right. Cells recognize nucleic acids by two main mechanisms: the endosomal toll-like receptors (TLRs) and the cytosolic DNA and RNA sensors. Accumulating evidence in humans and mice suggests essential roles for TLR7 and TLR9 in systemic lupus erythematosus pathogenesis. 98-102 Similarly, recent studies have emphasized the importance of the cytosolic nucleic acid recognition system in systemic lupus erythematosus, particularly the cyclic GMP- AMP synthase/stimulator of interferon genes (cGAS/ STING) pathway. 103-105 The TLRs and cytosolic nucleic acid sensing pathways converge into the stimulation of type I interferon production; a protective response when the source of nucleic acids is viral, but almost certainly a key step in systemic lupus erythematosus pathogenesis when the source is the host. Evidence of exaggerated type I interferon responses is a common finding in systemic lupus erythematosus, and as noted below, blockade of type I interferon signaling has been shown to be a successful therapeutic approach in systemic lupus erythematosus. 106 About half of patients with systemic lupus erythematosus have elevated circulating type I interferon levels, and over two-thirds exhibit an interferon gene expression signature in peripheral blood that is rarely found in healthy individuals. 75 107 Elevated circulating levels of type I interferon are also identified in unaffected relatives of patients with systemic lupus erythematosus, supporting the role of genetics in susceptibility to autoimmunity. 108 The detection of interferon alfa in peripheral blood was shown to be a risk factor for flare in a prospective study of 254 patients in remission, 109 while accordingly, high interferon gene signatures were associated with a higher average disease activity and lower likelihood of reaching treatment goals in a longitudinal study of 205 patients with systemic lupus erythematosus. 76 A recent study using data from a 1756 patient gene expression array dataset with in vitro experimental confirmation observed that while glucocorticoids hardly affect interferon signatures, interferon markedly suppressed glucocorticoid induced genes. 110 These data suggest that interferon contributes to reduced glucocorticoid sensitivity in systemic lupus erythematosus. This conclusion is supported by the enhanced ability to taper glucocorticoids of patients treated with the interferon receptor antibody anifroluma. 111-113 [is this OK or is it anifrolumab?] The source of excess type I interferon activity in systemic lupus erythematosus is not yet certain. Plasmacytoid dendritic cells are distinguished by their ability to produce large amounts of interferon alfa on endosomal TLR stimulation. However, whether
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doi: 10.1136/bmj-2022-073980 | BMJ 2023;383:073980 | the bmj
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