Overview

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.

Further reading:

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

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