What Is an Autoimmune Disease?

When the body’s immune system is working correctly, it recognizes invaders like bacteria and viruses as “foreign”, and attacks them using white blood cells and antibodies. In contrast, it recognizes the body’s own cells as “self” or “not foreign” and does not attack them. Autoimmune diseases – like rheumatoid arthritis, Crohn’s disease, and lupus – develop when the body’s immune system mistakenly starts to recognize the body’s own tissue as foreign and attacks it. This can cause inflammation in tissues and organs that, over time, can lead to serious damage.

What Causes Lupus and What Are Its Symptoms?

The exact causes of lupus are unknown, but it is thought to be caused by a combination of genetic and environmental factors. A number of genetic mutations (changes in genes) have been reported that seem to be linked to a person being susceptible to developing lupus. Women are most likely to be affected by the disease, and there is some evidence that hormonal changes that occur during a woman’s lifetime (such as during puberty, pregnancy, and menopause) may play a role. Lupus can be difficult to diagnose because signs and symptoms can differ from one person to another. They can also vary in their severity and develop slowly or quickly.

There are several different types of lupus. Some only affect the skin but the most common type, called systemic lupus erythematosus (SLE), can affect many parts of the body. SLE is characterized by the release of autoantibodies that bind to contents of the cell nucleus (the part of the cell that houses the DNA and is where genes are activated), including double-stranded DNA. The most common symptoms are extreme fatigue or exhaustion, swelling of or pain in the muscles or joints, skin rashes (particularly on the wrists and hands, or a butterfly-shaped rash across the cheeks and nose), mouth ulcers that keep coming back, hair loss, and fever. In addition, a form of kidney disease called lupus nephritis can develop.

What Is Lupus Nephritis?

The kidneys help to control blood pressure and make red blood cells, and remove waste products and extra water from the body to make urine. Lupus nephritis develops when the immune system starts to attack the part of the kidney that filters the waste products out of your blood, called the glomeruli, and is estimated to affect around 50% of patients with SLE. Although it can often be successfully controlled, lupus nephritis can lead to kidney failure, where a person’s kidneys stop working and they need kidney replacement therapy (in the form of dialysis or kidney transplant) to survive. In addition, it can cause high blood pressure, which can increase the risk of stroke or heart attack. Symptoms of lupus nephritis include blood or protein in the urine, weight gain, and the extra fluid that the kidneys cannot remove causing swelling (known as “edema”) in body parts like your legs or ankles.

What Happens to Glomeruli When Lupus Nephritis Develops?

There are around 1 million glomeruli in each kidney. They are made up of bundles of looping blood vessels and several specialized types of epithelial cells (this is the name given to types of cell that cover the inside and outside surfaces of your body, such as the skin, the outer surfaces of organs and internal cavities, and blood vessels). When lupus nephritis develops the glomeruli stop working properly, partly because of swelling or scarring of the small blood vessels, but also because epithelial cells in the glomeruli do not function properly. One cell type that is affected is the podocytes. These are highly specialized cells that wrap around the outer surfaces of the blood vessels in the glomeruli and play an essential role in filtering the blood by stopping proteins from being filtered out. Exactly how podocytes become damaged in lupus nephritis is unknown, but it may be caused by a combination of genetic, inflammatory, and metabolic (the processes that convert food and drink to energy in the body) factors.

What Did This Study Investigate?

The number of cells in the body is tightly regulated and a number of processes exist that check that cells and the molecules inside them are functioning normally. There are also processes that repair or remove damaged cells and molecules if things go wrong. There have been some reports that one such process called “autophagy” is linked to the development of lupus nephritis. Autophagy, which means “self-eating”, is a process by which old and damaged proteins or parts of cells are broken down and destroyed. The breakdown products are then recycled inside the cell and reused, especially during periods of starvation or stress. Autophagy plays an essential role in the immune system because it helps to destroy bacteria or viruses and is involved in inflammation.

Autophagy is typically a protective process; however, its activity is tightly regulated because if too much autophagy is taking place, it can result in programmed cell death (a method by which the body gets rid of cells that have become damaged or are no longer needed). Similarly, if the level of autophagy activity in a cell is too low, faulty proteins and parts of cells are not removed and can contribute to the development of disease. Autophagy is known to be involved in autoimmune diseases and changes in the normal functioning of autophagy have been linked to the development of cancer. The authors of this study investigated how autophagy affects podocytes in lupus nephritis, particularly regarding its effects on the levels of two proteins called A20 and RNF168.

How Are A20 and RNF168 Linked to Lupus Nephritis?

A20 is an enzyme (a type of protein that speeds up a chemical reaction) that is involved in regulating a process called “ubiquitination”, where a small protein called ubiquitin is attached to a protein and acts as a tag indicating that something should happen to it (such as the activation of another process, that it should move from one part of the cell to another, or that the protein should be broken down). Abnormal levels or functioning of A20 is known to be involved in chronic inflammation and tissue damage.

RNF168 is another enzyme and is involved in the cell’s DNA damage repair process. It helps to repair breaks in double-stranded DNA by tagging histone proteins. Histones are found in chromosomes and act as spools that the DNA winds around to become more compact and form chromosomes. They can also be marked with different types of tags that indicate whether a particular gene is “on” or “off”. In the case of RNF168, it tags histones with ubiquitin molecules near the sites of breaks in double-stranded DNA that enable proteins to bind that can repair the break.

What Did the Study Show?

The results of the study showed that autophagy in podocytes is over-activated in lupus nephritis and that this leads to the activity of A20 being reduced. At the same time, the activity of RNF168 is increased, leading to increases in both the amounts of DNA damage in podocytes and the activation of a protein called NF-κB, which activates genes involved in inflammation. In contrast, when autophagy is inhibited (this means that something is slowed down or prevented from happening), levels of A20 increase and those of RNF168 decrease, leading to an increase in DNA damage repair. These findings suggest that increasing the level of DNA damage repair that takes place in podocytes may limit the damage that occurs as lupus nephritis progresses. They also raise the possibility of autophagy, A20, and RNF168 becoming future targets in the development of therapies for its treatment and prevention.