The Pathogenesis, Diagnosis, And Treatment of Systemic Mast Cell Disorders

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GATA proteins are lineage-restricted transcription factors that modulate tissue-specific patterns of gene expression during development. GATA-2 is expressed in multi-lineage hematopoietic stem progenitors and plays an essential role in their maintenance and proliferation. In Fiscal Year (FY)2020 we participated in a study which provided evidence that GATA-2 deficient subjects exhibit impaired IgE-mediated mast cell activation and diminished IgE-mediated allergic disease. These findings were associated with reduced KIT and FcRI expressed and not dependent on antigen. Short-term inhibition of GATA-2 with a small molecule successfully targeted both FcRI and KIT expression, thereby limiting IgE-mediated mast cell activation in vitro which may provide a basis targeted therapy to inhibit untoward systemic allergic manifestations. Children with cutaneous mastocytosis may exhibit a unique pattern of skin lesions called diffuse cutaneous mastocytosis (DCM). In FY2020 we report a case of a neonate with DCM caused by a rare activating KIT mutation Ala502Tyr503, and a review of the literature in the management of DCM in pediatric patients. We also published a case series of manifestations of DCM in diverse populations. Regarding children with mastocytosis, a study was initiated which suggested that despite their mast cell disease there was a relatively low rate of adverse reactions to routine childhood vaccines. There is a precedent in the literature for enhanced mast cell responses to therapeutics in patients with mastocytosis. In FY2020 we published a comprehensive guide for providers who need to decide on therapeutic options in the management of patients with clonal MC disease. Laboratory of Allergic Diseases 2 (LAD2) human mast cells derived in the MCBS over 15 years ago from a patients CD34+ bone marrow cells have been distributed worldwide for studying mast cell proliferation, receptor expression, mediator release/inhibition, and signaling. In FY2020 a second line has been re-established using similar conditions from another bone marrow aspiration giving rise to a second cell line called LADR. LADR cells exhibit unique features such as slower proliferation rate, increased FcRI/CD117 and tryptase expression in comparison to LAD2 cells and thus are a valuable addition to the few FcRI+ human mast cell lines available for scientific investigations. In FY2020 we completed and published a report that examined lymphocyte populations in patients with mastocytosis that explored whether an excess mast cell burden might influence specific subsets of lymphocytes. We found that patients with mastocytosis exhibited a significantly lower median frequency and absolute cell count of both circulating CD8+ T cells and Natural Killer cells accompanying a significantly increased ratio of CD4+/CD8+ T cells. Stratification of patients according to clinical manifestations further revealed that CD19+CD21lowCD38low B cells were significantly higher in patients with a history of autoimmune disease and counts of terminally differentiated CD4+ T cells were significantly higher in patients with osteoporosis or osteopenia. These data suggest the need for further studies on abnormalities in lymphocyte subsets and the attendant clinical consequences in both mast cell proliferative and activation disorders. While elevated basal serum tryptase (BST) is associated with mastocytosis and severe systemic anaphylaxis, the presence of clonal mast cells does not fully explain this association. In FY2020 we participated in a study that determined the prevalence and associated impact of tryptase genotypes on anaphylaxis through genotyping national and international cohorts with systemic mastocytosis, venom and idiopathic anaphylaxis. Those subjects with hereditary tryptasemia (HT), a genetic trait caused by increased tryptase encoding TPSAB1 copy number, displayed elevated BST. HT was common in healthy individuals (5.6%, N=7/125) and non-atopic disease controls (5.3%, N=21/398) but more prevalent in those with venom anaphylaxis and even more prevalent in both idiopathic anaphylaxis (N=47, 17%, P=0.006) and systemic mastocytosis (N=10/82, 12.2%, P=0.03). This report determined that severe anaphylaxis in humans is associated with inherited differences in -tryptase-encoding copies at TPSAB1. Patients with indolent (non-aggressive) systemic mastocytosis are not candidates for cytoreductive therapy and are generally treated with symptomatic therapy that only partly decreases symptoms. There is, however, a documented association between severity of mastocytosis and elevated serum levels of interleukin IL-6. Furthermore, mast cells have been shown to double their rate of division and exhibit increased reactivity and release of mediators when cultured in the presence of IL-6. In addition, in an animal model of mastocytosis, anti-IL-6 has been shown to slow disease progression. In FY2020 we enrolled several patients in a new clinical trial where adults with indolent systemic mastocytosis are randomized and treated with sarilumab which binds to the IL 6 receptor and inhibits IL 6 associated human mast cell signaling, proliferation and reactivity (decreased mediator release). Over a four-month period, evaluations at study visits will include quality of life and symptom assessments and measurement of serum tryptase levels. Bone marrow examinations will be performed at the onset and conclusion of the study. The COVID-19 (SARS-CoV-2) pandemic has knowingly distorted our health care and caused devasting consequences in our affected communities. In FY2020 we participated in a report that based on expert medical opinion, assessed the risk and impact of COVID-19 in patients with mastocytosis and mast cell activation syndromes. It was determined that whereas the overall risk to acquire the SARS-CoV-2 virus may not be elevated in mast cell disease, it perhaps may be more significant in patients with mast cell activation-related events affecting the cardiovascular or bronchopulmonary system and chemotherapy or immunosuppressive drugs. Therefore, such treatments should be carefully evaluated on a case-by-case basis during a COVID-19 infection and patients with mast cell disorders should follow the general and local guidelines in the COVID-19 pandemic and advice from their medical provider.