ReviewRole of apoptosis in common variable immunodeficiency and selective immunoglobulin A deficiency
Introduction
Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by defective antibody production and an increased incidence of recurrent bacterial infections, inflammatory and autoimmune disorders, malignancies and granuloma (Cunningham-Rundles and Bodian, 1999, Aghamohammadi et al., 2005, Chapel and Cunningham-Rundles, 2009, Aghamohammadi et al., 2010). CVID has prevalence rate of about 1:50,000 to 1:25,000 (Cunningham-Rundles, 2010, Jolles, 2013). The diagnostic criteria for CVID includes marked reduction of serum IgG, IgA, and/or IgM levels, defective specific antibody responses to protein and polysaccharide antigens and also increased susceptibility to recurrent bacterial infections as well as no evidence of profound T-cell deficiency in patients older than 4 years (Aghamohammadi et al., 2005, Chapel et al., 2008). CVID has a complex genetic basis and may arise from a number of different gene defects involved in B-cell activation and differentiation, for instance inducible T-cell costimulator (ICOS) (Grimbacher et al., 2003), transmembrane activator and CALM interactor (TACI) (Salzer et al., 2005), B-cell activating factor-receptor (BAFF-R) (Warnatz et al., 2009), CD19, CD21, CD81 (van Zelm et al., 2006, van Zelm et al., 2010, Thiel et al., 2012, Yazdani et al., 2014), CD20 (Kuijpers et al., 2010), Lipopolysaccharide-responsive and beige-like anchor protein (LRBA) (Lopez-Herrera et al., 2012) and Phospholipase Cγ2 (PLCγ2) (Ombrello et al., 2012) genes. In spite of the results obtained from recent years, many underlying defects are not yet known (Eibel et al., 2010).
Selective IgA deficiency (SIgAD) is the most common primary antibody deficiencydescribed as serum IgA level of less than 7 mg/dl, in the presence of normal IgG subclasses and IgM as well as normal specific antibody response in individuals older than 4 years and exclusion of other causes of hypogammaglobulinaemia (Aghamohammadi et al., 2009, Wang and Hammarström, 2012). Prevalence of SIgAD differs among racial groups, ranging from lowest frequency in Asian and oriental populations to the highest frequency in Caucasians and western countries (Yel, 2010, Modell et al., 2014, Yazdani et al., 2015). Individuals with SIgAD usually are asymptomatic, however abnormality of immunoglobulin production and wide variety of several disorders including gastrointestinal diseases, autoimmune diseases, respiratory tract infections and allergies has been observed (Burrows and Cooper, 1997, Hammarström et al., 2000, Cunningham-Rundles, 2001, Yazdani et al., 2015). The exact mechanism of SIgAD is not fully understood, but an impairment of isotype switching, terminal B-cell differentiation, premature death of precursors of IgA-producing B-cells and a failure in Sμ to Sα recombination associated with decreased levels of Cα membrane mRNA are all identified as causes of pathogenesis in the SIgAD patients (Islam et al., 1994, Truedsson et al., 1995). Furthermore, impairment of multiple cytokines such as IL-4, IL-6, IL-7, IL-10, TGF-β and IL-21 are also identified in relation to the disease (Ramsay et al., 1994, Cunningham-Rundles, 2001, Borte et al., 2009).
Both CVID and symptomatic SIgAD share similar clinical manifestations and development of both disorders in the members of one family has been observed. Some patients with SIgAD can progress to CVID (Aghamohammadi et al., 2007, Cheraghi et al., 2014). Development of both disorders in the members of one family (Truedsson et al., 1995) along with TACI deficiency, are frequently observed in CVID and SIgAD patients (Castigli et al., 2005). Furthermore, impairment of long-term survival of B-cells, defective plasma cell differentiation, decreased class-switch recombination and abnormal apoptosis of B-cells may be the basis for both CVID and SIgAD disorders (Asano et al., 2004, Husain et al., 2006, Sekine et al., 2007). These data demonstrate that both diseases might have different phenotypic manifestations with identical genetic background. For the first time, we reviewed the role of apoptosis with emphasis on altered expression of apoptosis-associated molecules as well as B and T lymphocytes abnormalities in patients with CVID and SIgAD.
Section snippets
Apoptosis in the immune system
Apoptosis induces the activation of intracellular enzymes called caspases that are present as inactive pro-enzymes and are activated by proteolytic cleavage. Generally, there are two main apoptotic pathways; the intrinsic (mitochondrial pathway) and the extrinsic (death receptor pathway) and both pathways are linked together (Fig. 1) (Guseva et al., 2002). Apoptosis is important in the development, function and maintenance of the immune system. Likewise, it has significant roles in limiting the
Conclusion
CVID and SIgAD are the most common primary immunodeficiencies in human and both diseases share clinical manifestation and molecular defects, as some patients with SIgAD can progress to CVID (Briere et al., 1994a, Espanol et al., 1996, Aghamohammadi et al., 2007) and occasionally vice versa (Seligmann et al., 1991). Although several investigations have been made to discover the exact etiology of CVID and SIgAD, it remains unknown yet. Increased apoptosis during an immune response could be
Conflict of interest
No conflict of interest is reported for any of the authors.
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