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Pathogenesis of tissue injury in the brain in patients with systemic lupus erythematosus
The brain and nervous system are important targets of immunological injury in people with systemic lupus erythematosus. The nature of this brain injury is complex and all levels of the neuroaxis can be affected, including the brain parenchyma, spinal cord, the cerebral vasculature, and the peripheral nervous system. Compared to other organ system, our mechanistic understanding of brain disease in lupus remains modest, and represents a critical knowledge gap in the field of lupus. Robust identification of the molecular mechanisms of neurolupus will be critical for precise diagnosis and treatment in the future.
The challenge of neurolupus
Researchers trying to unpick neurolupus face a complex multidimensional challenge at the neuroanatomical level, the immunological level, and the individual patient level. Brain disease in lupus can manifest with many different clinical syndromes, from focal deficits to diffuse brain disease. Lupus brain disease has been notoriously difficult to study, and basic definitions of neurolupus have been problematic. In 1999 the American College of Rheumatology proposed a basis for classification, based on a broad division between central nervous system and peripheral nervous system. The strengths and limitations of this system are discussed in detail in Chapter 49 , but it is important to emphasize two points which are relevant to discovering mechanisms of lupus brain disease. Firstly, this classification is based largely on clinical symptomatology rather than pathophysiology. This contrasts with renal lupus, where classification is largely based on pathological findings. Secondly, the heterogeneity of lupus makes classification complex and fragmented. As such neurolupus lacks standardized reproducible diagnostic criteria, and therefore definitions vary substantially between human studies. Individuals with lupus often have complex immune phenotypes, as well as multiple comorbidities. Therefore many clinical findings and associations in descriptive epidemiological studies have the potential to be confounded, and attributing disease-relevance to specific immunological factors, such as autoantibodies, can be very challenging. Compounding this difficulty is a near-complete absence of interventional studies in neurolupus. Indeed brain metrics are rarely, if ever, captured in a meaningful way in pivotal trials of lupus therapeutics.
Models of neurolupus
Neurological disease in lupus-like states can be studied in humans, but also in other model systems, principally the mouse. Brain disease is observed in mouse models of lupus, but often CNS disease in these models is subtle. Findings from mouse models need to be interpreted with caution and may not generalize to human neurolupus. Among the many different models of lupus-prone mice, the MRL/MPJ-Fas lpr substrain has been particularly closely studied. The central defect of this mouse is a spontaneous mutation in Fas which results in multiple immunological defects, including accumulation of T-lymphocytes which fail to undergo apoptosis. Like many of the lupus mouse strains, the MRL-lpr mice develop circulating autoantibodies, including those against dsDNA and brain antigens, and the clinical phenotype includes immunological damage to kidney, skin, joints, and heart. In this model, the onset of systemic autoimmunity coincides with the development of brain dysfunction. These mice spontaneously develop mild neurological dysfunction, in particular these mice exhibit behavioral and mood abnormalities such as anhedonia and altered spatial learning. Neuropathological changes observed in these mice are subtle and include increased neuronal apoptosis during development, atrophic changes and loss of neuronal complexity in the hippocampus. Neurological deficits are also observed in other lupus models, including NZB mice, although the presence of congenital neuroanatomical abnormalities makes these findings more difficult to interpret. Other mouse models based on transgenic overexpression of cytokines such as interferon-alpha and interleukin-6 (IL-6) within the brain offer a tractable approach to the detailed study of cytokine neurotoxicity, but are limited by their physiological relevance and restriction to single immune pathways.
Genetics of brain disease
The past two decades have seen major advances in our understanding of the genetic architecture of lupus, through both genome-wide association studies and the identification of monogenic forms of lupus. A recent metanalysis of case-control studies of neuropsychiatric lupus suggested association with pathways of immune complex clearance, including FcγRIIIa, FcγRIIIb, and ITGAM. However the results of this metanalysis should be interpreted with caution given the variability in definitions used to define neurolupus. Another significant genetic association has been identified through a study of TREX1 , a 3’-5’ exonuclease associated with SLE. In this well-powered analysis of 8000 individuals with lupus, a relatively common risk haplotype was identified in European lupus patients with neurological manifestations (Odds ratio 1.73 P = 0.0008). TREX1 is a negative regulator of the type I interferon response, which is typically constitutively activated in people with lupus. Loss of enzymatic activity of the TREX1 enzyme is associated with an increase in intracellular immunostimulatory nucleic acids and dominant mutations in TREX1 can cause familial chilblain lupus, while biallelic mutations cause Aicardi-Goutieres’ Syndrome, a monogenic “interferonopathy” with severe neurological manifestations. These data are consistent with growing evidence that immunostimulatory nucleic acid accumulation can trigger neuroinflammation in lupus-like states, providing a glimpse of possible factors which regulate neurological disease tropism in lupus.
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