*9.2. Diagnosing Autoimmunity in Children with PIDs*

Periodic surveillance for autoimmune manifestations is mandatory in all patients with PIDs. This is particularly relevant for children carrying genetic mutations with a well-defined association with autoimmunity (i.e., CTLA-4, LRBA, PI3K mutations). Moreover, there is increasing interest in the identification of potential immunological predictors of autoimmunity in patients with PIDs. Although there are no specific immunological markers with high predictive value for the development of autoimmunity, literature data from patients with primary antibody deficiencies and CID have identified several potential candidates.

A large cohort study on CVID patients with immune cytopenia demonstrated higher levels of serum immunoglobulin, CD19hi B cells, and T CD4 effector T cells, accompanied by reduced naïve T cells [128]. Absence or reduced switched memory B cells have been associated with autoimmune cytopenias, systemic autoimmune diseases, splenomegaly, granulomatous diseases, and lymphadenopathy [129,130]. An expansion of CD21low B cells has been described in association with reduced Tregs in CVID patients with autoimmunity [131]. It has been found that CD21low B cells produce significantly more IgM than naïve B cells after stimulation with CD40L, IL-2, and IL-10 and that CVID patients with autoimmunity have higher levels of IgM compared with non-autoimmune phenotypes [15,132], thus suggesting that increased IgM levels may be a marker of autoimmunity and they may have a pathogenic role. Additionally, lower naïve CD4+ and CD8+ T cells and increased differentiated T cells have been described in CVID patients with autoimmunity [18].

Concerning combined immunodeficiencies, a recent study by Montin et al. in patients with 22q11.2DS highlighted that some immunological features, including a reduced number of naïve T cells, reduced RTE, and elevation of naïve B cells are associated with the development of hematologic autoimmunity and can be evidenced significantly before the onset of autoimmunity [133]. Moreover, the degree of T-cell lymphopenia has been suggested as a contributing factor for the development of autoimmunity in this disease [75].

## **10. Conclusions**

It is well recognized that autoimmune manifestations are observed in a significant percentage of patients with PIDs, often representing the first sign of these conditions. Patients with early-onset autoimmunity, an association between two or more autoimmune manifestations, or increased susceptibility to infections should be promptly screened for PIDs. Although the intriguing mechanisms underlying the development of autoimmunity in patients with PIDs are far to be completely elucidated, the rapidly evolving knowledge in the genetic background of PIDs will hopefully help to characterize the defects linking immunodeficiency and autoimmunity, thus providing interesting diagnostic and therapeutic implications.

**Author Contributions:** G.C. and S.C. wrote the initial draft of this paper, which was critically revised by R.C. All the authors contributed to conceptualizing this work. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**

