SYSTEMIC lupus erythematosus (SLE) is considered a prototypical autoimmune disease by clinicians and researchers alike, but a fundamental definition of lupus remains elusive.
The diagnosis relies on a constellation of clinical and laboratory manifestations. Serum autoantibodies provide a signature of aberrant immune responses, and in lupus these are targeted at a curious subset of self-antigens, enriched for chromatin, ribonuclear proteins and phospholipids. Favourable responses to immune suppression provide strong support that lupus is immune-mediated.
Despite these therapeutic advances, however, we still have some way to go before definitive diagnoses guide effective treatments in all patients for lupus. It is nevertheless worth considering how progress to date has flowed from integrating clinical observations, clinical trial results, underlying cellular defects, and insights into genetic susceptibility.
Lupus was first described as a skin disease and, of course, for some patients, lupus remains cutaneous. As the systemic manifestations became recognised, so did their protean nature.
Diagnostic criteria for lupus have been formulated, mainly for use in research and recruitment to clinical trials. The diagnostic criteria illustrate the heterogeneity of lupus manifestations as two patients may fulfil them yet have completely non-overlapping manifestations. One explanation for the heterogeneity of clinical manifestations is diversity of underlying disease mechanisms, and this could have implications for treatment, although until recently, lupus has been largely managed with broad-acting immunosuppressives (eg, corticosteroids, azathioprine) and cytotoxics (eg, cyclophosphamide). Elucidation of disease pathways that permit treatment to be personalised is likely to become more important when we employ precision medicines that act on single molecules (eg, belimumab).
Substantial progress in understanding the cellular immunology of lupus began with the description of the association between lupus and LE cells (neutrophils phagocytosing nuclear debris in bone marrow preparation) in 1948. This was a crucial diagnostic and mechanistic insight.
LE cells led to the identification of anti-nuclear antibodies, anti-double-stranded DNA antibodies, and characterisation of other autoantibodies. While many lupus autoantibodies are probably not pathogenic, they precede clinical diagnosis, sometimes by years. The cellular mechanisms that explain the presence of autoantibodies hinge on two important immunological concepts. First, autoimmune disease results from a breakdown in immunological tolerance, a summary term for many complex events that take place to purge T and B cells bearing autoreactive antigen receptors from the stochastically generated lymphocyte repertoire. In lupus, B cell-intrinsic defects that alter the threshold of B cell activation, and B cell survival, plus extrinsic defects including abundance of B cell-activating factor result in B cells evading normal self-tolerance mechanisms that would normally exclude a self-reactive population from the repertoire.
Second, some lupus-associated autoantibodies, including those against dsDNA, bind with high-affinity, a characteristic shared with antibodies formed in response to foreign antigens and vaccines. High-affinity antibodies arise from the sophisticated process of affinity maturation that takes place when B cells respond and proliferate under the influence of T cell help within germinal centres in secondary lymphoid organs. Mouse models of lupus have demonstrated that defects in tolerance, and germinal centre function, yield accurate models of human lupus. The spectrum of lupus autoantigens (chromatin, ribonuclear proteins and phospoholipids) that appear to reflect defects in the normally efficient apoptotic cell disposal mechanisms contribute to lupus. These antigens are displayed on cells undergoing apoptosis, and apoptotic cells are abundant in germinal centres. Several lines of evidence indicate that defects in the normally efficient apoptotic cell disposal mechanisms contribute to lupus as the antiviral mechanism.
There is a significant genetic contribution to lupus.
Rates of concordance amongst monozygotic twins are estimated at 30-60%, compared with 1-2% between dizygotic twins. Several approaches have been taken to identify the genetic loci and even precise genetic variants responsible for this association. In mouse models, complex breeding strategies identified lupus-associated genomic loci, which in some cases have been resolved to susceptibility alleles. In parallel, linkage analysis in humans identified lupus susceptibility loci. Interestingly, some of these are syntenic to those identified in mouse studies. More recent genetic discovery programs have focused on human genome-wide association studies. Collectively, these have yielded more than 50 signals, although for each, the odds ratio is small (about 1.5–2.0), which makes understanding the mechanisms underpinning these statistical associations difficult.
By contrast, in rare cases of monogenic lupus, which were previously identified by positional cloning, and more recently by whole exome or whole genome sequencing, the strength of effect of the disease-causing allele is substantial, and this makes elucidation of the mechanism more feasible. Excessive production of interferon-a by a minor subset of cells called plasmacytoid dendritic cells is a signature response in many lupus patients. Rare monogenic cases of lupus have revealed mechanisms that might account for this signature. Interestingly, these defects result in accentuation of the normal immune adaptations for recognition and response to viral infections, as a result of unusually sensitive detection of intracellular nucleic acids. These discoveries illustrate how rare diseases can yield important mechanistic insights into more common diseases.
Genetic associations and cellular immunology have yielded unexpected mechanisms to account for cellular and biochemical phenotypes in lupus. Calibration of lupus discoveries against observations in the clinic has been an important exercise in quality control for lupus research.
In other words, mechanisms that square with phenotypes consistently observed in lupus patients represent significant advances, but these can only be considered truly validated once antagonists of putative pathogenic pathways are demonstrated to be effective in randomised clinical trials.
Genetic, cellular or biochemical signatures of specific mechanism (so-called endophenotypes) are a necessary counterpart of precision therapy. This is because lupus is heterogeneous, so it will be necessary to target novel treatments appropriately to those patients most likely to benefit from them, according to mechanistic insights that identify subsets of lupus. Different mechanisms could also account for different patterns of end-organ involvement (eg, renal v CNS lupus). Failure to resolve lupus heterogeneity according to mechanisms at the time of recruitment to RCTs may dilute the measurable effect of new agents.
Professor Matthew C Cook is professor of medicine at the Australian National University, and director of immunology at Canberra Hospital. He is also the director of the NHMRC Centre for Research Excellence in Personalised Immunology at the John Curtin School of Medical Research, ANU.
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