Overview 

Tangier disease is a genetic disorder that causes a severe deficiency of high-density lipoproteins (HDL). It occurs due to a mutation in ABCA1 or APOA genes that help in HDL production. As a result, HDL levels become abnormally low.¹

HDL is a fundamental lipoprotein that carries cholesterol through the bloodstream. Low levels contribute to more cholesterol in the tissues, which increases the risk of developing atherosclerosis and cardiovascular diseases. Also, research has shown that HDL play a functional role in the immune system. For example, HDL contains anti-inflammatory lipids that help fight infections by blocking harmful substances released by pathogens. These substances, like toxic lipoproteins, can damage the body and provoke sickness. Thus, low levels of HDL promote reduced immunity to infections.²

With the help of this article, you will discover the link between Tangier disease and increased susceptibility to infections.

What is Tangier Disease?

Tangier disease is a rare inherited condition that leads to very low levels of HDL. This condition is due to a defect in the ABCA 1 gene, which plays a crucial role in the production of HDL. 

This gene helps move cholesterol from inside the cells to the bloodstream, where it is used to form HDL. When this gene is defective, cholesterol cannot be transported from the cells, this leads to a buildup of cholesterol inside the cells. As a result, HDL levels become depleted, engendering different health problems. 

The defective gene is inherited from parents, with the stipulation that the person must inherit two faulty genes for the symptoms to appear, one from each parent, resulting in very low HDL levels, usually below 5 mg/mL, though the severity can vary across individuals. If a person inherits only one faulty gene, their HDL levels will still be lower than normal (5–24 mg/mL), but they will not show visible symptoms.¹

Clinical features and symptoms of tangier disease

Tangier disease is characterised by the buildup of cholesterol in various organs of the body due to very low levels of high-density lipoproteins (HDL).

People who inherit only one faulty gene (heterozygous) typically have relatively reduced HDL levels but do not experience cholesterol accumulation or visible symptoms. However, individuals who inherit two faulty genes (homozygous) develop very low HDL levels, usually below 5 mg/dL, leading to cholesterol deposits in tissues and organs, which result in several clinical features. Some symptoms include:

• Enlarged, yellow-orange tonsils: This is one of the earliest signs of Tangier disease, especially in children and young adults
• Premature heart disease: Due to cholesterol buildup in blood vessels, increasing the risk of early-onset atherosclerosis, heart attacks, or stroke
• Nerve problems: Such as numbness, tingling, or weakness, especially in the arms and hands. This is caused by cholesterol buildup damaging the protective covering of nerves
• Cloudy cornea: Mild clouding of the eye surface, though this rarely affects vision
• Swollen liver and spleen (hepatomegaly): This occurs when cholesterol deposits accumulate in these organs, which may also lead to a low platelet count¹

How tangier disease affects HDL function in the immune system

HDL does more than carry fat in the bloodstream. It also supports the immune system in different ways.

Helping immune cells recognise and respond to infections

When infectious organisms like bacteria or viruses enter the body, cells need to send a signal to alert the immune system. There are tiny areas on the surface of these cells called lipid rafts, they act like “meeting points” where the main proteins gather to detect invaders and send signals. HDL helps by keeping the correct balance of cholesterol in these rafts. This balance is fundamental for the rafts to work adequately. 

When HDL is very low, as in Tangier disease, these rafts fail to function well. This weakens the body’s ability to detect infections and signal immune cells like macrophages and T-cells to fight them off.³

Binding and neutralising pathogen-associated molecules

When harmful bacteria or viruses enter the body, they release molecules like lipopolysaccharides (LPS), which can trigger an overactive immune response. HDL helps by binding to these molecules and neutralising their harmful effects. It’s like HDL acts as a “scavenger,” picking up dangerous molecules and preventing them from triggering an intense immune reaction.

HDL does this through both its protein (like apolipoprotein A-I) and lipid components. These components work together to trap LPS and other pathogens, stopping them from activating immune cells and causing excessive inflammation. Studies have shown that higher levels of HDL can reduce the harmful effects of LPS and even protect against bacterial infections. When HDL levels are low, like in Tangier disease, the body struggles to neutralise these damaging pathogens, which can lead to more severe infections.⁴

HDL function on macrophages

Macrophages are cells that help the body fight infections. They do this by "eating" harmful germs and sending signals to other immune cells. Macrophages are classified into two types: 

M1, which causes inflammation, and M2, which helps calm inflammation and promote healing. A balance between these two is important for an effective immune system.⁵

HDL helps by boosting M2 markers on macrophages, encouraging them to reduce inflammation and tissue damage.

