Toll Like Receptors (TLR) - Immunology Animation



This is part of series of videos from the Armando Hasudungan's YouTube channel:

https://www.youtube.com/user/armandohasudungan/videos

Signaling pattern-recognition molecules, for example, toll-like receptors (TLRs), lead to activation of genes which in turn lead to a specific immune response. TLRs got their name from toll, a membrane receptor in the Drosophila fly which provides resistance to fungi. TLRs are the first point of contact between the immune system and a pathogen.


The curved leucine-rich repeat region of toll-like receptors, represented here by TLR3. Image source: Wikipedia.

Mnemonics: Toll-like receptors (TLRs)

TLR 2
Two
TB and other mycobacteria

TLR4 (for LPS)
CD14

TLR 5
Five
Flagellin
Flagelated bacteria

TLR 7
Seven
SS RNA

TLR 9
Nine
Nonmethylated
Nucleotide motifs - CpG

TLR 3
Three is "Free" of MyD88

Comments from Twitter:

Roisin Thomas @RoisinThomas: @Allergy There is a mistake in that video. TLR-4 recognises lipopolysaccharide from gram negative bacteria not gram positive.

@Allergy: yes, TLR-4 binds to LPS (Gram neg) - explanation added in the text, with your comment: http://allergynotes.blogspot.com/2014/09/toll-like-receptors-tlr-immunology.html

Philippe Auriol @PhilAllergie: #fun #Biology

Dr John Weiner @AllergyNet: Spellbinding video and summary, loved it, I must get a life

References:

Toll-like receptors (TLRs) http://buff.ly/1mapOI7
Mnemonics: Toll-like receptors (TLRs) http://buff.ly/XBMo0Q

ABCs of Asthma and Allergies in Children - ACAAI video

From ACAAI: ABCs of Asthma and Allergies in Children -- "What are the most common asthma and allergy symptoms in children? How is allergy testing in children done? Will your child always be at risk in school and every new environment? Get answers to these and many other allergy and asthma questions in this segment of "Why See an Allergist."

Children treated daily with ICS grow 0.5 cm less during the first year of treatment, no difference second year

Two literature reviews by The Cochrane Collaboration evaluated the effect of inhaled corticosteroids (ICS) on growth in children with asthma. The first review included 25 trials with 8471 children (5128 ICS-treated and 3343 control) with mild to moderate persistent asthma. The second review included 17 group comparisons derived from 10 trials (3394 children with mild to moderate asthma). Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy.

Regular use of ICS at low or medium daily doses was associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose. ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. Findings support use of the minimal effective ICS dose in children with asthma.



Asthma Inhalers (click to enlarge the image).

References:

Inhaled corticosteroids in children with persistent asthma: effects on growth. Linjie Zhang et al. DOI: 10.1002/14651858.CD009471.pub2
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009471.pub2/abstract

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth. Aniela I Pruteanu et al. DOI: 10.1002/14651858.CD009878.pub2
http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD009878.pub2/abstract

Role of macrolides in asthma: promise of efficacy, search for responsive phenotype continues

Macrolides, such as clarithromycin and azithromycin, possess antimicrobial, immunomodulatory, and potential antiviral properties. They are a potential therapeutic option for asthma but the results from clinical trials have been contentious. The findings could be confounded by many factors, including the heterogeneity of asthma, treatment duration and dose.

Recent evidence suggests effectiveness of macrolides in patients with uncontrolled severe neutrophilic asthma and in asthma exacerbations.

At present, the use of macrolides in chronic asthma or acute exacerbations is not justified.

Further work, including proteomic, genomic, and microbiome studies, will advance our knowledge of asthma phenotypes, and help to identify a macrolide-responsive subgroup.

References:

The role of macrolides in asthma. The Lancet Respiratory Medicine, Early Online Publication, 17 June 2014, doi:10.1016/S2213-2600(14)70107-9
http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(14)70107-9/fulltext
(free full text after registration)

Image source: Clarithromycin structure, Wikipedia, public domain.

Comments from Twitter:

Dr John Weiner @AllergyNet: 40 yrs of reports but unsolved

Antimalaria drug hydroxychloroquine use for chronic urticaria is based on only one published study

What is it?

Hydroxychloroquine is an antiinflammatory drug and antimalarial agent. The relative safety of the low doses, and the low cost of hydroxychloroquine makes it a reasonable agent in the treatment of refractory chronic urticaria (CU). One of the disadvantages is the relatively slow onset of action.

How the works?

The mechanism of action includes suppression of T lymphocyte activation and antigen processing.

Paucity of research data

Apparently, there is only one published study in PubMed, from 10 years ago, which included only 18 patients with chronic urticaria (http://www.ncbi.nlm.nih.gov/pubmed/15086698). The patients were treated with a combination of therapies for CU (H1 antihistamines, H2 antihistamines, glucocorticoids, and doxepin) and randomized to receive either:

- hydroxychloroquine (5 mg/kg daily)
- or no additional drug

After 3 months of treatment, patients in the hydroxychloroquine arm had improved quality of life. Hydroxychloroquine was well tolerated for 12 weeks (200 mg of hydroxychloroquine twice daily). However, because of small size and 3 dropouts (from 21 to 18), the study was underpowered to detect significant differences.

Expert recommendations

The 2014 edition of UpToDate includes the expert recommendation to start hydroxychloroquine with a dose of 200 mg twice a day. A 3-month trial is usually required to determine effectiveness. Hydroxychloroquine rarely causes serious side effects. The most common adverse reactions are related to the gastrointestinal tract (nausea), skin (various macular lesions), and central nervous system (headache).

Ophthalmologic problems, including corneal deposits (reversible) and retinopathy (potentially vision threatening) are possible, but rare with the low daily doses of hydroxychloroquine used in CU.

No studies have evaluated the ideal length of treatment.

Eye screening

 The risk of retinopathy is low in the first 5 years of use, but after 5 years of use it increases to approximately 1%.

Recent recommendations from the American Academy of Ophthalmology (http://www.ncbi.nlm.nih.gov/pubmed/21292109) are:

- baseline ophthalmologic examination within the first year of starting hydroxychloroquine
- annual examinations after 5 years of therapy



Chronic Urticaria Treatment Options in 6 Steps (click to enlarge the image).

References:

Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and evaluation. Intern Med J. 2004 Apr;34(4):182-6.
http://www.ncbi.nlm.nih.gov/pubmed/15086698

PubMed search for "hydroxychloroquine chronic urticaria" shows the lack of research on the topic, most results are from review articles http://buff.ly/1zEUBxo

Chronic urticaria: Treatment of refractory symptoms. UpToDate, 2014.

Alternative agents in refractory chronic urticaria: evidence and considerations on their selection and use. J Allergy Clin Immunol Pract. 2013 Sep-Oct;1(5):433-440.e1. doi: 10.1016/j.jaip.2013.06.003. Epub 2013 Aug 2.

http://www.jaci-inpractice.org/article/S2213-2198(13)00281-X/fulltext

Image source: Urticaria, Wikipedia, public domain.
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