The Role of IFNγ in the Pathogenesis of Good Syndrome

BackgroundThymoma, a neoplasm of the thymus, leads to hypogammaglobulinemia in ∼10% of affected patients, resulting in Good syndrome that frequently coexists with autoimmunity and mucosal candidiasis. Thymomas lose the expression of autoimmune regulator (AIRE), causing thymic escape of autoreactive T cells, mirroring the inherited AIRE deficiency Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED). However, the pathogenesis of Good syndrome and the mechanism-based treatment for hypogammaglobulinemia are poorly understood.ResultsWe investigated B cell development in 12 patients with Good syndrome. Hypogammaglobulinemia was associated with a block at two stages of B cell development. The majority (n = 9) of Good syndrome patients had an absence of circulating B cells. Their bone marrow revealed lymphocyte aggregates, increased effector T cells with heightened clonality and IFNγ secretion, and associated arrest in B cell development. In the remaining three patients, bone marrow B cell production was intact; instead, peripheral diversion of B cell maturation to inflammatory CD21loCD38- B cells appeared to underlie hypogammaglobulinemia. Notably, these changes were not limited to patients with Good syndrome, as B cell lymphopenia was seen in half of the additional 21 patients with thymoma-associated autoimmunity. In addition to the bone marrow, IFNγ-driven T cell inflammation was present in 9 different tissues affected by thymoma-associated autoimmunity. These included mucosae affected by candidiasis, whereas anti-IL17 antibodies were present in only half of the thymoma patients with candidiasis. Based on these findings, we targeted bone marrow IFNγ responses with cyclosporine in a patient with Good syndrome and associated pure white cell aplasia and depleted infiltrating T cells with alemtuzumab in a patient with APECED-associated pure red cell aplasia and paucity of B cell production. Both treatments led to suppression of bone marrow IFNγ-associated inflammation with normalization of B cell production in the bone marrow.ConclusionsIn thymoma, a shared IFNγ-driven immunopathology in tissues affected by autoimmunity—including the bone marrow and mucosa affected by candidiasis—helps explain how a neoplasm at the site of T cell development may cause both autoimmunity and immunodeficiency. Good syndrome accounts for ∼5% of adult-onset primary hypogammaglobulinemia. Early recognition and intervention could potentially change the trajectory of developing immunodeficiency, avoiding both infectious complications and expensive immunoglobulin replacement.