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.

Infection and Activation of B Cells by Theiler’s Murine Encephalomyelitis Virus (TMEV) Leads to Autoantibody Production in an Infectious Model of Multiple Sclerosis

“…This was consistent with clinical results indicating that microbial infections exacerbate SLE [74,75] and MS [76,77]. Although B cell activation in these SLE-prone mice appeared to be associated with TLR7, other TLRs may also participate in the B cell activation via NF-κB and critical cytokines affecting B cell activation, such as IFN-α/β, IL-1, and IL-6 [78][79][80]. In fact, splenic B cells from SJL mice showed upregulated expression of CD80/86 costimulatory molecules, as well as the CD69 activation marker upon treatment with ligands of TLR2, TLR3, TLR4, TLR7, and TLR9, strongly suggesting that any of these TLRs might be able to stimulate B cells ( Figure S1).…”

Approach to the Management of Autoimmunity in Primary Immunodeficiency

“…Also, mutations in CD40L (coding for CD40 ligand, 70%) and TNFRSF13B (coding for TACI, 10%) are the most common causes of class‐switching defects and terminal B cell defects, respectively . According to the result of different PID registries in the world, IgAD represents the most common PAD, followed by CVID . Hypogammaglobulinemia is the major hallmark of patients with PAD and present with a clinical phenotype including chronic and recurrent infections, chronic inflammation and autoimmunity [particularly haematologic abnormalities, autoimmune thyroiditis (AIT), autoimmune nephritis, inflammatory bowel disease (IBD) and RA], leading to recurrent hospitalization and a decrease in the patients’ quality of life .…”

Common Variable Immunodeficiency: Epidemiology, Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management

“…In recent years, several monogenic disorders involved in the presentation of CVID have been identified; however, these affect less than 20% of CVID patients in nonconsanguineous cohorts [3] and approximately 70% of CVID patients in consanguineous cohorts [4]. Furthermore, several abnormalities in the innate and adaptive immune systems have been reported [5][6][7], although the exact molecular defects leading to CVID remain unknown.…”