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In common variable immune deficiency disorders, CTLA\u20104 deficiency, autoimmune lymphoproliferative syndrome, or in collagen VII deficiency, genetic defects in molecules regulating development, activation, maturation, and ECM composition alter the generation of B cells, resulting in immunodeficiency. Paradoxically, at the same time, the defective immune processes favor autoantibody production and immunopathology through impaired establishment of tolerance. The development of systemic autoimmunity in the framework of defective BCR signaling is relatively unusual in genetic mouse models. In sharp contrast, such reduced signaling in humans is clearly linked to pathological autoimmunity. The molecular mechanisms by which tolerance is broken in these settings are only starting to be explored resulting in novel therapeutic interventions. For instance, in CTLA\u20104 deficiency, homeostasis can be restored by CTLA\u20104 Ig treatment. Following this example, the identification of the molecular targets causing the reduced signals and their restoration is a visionary way to reestablish tolerance and develop novel therapeutic avenues for immunopathologies.<\/jats:p>","DOI":"10.1002\/eji.202149529","type":"journal-article","created":{"date-parts":[[2022,4,20]],"date-time":"2022-04-20T16:54:56Z","timestamp":1650473696000},"page":"1396-1405","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inborn errors of immunity and immunodeficiencies: Antibody\u2010mediated pathology and autoimmunity as a consequence of impaired immune reactions"],"prefix":"10.1002","volume":"52","author":[{"given":"Susana","family":"Minguet","sequence":"first","affiliation":[{"name":"Faculty of Biology Albert\u2010Ludwigs\u2010University of Freiburg  Freiburg Germany"},{"name":"Signalling Research Centres BIOSS and CIBSS University of Freiburg  Freiburg Germany"},{"name":"Center 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