**1. Introduction**

In recent years, the association between primary immunodeficiency disorders (PIDs) and autoimmunity has been extensively studied. Patients with PIDs can develop an immune dysregulation of variable degree, which is responsible for a clinical picture featured by infectious complications and autoimmunity [1,2]. Autoimmune manifestations are observed with considerable frequency in patients with primary antibody deficiencies, including common variable immunodeficiency (CVID) and selective IgA deficiency (sIgAD), but can also be evidenced in patients with combined immunodeficiency disorders (CID) [3]. Notably, autoimmunity can represent the presentation sign of PIDs in a significant number of patients [1]. The molecular mechanisms responsible for the immune dysregulation in patients with PIDs are multiple and not completely elucidated; impaired B cell differentiation and germ-center reactions, altered T cell central or peripheral tolerance, uncontrolled lymphocyte proliferation and differentiation, dysfunctional complement, and innate immune activation can participate in the complex pathogenic process leading to autoimmunity. In patients with PIDs, the association with autoimmunity leads to a significant impact on the quality of life, higher medicalization, and increased mortality [2]. Furthermore, the increasing use of new sequencing techniques allowed the identification of different

**Citation:** Costagliola, G.; Cappelli, S.; Consolini, R. Autoimmunity in Primary Immunodeficiency Disorders: An Updated Review on Pathogenic and Clinical Implications. *J. Clin. Med.* **2021**, *10*, 4729. https:// doi.org/10.3390/jcm10204729

Academic Editor: Burkhard Möller

Received: 17 September 2021 Accepted: 13 October 2021 Published: 15 October 2021

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monogenic causes of PID, the better understanding of genotype-phenotype correlations, and the improvement of the therapeutic strategies targeting the immune dysregulation in PIDs [4,5].

In this paper, we review the main autoimmune manifestations observed in patients with PIDs, focusing on the molecular mechanisms implicated in the pathogenesis of the immune imbalance in each condition. Furthermore, we provide some key issues for the diagnostic and therapeutic approach to autoimmunity in patients suffering from PIDs.

#### **2. Autoimmunity in Primary Antibody Deficiency Disorders**

Among primary antibody deficiencies, autoimmunity has been described with considerable frequency in patients with CVID, sIgAD, and hyper-IgM syndrome (HIGM), with the clinical phenotype being significantly associated with the variability of the genetic background (Table 1).


**Table 1.** Autoimmune/inflammatory manifestations in primary antibody deficiencies.

ITP, Immune thrombocytopenic purpura; AIHA, autoimmune hemolytic anemia; T1D, Type 1 Diabetes; ILD, interstitial lung disease; IBD, inflammatory bowel disease; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; NF-kB1, Nuclear factor kappa-light chain enhancer; LRBA, LPS, responsive beige-like anchor protein; CTLA-4, cytotoxic lymphocyte antigen 4; PI3Kδ, Phosphoinositide 3-kinase δ; STAT3, signal transducer and activator of transcription; sIgA, selective immunoglobulin A deficiency; XHIM, X linked variant of hyper-IgM syndrome; AID, activation induce cytidine deaminase; DM: dermatomyositis.

#### *2.1. Common Variable Immunodeficiency*

CVID is characterized by a reduction in serum immunoglobulin (Ig) G and IgA, by at least two standard deviations below age-appropriate reference levels, with or without low Ig M levels, accompanied by poor antibody response to vaccines or low switched-memory B cells. Clinical diagnosis of CVID requires at least one between increased susceptibility to infections, autoimmune manifestations, granulomatous disease, lymphoproliferation, or an affected family member with antibody deficiency [6]. A total of 30–50% of CVID patients have non-infectious manifestations, including autoimmune, gastrointestinal, pulmonary, lymphoproliferative, and malignant complications [7–9], which strongly contribute to morbidity and mortality [7,10]. Autoimmune diseases occur in 20–30% of CVID patients. Autoimmune cytopenias, and in particular immune thrombocytopenic purpura (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome [9,11], are the most commonly reported, but organ-specific and systemic autoimmune diseases are also described. Interestingly, cytopenia may be the first manifestation of the immune defect, in patients without a typical history of infections [12]. Concerning systemic autoimmune diseases, in a recent study of 870 CVID patients from the United States Immunodeficiency Network (USIDNET) registry, 5% were found to have a rheumatologic disease [13]. The most common rheumatologic manifestation reported in CVID is inflammatory arthritis, occurring in about 3% of patients, but systemic lupus erythematosus (SLE), Sjögren's disease, Behçet disease, and psoriasis have also been described [10,13–15]. Among organ-specific autoimmune diseases, in a European Society of Immune Deficiencies (ESID) registry of 2700 CVID patients, hypothyroidism was the most prevalent at 3.5%, followed by alopecia areata, vitiligo, and type I diabetes (T1D) [9]. Among autoimmune manifestations, only cytopenias have been associated with decreased survival and CVID-associated noninfectious complications, including lymphoproliferation, granulomatous disease, lymphoma, hepatic disease, pulmonary involvement (granulomatous lymphocytic interstitial lung disease (GLILD)), and enteropathy [7].

Different studies suggested that both genetic background and immunological abnormalities play a significant role in explaining the link between CVID and autoimmunity. CVID patients can show deregulated immune responses at different levels, involving altered germ center reactions, class switch, and B cell proliferation [11]. Additionally, an impaired suppressive function of Bregs on activated T cells leading to excessive T cell activation has been described [16]. T cell dysfunction is a contributing factor in the development of autoimmunity in CVID [17]. Hyperactivated T cell phenotype [18], reduced number and function of regulatory T cells (Tregs) [19], and an increase in T helper type 1 (TH1), type 17 (TH17), and T helper follicular cells have been observed in CVID patients with autoimmunity [11,20,21]. Moreover, autoimmunity may be caused not only by a break in tolerance to self-antigens but also by the inability of CVID patients to completely eradicate microbial antigens, resulting in compensatory, often exaggerated, and chronic inflammatory responses [2].

Even if many CVID patients may have a polygenic disease, in about 15–30% of CVID cases, a monogenic cause has been found [22]. CVID patients with *TNFRSF13B* mutation (encoding for the B cell-activating factor (BAFF) and APRIL receptor, TACI), especially if heterozygous, have a propensity to autoimmune manifestations and lymphoid hyperplasia potentially due to lack of normal mechanisms required to establish tolerance [23]. *BAFF-R* mutations, which may impair B-cell maturation, have also been described in association with autoimmunity [24,25]. Autoimmunity and other clinical manifestations (including lymphoproliferation) have been associated with the deficiency of *NF-kB1* and *NF-kB2*, which are transcription factors that are crucial for B-cell maturation, survival, differentiation, class switching, and self-tolerance. Additionally, it is described in patients with mutations affecting the inducible T-cell co-stimulator (*ICOS*), a T cell surface receptor that is closely related to NF-kB activation and is essential for terminal B cell differentiation and immune tolerance [25]. Finally, autoimmunity has been described in patients with mutations in other genes implicated in B cell activation and proliferation, including PLCγ2, which is responsible for the PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) [25,26].
