In-depth blood immune profiling of Good syndrome patients

Abstract

IntroductionGood syndrome (GS) is a rare adult-onset immunodeficiency first described in 1954. It is characterized by the coexistence of a thymoma and hypogammaglobulinemia, associated with an increased susceptibility to infections and autoimmunity. The classification and management of GS has been long hampered by the lack of data about the underlying immune alterations, a controversy existing on whether it is a unique diagnostic entity vs. a subtype of Common Variable Immune Deficiency (CVID).MethodsHere, we used high-sensitive flow cytometry to investigate the distribution of up to 70 different immune cell populations in blood of GS patients (n=9) compared to age-matched CVID patients (n=55) and healthy donors (n=61).ResultsAll 9 GS patients displayed reduced B-cell counts -down to undetectable levels (<0.1 cells/μL) in 8/9 cases-, together with decreased numbers of total CD4+ T-cells, NK-cells, neutrophils, and basophils vs. age-matched healthy donors. In contrast, they showed expanded TCRγδ+ T-cells (p ≤ 0.05). Except for a deeper B-cell defect, the pattern of immune cell alteration in blood was similar in GS and (age-matched) CVID patients. In depth analysis of CD4+ T-cells revealed significantly decreased blood counts of naïve, central memory (CM) and transitional memory (TM) TCD4+ cells and their functional compartments of T follicular helper (TFH), regulatory T cells (Tregs), T helper (Th)2, Th17, Th22, Th1/Th17 and Th1/Th2 cells. In addition, GS patients also showed decreased NK-cell, neutrophil, basophil, classical monocyte and of both CD1c+ and CD141+ myeloid dendritic cell counts in blood, in parallel to an expansion of total and terminal effector TCRγδ+ T-cells. Interestingly, those GS patients who developed hypogammaglobulinemia several years after the thymoma presented with an immunological and clinical phenotype which more closely resembled a combined immune humoral and cellular defect, with poorer response to immunoglobulin replacement therapy, as compared to those in whom the thymoma and hypogammaglobulinemia were simultaneously detected.DiscussionOur findings provide a more accurate definition of the immune cell defects of GS patients and contribute to a better discrimination among GS patients between those with a pure B-cell defect vs. those suffering from a combined immunodeficiency with important consequences on the diagnosis and management of the disease.

B-cell immune dysregulation with low soluble CD22 levels in refractory seronegative myasthenia gravis

“…Similar to our study, Torres-Valles et al. also reported reduced B-cell counts in the patients diagnosed as Good’s syndrome (GS), a rare immunodeficiency by coexistence of a thymoma and hypogammaglobulinemia, and MG have also been frequently reported in GS patients ( 42 ). Rituximab treatment eliminates most CD20-positive B cells, including memory cells.…”

Autoimmunity in thymic epithelial tumors: a not yet clarified pathologic paradigm associated with several unmet clinical needs

“…It has been suggested that autoreactive cytotoxic T cells derived from aberrant T cell maturation in the thymic tumor microenvironment may be involved in B cell lymphopenia ( 41 ), but the pathogenesis of GS is largely unknown. A recent study by Torres-Valle and colleagues demonstrated that immune defects in GS patients involve not only B and T cells, but also several populations of innate immune cells ( 42 ), suggesting that GS may represent an interesting model to investigate the immune dysregulation mechanisms underlying the association between autoimmunity and thymic epithelial tumors.…”