Abstract
Autoimmune disorders (AID) have been increasingly observed in association with primary immunodeficiencies (PIDs). Here, we discuss the interface between PID and AID, focusing on autoimmune manifestations early in life, which can be diagnostic clues for underlying PIDs. Inflammatory bowel disease in infants and children has been associated with IL-10 and IL-10R deficiencies, chronic granulomatous disease, immunedysregulation-polyendocrinopathy-enteropathy-X-linked syndrome (IPEX), autoinflammatory disorders, and others. Some PIDs have been identified as underlying defects in juvenile systemic lupus erythematosus: C1q-, IgA-, IgM deficiencies, alterations of the IFN-α pathway (in Aicardi–Goutières syndrome due to TREX1 mutation). IPEX (due to FOXP3 mutation leading to Treg cell deficiency), usually appearing in the first months of life, was recently observed in miscarried fetuses with hydrops who presented with CD3+ infiltrating lymphocytes in the pancreas. Hemophagocytic lymphohistiocytosis due to perforin deficiency was also identified as a cause of fetal hydrops. In conclusion, PID should be suspected in any infant with signs of autoimmunity after excluding transferred maternal effects, or in children with multiple and/or severe AID.
Highlights
An increasing number of reports have shown that a substantial proportion of patients with primary immunodeficiencies (PID) develop autoimmune disorders (AID), in addition to increased susceptibility to infections [1, 2]
These findings are paradoxical if natural tolerance is thought to result from negative selection, but they are compatible with the notion that physiological autoimmunity is necessary for self-tolerance
Studies of immunedysregulationpolyendocrinopathy-enteropathy-X-linked syndrome (IPEX), which is caused by FOXP3 gene mutations, have critically established the fundamental role of regulatory T cells (Tregs) in natural tolerance, and PID-AID associations have consolidated the notion of dominant tolerance
Summary
An increasing number of reports have shown that a substantial proportion of patients with primary immunodeficiencies (PID) develop autoimmune disorders (AID), in addition to increased susceptibility to infections [1, 2] These findings are paradoxical if natural tolerance is thought to result from negative selection, but they are compatible with the notion that physiological autoimmunity is necessary for self-tolerance. Note that different autoimmune phenotypes are associated with different genetic defects [1], and a major question concerning the mechanisms of disease continues to be the restricted tissue “targeting” of these conditions There is another group of PIDs that are strongly associated with AID (more than 20% of affected patients demonstrate autoimmune manifestations), in which two of the most frequent PIDs are included: IgA deficiency and common variable immunodeficiency (CVID) (Table 2) [1, 2]; the mechanisms underlying pathogenic autoreactivity are not entirely clear yet. Examples of such PIDs include IL-12/IL-23 – IFN-γ axis deficiencies, IRAK-4 deficiency, autosomal dominant Hyper-IgE syndrome (due to STAT3 mutations leading to deficiency of Th17 cells), and congenital asplenia
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