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

National Institute Of Allergy And Infectious Diseases

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Abstract

Patients with non-aggressive indolent systemic mastocytosis (ISM) are not in general 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 he 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 2019, we initiated a clinical trial of adults with ISM that 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). In FY2023, the clinical trial was complete, and the patients were unblinded. The safety profile was favorable, we are now in the process of analyzing the data in terms of quality of life and other biomarkers of mast cell disease. In FY2023 participants with mast cell diseases contributed to a large-scale whole exome analysis utilizing a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in of 1505 individuals from 1000 families evaluated at the NIH clinical center with suspected or known inborn errors of metabolism. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale. Serum tryptase is a biomarker used to aid in the identification systemic mastocytosis, where basal serum tryptase (BST) levels >20 ng/mL are a minor criterion for diagnosis. Elevation in levels of tryptase may also be the result of increased germline TPSAB1 copy number resulting in the genetic trait hereditary -tryptasemia (HT). In FY2023 modeling BST levels based on TPSAB1 replication number, new individualized clinical reference values were generated for the upper limit of normal. The clinical utility of tryptase genotyping, could modify the lower limit cut off for tryptase as a criterion for diagnosis of indolent systemic mastocytosis and exclude others with high elevations from diagnosis if this was a result of TPSAB1 replications alone. Mas-related G proteincoupled receptor X2 (MRGPRX2) has been described to play a significant role in stimulation of MCs by various drugs, insect venom, and infections. Unregulated activation of MRGPRX2 may contribute to the pathogenesis of MC-related diseases. However, it is still not completely clear if and how MRGPRX2 is involved in mastocytosis. In FY2023, Utilizing data from patients with mastocytosis our data show that serum levels of MRGPRX2 are not significantly elevated in SM and do not correlate with established biomarkers in mastocytosis. Thus, the significance of MRGPRX2 for mastocytosis is still not completely understood and functional studies in preclinical models are needed to further clarify its specific role. Building on a previous study we determined in FY2023 that not only are specific biomarkers of GI permeability elevated in mastocytosis but also at baseline in patient diagnosed with idiopathic anaphylaxis (IA). Serum concentrations of zonulin, intestinal fatty acid binding protein (I-FABP), and soluble CD14 (sCD14) measured in 54 patients with IA were compared with concentrations in healthy controls (HCs); and correlated with clinical and laboratory parameters. The I-FABP and sCD14 are elevated in the serum of patients with IA. We found both an overlap and a divergence in the MTM profiles associated with IA versus mastocytosis, Elevations in both I-FABP and sCD14 are thus observed in both conditions. However, the MTM profile of IA diverges from that of mastocytosis, with a lack of zonulin elevation in those with IA. One conclusion appears to be that various mast cell disorders carry specific profiles of MTMs. Elevations in these biomarkers of IA provides evidence that increased GI permeability, as is observed in other allergic conditions such as food allergy, is a common finding in those with IA and offers possible insight into the pathogenesis of this disease. Autoantibodies to type-I interferons (IFN-I) have been identified in association with a variety of inflammatory and autoimmune diseases. IFN-Is have demonstrated inhibitory effects on mast cell proliferation and degranulation. Systemic mastocytosis (SM) is a disease characterized by increased mast cell burden and mediator release. In FY2023 we sought to determine whether autoantibodies to IFN-I are present in the serum of patients with SM and if so, whether they correlate with characteristics of disease. We analyzed sera from 89 patients with SM for concentrations of autoantibodies to IFN-I using a multiplex particle-based assay and signal-neutralization capacity using a STAT1 activity assay and compared these measurements to those of a database of 1284 healthy controls. In our cohort 13 produced autoantibodies to IFN-, 3 to IFN-, and 0 for IFN-. Of these, no patient serum demonstrated signal-neutralization nor was the concentration of autoantibodies nor signaling inhibition measurements correlated with tryptase concentrations or D816V allele burden. Overall, we did not find a correlation between autoantibody production and signaling inhibition which is consistent with the conclusion that autoantibodies to IFN-I do not play a significant role in the pathogenesis or severity of systemic mastocytosis. Patients with mastocytosis report less viral and bacterial infections than their family members and tolerated COVID infections without serious sequela. We performed a retrospective query of 2274 laboratory values of 320 patients for low immunoglobulin levels. We reported low prevalence of abnormal values and when present, were not associated with recurrent or chronic infections, resolved without intervention, and was not associated with other factors of CVID such as autoimmune diseases. The mastocytosis consensus documents are important for diagnosis and management of clonal and non-clonal mast cell disorders. Most of the centers, worldwide, consist of adult patients. We have one of the largest pediatric populations in the world and information from our pediatric cohort is valuable for the long-term follow-up (40 years) and prognostic indicators for disease management particularly for cutaneous disease and allergy profiles that are different from patients with adult-onset disease.