The participants provided their written informed consent to participate in this study. Author contributions PW: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Visualization, Writing C original draft, Writing C review & editing. with IgGsd had decreased levels of activated T cells and B cells and plasma levels of negative immune checkpoint molecules correlated negatively with T cell and B cell activation. The decreased T cell activation level was unaffected by IgRT, while the B cell activation was partly restored. Of note, decreased levels of activated regulatory T cells (Tregs) were found in IgGsd patients and was partly restored during IgRT. The profile of comorbidities Taurodeoxycholate sodium salt did not associate with Treg levels. Discussion IgGsd is associated with decreased B cell and T cell activation including Tregs, and increased plasma levels of negative immune checkpoint molecules. The consequence of reduced activated Tregs in IgGsd remains unclear. Decreased immune cell activation was partly restored during IgRT, demonstrating that IgRT may contribute to improved immune function in patients with IgGsd. Keywords: predominantly antibody deficiency, IgG subclass deficiency, Ig replacement therapy, T cells, B cells, Tregs, immune checkpoints Introduction Predominantly antibody deficiencies (PAD) comprise a group of inborn errors of immunity with poor antibody responses (1). PAD is associated with increased Taurodeoxycholate sodium salt susceptibility to infections and with chronic inflammatory disorders (2). Immunoglobulin G subclass deficiency (IgGsd) is a mild form of PAD characterized by increased frequencies of infections, and reduced levels of at least one IgG subclass. According to the international classification, which aligns with Swedish classification, IgGsd characterized by reduced levels of least one of IgG subclass and is mostly an asymptomatic PAD, but IgGsd can also be associated with increased frequencies of Taurodeoxycholate sodium salt infections. IgGsd can be associated with subnormal levels of IgA or moderately reduced IgG (1). According to the European Society of immunodeficiency, IgGsd should be accompanied by normal levels of IgG, IgM and IgA otherwise it is considered an unclassified antibody deficiency (3). The clinical presentation of IgGsd varies from asymptomatic to recurrent infections and symptomatic IgGsd is often associated with atopic disease and chronic lung disease (4C6). Bronchiectasis, affect 38%-48% of patients with IgGsd. Recurrent airway infections may contribute to airway remodeling and deteriorated lung function in patients with IgGsd (7C9). Autoimmune conditions are also frequent among patients with IgGsd. The prevalence Taurodeoxycholate sodium salt of autoimmune conditions, such as rheumatoid arthritis, thyroiditis and Sj?gren syndrome, was over 40% in a large cohort of patients with IgGsd (10). Furthermore, in a study on inborn errors Taurodeoxycholate sodium salt of immunity, rheumatologic complications were most common in patients with IgGsd (11%) when compared to other groups of patients with predominantly antibody deficiencies (11). Hence, low IgG subclass levels may reflect an underlying immune dysregulation, but the understanding of factors contributing to autoimmune complications in IgGsd is scarce. To date, there is no pathogenic gene variant associated with IgGsd, or with any other PAD characterized by reduced IgG levels not fulfilling the criteria of common variable immunodeficiency (CVID). Common variable immunodeficiency (CVID) refers to a group of heterogenic severe PAD characterized by significant hypogammaglobulinemia, in combination with perturbations of circulating B cell and T cell subsets (12). In CVID an increasing number of pathogenic gene variants have been reported (1). As in unspecified PAD and IgGsd, autoimmunity F3 and lung disease affect many patients with CVID (13). In contrast to IgGsd, lymphoproliferation (i. e polyclonal lymphocytic infiltration of non-lymphoid tissues) may complicate CVID, and CVID is associated with markers of more severe immune defects than IgGsd (14). Patients with CVID are characterized by decreased class-switched memory B cells (15) and low regulatory T cells (Tregs) associates with autoimmune manifestations in CVID (16). There is, to our knowledge, there is only one previous report on circulating lymphocyte subsets, e.g., B cells, CD4+ helper (h) T cells, CD8+ cytotoxic T cells and natural killer (NK) cells, in patients with IgGsd. In a study of 16 patients with IgG2 deficiency, the only anomaly found among lymphocytes, was subnormal levels of Th cells in one patient (10). In the vast majority of the patients in a cohort of 17 patients with IgG3 deficiency, there were.