He shoots, He scores! 2!
Mast Cell Responses to Viruses and Pathogen Products
by ļæ¼Jean S. Marshall 1,2,*ļæ¼,ļæ¼Liliana Portales-Cervantes 1,2 andļæ¼Edwin Leong 2
"Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings.
However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts.
There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge.
However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses.
In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products."
How mast cells set immune defense on the right track
"Thus, mast cells determine very early which direction the immune defence is taking.
Important for this decision making are receptors on the surface of all immune cells: So-called āToll-like receptorsā activate mast cells as soon as a pathogen enters the body.
When the receptors are triggered, mast cells produce a number of messenger substances that attract cells or keep them at distance, activate or inhibit them and thus regulate an optimised immune response."
https://www.pnas.org/content/107/19/8748
Journal Paper- Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria
Want to know what grinds your doctors gears? EHR software. Billions pissed away, mandated by federal and state bureaucrats, using Window 3.1 level user interfaces.
Mine hired a āscribeā out his own pocket to let him.
deal with the patient, not spend 75 per cent of the contact time typing and clicking crap into a tiny little laptop with his big fat doctor fingersā¦
Interesting perspective from another disease direction.
Anti-IgE Treatment In Severe Asthma
Thomas B. Casale, MD
Professor of Medicine Chief, Allergy/Immunology
Creighton University Omaha, NE
http://www.worldallergy.org/UserFiles/file/Anit-IgE%2520treatment-Casale.pdf
Allergic Response Pathway
Atopy or Allergic disease is a complex familial disorder with multiple manifestations, including allergic asthma, rhinitis, conjunctivitis, and dermatitis.
Allergens are derived from different sources such as cockroaches, ragweed pollens, and house dust mites.
The primary immune cell lineages involved in the initiation and progression of allergic inflammation include DCs (Dendritic Cells), mast cells, basophils, eosinophils, and Th2 (Type-2 Helper T) cells. The responses of these principal players in allergic reactions are influenced by the local environments in which they reside.
When susceptible or atopic individuals are initially exposed or sensitized to allergens, Antigen-presenting cells capture, process, and present allergen as an allergen-derived peptide fragment in the contest of specific MHC II (HLA II) molecules this induces allergen-specific acquired immune responses, which are characterized by CD4+ T cells that produce a Th2 profile of cytokines for example, IL-4(Interleukin-4), IL-5, IL-9 and IL-13, IL-10 and the presence of allergen-specific IgE.
Subsequent challenge with allergen causes the rapid activation of mast cells through allergen and IgE crosslinking, and the release of mediators such as histamine and leukotrienes causes increases in vascular permeability, smooth-muscle contraction and mucus secretion.
Late-phase allergic responses are characterized by the additional recruitment and activation of eosinophils and Th2 cells at the site of allergen challenge (Ref.1, 2 & 3).
Mast-cell activation by IgE crosslinking with allergen requires access of allergen into the tissue and input from the adaptive immune system to be effective.
Mast-cell activation requires not only the synthesis of specific IgE by B cells (regulated by interleukin-4 (IL-4) and IL-13 derived from Th2 cells and basophils), but also mast-cell priming by IL-4 for enhanced mediator release. The subsequent release of mast-cell mediators such as histamine, LTC4 (Leukotriene C4) and PGD2 (Prostaglandin D2) leads to an early reaction, consisting classically of a āwheal and flareā reaction of the skin or the mucosa. These mediators affect the mucosa, the blood vessels and sensory nerves (pain).
Other mast-cell mediators, such as IL-3, IL-5, IL-8,IL-33, TNF (Tumor-Necrosis Factor),NT3 (Neurotrophin 3) and proteases contribute to the initiation of a facultative latephase reaction by recruiting and activating eosinophils, neutrophils and Th2 cells, and by interaction with tissue cells such as nerve cells, smooth-muscle cells, endothelial cells and the epithelium.
Ongoing dysregulation of such cell types not only causes symptoms of allergy, but also organ dysfunction, including loss of barrier function and, subsequently, increased bacterial translocation. This enables non-specific triggers to access mast cells, dendritic cells and other cells.
Triggers such as bacterial products, or immunoglobulin such as monomeric IgE and light chains might perpetuate the inflammatory process, even in the absence of allergen (Ref.4 & 5). Eotaxin is mainly produced by epithelial cells, but in some conditions it is also produced by other cell types, such as mast cells and alveolar macrophages.
