I know that it can be difficult receiving a diagnosis of APDS – then finding that you don’t know anyone else with the condition. It can feel isolating and frightening for patients. After a couple of patients and families approached me directly I have decided to set up a Facebook support group.
I’d love it if you applied to join. You can find the group here.
You are not alone.
This website was established by a group of clinicians and scientists working on APDS at the time of its discovery.
|Dr Helen Baxendale|
Consultant clinical immunologist
|Dr Sergey Nejentsev|
|Professor Andrew Cant|
Professor of paediatric immunology
University of Newcastle
Royal Victoria Infirmary
Newcastle Upon Tyne
Professor of respiratory medicine
Department of infection, immunity and cardiovascular disease
University of Sheffield Medical School
|Dr Klaus Okkenhaug|
The Babraham Institute
|Dr Philip Hawkins|
The Babraham Institute
|Dr Edward Banham-Hall|
Consultant in acute medicine and Clinical Trials Physician
Contact details for clinicians and scientists working in the field of APDS.
Academics with an interest in APDS
The following clinicians and scientists have been involved in researching Activated PI3 Kinase Delta Syndrome and welcome enquiries from other scientists with an interest in forming collaborations and joint research interests:
Non-clinical basic science
Dr Klaus Okkenhaug
Group webpage • Contact by email
Dr Philip Hawkins
Group webpage • Contact by email
Professor Andrew Cant
Group webpage • Contact by email
Dr Helen Baxendale
Webpage • Contact by email
Dr Alison Condliffe
Group webpage • Contact by email
Dr Sergey Nejentsev
Group webpage • Contact by email
This is a non-technical overview of APDS that covers questions commonly asked by patients with APDS.
What is Activated PI3 Kinase Delta Syndrome?
Activated PI3 Kinase Delta Syndrome (APDS) is a rare cause of immunodeficiency that can cause recurrent infections of the ear, sinuses, and lungs (sometimes called “pneumonia” or “bronchiectasis”). Some patients also suffer from severe infections by a type of virus caused by Herpesvirus, such as Chickenpox. These infections are so severe and so frequent that a doctor makes a diagnosis of “immunodeficiency”. Having had one nasty infection on one occasion is not enough – all the patients discovered so far have been registered with a specialist hospital clinic for patients with known immune problems.
How do I know if I have APDS?
Currently the only way to prove whether or not you have APDS is if your doctor organises genetic testing. For now, we are only recommending this in patients with Primary Immunodeficiency or Hyper-IgM Syndrome. If you have one of these diagnoses, consider asking your clinician at your next outpatient appointment.
If you are not already diagnosed with a Primary Immunodeficiency or Hyper-IgM Syndrome it is unlikely that you have the genetic mutation that causes APDS, and testing is not currently recommended.
How does APDS affect people?
APDS can affect different patients in different ways. The most common feature is being prone to severe infections that lead to having to come into hospital. However some patients may also have very severe infections from Chickenpox, an enlarged spleen, or swollen lymph nodes (“glands”).
Can I catch ADPS?
No. APDS is a genetic mutation, so can’t be transmitted like an infection. If one of your parents has APDS there is a 50% chance that you could inherit the mutation. Additionally some patients have healthy parents, but acquire the mutation through a random new mutation.
How can I find out more about APDS?
This website has been set up by a group of scientists who discovered APDS to provide education and resources for patients and doctors. If you have questions you can contact us by email and we’ll do our best to help out.
This article provides an overview of the basic science underpinning the discovery and pathology of APDS.
APDS patients have in common that they carry an activating mutation in the PIK3CD gene, such as (c.3061G>A) which causes a glutamic acid to lysine substitution (E1021K) in the PI3K subunit p110δ (Angulo et al, 2013; Lucas et al, 2013; OMIM #615513). How does such a mutation result in primary immunodeficiency? We are only beginning to understand the answer to this question. In order to get some insight into this, it is worth summarising what is already known about the PI3K p110δ and how the E1021K mutation affects p110δ’s function.
PI3K is shorthand for phosphoinositide 3-kinase. The PI3Ks are a family of eight enzymes in mammalian cells, all of which have in common that they phosphorylate the phosphatidylinositol (PtdIns) headgroup inside cells. The class I PI3Ks, of which p110δ is a member, phosphorylate PtdInst(4,5)P2 to generate PtdIns(3,4,5)P3 (also known as PIP3.). There are four members of the class I PI3K subfamily, namely p110α, p110β, p110δ and p110γ. The first three of these form obligate heteordimers with a p85 regulatory subunit. Sometimes, the p85/p110δ heterodimer will be referred to as PI3Kδ. P85 can bind to proteins that have been phosphorylated on tyrosines. Hence, p110α and p110δ are usually activated downstream of tyrosine kinases, such as growth factor receptors and antigen receptors. The fourth class I PI3K member, p110γ associates with different adapter subunits (p101 or p84) and is activated primarily by G-protein coupled receptors. As it turns out, p110β also prefers to be activated by G protein coupled receptors, even though it forms a heterodimer with p85 adapters.
