Leptin: the obesity hormone released by mast cells

Leptin is a hormone that is primarily secreted by adipose tissue, but is also produced and released by mast cells. In turn, mast cells also have leptin receptors. Leptin is primarily known for its action of part of the hypothalamus to inhibit the hunger response. Importantly, the body responds forcefully to leptin levels by engaging both biological and behavioral mechanisms to conserve energy. It is seen by researchers as less of a “hunger satiety” signal and more of a “starvation” signal.

Patients with obesity often have higher circulating levels of leptin than those without obesity. This occurs because leptin is secreted by adipose tissue, which obese patients have in higher amounts due to their higher percentage of body fat. These people seem to be resistant to the chemical action of leptin, possibly through a change in activity of leptin receptors in the hypothalamus. Some studies suggest that in obese patients, less leptin leaves the blood stream and crosses into the brain.

Leptin is now known to have a variety of other effects on the body, including modulating the immune system. It activates inflammatory cells, promotes T cell responses and mediates production of TNF, IL-2 and IL-6. In many inflammation models, cells express more leptin receptors than usual. In diet induced obese mice, mast cells have been observed to store and secrete TNF. In immune mediated diseases like autoimmune diseases, circulating levels of leptin are increased, and this in turn translates to higher levels of inflammatory cytokines.

Interestingly, leptin suppresses signals from the IgE receptor to make mediators. In leptin receptor deficiency models, magnified IgE anaphylaxis was observed. Leptin also seems to control the number of mast cells through some unclear mechanism. In leptin deficient mice, mast cell density is significantly higher in abdominal lymph nodes and fat deposits.

Leptin influences the release of many other molecules, including ghrelin. Ghrelin is the “hunger hormone,” released in the stomach and possibly elsewhere. It stimulates the hunger response in the body and also acts on the hypothalamus. The relationship between leptin and ghrelin is very complex and still being elucidated. However, it is thought that high levels of circulating leptin suppress secretion of ghrelin. This is especially of interest in inflammatory conditions as ghrelin suppresses production of a number of inflammatory markers, including TNF, IL-8, MCP-1, IL-1b, IL-6, CRP and others. This effect is so pronounced that it is being investigated as a treatment option for many conditions. Ghrelin has also been observed in one study in induce mast cell activation through a receptor independent pathway.



Baatar D, Patel K, Taub DD. The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011 Jun 20; 340(1): 44-58.

Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides. 2010 Nov;31(11):2109-13

Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan; 8(1): 21-34.

Taildeman J, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol. 2009 Jun; 131(6): 703-11.

Patricia Fernández-Riejos, Souad Najib, Jose Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes, and Víctor Sánchez-Margalet. Role of Leptin in the Activation of Immune Cells. Mediators of Inflammation, Volume 2010 (2010), Article ID 568343, 8 pages.

Altintas et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids in Health and Disease 2012, 11:21

Lesser known mast cell mediators (Part 6)

Granulocyte macrophage colony-stimulating factor (GM-CSF) is a growth factor for white blood cells. It induces stem cells to make granulocytes (neutrophils, eosinophils, basophils, mast cells) and monocytes. The molecule activates STAT5, a protein that initiates gene expression. It is found at high levels in the joints of rheumatoid arthritis patients.

Fibroblast growth factor 2 (FGF2, also known as basic fibroblast growth factor, bFGF) is involved in angiogenesis, proliferation and wound healing. FGF2 binds heparin. It is thought that during wound healing, heparin degrading enzymes activate FGF2, driving the development of new blood vessels.

Neutrophin 3 is a nerve growth factor that regulates the survival and growth of neurons and synapses.

Nerve growth factor (NGF) regulates neuron survival and axonal growth. In its absence, neurons undergo apoptosis. It has been found to induce ovulation in some mammals. NGF is often elevated in inflammatory conditions as it suppresses inflammation. Children with autism sometimes have high levels of NGF in their cerebral spinal fluid. Low levels of NGF are seen in metabolic syndromes, type 2 diabetes and obesity.

Platelet derived growth factor (PDGF) is a growth factor that participates in blood vessel growth. It is a required factor for the division of fibroblasts, connective tissue cells important in wound healing.

