CD40 ligand deficiency: treatment strategies and novel therapeutic perspectives

ABSTRACT

Introduction: CD40 ligand (CD40L) deficiency or X-linked Hyper-IgM syndrome is a severe primary immunodeficiency caused by mutations in the CD40L gene. Despite currently available treatments, CD40L-deficient patients remain susceptible to life-threatening infections and have poor long term survival.

Areas covered: Here, we discuss clinical and immunological characteristics of CD40L deficiency as well as current therapeutic strategies used for patient management. This review highlights that beyond B cell defects, patients’ susceptibility to opportunistic pathogens might be due to impaired T cell and innate immune responses. In this context, we discuss how better knowledge of CD40L function and regulation may result in the development of new treatments.

Expert opinion: Despite the introduction of hematopoietic stem-cell transplantation, immunoglobulin replacement, granulocyte colony-stimulating factor (G-CSF) administration, and prophylactic antibiotic therapies, life-threatening infections still cause high morbidity and mortality among CD40L-deficient patients. The reasons for this inadequate response to current therapies remains poorly understood, but recent reports suggest the involvement of CD40L–CD40 interaction in early stages of the innate immune system ontogeny. The development of novel gene therapeutic approaches and the use of redirected immunotherapies represent alternative treatment methods that could offer reduced morbidity and mortality rates for patients with CD40L deficiency.

KEYWORDS:

• CD40 ligand
• CD40L deficiency
• treatment
• primary immunodeficiency

Article highlights

• The absence of CD40L impairs both adaptive (B and T cells) and innate immune responses (dendritic cells and phagocytes).

• With few exceptions, there is no clear phenotype-genotype correlation in CD40L deficiency and the clinical manifestations are broad and heterogeneous.

• Even when on antibiotic prophylaxis, G-CSF administration, and Ig replacement therapy, CD40L-deficient patients are still susceptible to life-threatening infections caused by opportunistic infectious agents such as fungi and intracellular bacteria.

• Patients treated in the last three decades by HSCT have shown improved quality of life, but overall survival post-transplantation is less favorable than that of other PIDs.

• The improved neutrophil function achieved by in vitro rhIFN-γ exposure suggests a new potential adjuvant therapeutic application for the treatment of life-threatening infections associated with CD40L deficiency.

• Site-specific gene editing of human hematopoietic stem-cells from CD40L deficiency using TALEN and CRISP-CAS9 approaches may revolutionize the treatment of CD40L deficiency and lead to a permanent cure.

Acknowledgments

We thank Dr. Nadia El Khawanky from Department of Hematology and Oncology, Faculty of Medicine, The University of Freiburg, Freiburg, Germany, for critically reviewing the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) process number 2017/04187-9 to T França, process number 2018/09407-0 to L Barreiros, and process number 2016/22158-3 to A Condino-Neto; and by The Jeffrey Modell Foundation to A Condino-Neto.