Signals that trigger the production of eotaxin by epithelial cells come from lymphocytes, but possibly also mast cells and dendritic cells. Eotaxin recruits Th2 cells that in turn produce IL-4 and IL-5 and amplify all the effects on epithelial cells and mast cells, resulting in the production of more eotaxin. Significant levels of eotaxin result in eosinophil recruitment and degranulation, further Th2 recruitment, basophil degranulation and mast cell migration and differentiation.
Antigen-activated basophils secrete soluble factors that stimulate tissue-resident nonhaematopoietic cells, such as fibroblasts, to produce various chemokines that in turn recruit inflammatory cells, including eosinophils and neutrophils, to the skin lesions. These results suggested that basophils have an important and nonredundant role in chronic allergic inflammation as initiators rather than effectors of the inflammatory response (Ref.6, 7 & 8).
Once attracted to the site of inflammation the eosinophil becomes activated and, as a result of this, secretes several tissue-toxic mediators. These are either basic or granule-stored proteins, ECP (Eosinophil Cationic Protein), EPO (Eosinophil Peroxidase), eosinophil protein/eosinophil-derived neurotoxin, and MBP (Major Basic Protein) or reactive oxygenfree radicals.
The eosinophil also produces a wide array of different cytokines, leukotrienes, chemokines, and lipid mediators, granulocyte/macrophage colony-stimulating factor, and is therefore, in addition to being an effector cell, thought to play an immunoregulatory role in inflammatory processes as well as taking part in tissue remodeling.
EDN (Eosinophil-derived neurotoxin), a member of the RNase A superfamily, is a mediator produced by human eosinophils and placental epithelial cells. In addition to its ribonuclease activity EDN reduces the infectivity of respiratory syncytial virus for target cells in vitro and is also responsible in part for the anti HIV-1 activity found in the supernatants of mixed lymphocyte cultures by identifying EDN (Ref.9, 10 & 11). TSLP emerged as a central player in the development of allergic symptoms, especially in the airways, and is a prime regulatory cytokine at the interface of virus- or antigen-exposed epithelial cells and DCs.
DCs activated by epithelium-derived TSLP can promote naĆÆve CD4+ T cells to adopt a Th2 phenotype, which in turn recruit eosinophilic and basophilic granulocytes as well as mast cells into the airway mucosa.
These different cells secrete inflammatory cytokines and chemokines operative in inducing an allergic inflammation and atopic asthma. TSLP is, thus, involved in the control of both an innate and an adaptive immune response (Ref.12).
References:
1.Regulation of allergic inflammation and eosinophil recruitment in mice lacking the transcription factor NFAT1: role of interleukin-4 (IL-4) and IL-5.
Viola JP, Kiani A, Bozza PT, Rao A.
Blood. 1998 Apr 1;91(7):2223-30.
2.The influence of TSLP on the allergic response.
Comeau MR, Ziegler SF.
Mucosal Immunol. 2010 Mar;3(2):138-47. doi: 10.1038/mi.2009.134.
3.Identification of antigenic epitopes on human allergens: studies with HLA transgenic mice.
Chapoval SP, David CS.
Environ Health Perspect. 2003 Feb;111(2):245-50.
4.Role of mast cells in allergic and non-allergic immune responses: comparison of human and murine data.
Bischoff SC.
Nat Rev Immunol. 2007 Feb;7(2):93-104.
5.Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma.
Hawrylowicz CM, OāGarra A.
Nat Rev Immunol. 2005 Apr;5(4):271-83.
6.Eotaxin: from an eosinophilic chemokine to a major regulator of allergic reactions.
Gutierrez-Ramos JC, Lloyd C, Gonzalo JA.
Immunol Today. 1999 Nov;20(11):500-4.
7.Improvement of cellulase activity using error-prone rolling circle amplification and site-directed mutagenesis.
Vu VH, Kim K.
J Microbiol Biotechnol. 2012 May;22(5):607-13.
8.Th2 cell-selective enhancement of human IL13 transcription by IL13-1112C>T, a polymorphism associated with allergic inflammation.
Cameron L, Webster RB, Strempel JM, Kiesler P, Kabesch M, Ramachandran H, Yu L, Stern DA, Graves PE, Lohman IC, Wright AL, Halonen M, Klimecki WT, Vercelli D.