Nitric oxide (NO, also endothelium derived relaxing factor, EDRF) is a cell signaling molecule and potent vasodilator. It is a precursor to nitroglycerin. It is produced by several nitric oxide synthase enzymes. NO maintains blood vessels by preventing vascular muscle contraction and aggregation of cells on the endothelium. NO has a well described variety of activities.

Leukotriene B4 is a cell signaling molecule. It facilitates the transition of white blood cells from the endothelium into tissues. It also forms reactive oxygen species.

Leukotriene C4 is one of the components of the slow reacting substance of anaphylaxis (SRS-A). It is secreted during anaphylaxis and contributes to the inflammatory processes. It causes prolonged, slow contraction of smooth muscle and bronchoconstriction. It is 5000x more potent than histamine in this capacity but acts more slowly and lasts longer.

Platelet activating factor (PAF) mediates a variety of immune activities, including various inflammatory processes and anaphylaxis. It is also a vasodilator and bronchoconstrictor. At high concentrations, PAF can cause severe airway inflammation to such degree as to be life threatening.


All mediators listed here are produced by mast cells upon stimulation and are not stored in granules.

Lesser known mast cell mediators (Part 5)

Interleukin-16 (IL-16) is a cytokine that attracts several types of cells that express the CD-4 receptor on their surfaces, including monocytes, eosinophils and dendritic cells. It acts by binding to the CD-4 receptor. IL-16 was previously known as lymphocyte chemoattractant factor (LCF).

Interleukin-18 (IL-18) is a cytokine with several defined functions. Working with IL-12, it triggers a cell-mediated immune response after infection. It causes natural killer (NK) cells and some types of T cells to release interferon-γ, and for this reason is sometimes called interferon-γ inducing factor. This interferon activates macrophages and other cell types. IL-18 and IL-12 can inhibit production of IgE and IgG1 when mediated by IL-4. IL-18 causes severe inflammatory reactions and has been implicated in various diseases. In adenomyosis patients, more IL-18 receptors are found in the endometrium. It is one of the molecules responsible for Hashimoto’s thyroiditis. It also increases production of amyloid-beta in neuron cells, which is associated with Alzheimer’s disease.

Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine that stimulates an acute immune response by binding to CD74. MIF level is associated with severity of rheumatoid arthritis. Glucocorticoids (steroids) stimulate white cells to release MIF.

Transforming growth factor beta (TGF-β) is secreted by mast cells and participates in the pathology of many diseases, including bronchial asthma, heart disease, diabetes, lung fibrosis, telangiectasia, Marfan syndrome, vascular Ehlers Danlos syndrome, Parkinson’s disease, chronic kidney disease, multiple sclerosis, AIDS, among others. (Note: I suspect that one of the links between mast cell disease and EDS is this molecule. Its signaling affects differentiation and regulation of vascular tissues and connective tissues. In a mouse model of Marfan syndrome, a connective tissue disorder, the characteristic Marfan features can be alleviated by administering a TGF- β blocker.)

Tumor necrosis factor (TNF-α) is part of a family of cytokines that cause apoptosis, cell death. It is an adipokine that participates in both general inflammation and the acute phase inflammatory response. It is produced by mast cells as well as many other cell types, including neutrophils, eosinophils and neurons, among others. TNF regulates immune cells, causes fever, weight loss, fatigue and tumor destruction. This molecule is dysregulated in several diseases, including several cancers, severe depression, IBD, Alzheimer’s and rheumatoid arthritis.

Macrophage inflammatory protein 1α (MIP-1α, chemokine ligand 3, CCL3) causes acute inflammation and recruitment of other white blood cells.

Stem cell factor (SCF) is a cytokine that binds to the CD117, better known as CKIT, receptor on mast cells. SCF regulates the mast cell life cycle, telling them when to make new cells and when to die. In CKIT+ mast cell patients, the CKIT receptor is misshapen so the cell mistakenly thinks SCF is bound to the receptor all the time. It also induces histamine release.


All mediators listed here are produced by mast cells upon stimulation and are not stored in granules.

Corticotropin releasing hormone, cortisol and mast cells

The term “HPA axis” refers collectively to the signals and feedback loops that regulate the activities of three glands: the hypothalamus, the pituitary gland, and the adrenal glands. The HPA axis is a critical component of the body’s stress response and also participates in digestion, immune modulation, emotions, sexuality and energy metabolism.

