**1. Introduction**

Common variable immunodeficiency (CVID) is the most common symptomatic primary antibody deficiency in adults. Most patients suffer from recurring respiratory tract infections; however, paradoxical autoimmunity, both systemic and organ related, is a secondary manifestation of CVID and affects 20–40% of cases [1]. Patients with a complicated CVID phenotype have the longest diagnostic delay, especially if autoimmune phenomena are the first manifestations of primary immunodeficiency [2]. Autoimmune phenomena might occur as the first symptom in 30% of patients with primary antibody deficiencies [3]. In a recent study focused on noninfectious CVID complications, autoimmune thrombocytopenic purpura (AITP) was most common (16.2%), followed by autoimmune hemolytic anemia (AIH 7.7%), amongst the 632 patients followed since 1974. Other associated autoimmune conditions include rheumatoid arthritis (2.7%) and uveitis (1%). Rarer autoimmune complications are psoriasis, psoriatic arthritis, vitiligo, alopecia, autoimmune thyroiditis,

**Citation:** Wi ˛esik-Szewczyk, E.; Rutkowska, E.; Kwiecie ´n, I.; Korzeniowska, M.; Sołdacki, D.; Jahnz-Rózyk, K. Patients with ˙ Common Variable Immunodeficiency Complicated by Autoimmune Phenomena Have Lymphopenia and Reduced Treg, Th17, and NK Cells. *J. Clin. Med.* **2021**, *10*, 3356. https://doi.org/10.3390/jcm10153356

Academic Editors: Rita Consolini and Giorgio Costagliola

Received: 26 May 2021 Accepted: 23 July 2021 Published: 29 July 2021

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antiphospholipid syndrome, Sjogren syndrome, vasculitis, type 1 diabetes, myasthenia gravis, autoimmune pancreatitis, and severe oral ulcers [4]. Polyclonal lymphadenopathy occurred in 20–40% of patients [4]. Clinically, this often presents as generalized lymphadenopathy and splenomegaly. The challenge is to differentiate it from lymphoma [5]. In 20% of patients with a CVID-like phenotype, monogenic defects responsible for immune deregulation have been identified. Examples include CTLA4 and LRBA deficiency [6,7], nuclear factor kB (NFkB) mutations [8,9] and mutations of the catalytic subunit of phosphoinositide 3-kinase delta (PI3Kdeta) [10]. However, in the majority of patients with CVID, the pathogenesis of noninfectious phenomena is still unknown.

Similar symptoms were observed in systemic lupus erythematosus (SLE): cytopenia, generalized lymphadenopathy, hepatomegaly, splenomegaly, and interstitial lung disease. The clinical symptoms of CVID and systemic rheumatic diseases overlap. Evidence has accumulated that the coincidence of primary immunodeficiency (PID) and autoimmune diseases is high [11–13]. A secondary immunodeficiency-like state is present in a significant number of rheumatologic patients. Low serum levels of main immunoglobulins (Ig) and subclasses IgG3 and IgG4 are frequent, although in many cases laboratory abnormalities are not related to increased susceptibility to infections [14]. A recent study of patients with rheumatic diseases identified genetic variants that are responsible for PID in participants who developed hypogammaglobulinemia [11].

Immunophenotyping of the B cell compartment in the peripheral blood is a routine evaluation in patients with primary hypogammaglobulinemia. In CVID, detailed findings of B cell maturation can be classified according to several systems, of which two of the most popular are Freiburg [15] and EUROclass [16]. Characterization of CD19+ B cell subsets in CVID is classified according to low Ig switched memory (CD19+ CD27+ IgM− IgD−), B cell (smB) proportions, and abnormally high proportions of CD21low B cells. In addition to these two cell subsets, the EUROclass classification also uses an abnormal expansion of transitional B cells (CD19+ CD27− CD38+) for further subgrouping [16].

Low smB cell subsets are an abnormality present in 80% of patients with CVID; however, it is not specific for CVID. More detailed studies that assessed the correlation between B cell maturation and the phenotype of CVID have produced mixed results. In some studies, diminished smB cell count [17], reduced naïve B cells [18], and expansion of B cells with reduced CD21 expression (CD21low B cells) correlated with autoimmune phenomena or splenomegaly [16,19].

Although CVID is a disease of defective B cell maturation, various reports have associated CVID with T cell compartment abnormalities, such as CD4+ T cell lymphopenia with reduced subset counts of naive CD4+ T cells [20] and naive CD8+ T cells [21]. A reduced percentage of naïve CD4+ T cells was associated with complications and poor prognosis in CVID [22].

Regulatory T cells (Tregs), T helper 17 (Th17), and follicular T helper 17 (Tfh17) cells are reduced in patients with complicated CVID phenotypes [18]. T cells in patients with CVID have lower proliferative capacities [23] and abnormal cytokine production [24]. Recent studies have shown the involvement of follicular T cells in CVID pathogenesis [25] An increase in the circulating memory CD4+ T cells of CVID patients with noninfectious complications has been reported [26].

In contrast to PID, immunophenotyping of B and T cells in SLE and other autoimmune diseases is mainly used in scientific research and clinical trials [27]. Therefore, physicians are not familiar with the interpretation and utility of lymphocyte subset counts in clinical practice. The data showed that IgM memory B cells were significantly decreased in patients with SLE. In contrast, transitional B cells were significantly increased in SLE and other autoimmune disorders [28]. The population of plasmablasts also increased in active SLE [29].

Until now, studies comparing B and T cell subsets from patients with PID and patients with rheumatic diseases are limited. In one study, patients with primary and secondary hypogammaglobulinemia in the course of different rheumatic diseases were observed [30]. Another study involved the analysis of polymyalgia rheumatica patients treated with systemic glucocorticoids [31]. Both studies aimed to identify the distinction between primary and secondary hypogammaglobulinemia.

We analyzed the maturation of B and T lymphocytes in the peripheral blood of patients with CVID who were divided into two groups: patients with a phenotype limited to infections (CVID-OI) and patients with noninfectious, autoimmune complications (CVID-C). These results were compared with those of patients diagnosed with SLE and healthy controls (HCs). The aim of this study was to identify immunological markers of autoimmune phenomena associated with CVID.
