Immunodeficiency with autoimmunity: unravelling the molecular origin of Good’s syndrome

The investigation of rare diseases offers the opportunity for diagnosis and gene discovery in disorders or phenotypes for which there is likely to be a single gene basis for the phenotype in the patients recruited to a project. The discovered genes and pathways can lead to novel therapies (orphan drugs) for the affected patients on the one hand, but also pave the way for a better understanding of pathways in more complex polygenic diseases on the other hand – an approach which has been quite successfully applied to rare deficiency disorders of the immune system. As such, especially severe combined immunodeficiency (SCID) syndromes can be defined as “experiments of nature”. By understanding the cellular and genetic basis of these immunodeficiency diseases, translational approaches to medicine can be improved. One of such diseases is Good’s Syndrome (GS), usually defined as a “thymoma with hypogammaglobulinemia”. It was first described in 1954 by Dr. Robert Good and is actually very rare, with only around 200 cases described worldwide. Recently, a relatively large series of 21 patients has been published by Malphettes et al.. In addition, Kelesidis and Yang systematically reviewed 152 cases from the clinical and immunological points of view, whereas most of the remaining papers are interesting case reports which nevertheless frequently provide a brief review of the literature. The incidence of GS is estimated to be 1 per 500.000. Good’s syndrome is an adult-onset primary immunodeficiency that usually starts in the fourth or fifth decade of life. Besides the thymoma and its potential local complications, it is clinically characterized by repetitive infections of the upper (sinuses) and lower (lungs) airways due either to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae) or to viruses, among whom the human cytomegalovirus (CMV) is most prominent. This picture frequently evolves to bronchiectasis. In addition, there is a susceptibility to mucocutaneous candidiasis and even to other opportunistic infections. Chronic Diarrhea is associated in around 50 % of the cases, due to bacteria (like Campylobacter, Salmonella, Shigella) or again CMV, although the causative agent can often not be identified. Autoimmune manifestations are frequent (76 % in the series of Malphettes et al.), and consist mostly of myasthenia gravis, oral lichen planus and pure red cell aplasia. The long-term prognosis of GS patients is usually considered as worse as for Common Variable Immunodeficiency (CVID) cases. For example, in one older review, the five year survival was 70 % in GS versus 100 % in CVID and the ten year survival was 33 % in GS versus 95 % in CVID, which might likely be due to the concomitant alteration of humoral and cellular immunity in GS. In the most recent report, seven out of 21 patients died during the study period of nine years. Regarding the management of GS, it consists first of all in the surgical removal of the thymoma. Infections can be quite efficiently prevented through Immunoglobulin replacement therapy (IgIV). Live vaccines should be avoided. There is of course no curative treatment yet. Importantly, the immunologic disturbances are usually not corrected by the thymectomy, whereas the autoimmune syndromes sometimes improve. Immunological abnormalities are first of all dominated by the disease-defining hypogammaglobulinemia which can affect one or more subclasses of immunoglobulins (IgG, IgM, IgA). Low or absent B lymphocytes are characteristic. CD4+ T lymphopenia and a decrease in NK cell numbers are likewise frequent. In contrast, the CD8+ T cell frequencies are elevated, which leads to a low CD4/CD8 ratio. The proliferative response to T cell mitogens like phytohemagglutinin (PHA) is reduced. The exact pathogenesis of GS is still elusive, even if some molecular abnormalities have been described in recent years. Based on the similarities between GS and CVID regarding B cell abnormalities and the reported association of CVID with mutations in the TNFRSF13B gene encoding the transmembrane activator and CAML interactor (TACI) molecule, Sáenz-Cuesta et al. undertook to search for such mutations in five patients with GS and found an alteration in one case. Another mutation in the same gene, leading to a premature stop codon, was subsequently reported by Margraf et al. in one out of two tested patients. TACI mutations might be relevant in GS as this protein is implicated in class switch recombination and the control of B cell functions. Like TACI, BAFF-R is another member of the Tumor Necrosis Factor Receptor superfamily critically involved in B cell development. The corresponding gene was found to have two missense mutations in a typical GS case, but the TACI gene was normal. BAFF-R knockout mice display a peripheral deficiency in B lymphocytes. More generally spoken, Kelesidis and Yang consider that the defect may originate from the bone marrow, as a pre-B cell arrest or the absence of pre-B cells have been noted and as the maturation of red and myeloid cell precursors is often disturbed. Other authors envisage two explanations: (i) bone marrow derived cytokines may have an effect on T and B cell precursors, and (ii) T cells and/or autoantibodies - the absence or rarity of peripheral B cells does not preclude their potential presence in lymphoid organs - might disturb the differentiation and maturation of red blood cells. For Martinez and Browne, it is the thymoma that is responsible, by producing abnormal T cells that do not react enough against pathogens but too much against autologous cells and tissues. This might be due to the lack of expression of the autoimmune regulator (AIRE) with the consequence of an abnormal microenvironment and a disturbed negative selection. In addition, anti-cytokine antibodies might play a role and interfere with normal immune responses. In 2011, Ng et al. described a GS patient in a letter published in the New England Journal of Medicine. They noticed that the immunological picture of this as well as of other GS cases is reminiscent of the phenotype of Ikaros C null KO mice, concerning in particular a lack of B cells and their precursors, NK cell deficiency and thymic hyperplasia. They recommend consequently to investigate Ikaros in the context of GS by searching for mutations or alternative splice variants. Ikaros is a transcription factor crucial for hematopoiesis and involved in the differentiation of lymphoid as well as myeloid lineages. Acquired Ikaros mutations have been described in acute lymphoblastic leukemia (ALL) and in chronic myeloid leukemia at the time of progression to blast crisis. In the presence of such mutations, the prognosis of ALL patients is seriously compromised. One might therefore consider that Ikaros could be a candidate gene implicated in the pathogenesis of GS, and this deserves further investigation. Interestingly, in a study of colorectal cancer cell lines and primary tumor samples, a promoter hypermethylation of the Ikaros gene was identified, leading to the dysregulation of several targets. As GS is an adult-onset immunodeficiency and as the patients have an unremarkable medical history until the diagnosis is established, potential hypotheses are that (i) epigenetic factors together with (ii) genomic factors (acquired dominant somatic mutations(s) due to spontaneous events or induced by chronic viral infections) could play a determinant role. This point has, to the best of our knowledge, not yet been investigated in the context of GS and we plan to address it in our proposed project.