We also found that memory B cells from our patients expressed higher levels of CD5 compared to healthy controls. These cells are known to produce low-affinity polyreactive antibodies (natural antibodies), which recognize autoantigens or conserved structures on self-antigens such as polysaccharide residues . They have a reduced capacity to enter the cell cycle and have a longer lifespan. Although the precise role of these cells in autoimmunity is still obscure, the numbers of peripheral CD5+ B cells were found to be increased CDK inhibitor in several autoimmune diseases, such as rheumatoid arthritis, primary Sjögren’s syndrome, autoimmune thyroid disease and multiple sclerosis . Therefore, it seems that these cells
might play a role in the pathogenesis of autoimmune diseases . The finding of low C4 levels, along with low functional C1INH in HAE, remains the most important immunological finding in this disease. C4 is important for the immune complex solubilization and removal . Therefore, inherited deficiencies of C1q and C4 are associated with the chronic activation of the classical complement pathway and the development of autoimmune disease
such as lupus-like disease early in life . Activation of the classical complement arm through immune complexes causes the production of C3 convertase, and the cleavage of C3 by C3 convertase leads to the production of C3b being an essential product for the immune complex removal. In addition, deficiencies of C4 render mice
GS 1101 unable to clear apoptotic cells/debris . Mevorach et al. demonstrated that apoptotic materials are immunogenic and accelerate the production of autoantibody in mice not prone to autoimmunity . Apoptotic material, especially when associated with microbial products in the form of immune complexes (ICs), might activate autoreactive B lymphocytes and induce serum autoantibodies . One can speculate that the persistence of ICs could possibly activate B cell receptors and up-regulate the expression of TLR-9, allowing HAE patients to overproduce autoantibodies. Another possible explanation for the over-activation of B cells in HAE could be through increased signalling of the human complement receptor type 2 (CR2) on B cells. GBA3 CR2 (CD21) plays a pivotal role in the activation and proliferation of B cells and is a prerequisite for T-dependent immune responses. Engagement of CR2 with the B cell receptor lowers the threshold required for B cell activation by an antigen, enhances cell activation, reduces inhibitory signals and prevents apoptosis [29–32]. Only seven of our 61 (11·4%) patients had a defined immunoregulatory disorder. This incidence of immunoregulatory disorders is similar to the 12% found by Brickman et al. and 11·5% that was found by Farkas et al. [11,13]. It is not yet clear if this finding represents increased incidence compared to that in the general population.