Autoimmunity in primary immune deficiency: taking lessons from our patients.

The elucidation of the genes leading to selected immune defects has accelerated our understanding of the molecular basis of tolerance in autoimmunity disorders. Mutations in genes of the immune system are known to lead to a catalogue of functional deficits, including loss of activation-induced Fas-mediated apoptosis, an inability to remove self-reactive T and/or B cells and insufficient numbers or functions of regulatory T cells. In most cases, microbial antigen stimulation occurs simultaneously, leading to further inflammatory responses. In each case, probing the molecular pathways involved in these primary immune defects has led to a better understanding of autoimmune diseases in general. While subjects with X-linked agammaglobulinaemia are almost devoid of autoimmune diseases, B cells which are present, but dysfunctional in other defects, lead to a significant incidence of autoimmune disease. Autoimmunity is also particularly common in the antibody deficiency states. Although organ-based autoimmunity also occurs, for unclear reasons the main conditions are immune thrombocytopenia purpura and autoimmune haemolytic anaemia. The common variable immune deficiency subjects most afflicted by these cytopenias are those with specific peripheral blood memory B cell phenotypes. B cells of these subjects have a retained autoimmune potential, lack of somatic hypermutation, profound loss of proliferative potential, accelerated apoptosis and loss of normal Toll-like receptor signalling. Treatment with high-dose immunoglobulin and/or steroids can be helpful, while rituximab provides benefits in the treatment of refractory cytopenias with apparently little risk, even with repeated use, due to ongoing immune globulin therapy.