Immunoglobulin class switch recombination deficiency type 1 or CD40 ligand deficiency: from bedside to bench and back again

Abstract

The immunoglobulin class switch recombination deficiency or hyper-IgM syndrome is characterized by normal or elevated serum IgM and low serum levels of other immunoglobulins. Since the first reported patient with hyper-IgM, more than 200 patients with this phenotype resulted from CD40 ligand deficiency have been reported. However, in addition to this common finding, they presented with different manifestations like opportunistic infections, autoimmunity and malignancies each of them are worth a detailed look. In this review, we will focus on different underlying mechanisms of these presentations to review what we have learned from our patients. In the end, we will discuss different treatment options available for these patients using this knowledge.

Keywords::

• autoimmunity
• CD40 ligand deficiency
• hyper-IgM syndromes
• immunodeficiency
• malignancy
• opportunistic infections

Acknowledgements

The authors would like to thank A Fischer, Unité d’Immunologie et d’Hématologie Pédiatrique, Hôpital Necker–Enfants Malades, Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France for critical reading of the manuscript.

Financial & competing interests disclosure

This study was supported by a grant from Tehran University of Medical Sciences (91-01-30-17703). The authors have no other 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 apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Our understandings of pathophysiology of CD40L deficiency and immune system are fellow travelers in an evolutionary road.

• The most common mutations reported in patients with type 1 hyper-immunoglobulin M (HIgM) were missense mutations followed by nonsense mutations, deletions, insertions and splice site mutations. Exon 5 and TNF homology domain and extracellular domain were the most common sites of mutations. Some mutations were associated with a milder phenotype.

• Several actions of B cells like isotype class switching, differentiation, proliferation of immature, mature B-cell subsets and memory B cells, rescue from apoptosis and production of some cytokines like IL-6, are dependent on CD40/CD40L interaction; therefore absence of CD40L results in lack of germinal centers and high production of IgM.

• Intermittent or chronic neutropenia, anemia and NK cell deficiency are important hematologic manifestations of CD40L deficiency and can be even the first presentations. CD40L acts as a double-edged knife in granulopoiesis and helps to preserve a balance in granulopoiesis. Absence of CD40L and chronic inflammatory conditions move this balance toward inhibition of granulopoiesis. In addition, autoimmune hemolytic anemia, anemia of chronic disease and infection with some agents like human parvovirus B19 contribute to anemia in these patients.

• CD40L is the Achilles’ heel of the immune system by playing a central role in the immune system and linking several parts of the immune system. Therefore, patients with type 1 HIgM are susceptible to various opportunistic infections due to major changes in cytokine profile, defects in humoral and cellular immunity and inflammatory response.

• Chronic inflammatory conditions along with defective antitumor immunity by T cells and NK cells predispose patients to various cancers.

• Bystander tissue damage as a result of chronic inflammation in response to persistent infections accompanied by defective peripheral tolerance results in paradoxical picture of autoimmunity in these patients.

• Conservative treatment in patients with HIgM type 1 includes several essential changes in lifestyle, intravenous immunoglobulin therapy, long-term antibiotic prophylaxis and careful monitoring for different cancers. For associated bone loss, options like IFN-γ, anti-RANK antibody and oral bisphosphonates are beneficiary. Genetic counseling and prenatal diagnosis should be offered to families with an affected member.

• Currently, only curative option for immune reconstitution is hematopoietic stem cell transplantation. However, recombinant CD40 ligand and gene therapy are possible future curative strategies.

Notes