In Tangier disease, where HDL levels are deficient, macrophages struggle to control inflammation and fight infections effectively. The lack of HDL makes it harder for the immune system to respond properly, leading to chronic inflammation and increased vulnerability to infections.³

Increased infection susceptibility in tangier disease

When pathogens enter the body, the immune system needs to act quickly to fight them off. It achieves this with the help of macrophages, immune cells that engulf and destroy these invaders.⁵

However, in people with Tangier disease, the immune system struggles to respond effectively. Since their body lacks enough HDL, which plays a crucial role in supporting immune functions. As a result, individuals with Tangier disease become more susceptible to infections. Harmful organisms remain in the body longer than they should, leading to infections that would unusually occur if the immune system were functioning properly.

Impact of infections on individuals with tangier disease

When infections occur, individuals with Tangier disease struggle to fight them off due to impaired immune function. The lack of HDL weakens macrophages, making it more difficult for the body to clear harmful pathogens. As a result:

• Bacterial infections (like pneumonia or skin infections) last longer and can lead to more severe damage, such as sepsis, which is harder to treat due to the lack of HDL
• Viral infections (such as the flu or HSV) tend to be more difficult to manage, with symptoms lasting longer
• Parasitic infections (like malaria) spread more easily, increasing the risk of complications.

This compromised immune response leads to prolonged illnesses and a higher risk of serious health issues.

Treatment and management of tangier disease

While there is no cure for Tangier disease, treatment mainly focuses on managing symptoms and raising HDL levels. The aim is to improve immune function, reduce the severity of associated health problems, and enhance the patient’s quality of life. Here is how Tangier disease is generally managed:

Lifestyle modifications

The primary strategy for increasing HDL levels in Tangier disease is through lifestyle changes. These changes help improve overall cardiovascular health and may reduce certain symptoms like peripheral neuropathies. Some recommended modifications include:

• Regular Aerobic Exercise: Can help raise HDL cholesterol levels and improve lipid metabolism
• Maintaining a Healthy Weight: Supports better cholesterol balance and reduces strain on the heart
• Smoking Cessation: Quitting can lead to improvements in HDL cholesterol levels and overall cardiovascular health
• Dietary Adjustments: Replacing saturated fats with monounsaturated fats in the diet can boost HDL cholesterol levels, thus promoting better lipid profiles

Lipid-lowering therapy

While there is no clear evidence that drugs targeting HDL levels directly help people with Tangier disease, some medications for other lipid problems may still be useful. These medications include:

• Statins: Primarily used to lower-density cholesterol (LDL–bad cholesterol), statins can help improve cholesterol levels overall and reduce the risk of heart disease
• Niacin: Niacin may help raise high-density cholesterol (HDL–good cholesterol) levels, though it's undetermined how effective it is in Tangier disease
• Fibrates: They help lower triglycerides (a type of fat in the blood) and improve overall cholesterol balance when used with other treatments¹

While these treatments can help regulate cholesterol, it’s not yet clear how much they directly affect HDL levels in Tangier disease. Therefore, treatment should be tailored to each person’s specific needs and their responses. 

Managing infections

Timely treatment of infections is vital for individuals with Tangier disease, due to their immunodeficiency system. Without enough HDL, the body struggles to detect and respond to harmful pathogens, making infections more likely to be prolonged and severe. Prompt use of antibiotics, antivirals, or other appropriate medications helps prevent complications and supports immune defense.

Interestingly, animal studies suggest that raising HDL levels might improve the outcome of infections. Although clinical trials are required, this recommends that in addition to treating the infection, raising HDL levels could improve the outcome of infections and may even help in cases of sepsis.³

FAQs

Is there a cure for Tangier disease?

Unfortunately, there’s no cure for Tangier disease at the moment. Treatment mainly focuses on managing the symptoms and preventing complications.

Why is HDL so important in Tangier disease?

HDL plays a key role in helping the immune system detect and fight infections. In Tangier disease, the body has very low HDL, which makes it harder to respond to infections.

How can HDL levels be raised?

Raising HDL levels typically involves making healthy lifestyle changes, like regular exercise, eating healthy foods, and quitting smoking. While medications can also help, their specific effects in Tangier disease are still being studied.