Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study

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• 作者：Elodie Elkaim ; MD^a ; ^b ; ^&lowast ; ; Benedicte Neven ; MD ; PhD^a ; ^b ; ^c ; ^&lowast ; ; Julie Bruneau ; MD ; PhD^c ; ^d ; Kanako Mitsui-Sekinaka ; MD^e ; Aurelie Stanislas ; MSc^f ; Lucie Heurtier ; MSc^b ; ^c ; Carrie L. Lucas ; PhD^g ; Helen Matthews ; BSc^g ; Marie-Cé ; line Deau ; MSc^b ; ^c ; Svetlana Sharapova ; PhD^h ; James Curtis ; BScⁱ ; Janine Reichenbach ; MD^j ; Catherine Glastre ; MD^k ; David A. Parry ; PhD^l ; Gururaj Arumugakani ; FRCPath ; PhD^m ; Elizabeth McDermott ; MDⁿ ; Sara Sebnem Kilic ; MD^o ; Motoi Yamashita ; MD^p ; Despina Moshous ; MD ; PhD^a ; ^b ; ^c ; Hicham Lamrini ; MSc^b ; ^c ; Burkhard Otremba ; MD^q ; Andrew Gennery ; MD^r ; Tanya Coulter ; MRCPI^s ; ^t ; Isabella Quinti ; MD^u ; Jean-Louis Stephan ; MD^v ; Vassilios Lougaris ; MD^w ; Nicholas Brodszki ; MD^x ; Vincent Barlogis ; MD^y ; Takaki Asano ; MD^z ; Lionel Galicier ; MD^aa ; David Boutboul ; MD ; PhD^aa ; Shigeaki Nonoyama ; MD ; PhD^e ; Andrew Cant ; MD ; PhD^r ; Kohsuke Imai ; MD^e ; ^bb ; Capucine Picard ; MD ; PhD^b ; ^c ; ^cc ; Sergey Nejentsev ; PhDⁱ ; Thierry Jo Molina ; MD ; PhD^c ; ^d ; Michael Lenardo ; MD^g ; Sinisa Savic ; FRCPath ; PhD^l ; ^dd ; Marina Cavazzana ; MD ; PhD^b ; ^c ; ^f ; ^&Dagger ; ; Alain Fischer ; MD ; PhD^a ; ^b ; ^c ; ^ee ; ^&Dagger ; ; Anne Durandy ; MD ; PhD^b ; ^c ; ^&Dagger ; ; Sven Kracker ; PhD^b ; ^c ; ^{sven.kracker@inserm.fr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Primary immunodeficiency ; phosphoinositide 3-kinase ; p85α ; p110δ ; activated phosphoinositide 3-kinase δ syndrome ; p110δ-activating mutations causing senescent T cells ; lymphadenopathy ; and immunodeficiency ; hyper-IgM ; adenopathy ; immunodeficiency ; antibody deficiency
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：138
• 期：1
• 页码：210-218.e9
• 全文大小：2841 K

文摘

Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]–R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases.

Objectives

We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort.

Methods

The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed.

Results

Mutations within splice acceptor and donor sites of exon 11 of the PIK3R1 gene lead to APDS2. Recurrent upper respiratory tract infections (100%), pneumonitis (71%), and chronic lymphoproliferation (89%, including adenopathy [75%], splenomegaly [43%], and upper respiratory tract lymphoid hyperplasia [48%]) were the most common features. Growth retardation was frequently noticed (45%). Other complications were mild neurodevelopmental delay (31%); malignant diseases (28%), most of them being B-cell lymphomas; autoimmunity (17%); bronchiectasis (18%); and chronic diarrhea (24%). Decreased serum IgA and IgG levels (87%), increased IgM levels (58%), B-cell lymphopenia (88%) associated with an increased frequency of transitional B cells (93%), and decreased numbers of naive CD4 and naive CD8 cells but increased numbers of CD8 effector/memory T cells were predominant immunologic features. The majority of patients (89%) received immunoglobulin replacement; 3 patients were treated with rituximab, and 6 were treated with rapamycin initiated after diagnosis of APDS2. Five patients died from APDS2-related complications.

Conclusion

APDS2 is a combined immunodeficiency with a variable clinical phenotype. Complications are frequent, such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1/PASLI-CD. Immunoglobulin replacement therapy, rapamycin, and, likely in the near future, selective phosphoinositide 3-kinase δ inhibitors are possible treatment options.