Editors' ChoicePRIMARY IMMUNODEFICIENCY

Immune System Crashes After a Brake Failure

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Science Translational Medicine  03 Sep 2014:
Vol. 6, Issue 252, pp. 252ec154
DOI: 10.1126/scitranslmed.3010401

Human primary immunodeficiencies (PIDs) are genetic disorders that result in an impaired immune response and recurrent infections. Approximately 1 in 1200 people in the United States are currently diagnosed with PIDs, with more than 200 diseases and more than 100 genetic etiologies uncovered. The discovery of new genotypes associated with PIDs is rapidly increasing as next-generation sequencing technologies flourish.

Phosphatidylinositol 3-kinase (PI3K) signaling is required for the development and function of T and B cells. However, somewhat surprisingly, hyperactivation of PI3K has also been linked to immunodeficiency. Now, Deau et al. have characterized the molecular defects in four patients diagnosed with hypogammaglobulinemia and recurrent infections and identified two heterozygous splice site mutations of PIK3R1, which encodes class IA PI3K regulatory subunit p85α. These mutations resulted in a shortened p85α protein that lacks inhibitory effects on PI3K p110 activity, as demonstrated by enhanced PI3K signaling in patient T cells. Hyperactivating mutations in PIK3CD gene, which encodes P110δ, cause Activated PI3K Delta Syndrome (APDS), a PID characterized with recurrent respiratory infections. Deau et al. went on to show that patients with shortened p85α exhibited lower frequency of naïve T cells in peripheral blood and that their T cells displayed enhanced apoptosis after activation, similar with those of APDS patients. Importantly, the authors showed that the addition of a PI3K inhibitor in the T cell culture could correct T cell apoptosis, suggesting a potential future therapeutic modality for these PIDs using PI3K inhibitors. Moreover, peripheral T and B cells from these patients proliferated much more weakly in response to antigenic stimulation as compared with T and B cells from healthy controls. Together, these data suggested that hypogammaglobulinemia and recurrent infections observed in those patients were caused by impaired T and B cell responses. The authors have suggested naming this newly identified immunodeficiency as “activated PI3Kδ syndrome 2” (APDS2).

Hyperactivating PI3K is a common feature of cancer cells, and PI3K inhibitors are currently being clinically tested in cancer treatment. Moving forward, it would be important to determine whether PI3K inhibitors can restore normal immune functions in those patients with hyperactivating PI3K, although caution should be taken, as hypo-activating PI3K mutations also lead to impaired B cell development and immunodeficiency.

M.-C. Deau et al., A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Invest., published online 18 August 2014 (10.1172/JCI75746). [Full Text]

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