J Immunol. 2006 Dec 15;177(12):8633-42.
9.Eosinophil cationic protein (ECP) is processed during secretion.
Woschnagg C, Rubin J, Venge P.
J Immunol. 2009 Sep 15;183(6):3949-54. doi: 10.4049/jimmunol.0900509.
10.Eosinophil-derived neurotoxin acts as an alarmin to activate the TLR2-MyD88 signal pathway in dendritic cells and enhances Th2 immune responses.
Yang D, Chen Q, Su SB, Zhang P, Kurosaka K, Caspi RR, Michalek SM, Rosenberg HF, Zhang N, Oppenheim JJ.
J Exp Med. 2008 Jan 21;205(1):79-90. doi: 10.1084/jem.20062027.
11.Inhibitory effects of ketotifen on eotaxin-dependent activation of eosinophils: consequences for allergic eye diseases.
Woerly G, Loiseau S, Loyens M, Schoch C, Capron M.
Allergy. 2003 May;58(5):397-406.
12.Signal transduction around thymic stromal lymphopoietin (TSLP) in atopic asthma.
Sebastian K, Borowski A, Kuepper M, Friedrich K.
Cell Commun Signal. 2008 Aug 25;6:5. doi: 10.1186/1478-811X-6-5.
The normal gastrointestinal (GI) mucosa is equipped with mast cells that account for 2ā3% of lamina propria cells under normal conditions.
Mast cells are generally associated with allergic disease, and indeed, food allergy that manifests in the GI tract is usually mast cell dependent. On the other hand, mast cells have a number of physiological functions in the GI tract, namely regulatory functions such as control of blood flow and coagulation, smooth muscle contraction and peristalsis, and secretion of acid, electrolytes, and mucus by epithelial cells.
One of the most intriguing functions of intestinal mast cells is their role in host defense against microbes like bacteria, viruses, or parasites. Mast cells recognize microbes by antibodydependent mechanisms and through pattern-recognition receptors. They direct the subsequent immune response by attracting both granulocytes and lymphocytes to the site of challenge via paracrine cytokine release.
Moreover, mast cells initiate, by releasing proinflammatory mediators, innate defense mechanisms such as enhanced epithelial secretion, peristalsis, and alarm programs of the enteric nervous system.
This initiation can occur in response to a primary contact to the microbe or other danger signals, but becomes much more effective if the triggering antigen reappears and antibodies of the IgE or IgG type have been generated in the meantime by the specific immune system.
Thus, mast cells operate at the interface between innate and adaptive immune responses to enhance the defense against pathogens and, most likely, the commensal flora.
In this respect, it is important to note that mast cells are directly involved in controlling the function of the intestinal barrier that turned out to be a crucial site for the development of infectious and immune-mediated diseases.
Hence, intestinal mast cells perform regulatory functions to maintain tissue homeostasis, they are involved in host defense mechanisms against pathogens, and they can induce allergy once they are sensitized against foreign antigens.
The broad spectrum of functions makes mast cells a fascinating target for future pharmacological or nutritional interventions."
Recent advances in the understanding and therapeutic management of mastocytosis
Julien Rossigno, et.al.
"A somatic KIT mutation is present in around 80% of cases of childhood-onset mastocytosis.
However, in contrast to adult cases, only 42% of the children present a mutation in codon 816 (exon 17); 44% of cases have a mutation outside exon 17 (mostly in the fifth Ig loop of the KIT extracellular domain, encoded by exons 8 and 9).
Although all of these KIT mutations cause the constitutive activation of kinase activity, they cannot fully explain the clonal expansion of MCs and the heterogeneous symptoms observed in different types of mastocytosis. Patients harboring the same mutation can present with very different clinical pictures. In childhood-onset mastocytosis, complete spontaneous remission is typically observed at puberty, despite the presence of KIT-activating mutations, including the D816V mutation.
Transgenic mice overexpressing KIT D816V exhibit slow expansion and indolent accumulation of MCs in the tissues, with incomplete penetrance, and they rarely develop aggressive mastocytosis.
Although most patients with mastocytosis did not have a family history of MC disease, around 100 familial cases worldwide have been reported in the literature. However, only 13 of these presented with germline KIT mutations (A533D, M541L, Del419D, S451C, K509I, V559A, R634W, or N822I).
