It’s Never Lupus? Think again…


Those of you familiar with a certain misanthropic maverick MD will no doubt be familiar with the phrase “it’s never lupus”. Unfortunately, in the real world, it IS sometimes lupus – but what is lupus and how does it arise?

Occurrence and Prevalence

Systemic Lupus Erythematosus (SLE or lupus) is a systemic autoimmune disease and is largely very poorly understood, and usually first occurs when the patient is ages 15-50. Whilst lupus is uncommon, it’s more prevalent than you may think. The disease has a significant gender and racial bias: around 90% of patients are women and whilst lupus occurs in around 1 in 5000 white females in the UK, it affects as many as 1 in 625 of the female African Caribbean UK population. That might not seem an awful lot, but there are certainly much rarer diseases out there!

Biology of Lupus

The disease biology of lupus is both complex and poorly understood, and the disease has a very large degree of clinical heterogeneity. As such, there is a large degree of variability in the severity of lupus, and mild forms are known as discoid lupus erythematosus (DLE) rather than SLE. DLE only affects the skin, whereas SLE is systemic; this variability in severity and symptoms can make lupus diagnosis tricky.

As an autoimmune disease, the mechanisms underlying the biology of lupus involve the body’s own immune system: patients often have defects in complement (an important part of the innate immune system), and complement deficiency syndromes are a major cause of lupus (but notably not all lupus patients have these deficiencies).

Antibodies against DNA and other endogenous markers are often, but not always, found in lupus patients, and these are key indicators of the autoimmune basis of the disease. One likely mechanism of the pathogenesis of lupus is an autoimmune reaction against the patient’s DNA, leading to damage and pathological inflammation.  It is thought that these reactions create immune complexes which are deposited at susceptible sites in the body, such as the kidneys and skin, which then causes the symptoms of lupus – which can include nephritis and a characteristic butterfly skin rash from deposition at these sites. One factor that is currently thought to perhaps begin the cascade of lupus-causing reactions is deregulation of apoptosis and decreased removal of apoptotic cells, leading to a build of dying cells and their DNA in the circulation.

Symptoms of Lupus

Common Symptoms of Systemic Lupus Erythematosus

The exact cause or trigger of lupus is unknown, although a lupus-like disease can be caused by a number of drugs. A variety of genetic and environmental factors are thought to contribute to an individual’s risk of acquiring the disease. Some of these factors have now been identified, including the role of Epstein Barr Virus infection in altering the risk of developing lupus.

Genetics of Lupus

A large number of genetic variations have been associated with increased susceptibility to developing lupus. Many of these – such as the genes encoding antibodies and complement components – have known roles in the immune system, and therefore have logical associations with the autoimmune condition. Other risk-modulating variations exist in genes that are not known to have a role in the immune system, or yet have no identified function at all. Crucially, alterations in susceptibility are often very small and can be either protective or predisposing to lupus, and so lupus itself is termed ‘genetically complex’.

The nature of these variations is variable, and range from single nucleotide polymorphisms (common single-base changes) to copy number aberrations (altered number of gene copies).

Epigenetics of Lupus

More recently it has been discovered that there are epigenetic factors associated with lupus susceptibility. Changes in DNA methylation patterns have been identified to alter the risk of disease, and hypomethylation (reduced methylation) of DNA in CD4 T cells is now known to be associated with increased lupus risk. CD4 T cells mediate and control immune responses, and altered methylation patterns can alter gene expression levels – so again these changes have logical effects on autoimmune condition susceptibility.

Epigenetics is an exciting avenue of investigation in many diseases, particularly in conditions where our understanding of their occurrence is poor or incomplete. The birth of whole-methylome analyses has kick-started these research areas, and we’ll likely be seeing a lot more of these links between epigenetics and disease risk in the near future (and indeed we already are seeing many of these publications).


And so we see that lupus is a disease of genetic, environmental and epigenetic complexity – there is still an awful lot of work going on to try and dissect how this chronic autoimmune condition arises!






Absher DM, Li X, Waite LL, Gibson A, Roberts K, Edberg J, Chatham WW, & Kimberly RP (2013). Genome-wide DNA methylation analysis of systemic lupus erythematosus reveals persistent hypomethylation of interferon genes and compositional changes to CD4+ T-cell populations. PLoS genetics, 9 (8) PMID: 23950730

Tiffin N, Adeyemo A, & Okpechi I (2013). A diverse array of genetic factors contribute to the pathogenesis of systemic lupus erythematosus. Orphanet journal of rare diseases, 8 PMID: 23289717






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