Defective peripheral B cell selection in common variable immune deficiency patients with autoimmune manifestations
Common variable immunodeficiency is the most common symptomatic primary immunodeficiency that is characterized by low levels of serum IgG, IgA and sometimes IgM. The patients suffer from recurrent infections of the upper and lower respiratory tract but many also develop more severe symptoms such as autoimmune manifestations, granulomas and lymphomas. Although autoimmune manifestations are commonly seen we still know little about B-cell selection in these patients. Therefore, we decided to investigate both central and peripheral B cell selection mechanisms in CVID by comparing patients with infection only to those with autoimmune manifestations. We demonstrate that the central B-cell tolerance is intact as measured by receptor editing. On the other hand, we found that peripheral B-cell selection in the germinal centre is defective. This was corroborated by the severely reduced number of somatic mutations, especially replacement mutations, in those patients with autoimmune manifestations. Finally, we show that in vitro activation of naive B cells in CVID B cells lead to suboptimal activation of the mismatch repair machinery, which could at least partially explain why the process of somatic hypermutation is not working optimally in these.
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