**2. IgA—Structure**

IgA is a class of immunoglobulins characterized by the presence of an alpha heavy chain. The daily synthesis of immunoglobulin A exceeds the total production of all other immunoglobulins [11]. In the human body, there are two subclasses of this immunoglobulin: IgA1 and IgA2. The most important difference between them lays in the structure of their hinge region and the number of the glycosylation sites [12].

In serum, IgA1 is predominant, accounting for as much as 90%, while in mucosal tissues, both subclasses are more evenly distributed, comprising 40% IgA1 and 60% IgA2. [13]. In human blood, IgA occurs mostly in monomeric form, while secretory IgA (SIgA) present on the surface of mucous membranes usually occurs in the form of dimers, much less often as trimers and tetramers [14,15]. Dimeric SIgA antibodies, covalently linked by a J-linking chain, are secreted onto the mucosal surface with their characteristic secretory complement (SC) [15].

#### **3. IgA—Function**

The majority of total IgA in the human body occurs in the mucosal tissues with a proven great role in the immune response. Serum level of IgA is 2–3 mg/mL, and it is the second most prevalent circulating immunoglobulin after IgG. However, until recently, the role of plasma IgA was still unclear. Now, we have some evidence that serum IgA has some immunological functions, which are independent of the role of secretory IgA.

Serum monomeric immunoglobulin A acting through Fc alpha receptor I (FcαRI) has important immunomodulatory functions [16,17]. FcαRI is expressed on cells of the myeloid lineage, including monocytes, neutrophils, eosinophils, some macrophages, intestinal dendritic cells, and Kupffer cells [18]. Its role is associated with activation of different signaling pathways, immunoreceptor tyrosine-based activation motif (ITAM), and ITAM inhibitory (ITAMi) [19]. Once a multimeric ligand binds FcαRI, activation of an inflammatory response through ITAM signaling takes place. On contrary, monovalent ligand, like monomeric IgA, acts through ITAMi signaling, which results in an anti-inflammatory response (Figure 1).

**Figure 1.** Regulation of immune responses by FcαRI, including ITAM-induced activation and ITAMi-control.

Instead, secretory IgA due to such a numerous representation within the mucous membranes is considered the body's first line of defense against harmful external factors [20]. It has been proven that they can eliminate pathogens, for example, by adsorption of food antigens, agglutination of bacteria, inhibition of epithelial adhesion to mucous membranes [16,18,21]. Reports indicate the ability to neutralize and inhibit the release of viral and bacterial particles, neutralize toxins and enzymes produced by numerous pathogens [22,23].

IgA has been shown to exert an anti-inflammatory function by inducing the expression of anti-inflammatory cytokines such as IL-10 and inhibiting releasing pro-inflammatory cytokines such as IL-6 [24–26]. Moreover, IgA activates complement only in a limited amount, but this class of immunoglobulin can block the activation of the complement mediated by IgG [21,27]. It is known that IgA silences some responses after bacterial cell activation, like for example, oxidative burst activity, phagocytosis, as well as chemotaxis [28]. Effector functions of IgA are complex. As mentioned before, IgA may interfere directly with immune cells of the myeloid lineage using FcαRI. After the interaction of IgA with monocyte-derived dendritic cells, antigen presentation, maturation, and production of IL-10 may occur [29]. Monocytes also have the ability to produce IL-10 after IgA ligation and to inhibit the production of IL-6 and TNF-alfa [30]. SIgA is important in eosinophil activation and degranulation and is more potent at stimulation of the release of reactive oxygen species than IgE, as well as it regulates oxidative burst and cytokine release by human alveolar macrophages [31,32]. Moreover, binding IgA with mannan-binding lectin (MBL) results in complement activation, which is a part of antimicrobial defense [33]. SIgA may act as a competitive blocker of IgG-mediated complement activation [30]. A

significant aspect influencing the proper development of humoral immunity is an adequate stimulation of the immune system and, as a result, the ability to maintaining an appropriate balance between the cellular and humoral response.