In the mastocytosis cohort at the CEREMAST, familial forms appear to be more prevalent than in the literature. Indeed, about 7% of our patients have a first- or second-degree relative with mastocytosis. The majority of these relatives do not have a mutation in the KIT gene (unpublished data).
Thus, KIT mutations do not account for all familial forms of the disease.
Lastly, BaF3 cells overexpressing KIT D816V do not display a transformed phenotype and are even driven towards maturation by the mutation32.
Taken as a whole, these observations strongly suggest the additional involvement of one or more germline or somatic mutations or polymorphisms in genes other than KIT; these would act synergistically with KIT mutations in the development of mastocytosis. "
Molecular Diagnosis of Mast Cell Disorders
A Paper from the 2005 William Beaumont Hospital Symposium on Molecular Pathology
Cem Akin
The most common molecular abnormality consistently detected in systemic mastocytosis is a somatic point mutation, AT in nucleotide 2468 of c-kit cDNA, affecting codon 816 with resulting replacement of an aspartic acid by valine (D816V)21 (Figure 3).
Codon 816 is a critical residue contributing to the structure of the activation loop of the tyrosine kinase enzymatic domain of Kit by forming a hydrogen bond with N819. Disruption of this bond by replacement of aspartic acid at codon 816 destabilizes the inactive conformation of the kinase domain and results in ligand-independent constitutive activation and autophosphorylation of Kit.
The D816V c-kit mutation accounts for more than 90% of all mutations described in mastocytosis and has been reported in all categories of disease (Table 1).
Military medicine prepares for epidemicā¦
Because Poop Happens. Just like C-Diff.
FROM JAMA
āThe toilet bowl, sink, and bathroom door handle of an isolation room housing a patient with the novel coronavirus tested positive for the virus, raising the possibility that viral shedding in the stool could represent another route of transmission, investigators reported. Air outlet fans and other room sites also tested positive.ā
My Doctor sent me this. He says heās now calling himself an āIgEāā¦Immunology galactic Expert, MD. Snortā¦
Why is the crackdown on contacts, schools, gathering such a good thing. This new virus is extremely highly infective. Here are some facts.
The infectivity of SARS CoV-2 (Covid -19) is 1000x that of SARS based on itās different glycoprotein spike which is more similar to Ebola or HIV.
That makes it way more infectious than the flu.
This spike is what punctures and attaches to your lung, gut, intestine cells to inject RNA and begin breeding millions of new virus particles to spread itself all over the place.
( Why COVID-19 is more insidious than other coronaviruses | Salon.com ) Links to real papers embedded.
It aerosolizes well. The tiny little virus particles travel well bazed on submicron size. Droplets from snot is primary but the virus sheds and can fly a ways. Its been found in exhaust fans and bathroom hand blowers.
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Weāre a cheap date. Why does the coronavirus spread so easily between people?
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It transmit in feces and urine and the aerosolizes, so move your toothbrush out of the bathroom
( The results are in, COVID-19 spreads through poop - Science ) Links to real papers embedded. -
Can reinfect after recovery. Based on 4 doctors self test -during and after quarantine, remains a viable virus as a carrier up to 35 days after recovery. ( https://jamanetwork.com/journals/jama/fullarticle/2762452 )
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Similar corona viruses last up to 9 days on hard non porous surfaces like plastic, glass, steel
( DEFINE_ME ) -
Hereās what happens when your lungs, gut, or kidneys are infected ( Redirect Notice )
Read the science folks, not the mass media or politician bullcrap.
Wash your hands, donāt touch your face, avoid other groups, donāt touch rails handles etc. if you can avoid it.
If you get sick, run a fever, and have other chronic health issues donāt wait to CALL your doctor. Hanging out in a waiting room is also not a good idea. You can have it and be infecting folks for 5 to 12 days before symptoms appear. You are infectious BEFORE symptoms appear.
When it hits, the avg time from symptoms to hospitalization is about 10 hours. In āsickā people who are most susceptible, a cytokine reaction can fill the lungs with fluid leading to secondary pneumonia, leaky blood vesels, and kidney damage. Since it attacks the ACE2 receptor as the front door it is suspected of heart damage as well.
Be careful with scents added to the mixture. Use gloves if sensitive. Wash hands after use.