What is primary immunodeficiency?

Primary immunodeficiency is an inherited condition caused by genetic mutations in a person’s DNA. It affects the immune system, weakening it or making components of it dysfunctional. As the immune system does not work properly, it is not able to fight infections or protect the body against cancer as effectively, leading to recurrent infections and increased risk of cancer.¹

Immune system overview

Before going into the different types of Primary Immunodeficiency it is important to understand the key players behind them. There are a number of cells critical to the correct functioning of our immune systems. These include phagocytes, B cells and T cells. Phagocytes are a collective term for any immune cells that are able to engulf and possibly digest any foreign particles like bacteria.² Some of these phagocytes, as well as B cells, are also able to present antigens (foreign molecules) to T cells.³ The T cells are then able to mount one of the two responses: they may differentiate into a cytotoxic T cell, which will kill infected cells, or they may become helper T cells, which will coordinate the immune response by signalling to other components of the immune system.⁴ T helper cells will signal B cells, which will produce antibodies that will bind to and neutralise the foreign particle. The B cells may also become memory B cells, which will remember the antigen, providing a faster response in potential future reinfection.⁵ Complement proteins work in harmony with the immune system by promoting microbe ingestion by phagocytes.⁶ They also induce inflammation, which will traffick immune cells to the area of infection, contributing to the healing process.⁷ 

Types of primary immunodeficiency 

The type of primary immunodeficiency depends on the immune system component that is being affected. There are multiple types such as:

• B cell deficiencies

B cell deficiencies are usually caused by molecular defects within the B cell or through failed interactions between T cells and B cells. When this occurs, B cells may be depleted and there will be lower levels of antibodies produced. Examples of Primary Immunodeficiencies that fall under this type are, for example, X-linked agammaglobulinemia and selective IgA deficiency.⁸

• T cell deficiencies

T cell deficiencies are when your body does not make sufficient amounts of T cells, or it makes T cells which do not work. As a result, your body struggles to fight off infections which makes you more prone to more serious illness.⁹ Some Primary Immunodeficiencies that are classed as T cell deficiencies are DiGeorge syndrome and chronic mucocutaneous candidiasis.¹⁰

• A combination of B cell and T cell deficiencies

Combined deficiencies result from either low levels of both T cells and B cells, or poor function of the two cells. They usually cause increased susceptibility to infection and even excess autoreactivity since the immune system is dysregulated.¹¹ Major Histocompatibility Complex deficiency and Wiskott-Aldrich syndrome are both examples of immunodeficiencies that fall under the combined type.¹⁰

• Defective phagocytes

Defective phagocytes tend to result from either an inability to produce their effectors (molecules that allow for the killing of pathogens), or a lack of receptors, which will prevent them from being able to travel to the site of infection. Examples of such diseases are chronic granulomatous disease and leukocyte adhesion deficiency.¹²

• Complement deficiencies

A complement deficiency involves the lack of one or more complement proteins. This deficiency may have certain disadvantageous effects on the immune system including inadequate opsonization (recognising and making a target out of the antigen for the phagocyte). This means that it will be more challenging for a phagocyte to ingest a particular pathogen, causing a less effective response. Another undesirable effect that complement deficiencies may cause is cell lysis (killing) defects, which will complicate the clearance of infection. Since complement proteins are also important for immune regulation, a deficiency of them may cause immune complex diseases like arterial thrombosis.⁶

• Idiopathic

These involve a lack of certainty about what is causing them; they are of unknown origin. An example of this type of disease is idiopathic CD4 lymphocytopenia which is defined by a low number of a type of T cell called a CD4 T helper cell, but the reason for the abnormal levels is unknown.¹³

Symptoms

Considering that immunodeficiencies make you more susceptible to infection common symptoms tend to be:

• Frequent infection or repeated infections such as pneumonia, thrush, and sinus infections
• Longer lasting infection
• Infections that show difficulty when treated with antibiotics or even resist treatment
• More severe infections may require hospitalisation
• Infection by opportunistic pathogens (microorganisms that do not usually cause disease in someone with a healthy immune system)

There may also be symptoms such as:

• Digestive issues like diarrhoea and nausea¹
• Weight loss
• Swollen lymph nodes
• Enlarged spleen¹⁴
• Blood disorders such as anaemia
• Autoimmune disease¹⁵

How is primary immunodeficiency diagnosed?

For a primary immunodeficiency diagnosis, your doctor would first take a personal and family history, as well as carry out a physical examination. They would also order one of the following tests:

• Blood tests will measure your levels of immunoglobulin, blood cell levels and immune cell levels to check if they are within range. If they are not, then that may point to an immunodeficiency¹⁶
• Genetic tests will look for any gene variants (when a DNA sequence of a gene is permanently altered)¹⁷ that are known to cause immunodeficiencies. 
• Flow cytometry to measure immune cell populations¹⁸

Management of primary immunodeficiency

There is no possible way of preventing the development of a primary immunodeficiency as it is genetic. However, there are a number of things that may be done to reduce the risk of acquiring an infection, which is extremely important for someone suffering from immunodeficiency. These include:

• Good hygiene-washing your hands with soap and warm water after using the toilet, before eating, and after touching pets or dirty surfaces. It is also key to maintain good oral hygiene by brushing your teeth and flossing twice a day
• Avoid large crowds or people who may be sick
• Consider any vaccinations that would be useful to you under a doctor’s advice
• Eating a balanced diet and exercising regularly is recommended to check with a doctor what type of diet and exercise plan is right for you
• Get enough sleep¹⁵

Treatment of primary immunodeficiency

There are a number of potential treatments, each will depend on the type of immunodeficiency you have and how severe it is. The treatments include:

• Antibiotics or antivirals for disease prevention
• Immunoglobulin replacement therapy aims to bring your immunoglobulin up to levels which are necessary to be able to fight off infection.
• Interferon-gamma replacement therapy to improve immune system function to decrease disease severity
• Administration of growth factors to increase white blood cell (immune cell) numbers
• Stem cell transplant to introduce healthy immune cells from another donor
• Gene therapy to correct the genetic mutation causing the immunodeficiency¹

Summary 

Primary immunodeficiency in adults is caused by genetic mutations that lead to immune cell or immune protein dysfunction. Therefore, symptoms commonly include signs of increased infection susceptibility and difficulty in achieving infection clearance. There are multiple ways to diagnose the condition through checking immune cell levels and gene variants. As the condition is genetic, there is no way to prevent it, it is key however to take preventative measures in terms of infection development. There are a few treatment options available for the condition including antibiotics and antivirals, replacement therapies to restore normal immune function, growth factors for cell growth, as well as stem cell transplants and gene therapies. 

FAQs

Can you live a normal life with primary immunodeficiency?

Yes, although there will be some precautions you may need to take, people with primary immunodeficiency should still be able to live full lives.

What is the most common primary immunodeficiency in adults?

Common variable immune deficiency

Can primary immunodeficiency be cured?

Primary immunodeficiency may be cured through stem cell transplantation or gene therapy.