Immunologic evaluation and genetic defects of apoptosis in patients with autoimmune lymphoproliferative syndrome (ALPS)

Abstract

Apoptosis plays an important role in controlling the adaptive immune response and general homeostasis of the immune cells, and impaired apoptosis in the immune system results in autoimmunity and immune dysregulation. In the last 25 years, inherited human diseases of the Fas-FasL pathway have been recognized. Autoimmune lymphoproliferative syndrome (ALPS) is an inborn error of immunity, characterized clinically by nonmalignant and noninfectious lymphoproliferation, autoimmunity, and increased risk of lymphoma due to a defect in lymphocyte apoptosis. The laboratory hallmarks of ALPS are an elevated percentage of T-cell receptor αβ double negative T cells (DNTs), elevated levels of vitamin B12, soluble FasL, IL-10, IL-18 and IgG, and defective in vitro Fas-mediated apoptosis. In order of frequency, the genetic defects associated with ALPS are germinal and somatic ALPS-FAS, ALPS-FASLG, ALPS-CASP10, ALPS-FADD, and ALPS-CASP8. Partial disease penetrance and severity suggest the combination of germline and somatic FAS mutations as well as other risk factor genes. In this report, we summarize human defects of apoptosis leading to ALPS and defects that are known as ALPS-like syndromes that can be clinically similar to, but are genetically distinct from, ALPS. An efficient genetic and immunological diagnostic approach to patients suspected of having ALPS or ALPS-like syndromes is essential because this enables the establishment of specific therapeutic strategies for improving the prognosis and quality of life of patients.

Keywords:

• ALPS
• ALPS-like
• apoptosis
• autoimmunity
• immune dysregulation

Acknowledgements

We are grateful to Guiomar Bautista, Javier Blas-Espada, Agurtzane Bilbao, Juana Gil-Herrera, Jorge Gil-Niño, Sara Guillén, Luis I. González-Granado, Josefa Melero, David Moreno, Rebeca Pérez de Diego, José T. Ramos, Marta Riñón, Carlos Rodríguez-Gallego, Rebeca Rodríguez-Pena, Carmen Rodríguez-Vigil, Jesús Ruiz-Contreras, Nerea Salmón for clinical and immunologic collaboration, and to Maria J. Díaz-Madroñero for her excellent technical assistance.

Author contributions

LMA conceived the idea for the review. LCP and MLN critically searched and evaluated the literature. LCP, MLN, and LMA drafted the manuscript, tables, and figures, with the contribution of EPA, AA, and FRL. All authors read and approved the final manuscript.

Disclosure statement

The authors report no conflicts of interest.

Additional information

Funding

This work was supported by grants from Fondo de Investigación Sanitaria (FIS-PI16/2053) to LMA. The project has been co-financed with FEDER funds. LCP and MLN were co-financed by Fondo Social Europeo, Programa Operativo de Empleo Juvenil y la Iniciativa de Empleo Juvenil (YEI). FRL was supported by the Institut National de la Santé et de la Recherche Médicale (INSERM), by government grants managed by the Agence National de la Recherche as part of the “Investment for the Future” program (ANR-10-IAHU-01 and ANR-18-RHUS-0010), by the Agence National de la Recherche (ANR-14-CE14-0026-01 “Lumugene”; ANR-18-CE17-0001 “Action”) and the Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH).