Taming lupus-a new understanding of pathogenesis is leading to clinical advances

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease that is characterized by the loss of tolerance to nuclear self antigens, the production of pathogenic autoantibodies and damage to multiple organ systems. Over the years, patients with SLE have been managed largely with empiric immunosuppressive therapies, which are associated with substantial toxicities and do not always provide adequate control of the disease. The development of targeted therapies that specifically address disease pathogenesis or progression has lagged, largely because of the complex and heterogeneous nature of the disease, as well as difficulties in designing uniform outcome measures for clinical trials. Recent advances that could improve the treatment of SLE include the identification of genetic variations that influence the risk of developing the disease, an enhanced understanding of innate and adaptive immune activation and regulation of tolerance, dissection of immune cell activation and inflammatory pathways and elucidation of mechanisms and markers of tissue damage. These discoveries, together with improvements in clinical trial design, form a platform from which to launch the development of a new generation of lupus therapies.

Figure 1

The spiral of disease progression in SLE. Individuals with identified genetic polymorphisms are at higher risk for SLE compared to the general population. Environmental triggers also probably contribute to the initiation and perpetuation of the disease. Activation of the innate immune system results in enhanced antigen presentation to T cells and the release of proinflammatory cytokines, including type I IFNs. These changes facilitate activation of the adaptive immune system and the development of autoantibodies. Autoantibodies bind to nucleic acids or cellular debris to form complexes that provide further stimulation to innate immune cells through TLRs. Autoreactive B cells act as antigen-presenting cells for the recruitment of more autoreactive T cells. These positive feedback loops that involve the innate and adaptive immune systems amplify clones of autoreactive lymphocytes during the preclinical stage of SLE. The onset of clinical manifestations is associated with systemic inflammation and injury of target organs, resulting in further amplification of immune activation. SLE becomes increasingly resistant to immune-modulating therapies and may eventually progress to irreversible tissue damage. The events that start to occur before or after the clinical onset are shown in green or blue, respectively.

Figure 2

The role of SLE risk alleles in the pathogenesis of SLE. A panoply of genetic variations has been linked to SLE susceptibility. Polymorphisms in genes involved in the immune clearance of apoptotic particles and nucleic-acid–containing immune complexes (clearance functions, with examples shown in orange) may induce the enhanced activation of pDCs and autoreactive B cells, leading to the production of type I IFN and the expansion of autoreactive effector cells, respectively. Polymorphisms in genes involved in innate immunity (with examples shown in green) regulate the induction of, as well as the response to, type I IFN. Abnormal function of innate immune cells in turn activates the adaptive immune system. Both the innate and adaptive immune systems contribute to the inflammatory response and tissue damage. A third major group of polymorphic genes is involved in ligand recognition, receptor signaling and other immunological functions of adaptive immune cells (with examples shown in blue). Dysregulation of the adaptive immune system results in loss of tolerance and the production of autoantibodies, which in turn bind to nuclear antigens and activate innate immune cells, completing a positive feedback loop that amplifies the pathogenic processes in SLE. Polymorphic alleles may also influence the severity of organ damage (with examples shown in purple). Ab, antibody; IRAK1, interleukin-1 receptor-associated kinase 1; ITGAM, integrin α M; TNFAIP3, tumor necrosis factor, α-induced protein 3; BANK, B cell scaffold protein with ankyrin repeats; BLK, B lymphoid tyrosine kinase; PCDCD1, programmed cell death 1; NA, nucleic acid; IC, immune complex; ACE, angiotensin I converting enzyme (peptidyl-dipeptidase A) 1.

Figure 3

Recognition of nucleic acids by innate immune cells triggers cytokine production. Nucleic acids or apoptotic particles can be taken up by B cells through the BCR, and immune complexes containing these antigens are taken up by monocytes, myeloid dendritic cells and pDCs through FcR-mediated recognition and internalization. Within endosomes, DNA and RNA then interact with TLR9 and TLR7, respectively. Viral RNA can also be delivered to endosomes by autophagosome formation in pDCs. The ligation of TLRs recruits the adaptor protein MyD88, which activates the NF-κB signaling cascade in B cells and leads to B cell activation and survival, as well as various effector functions. In pDCs, the recruitment of MyD88 preferentially triggers an IRF7-mediated signaling pathway, which initiates type I IFN production. In other cell types, MyD88 recruitment in late endosomes leads to inflammatory cytokine production. Cytosolic DNA and RNA can be recognized by sensors that, through adaptors, lead to type I IFN production. Cytosolic DNA can also be recognized by AIM2, which activates caspase-1, leading to proteolytic cleavage of pro–IL-1 and pro–IL-18 into active forms. Immune complexes may signal directly through both activating and inhibitory FcRs whose relative expression on the cell surface varies with cell activation status. How these positive and negative signals are integrated with each other and with TLR-mediated signals has not yet been fully elucidated. cDC, conventional dendritic cell; RLR, RIG-I like receptors; DDX41, a member of the DEXDc family of helicases; TBK1, TANK-binding kinase 1; ER, endoplasmic reticulum; Ig, immunoglobulin.

Figure 4

Mechanisms for organ damage. Organ damage is caused by immune activation and inflammation but is also influenced by genetic and nonimmunologic environmental factors. Autoantibodies and circulating inflammatory mediators trigger tissue injury in target organs by a variety of mechanisms. In the kidneys, immune complex deposition induces complement- and FcR-mediated inflammatory cascades that lead to the activation or injury of renal resident cells, which in turn release inflammatory mediators, leading to the recruitment of inflammatory cells. Long term renal damage is caused by ongoing inflammation, vascular injury by systemic and local mediators, hypoxia and fibrosis. Nephritis occurs in approximately 50% of adult and 80% of pediatric patients with SLE, and the rate of end-stage renal disease in the United States caused by SLE seems to be increasing, especially in minority patients. In the cardiovascular system, autoantibodies and soluble inflammatory mediators cause vascular endothelial injury by inducing endothelial apoptosis or activation. Recruitment of monocytes to the injured site is also crucial for plaque formation. Other proatherogenic factors in addition to traditional risk factors include oxidized low-density lipoproteins, antibodies to oxidized lipids and proinflammatory high-density lipoproteins. The 10-year risk for a coronary event or stroke is 7.5- to 17-fold increased in patients with SLE compared with healthy individuals. In the central nervous system, autoantibodies access the brain when the BBB is attenuated by inflammatory mediators or environmental factors, such as cigarette smoke or neurotransmitters released by stress. Once deposited in the brain, autoantibodies may induce neuron apoptosis or alter neuronal synaptic transmission. Neurologic injury can also result from secondary causes, such as thrombosis or infections. All these pathogenic changes lead to a wide range of neuropsychiatric manifestations of SLE, including progressive cognitive dysfunction. Neuropsychiatric manifestations may occur relatively early in the disease process, and they affect up to 40% of patients.