*2.4. X-Linked Agammaglobulinemia*

X-linked agammaglobulinemia (XLA) is caused by a B lymphocyte differentiation arrest caused by mutations in the BTK gene, and is predominantly featured by recurrent infections (especially with encapsulated bacterial pathogens) caused by antibody deficiency with nearly undetectable levels of peripheral B cells [51]. XLA patients appear to be at an increased risk of developing autoimmune diseases, which can be found in up to 15% of patients [52]. Arthritis is the most frequent autoimmune presentation of XLA patients [52] but dermatomyositis, inflammatory bowel diseases (IBD), AIHA, scleroderma, alopecia, T1D, and glomerulonephritis have also been described [53–55]. Chronic inflammation due to subclinical infections significantly contributes to immune dysregulation in XLA patients. Evidence supports the notion that BKT-dependent, but antibody-independent, mechanisms may be involved in the pathophysiology of autoimmunity in XLA [56]. Excessive stimulation by pathogen molecules of Toll-like receptors (TLRs) may contribute to inducing autoimmunity. Indeed, by certain mutations of BTK and recurrent infections, in XLA patients, overstimulation of TLR9 and its secondary messengers, NF-kB, may occur [57], thus causing enhanced production of autoantibodies from innate B-1 cells [58].

#### *2.5. Therapeutic Approach to Autoimmunity in Primary Antibody Deficiencies*

The treatment strategies of autoimmune manifestations in patients with PADS are generally the same as in immune-competent patients and include the use of high dose intravenous immunoglobulins (IVIg) and immunosuppressive agents, such as corticosteroids, methotrexate, and azathioprine (resulting in an increased risk of infections). As a second-line therapy, rituximab appears to be highly effective and relatively safe for the management of severe immune cytopenias [59]. On the other hand, splenectomy is reserved as a last resource in patients who have failed all other therapies [60] and is generally disfavored because of the risk of subsequent infections.