PIP3 acts as tether on the inner leaflet of the plasma membrane where it binds to proteins with pleckstrin homology (PH) domains. The most prominent such proteins are Pdk1 and Akt. When these are bound by PIP3 at the plasma membrane, Pdk1 phosphorylates Akt (on Thr308). Akt is itself a serine/threonine kinase that phosphorylates multiple proteins in the cell and initiates signal transduction cascades that control mRNA transcription and translation as well as metabolic changes and survival pathways.
The p110δ subunit is expressed at high levels in blood cells, but not in most other tissues. P110δ become activated when a T cell of B cell is exposed to foreign antigens or when these cells respond to growth factors for immune cells called cytokines. P110δ also becomes activated when neutrophils are exposed to bacteria. In general, it is considered that suppressing p110δ activity will also dampen immune responses. For this reason, p110δ-selective inhibitors are being evaluated in clinical trials in rheumatoid arthritis and asthma.
Scientist and clinicians where therefore surprised to find that the E1021K mutation carried by APDS patients increases, rather than inhibits, the enzymatic activity of p110δ. While this made sense of observed pattern of inheritance of this mutation (affected individuals carry one mutated and one normal version of the PIK3CD gene; if the mutation disrupted the function of p110δ, then both copies would normally have to be inherited so observe an effect). However, it is not immediately obvious why increased activity of this kinase should suppress immunity against pathogens as evidenced by the recurrent infections experienced by most APDS patients. In fact, never before has an active kinase been shown to cause immune deficiency. However, similar mutations in the p110α isoform are often found in cancerous tissues from the breast, colon and endometrium. Some patients with the p110δ E1021K mutation have developed B cell lymphomas.
There are different theories for how the activated form of p110δ could cause immune suppression. Some immune cells not only need to turn PI3K on to function, but also need, at various stages, to turn PI3K off in order for genes that are negatively regulated by PI3K to be expressed. Another possibility is that cells, in which PI3K activity is constitutively active, eventually become exhausted. This concept is familiar to immunologists who study chronic infections – if the immune system is unable to eliminate a particular pathogen, the cells involved eventually become exhausted and ineffective. Finally, hyperactive PI3K signalling may interfere with the ability of innate immune cells, such as neutrophils, to eliminate bacteria effectively without causing collateral damage in the lung. At the moment, there are good arguments for and against each of these possibilities and the exact mechanism needs to be elucidated further.
Regardless of the mechanisms, the fact that p110δ-selective inhibitors have been tested in humans and found to be well tolerated offers a possible treatment strategy for APDS patients in addition to current therapies which are not always effective or appropriate for a given patients. This distinguishes APDS from most other immune deficiencies and offers hope for improved management of the disease.
Online Mendelian Inheritance in Man: APDS (OMIM #615513).
Angulo, I., O. Vadas, F. Garçon, E. Banham-Hall, V. Plagnol, T.R. Leahy, H. Baxendale, T. Coulter, J. Curtis, C. Wu, K. Blake-Palmer, O. Perisic, D. Smyth, M. Maes, C. Fiddler, J. Juss, D. Cilliers, G. Markelj, A. Chandra, G. Farmer, A. Kielkowska, J. Clark, S. Kracker, M. Debré, C. Picard, I. Pellier, N. Jabado, J.A. Morris, G. Barcenas-Morales, A. Fischer, L. Stephens, P. Hawkins, J.C. Barrett, M. Abinun, M. Clatworthy, A. Durandy, R. Doffinger, E. Chilvers, A.J. Cant, D. Kumararatne, K. Okkenhaug, R.L. Williams, A. Condliffe, and S. Nejentsev.
Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage.
Science, 2013.Vol. 34:866-871 Abstract.
Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G.
Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.
Nat Immunol. 2014. Vol 15, Pages:88–97. Abstract
Kracker, S., J. Curtis, M. A. Ibrahim, A. Sediva, J. Salisbury, V. Campr, M. Debre, J. D. Edgar, K. Imai, C. Picard, J. L. Casanova, A. Fischer, S. Nejentsev, and A. Durandy. 2014.
Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase delta syndrome.
The Journal of allergy and clinical immunology 2014 134:233-236 e233.
Crank, M. C., J. K. Grossman, S. Moir, S. Pittaluga, C. M. Buckner, L. Kardava, A. Agharahimi, H. Meuwissen, J. Stoddard, J. Niemela, H. Kuehn, and S. D. Rosenzweig. 2014.
Mutations in PIK3CD Can Cause Hyper IgM Syndrome (HIGM) Associated with Increased Cancer Susceptibility.
J Clin Immunol 2014. 34:272-276.
Okkenhaug K. (2013).
Signaling by the phosphoinositide 3-kinase family in immune cells.
Annu Rev Immunol. Mar 21;31:675-704. Free copy here
Banham-Hall E, Clatworthy MR, Okkenhaug K. (2012).
The Therapeutic Potential for PI3K Inhibitors in Autoimmune Rheumatic Diseases.
