Our immunodeficiency research

Primary Immunodeficiencies (PIDs) are relatively rare diseases with potentially devastating consequences. They are caused by single genetic mutations that lead to a failure of the body’s immune system to respond to microbial, viral or fungal attack.

Research using the latest technologies in the genomic toolkit can not only save the lives of these desperately vulnerable children, but also fill in the gaps in immunological knowledge that will lead to better vaccines and therapeutic approaches to a host of diseases.

Professor Stuart Tangye, Head of Garvan’s Immunology Division and Head of the Immunology and Immunodeficiency Laboratory, has been recognised for his outstanding research in this field with the award of the Gottschalk Medal from the Australian Academy of Sciences in 2011 and a Fulbright Senior Scholarship in 2015.

His lab is recognised as a leader in the fields of human immunology and immunodeficiency. The focus of his research is to understand the development and function of the immune system that protect us against infectious diseases and underlies the success of vaccination strategies.

“We study B cells, which develop in the bone marrow and produce antibodies; and T cells that develop in the thymus, a gland in the upper front part of the chest. We focus on ‘helper’ T cells that coordinate the activity of B cells, allowing them to produce antibodies, as well as ‘cytotoxic’ or ‘killer’ T cells which are responsible for recognising and killing virus-infected or cancer cells”, said Professor Tangye.

The goal of our research is to determine how specific gene defects in B cells and T cells result in the clinical features of various human PIDs. We do this by studying immune cell development and function in patients with PIDs, as well as in corresponding mouse models of these human conditions.

Although these patients are very rare, they are incredibly instructive as they can provide us with information as to which genes are required for the generation and function of different immune cells, and establish how these cells operate in the context of an immune response to protect us against infection. They also can identify which pathways are needed to generate successful vaccines.

Understanding what these genes do in specific immune cells also indicates whether we might be able to overcome these functional defects by developing approaches to treat not only these patients, but also other individuals who have similar clinical features.”

There have been more than 300 genes reported to have errors that will lead to a PID and hospital staff know the symptoms to look for in a child and so they can sequence these genes to look for errors. If they can’t find the genetic defect, whole genome sequencing is available at Garvan’s Kinghorn Centre for Clinical Genomics.

We now have a service in place where patients can be consulted, counselled and consented to have their entire DNA sequenced, along with that of their parents, which will be able to pick up new and unexpected gene mutations. While this may not necessarily help the patient therapeutically, having a diagnosis can be important for family planning and for the health of siblings who have the same gene but who are not yet sick. Screening the family and knowing if the PID is ‘X-linked’ (where mothers carry the gene and pass it only to sons) will reveal if other females in the family might also be carriers.

Once we have identified a mutation and know how it works, it is possible that there is an existing drug that can be used to treat them. These days, with 100 years of drug testing, there many ‘orphan’ drugs with a known safety profile, some of which might be good treatment options. It also presents the opportunity to trial drugs known to be effective in other diseases, but that have not been trialled in PIDs.

The immune system rapidly responds to infection to eradicate bacteria and viruses and limit the damage they can inflict. The immune response is also what underlies the success of most available vaccines, which create an immunological ‘memory’ so when we encounter the virus or bacteria that we have been vaccinated against our responses are recalled and strengthened.

“As well as being highly susceptible to infections, people with PID have problems generating immune responses following vaccination, increasing their likelihood of suffering from infections that can be prevented by vaccines”, said Professor Tangye.

Activation of immune cells is required to generate appropriate immune responses that protect us from disease. Immune disorders are caused by the inability of the immune cells to receive the correct type of signal that would activate them. Professor Tangye and his team have found that the PI3K pathway is central to immune cell activation – and that genetic errors in this pathway compromise the functioning of immune cells.

“We are now investigating individuals with PID due to a mutation in a gene called PIK3CD, which is important for delivering messages within immune cells to direct them to respond to infections. We are looking at the effects of these mutations on the development and function of B cells, to explain some of the patients’ clinical features and find molecules that could be targeted by drugs to treat this disease.

“We have found that overactive PIK3CD leads to numerous B cell defects and we are looking for ways to reduce this overactivity. These findings can also be used to treat conditions with similar symptoms, but unknown causes, highlighting the power of studying rare PIDs as a means of understanding more common immunological illnesses.”

Epstein Barr virus (EBV), a type of herpes virus, infects more than 90% of the population. It is often asymptomatic, however around 15-20% of infected individuals will develop glandular fever. In healthy people, the body runs continuous immune surveillance to control EBV infection and so most healthy individuals will never show any effects of the infection.

However, EBV was the first virus shown to cause human cancer – it is now associated with the development of at least seven different cancers including various lymphomas, nasopharyngeal carcinoma (affecting the upper part of the throat) and smooth muscle tumours. Each year, approximately 200,000 new cases of EBV-associated cancer are reported worldwide. To date, efforts to develop an EBV vaccine have been unsuccessful.

EBV infection can also cause severe and often fatal disease in people with compromised immune systems.

“An error in one gene can give a heightened susceptibility to a specific virus or bacteria. There are some boys with a PID called X-linked lymphoproliferative (XLP) disease, who have a very poor immune response to EBV. This tells us that the defective gene in these boys is essential to defend us against EBV.”

In people with inherited or acquired immune disorders, EBV has been strongly linked to the development of lymphoma.

“Although they are caused by different gene mutations, we have identified several PIDs that share a great vulnerability to EBV-induced disease and B-cell lymphoma. In people with immune disorders, mutations in signalling pathways compromise the ability of their B and T cells to respond to infection, including cancer-causing viruses such as EBV.”

The overall incidence of cancers in people with immune disorders is up to 300 times greater than the normal population. This includes cancers in PID patients, patients with acquired immune disorders due to HIV infection, and patients undergoing stem cell transplants. These cancers highlight a severe impairment in the body’s tumour surveillance in people who are immunodeficient.

“We are looking at ways to improve immune responses (anti-viral, anti-cancer) not only in these specific PIDs, but also in the broader population of immunosuppressed individuals susceptible to EBV infection, including patients with other EBV-related cancers. Our work will contribute to the development of effective EBV vaccines, in the way that the HPV vaccine has been so successful in preventing cervical cancer.

“We are at a point of the greatest changes in medicine – using the power of the immune system to fight cancer. As we work to identify the means to improve the immune response in these rare people with immune disorders, we are looking to translate this basic research into new treatments for the greater population.”