The hypothalamus is part of the brain. It performs several integral functions. It regulates metabolism, makes and releases neurohormones, and controls body temperature, hunger, thirst, circadian rhythm, sleep and energy level. It is also known to affect parenting and attachment behaviors. It effectively turns nervous system signals into endocrine signals by acting on the pituitary gland.

The pituitary gland is a small gland at the bottom of the pituitary. The anterior portion of the pituitary is part of the HPA axis. It makes and releases several hormones, including human growth hormone, thyroid stimulating hormone, adrenocorticotropic hormone (ACTH), prolactin, luteinizing hormone and follicle stimulating hormone. All of these hormones are released when hormones released by the hypothalamus act on the pituitary.

The adrenal glands are located on top of the kidneys. They primarily synthesize and release corticosteroids like cortisol and catecholamines like epinephrine and norepinephrine in response to action by the pituitary.   It also produces androgens and aldosterone.

The hypothalamus synthesizes vasopressin and corticotropin releasing hormone (CRH).   Both of those hormones stimulate the release of ACTH by the pituitary gland. ACTH stimulates the adrenals to make glucocorticoids (mostly cortisol). The cortisol then tells the hypothalamus and pituitary to suppress CRH and ACTH production. This is called a negative feedback loop.

Cortisol acts on the adrenals to make epinephrine and norepinephrine. Epi and norepi then tell the pituitary to make more ACTH, which stimulates the production of cortisol.

When you take steroids regularly, it suppresses ACTH so that your body stops making its own steroids. This is why weaning steroids is very important. By weaning, your body should gradually start making its own cortisol to replace the deficit when you lower your steroid dose. However, this doesn’t always work. People who do not make enough cortisol on their own are called adrenally insufficient and are steroid dependent. People with this condition can suffer “Addisonian crises” if their steroid levels drop dangerously low. This is a medical emergency.

CRH is released by the hypothalamus in response to stress. This drives the production of cortisol to help manage stressful situations of either a physical or emotional nature. Mast cell attacks and anaphylaxis are examples of physically stressful situations that stimulate release of CRH.

CRH binds to CRHR-1 and CHRH-2 receptors on various cells, including mast cells. When it binds to mast cells, it stimulates the release of VEGF, but not histamine, tryptase or IL-8. This type of release is called selective release as it does not involve the release of preformed granules (degranulation.) Additionally, CRH is also released by mast cells. This can act on the mast cells or other cells with CRHR receptors, like those in the pituitary. The exact purpose of mast cells releasing CRH is not clear.



Theoharis C. Theoharides, et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.


Lesser known mast cell mediators (Part 4)

Interleukin-1a (IL-1a) is largely responsible for inflammation, fever and sepsis. It activates TNF-a and the work very closely together. Their cofunctions include PGE2 synthesis, nitric oxide production, insulin resistance and IL-8 and chemokine production.

Interleukin-1b (IL-1b) has been implicated in several autoinflammatory syndromes. It is also important in cell proliferation, differentiation and apoptosis. Its induction of COX2 cytokine in the nervous system contributes to inflammatory pain hypersensitivity.

Interleukin-2 (IL-2) is crucial in prevention of autoimmune disease by regulating T cell differentiation. It is also thought to be involved in itchiness and psoriasis. IL-2 is used in the treatment of cancers.

Interleukin 3 (IL-3) drives the differentiation of multipotent hematopoietic stem cells into myeloid progenitor cells. If IL-7 is also present, they can work synergistically to trigger differentiation into lymphoid progenitor cells. IL-3 induces proliferation of all myeloid cells (including mast cells) along with other cytokines like IL-6. It supports growth and differentiation of T cells from bone marrow when an immune response is triggered.

Interleukin 4 (IL-4) changes naïve T cells to T helper cells, which secrete chemicals to drive actions of other immune cells. T helper cells then secrete additional IL-4 to perpetuate the cycle. IL-4 participates in the airway inflammation seen in allergic asthma.

Interleukin 5 (IL-5) encourages growth of B cells and antibody secretion as well as eosinophil activation. It is heavily involved in allergic diseases, particularly those in which eosinophils are notably increased. Mepolizumab is a monoclonal antibody against IL-5 that can reduce excessive eosinophils.