## **4. Pathogenesis of IgA Deficiency**

The pathogenesis of the disease is not yet fully understood. It is possible that sIgAD can be caused by the overlap of some of these mechanisms [34].

One of them, which has been widely described, is the presence of errors in the differentiation of IgA+ plasmablasts causing a low number of IgA-secretory cells, difficulties with switching IgA to SIgA, and a low number of mRNA in B-cells producing IgA [7,35–38]. Another mechanism concerns cytokines that are involved in IgA production (IL-10, IL-4, IL-6, IL-12, IL-21) and is caused by dysregulation of their pathways, especially in secondary lymphoid organs [8,9,39–44]. In patients with sIgAD, IL-10 is proven to be crucial in the differentiation of the B cells to IgA-secreting cells. Furthermore, it has a synergic effect with IL-4 [43,45]. Another cytokine that causes IgA production is TNF-B, it also possesses the ability to act as an isotype "switch" factor for IgA production [46,47]. Lowered level of TGF-B may lead to a low IgA level in patients with sIgAD [9]. Il-21 stimulation is even more effective in inducing IgA production than IL-4 and IL-10, as well as it prevents CD19 + B cells spontaneous apoptosis [39]. This increased apoptosis could cause a reduction in survival of B cells and, therefore, decreased production of normal levels of IgA immunoglobulin [48]. Additionally, it is possible that T-cells impairment is connected with sIgAD. Soheili et al. suggest a direct association between decreased level of T regulatory (Treg) and the severity of clinical presentation of sIgAD [49]. In this study, patients were divided into two groups—G1 with a lower-than-cut-point Treg value, where there was a higher risk of developing autoimmunity and class switching recombination defects, and G2 with a higher Treg value, where only one person had autoimmunity and no one had the described antibodies defect. The link between Treg cells and IgA production is complex and multifaceted. Treg cells colonize the intestinal mucosa where they produce TGF-beta and IL-10, which are essential in the production of IgA. Reduced amount of Treg negatively affects the amount of IgA<sup>+</sup> B lymphocytes, and restoration of the correct amount of Treg, consequently, restores normal IgA production in the intestines [50–52] Interestingly, according to the meta-analysis by Bronson et al. there is a multiple gene linkage between the "Intestinal Immune Network for IgA production" and "Treg" [53]. Besides, the highest levels of APRIL (a proliferation-inducing ligand), which is connected with IgA-synthesis as a compensatory mechanism, are observed in patients with sIgAD [20,54]. It has been proved that there is a genetic background to sIgAD [55–57].

Moreover, level of these immunoglobulins may be influenced by drugs that are often used in everyday practice—non-steroid anti-inflammatory drugs (NSAIDs), angiotensin convertase enzyme inhibitors (ACEI), several anti-epileptic drugs, or drugs used in rheumatology. They can even trigger iatrogenic isolated sIgAD [58,59]. Moreover, some of the viral infections, e.g., EBV, hepatitis type C may induce post-infection IgA deficiency [60,61].

#### **5. Clinical Presentation of sIgAD**

Based on clinical presentation, sIgAD patients can be classified into different phenotypes. Yazdani et al. [8] in their work from 2015 divided these phenotypes into five main categories: asymptomatic, minor infections, autoimmunity, allergy, severe. It was reported that there is no correlation between serum IgA levels and clinical phenotype and disease severity [34].

Diagnosis of sIgAD is a diagnosis of exclusion. Immunologists should take into consideration infection-induced or drug-induced IgAD, as well as drug-induced IgAD/IgG2 subclass deficiency [62–64]. Important factors in establishing the diagnosis of IgA deficiency are family background and other laboratory parameters, which are relevant in order to differentiate sIgAD from CVID (lowered IgA/IgG and sometimes IgM levels), secondary hypogammaglobulinemia (moderately low levels of IgA), single-gene primary

immunodeficiencies, hypoglobulinemia due to the protein loss as the result of enteropathy or nephrotic syndrome and malignancies such as thymoma, myeloma, and chronic lymphocytic leukemia [64,65].
