The-Cause-Effect

THE CAUSE EFFECT

The chronic mast cell activation is based on a combination of genetic functional alterations leading to constitutive mast cell activation and secondary factors triggering mast cell activation, e.g. allergens, infections, vaccines, injuries, traumatic incidents and many other. Recent science has revealed that MCAD is an epigenetic and polygenetic driven disease [3, 4, 5], for example by functional alterations in the DNA methylation genes (e.g. TET2, ASXL1, DNMT3, IDH1), transcription-regulating genes (e.g. RUNX1, ETV6, SETBP1), RNA-splicing genes (e.g. SRSF2, SF3B1, U2AF1), the tyrosine kinase KIT (KIT gene), and signaling pathways (e.g. IL13, NRAS, RASGRP4, CBL).

Abnormal chronic mast activation is commonly triggerd by pathologically altered, (autonomically) constitutively activated mast cells in organs and tissues with constitutive release of mast cell mediators and cytokines. It is important to highlight, that abnormal permanently activated mast cells don‘t undergo early apoptosis, but further induce a secondary unregulated activation of the bulk of normal mast cells in the organism resulting in a cascading systemic accumulation of more and more permanently activated mast cells in varying tissues and organs.

In some cases, the number of mast cells is not increased, however, the mast cells are chronically activated, in other cases also the number of mast cells is increased and sometimes continuously increasing driven by decreased natural apoptosis (due to the chronic activation state) and / or pathological driven increased proliferation.

The resulting permanent mast cell activation in combination with the widespread distribution of mast cells and the heterogeneity of excessive mediator release leads to widespread individual symptoms that can occur in any organs, tissues, systems. The clinical presentation is very diverse and can be devastating including, for example, constitutional, dermatologic, gastrointestinal, neurologic, pulmonary, cardiovascular, musculoskeletal and immunologic symptoms (see description of clinical symptoms in MCAD).

In summary, a combination of a primary genetic disposition and potential amplifying triggers, such as viral or bacterial infections, parasites, injuries, exposure to toxins, intense stress or microbiome changes can lead to chronic abnormal mast cell activation (and potentially mast cell accumulation) and the manifestation of several chronic illnesses, such as IBS, fibromyalgia, chronic fatigue syndrome, allergies, asthma, chronic lyme disease, rheumatic diseases, neuro-inflammatory diseases and more.

Often after the trigger has been eliminated (for example lyme disease), the chronic mast cell activation and the chronic illness prevails, mostly because the cascading mast cell activation has become permanent together with the natural mast cell apoptosis being disrupted.

Scientific Sources
  1. Lawrence B Afrin, Gerhard J. Molderings, A concise, practical guide to diagnostic assessment for mast cell activation disease, World J Hematol 2014 February 6; 3(1): 1-17
  2. Gerhard J. Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin, Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options, Molderings et al. Journal of Hematology & Oncology 2011, 4:10
  3. Janine Altmüller, Britta Haenisch, Amit Kawalia, Markus Menzen, Markus M. Nöthen, Heide Fier, Gerhard J. Molderings, Mutational profiling in the peripheral blood leukocytes of patients with systemic mast cell activation syndrome using next-generation sequencing, Immunogenetics (2017) 69:359–369
  4. Britta Haenisch, Holger Fröhlich, Stefan Herms, Gerhard J. Molderings, Evidence for contribution of epigenetic mechanisms in the pathogenesis of systemic mast cell activation disease, Immunogenetics (2014) 66:287–297
  5. Gerhard J. Molderings, Transgenerational transmission of systemic mast cell activation disease – genetic and epigenetic features, Translational Research 2016;174:86–97