Interleukin 6 (IL-6) mediates fever and the acute phase inflammatory response. It is secreted to stimulate bone resorption and inhibitors of IL-6 are used to treat osteoporosis (including estrogen.) It inhibits TNF-a and IL-1. Unusually, it also has anti-inflammatory behaviors, particularly during exercise in the muscle.

Interleukin 9 (IL-9) increases cell proliferation and impedes apoptosis, cell death, of hematopoietic cells. It is particularly important in asthma and bronchial hyperresponsiveness.

Interleukin 10 (IL-10) is an anti-inflammatory molecule involved in regulating the JAK-STAT pathway. It counteracts many of the inflammatory effects of mast cells, often by interfering with production of substances like interferons and TNF-a.   Exercise increases levels of this molecule.

Interleukin 13 (IL-13) is critical in initiation of airway disease. It induces matrix metalloproteinases to act. IL-13 can also induce IgE release from B cells. It is effectively a link between allergic inflammatory cells and the non-immune cells they interact with. Excessive , IL-13 causes airway hyperresponsiveness, goblet cell metaplasia and oversecretion of mucus.


Lesser known mast cell mediators (Part 3)

Substance P is a neurotransmitter and modulates neurologic responses. It is found in many sensory nerves as well as the brain and spinal cord. It participates in inflammatory responses and is important in pain perception. It is involved in mood disorders, anxiety, stress, nerve growth, respiration, neurotoxicity, nausea, vomiting and pain perception. Its release from nerve fibers into the skin, muscle and joints is thought to cause neurogenic inflammation.

Urocortin is related to corticotropin releasing factor (CRF.) It strongly suppresses blood pressure and increases coronary blood flow. It is thought to have a role in increasing appetite during times of stress.

VEGF-A (vascular endothelial growth factor A) is a member of the platelet derived growth factor (PDGF)/VEGF family. It is important in nerve biology and is the substance mainly involved in inducing growth of blood vessels. It is heavily involved in diseases that involve blood vessels, like diabetic retinopathy and macular degeneration. It is a vasodilator and increases permeability of the smaller vessels.

VIP (vasoactive intestinal peptide) is a small protein like molecule used by nerve cells for communication. It stimulates heart contraction, vasodilation, lowers blood pressure, and relaxes the smooth muscles of the trachea, stomach and gall bladder. It also inhibits gastric acid secretion and absorption in the intestine.

Mast cell kininogenase removes a portion of a compound to release active bradykinin. This is important in the kinin system.

Phospholipase A2 promotes inflammation by initiating formation of arachidonic acid, the precursor needed to form many inflammatory molecules, including prostaglandins. Excessive levels of phospholipase A2 can lead to increased vascular inflammation, such as a seen in coronary artery disease and acute coronary syndrome. Elevated PLA2 is found in the cerebrospinal fluid of people with Alzheimer’s disease and multiple sclerosis.

Corticotropin releasing hormone (CRH) is a hormone and neurotransmitter. High CRH levels have been associated with Alzheimer’s disease and severe depression. CRH is produced in the hypothalamus and is carried to the pituitary gland, where it stimulates secretion of adrenocorticotropic hormone (ACTH.) ACTH drives synthesis of cortisol and other steroids. Imbalance of these hormones can have dire consequences.

Endothelin is the most potent vasoconstrictor currently described. It raises blood pressure and if uncontrolled, hypertension may result. It is involved in many disease processes, including cardiac hypertrophy, type II diabetes and Hirschsprung disease.

Chondroitin is found largely in connective tissues and is a principal component of cartilage. It is typically bound to other components when released from mast cells and interacts with a variety of molecules.

Hyaluronic acid is widely found in epithelial, neural and connective tissues. It participates in a variety of reactions and sees significant turnover daily. When hyaluronic acid is degraded as part of the turnover, its degradation products can cause inflammatory responses.

Lesser known mast cell mediators (Part 2)

Arylsulfatase A, also called cerebroside sulfatase, breaks down compounds to yield cerebrosides and sulfates. Cerebrosides can be either galactocerebrosides, which are found in all tissues of the nervous system; or glucocerebrosides, which are found in the skin, spleen, red blood cells and, to a lesser extent, tissues of the nervous system.

