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Dr Sven Kracker discusses how PI3K dyregulation can cause severe health problems.
Phosphatidylinositol 3-kinases (PI3Ks) play a role in several biological processes, from cell survival, metabolism and proliferation, to disease such as cancer and diabetes1. PI3Ks are a family of enzymes composed of a catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85α, p55α, p50α, p85β, or p55γ)2. p85α and p110δ, encoded by the genes PIK3R1 and PIK3CD respectively, are involved in normal lymphocyte function3.
APDS and PIK3CD
A gain of function mutation in the PIK3CD gene causes hyperactivation of p110δ, leading to the primary immunodeficiency known as activated PI3K-δ syndrome (APDS)4–6. APDS patients experience recurrent respiratory infections, decreased circulating B cells and impaired vaccine responses. There is also a reduction in naïve T cells and an increase in senescent effector (CD8+) T cells6.
In 2014, the group headed by Dr Kracker identified two new different splice site mutations in human patients who suffered from recurrent infections. Mutations in PIK3R1 gene produce a shortened p85α protein lacking part of the p110-binding domain2.
Dr Kracker’s group analyzed the clinical manifestations in a cohort of patients affected by splice site mutations in p85α. All of them suffered from infections and presented with T and B cell defects. The development of B cell lymphoma was identified as a very important complication. Immunologically, there was a broad spectrum of levels of IgM, low levels of IgG and IgA and B cell lymphopenia. Given the many similarities between the p85α patients and APDS patients, Dr Kracker and colleagues suggested the name APDS2 for this new immunodeficiency2.
SHORT syndrome and PI3K activity
Preliminary work from Dr Kracker on other disorders in which PI3K is involved has focused on SHORT syndrome and a disorder associated with p85α. The SHORT syndrome is a rare disorder characterized by short stature, hyperextensibility of joints and/or hernias, ocular depression, Rieger anomaly, and delays of tooth eruption7. Early work on three SHORT patients has shown a normal IgM/G/A titer; however, memory B cells were found decreased in the patients and in addition a slight increase of effector memory CD8 was observed.
At the molecular level, the SHORT syndrome results from mutations in the C-terminus of p85α, leading to loss of PI3K activity. p85α is also mutated in the case of an autosomal recessive disease, where a stop codon at W298 truncates the protein, causing absence of the B lineage, leading to agammaglobulinemia in these patients8.
Most of the APDS patients are treated with IgG substitution to control primary antibody deficiency9, and some are treated with rapamycin (an mTOR inhibitor) to compensate for the dysregulation in p110δ. Rapamycin treatment was reported to restore the abundance of naïve T cells in vivo, although not completely6. Dr Kracker discussed how selective p110δ inhibitors such as IC87114 and GS-1101 (CAL-101 or Idelalisib) have successfully blocked p110δ dysregulation both in vitro and ex vivo9.
The research efforts of Dr Kracker and his lab have shown how APDS is a new and frequent cause of autosomal dominant immunodeficiency by hyperactivation of the PI3K signaling pathway. Distinct PI3K isoforms are becoming attractive targets for novel drugs against immunodeficiency, inflammatory diseases and cancer. Inhibitors specific for p110δ for example, might form a novel therapy for APDS1 and APDS2 patients.
1. Ghigo, A., Morello, F., Perino, A. & Hirsch, E. Phosphoinositide 3-kinases in health and disease. Subcell. Biochem. 58, 183–213 (2012).
2. Deau, M.-C. et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest. 124, 3923–3928 (2014).
3. Okkenhaug, K. & Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat. Rev. Immunol. 3, 317–330 (2003).
4. Angulo, I. et al. Phosphoinositide 3-Kinase δ Gene Mutation Predisposes to Respiratory Infection and Airway Damage. Science (80-. ). 342, 866–872 (2013).
5. Crank, M. C. et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J. Clin. Immunol. 34, 272–6 (2014).
6. Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI ( 3 ) K catalytic subunit p110 δ result in T cell senescence and human immunodeficiency. Nat. Immunol. 15, 88 (2014).
7. Dyment, D. a et al. Mutations in PIK3R1 cause SHORT syndrome. Am. J. Hum. Genet. 93, 158–66 (2013).
8. Kracker, S. et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J. Allergy Clin. Immunol. 134, 233–6 (2014).