The role of toll-like receptors in B-cell development and immunopathogenesis of common variable immunodeficiency

ABSTRACT

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary immune deficiency and is characterized by hypogammaglobulinemia, defect in specific antibody response and increased susceptibility to recurrent infections, malignancy and autoimmunity. Patients with CVID often have defects in post-antigenic B-cell differentiation, with fewer memory B cells and impaired isotype switching. Toll-like receptors (TLRs) are expressed on various immune cells as key elements of innate and adaptive immunity. TLR signaling in B cells plays multiple roles in cell differentiation and activation, class-switch recombination and cytokine and antibody production. Moreover, recent studies have shown functional alteration of TLRs responses in CVID patients including poor cell proliferation, impaired upregulation of co-stimulatory molecules and failure in cytokine and immunoglobulin production. The purpose of the present review is to discuss the role of TLRs in B-cell development and function as well as their role in the immunopathogenesis of CVID.

KEYWORDS:

• Common variable immunodeficiency
• Toll-like receptor
• B cell
• hypogammaglobulinemia
• isotype switching

Financial & competing interests disclosure

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.

Key issues

• Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by hypogammaglobulinemia and poor specific antibody responses and susceptibility to recurrent infections.

• CVID include a group of heterogeneous patients with no genetic cause of their disease.

• For finding the etiology of CVID, different options are proposed but according to hypogammaglobulinemia as the most important finding in CVID, B cells were studied frequently in aspects of the reported defects.

• TLRs are an important group of Pattern Recognition Receptors primarily involved in innate immunity but there are increasing evidence that elucidate they participate in humoral immunity.

• In B cells, TLR signaling plays multiple roles in cell differentiation and activation, class switch recombination, cytokine and antibody production.

• It is found that after TLR ligation, CVID B-cells proliferation, up-regulation of co-stimulatory molecules, cytokine and immunoglobulin production are impaired.

• Activation of TLRs leads to poor IFN-α production in PBMCs and pDCs of CVID patients.

• It seems that TLRs are associated with autoimmunity and complicated clinical condition of CVID patients.