Arylsulfatase B, which has several other names, breaks down large sugar compounds, especially dermatan sulfate and chondroitin sulfate. Arylsulfatase B is mostly found in the liver, pancreas and kidneys.

Mutations in the gene for either arylsulfatase can lead to a variety of heritable disorders, including mucopolysaccharidosis VI and metachromatic leukodystrophy.

Chymases include mast cell protease 1, mast cell serine proteinase, skeletal muscle protease and so on. They are found almost exclusively in mast cells, but are present in small amounts in the granules of basophils. They have several functions, including generating an inflammatory response to parasites. They convert angiotension I to angiotensin II and therefore impact hypertension and atherosclerosis.

Bradykinin causes dilation of blood vessels, which induces a corresponding drop in blood pressure. It achieves its action by triggering release of prostacyclin, nitric oxide and endothelium derived hyperpolarizing factor. It also causes contraction of non-vascular smooth muscles in the respiratory and GI tracts, and is involved in the way the body senses pain. Bradykinin is important in angioedema.

Angiogenin, also called ribonuclease 5, stimulates the formation of new blood vessels. It drives the degradation of the basement membrane and local matrix so that endothelial cells can move toward the vascular spaces.

Leptin is the hormone that regulates hunger. It is mostly produced by fat cells, but is released by mast cells as well. When a specific amount of fat is stored in the body, leptin is secreted and tells the brain that it is full. It opposes the action of ghrelin, the hormone that tells your body it is hungry.

Renin, also called angiotensinogenase, is a critical component of the renin-angiotension system (RAS) that controls the volume of fluids not in cells, including blood plasma, lymph and interstitial fluid. It regulates the body’s mean arterial blood pressure. It converts angiotensinogen to angiotensin I.

Somatostatin, also growth hormone inhibiting hormone (GHIH), regulates the endocrine system, transmission of neurologic signals and cell growth by acting on somatostatin receptors and inhibiting the release of various secondary hormones. It inhibits secretion of glucagon and insulin. It is secreted throughout the GI system and decreases stomach acid production by downregulating the release of gastrin, secretin and histamine.

Lesser known mast cell mediators (Part 1)

I have posted at length about the roles of histamine and serotonin. Here are some less well known mast cell mediators. I will be doing in depth posts on the more relevant substances in the near future.

Monocyte chemotactic protein 1 (MCP-1), also known as chemokine ligand 2 (CCL2), draws other white blood cells, including memory T cells, monocytes and dendritic cells, to the site of injury or infection. It has important functions in neuroinflammation as seen in experimental autoimmune encephalitis, traumatic brain injuries, epilepsy and Alzheimer’s disease; and in diseases with pathologic infiltration of monocytes, like rheumatoid arthritis.

Chemokine ligand 3 (CCP7) recruits monocytes and regulates macrophage activity. It is known to interact with MMP2.

MMP2 (matrix metalloproteinase 2) is involved in tissue remodeling, reproduction and fetal development. It degrades type IV collagen. It has regulatory effects on the menstrual cycle and has been tied to growth of new blood vessels.

Interleukin 8 (IL-8), also known as neutrophil chemotactic factor (NCF), draws other white cells, mostly neutrophils, to a site of infection. It can activate multiple cells types, including mast cells, and promotes degranulation. It has been linked to bronchiolitis, psoriasis and inflammation.

MCP-4 (CCL13) attracts T lymphocytes, eosinophils, monocytes and basophils to an area of inflammation. Improper regulation can exacerbate asthma symptoms. Mast cells can release MCP-1 when stimulated by TNF-a and IL-1.

CCL5 (RANTES) attracts T cells, eosinophils and basophils. When IL-2 and interferon-γ are present, CCL5 activates natural killer cells and causes proliferation of the same. It is also important in bone metabolism.

CCL11 (eotaxin-1) specifically recruits eosinophils and is heavily involved in allergic inflammatory responses.

CPA3 (carboxypeptidase A3) digests proteins. It is released complexed with heparin proteoglycan along with chymase and tryptase.