Open Rheumatol J. 2012;6:245-58. Free copy here
All about APDSyndrome.org and what we do
APDSyndrome.org is a website established by the scientists and clinicians who first discovered Activated PI3 Kinase Delta Syndrome in 2013. This site serves several purposes:
- To act as a information hub for patients and clinicians wanting to learn more about APDS;
- To promote collaboration, best practice and advances in understanding of APDS;
- To provide a portal for a patient registry for individuals affected by APDS, allowing dissemination of new information about clinical advances and trials of new treatments for APDS (this work is underway but not ready for recruitment yet).
Our goal is to promote understanding of APDS. If you would like to learn more, feel free to contact us.
This post describes how to diagnose APDS, and immunological lab results that should raise concern.
The clinical laboratory phenotype of patients identified to date with the E1021K mutation and APDS phenotype is distinctive in both children and adults and may be easily identified using standard diagnostics available in Primary Immunodeficiency Centres. Overall there is picture of altered humoral and cellular immunity although the serological profile may be more subtle than is seen in known humoral immune defects such as X-Linked Agammaglobulinaemia or Common Variable Immunodeficiency and is more similar to that reported in Hyper IgM Syndromes.
Immunoglobulin isotypes may show an increase in IgM and reduction in IgG2 with a normal or low total IgG. Vaccine responses may be suboptimal, however the profile is variable with some patients demonstrating normal vaccination responses particularly to protein antigens. As with other humoral immune deficiencies, suboptimal response pneumococcal vaccines (both plain polysaccharide and conjugate vaccine) is more consistently impaired. Lymphopaenia affecting both T and B cell subsets is seen in some patients. Extended lymphocyte profiling has however provided the most distinctive signature. Using the Euroclass B cell profiling panel (Wehr et al. 2008), there is trend for reduced number of class switched (IgM-CD27+) and IgM memory (IgM+CD27+) B cells and a dramatic expansion of cells of Transitional phenotype (CD38high, IgMhigh) with numbers reaching up to 90% of the circulating B cell population. T cell profiling is also distinctive. Whilst absolute T cell counts may be normal, a marked expansion of cells of CD25-CD45RA-/CD127- phenotype (consistent with effector memory T cells) in both CD4 and CD8 compartments is seen. This is a population that has best been described in the context of chronic HIV infection and is thought to represent chronic immune activation. A summary of routine investigations that may help in the diagnosis of APDS is given in the table below:
|Serum IgG||Normal or reduced|
|Vaccine responses to Streptococcus pneumonia||Normal or reduced|
|Vaccine responses to Haemophilus influenzae||Normal or reduced|
|Vaccine responses to Tetanus||Normal or reduced|
|CD19+IgM+CD27+ B cells||Normal or reduced|
|CD19+IgM-CD27- B cells||Normal or reduced|
|CD19+IgM+CD38+ B cells||Significantly increased|
|CD3+CD4+CD25-CD127- Helper T cells||Increased|
|CD3+CD4+CD25-CD45RA- Helper T cells||Increased|
|CD3+CD8+CD25-CD127- cytotoxic T cells||Significantly increased|
|CD3+CD8+CD25-CD45RA- cytotoxic T cells||Significantly increased|
A detailed account of the clinical features of APDS
The majority of patients with APDS present with recurrent respiratory infections from early infancy or childhood. Lower respiratory tract infections, otitis media and sinusitis are the commonest manifestations, usually secondary to encapsulated bacterial pathogens, particularly Haemophilus influenzae and Streptococcus pneumoniae. These infections are often severe and lead to progressive end-organ damage, particularly bronchiectasis and hearing loss. For this reason, prompt and vigorous treatment of these infections is recommended to prevent or limit such damage. Other bacterial infections have included cellulitis and abscess formation (usually secondary to Staphylococcus aureus), but these are less common. Many patients also suffer recurrent viral infections, with several incidences of severe systemic disease caused by Herpes group viruses (including HSV and VZV pneumonitis, EBV colitis and disseminated CMV). Several patients have also had less severe but frequent problems with recurrent adenovirus or Coxsackie virus infections (particularly respiratory infections and conjunctivitis).
Splenomegaly, lymphadenopathy (particularly cervical and mediastinal) and hepatomegaly are also often (but not always) noted on clinical or radiological examination of these patients; in several cases splenomegaly has been noted before the onset of recurrent infections. Histopathology of lymph nodes, when available, has suggested a picture of reactive hyperplasia consistent with immune deficiency. Importantly, and in keeping with the known signalling role of PI3K in malignant disease, there seems to be an increased incidence of lymphoproliferative disease in this patient cohort. There may also be a risk of autoimmune disease, with 2 cases to date of haemolytic anaemia and one of immune complex glomerulonephritis noted to date. Several patients have been noted to have developmental delay, although this may be secondary to recurrent infections; intriguingly, some patients have exhibited developmental abnormalities including short stature due to growth hormone deficiency (2 patients), micro-ophthalmia (1 patient) and abnormal dentition (1 patient) – the significance of these findings is currently unclear.
It is important to note that the family history may be of major importance – several (but not all) of these patients have affected relatives or a family history of early death from infection-related causes. Likewise, there is a spectrum of severity, and some individuals with relatively mild disease have been identified because of their relationship to more severely affected patients, and it may be that at present we are seeing just the tip of the APDS iceberg.