Both interferon α (IFN- α) and interferon β (IFN-β) are made in response to viral infections. Their activities are regulated by IFN- γ. IFN- γ also draws white cells to the site of inflammation. Failure to properly regulate interferon levels can cause autoimmune disease. Interferons are so called because of their ability to “interfere” with viral infection. They are responsible for “flu type symptoms,” such as fever, muscle aches and lethargy.

All mediators listed here are produced by mast cells and stored in granules until degranulation.


Mast cells, eosinophils and the perfect storm of inflammation

Mast cells and eosinophils have a lot of common functions.  In allergic and inflammatory states, these cells come into physical contact with each other, as well as communicate using chemical signals called cytokines and chemokines.  Mast cells and eosinophils are often found together in affected tissues in disorders like allergic rhinitis, atopic dermatitis, and asthma.  Mast cells initiate the allergic inflammatory response once activated.  This signals for eosinophils to come to the tissue.  Increased numbers of mast cells and eosinophils are found in diseases like eosinophilic esophagitis, chronic gastritis, GI neoplasms, parasitic infections and IBD.  Both mast cells and eosinophils respond to eotaxins, molecules that draw eosinophils to the inflamed area.  So one signal causes both cell types to go to the affected tissue. 

Mast cells and eosinophils interact a lot by using chemicals.  Mast cell released heparin stabilizes eotaxins.  Mast cells produce IL-3 and IL-5, which lengthen the lives of eosinophils in tissue.  Mast cell mediator chymase suppresses eosinophil death and causes eosinophils to release several chemicals.   Tryptase can limit eosinophil activation.  In turn, eosinophils produce stem cell factor (SCF), which attract mast cells and protects them from cell death.  Both cell types express some common receptors, like Siglec-8, which induces eosinophil death and inhibits IgE-mediated mast cell activation.  Interactions between these cells increase activation and proliferation. 
Patients with SM may have another blood disorder, including CEL or hypereosinophilic syndrome (HES.)  SM-HES and SM-CEL with the D816V CKIT mutation has been found, and the mutation is present in both the mast cells and the eosinophils.  However, it is likely that the FIP1L1-PDGFRA fusion gene (an aberrant tyrosine kinase) is the cause of the coexistent eosinophilic and abnormal mast cell proliferations.  The FIP1L1-PDGFRA fusion has been found in several cell types, including neutrophils, monocytes and mast cells.  This finding is consistent with a mutational origin in a blood stem cell that makes mutated mast cells and overproduces eosinophils.  When these cells are not neoplastic, they are derived from separate stem cell lineages.
Shortly after the discovery of this fusion gene, there was significant debate over whether FIP1L1-PDGFRA+ disease was an eosinophilic neoplasm with increased mast cells or systemic mastocytosis with eosinophilia.  Patients with FIP1L1-PDGFRA+ eosinophilia have a lot of symptoms in common with SM: swollen spleen, hypercellular bone marrow, high numbers of abnormally shaped bone marrow cells, marrow fibrosis and elevated serum tryptase.  However, these bone marrows show less dense clusters of mast cells.  In some cases, mast cells were spindled and expressed CD2 or CD25.  Still, the WHO considers it a distinct entity and not a subset of SM.
In CKIT+ patients, GI symptoms, UP, thrombocytosis, serum tryptase value, and dense mast cell clusters aggregates in bone marrow are significantly increased.  Cardiac and pulmonary symptoms, eosinophilia, eosinophil to tryptase ratio, elevated serum B12 and male sex were higher in FIP1L1-PDGFRA+ group.
Eosinophilia in SM patients has no effect on prognosis.  Eosinophilia in MDS patients predicted significantly reduced survival.  In T lymphoblastic leukemia, eosinophilia was unfavorable for survival.  Density and activation of tissue eosinophils is related to disease progression in several neoplasms.  Mast cells and eosinophils are found in increased numbers in neoplastic disorders like Hodgkin lymphoma. 
Presence of FIP1L1-PGDFRA indicates treatment with imatinib (Gleevec), regardless of organ dysfunction.  It can show remission within 4 weeks, even at low doses.  Some patients with CKIT+ SM with HES or CEL have rapid and complete normalization of severe eosinophilia with midostaurin treatment. 

Gotlib, Jason, Akin, Cem.  2012.  Mast cells and eosinophils in mastocytosis, chronic eosinophilic leukemia, and non-clonal disorders.  Semin Hematol 49:128-137.