Transcription factor PU.1 regulates TCR expression via GATA-3

The Ets transcription factor PU.1 is a master regulator for the development of multiple lineages during hematopoiesis. The expression of PU.1 is regulated during early T lineage development in the thymus.


Spi-1 (PU.1) 5' UTR regulatory element. Image source: Wikipedia, public domain.

PU.1 modulates the levels of TCR expression in CD4(+) T cells by regulating the DNA-binding activity of GATA-3.

GATA-3-dependent regulation of TCR expression is also observed in Th1 and Th2 cells.

Increased GATA-3 function in the absence of the antagonizing activity of PU.1 leads to:

- increased TCR expression
- reduced activation threshold
- increased homogeneity in Th2 populations

References:
PU.1 regulates TCR expression by modulating GATA-3 activity. Chang HC, Han L, Jabeen R, Carotta S, Nutt SL, Kaplan MH. J Immunol. 2009 Oct 15;183(8):4887-94.

IL-33 is a new marker of severe and refractory asthma

IL-33 is a new member of the IL-1 cytokine family that promotes Th2 inflammation.


Video: Interleukin-1 binding to its receptor on a cell surface, created from structural data.

Endobronchial biopsies were obtained from adults with mild, moderate, and severe asthma, and from control subjects.

Higher levels of IL-33 transcripts were detected in biopsies from asthmatic compared with control subjects, and especially in subjects with severe asthma.

Airway smooth muscle cells (ASMC) are a source of the IL-33 cytokine and show IL-33 expression at both protein and mRNA levels.

TNF-alpha up-regulates IL-33 in a dose-dependent manner. Dexamethasone fails to abolish TNF-alpha-induced IL-33 up-regulation. IFN-gamma also increases IL-33.

IL-33 appears to be a novel inflammatory marker of severe and refractory asthma.



Severe asthma - differential diagnosis and management (click to enlarge the image).

References:

Increased expression of IL-33 in severe asthma: evidence of expression by airway smooth muscle cells. Préfontaine D, Lajoie-Kadoch S, Foley S, Audusseau S, Olivenstein R, Halayko AJ, Lemière C, Martin JG, Hamid Q. J Immunol. 2009 Oct 15;183(8):5094-103.
Interleukin 33 (IL-33)
IL-33 and its receptor ST2 play important roles in allergic rhinitis http://goo.gl/xYCga
IL-33/ST2 pathway may provide new therapeutic targets for allergic rhinitis and asthma http://goo.gl/3utyB

Helminth Trichuris suis (pig whipworm) had no effect as therapy for allergic rhinitis

Parasitic helminth infections may protect against allergic airway inflammation and have been associated with a reduced risk of atopy.

The helminth Trichuris suis (pig whipworm) has demonstrated efficacy in treatment of inflammatory bowel disease.

The authors conducted a double-blind, placebo-controlled trial in which 100 subjects age 18 to 65 years with grass pollen-induced allergic rhinitis were assigned to ingest 8 doses with 2500 live T suis ova or placebo.

Treatment with T. suis ova caused transient diarrhea peaking at day 41 in 33% of participants and increased eosinophil counts and T. suis-specific IgE, IgG(4) and IgA.

There was no significant change in symptom scores and wheal reaction on skin prick testing with grass or other allergens.

The authors concluded that treatment with the helminth T. suis induced a clinical and immunologic response as an infection, but had no therapeutic effect on allergic rhinitis.

References:
Trichuris suis ova therapy for allergic rhinitis: A randomized, double-blind, placebo-controlled clinical trial. Bager P, Arnved J, Rønborg S, Wohlfahrt J, Poulsen LK, Westergaard T, Petersen HW, Kristensen B, Thamsborg S, Roepstorff A, Kapel C, Melbye M. J Allergy Clin Immunol. 2009 Oct 2.
Image source: Trichuris egg in stool sample (40x). Wikipedia, GNU Free Documentation License, Version 1.2.

20% of children with allergic rhinitis have previously undiagnosed bronchial obstruction

A relationship exists between upper and lower airways. Bronchial obstruction is a paramount feature of asthma and its reversibility is diagnostic of asthma.

200 children with allergic rhinitis and 150 normal subjects were evaluated with skin prick test, spirometry, and bronchodilation test.

"Rhinitics" showed a significant FEV1 increase after bronchodilation test. More than 20% of rhinitics had reversibility (greather than 12% above baseline levels).

Patients with reversibility had lower FEV1 levels, longer rhinitis duration, and perennial allergy.

This study highlights the close link between upper and lower airways and the relevance of performing bronchodilation test in patients with allergic rhinitis.

References:
Impact of allergic rhinitis on asthma in children: effects on bronchodilation test. M. Capasso, A. Varricchio, G. Ciprandi. Allergy, 2009.
Image source: Flow-Volume loop showing successful FVC maneuver. Wikipedia, GNU Free Documentation License, Version 1.2.



Treatment Options for Allergic Rhinitis (click to enlarge the image).

Related:
Forced expiratory flow between 25-75% of vital capacity may be a marker of bronchial impairment in allergic rhinitis http://goo.gl/yTNW2

Parvalbumins are the most important fish allergens, mediate cross-reactivity between fish species

Parvalbumin is a calcium binding protein with low molecular weight structurally related to calmodulin and troponin C. Parvalbumin is localised in fast-contracting muscles, brain and some endocrine tissues.

Parvalbumins are the most important fish allergens. Polysensitization to various fish species is common and linked to the cross-reactivity of their parvalbumins.

Dark-muscled fish such as tuna may be less allergenic.

Total protein extracts and purified parvalbumins from cod, whiff, and swordfish were tested for IgE-binding properties with 16 fish-allergic patients' sera from Spain.

Parvalbumins levels from cod were 20 times higher than from swordfish (whiff 30 times higher).

Parvalbumins were recognized by 94% of the patients in extracts of cod and whiff, but only by 60% in swordfish extracts.

The parvalbumins of cod, whiff and swordfish are highly cross-reactive due to high amino acid sequence.

The low allergenicity of swordfish is due to the low expression levels of its parvalbumin.

Fish-allergic patients should avoid all fish species until a species can be proven safe to eat by provocative challenge (Annals of Allergy and Imm, 1999).

References:

Expression levels of parvalbumins determine allergenicity of fish species. U. Griesmeier, S. Vázquez-Cortés, M. Bublin, C. Radauer, Y. Ma, P. Briza, M. Fernández-Rivas, H. Breiteneder. Allergy, 2009.
Epitope Mapping of Atlantic Salmon Major Allergen by Peptide Microarray Immunoassay http://goo.gl/OGCnn
Cross Reactions Among Foods (PDF).
Image source: Gadus morhua, Atlantic cod. Wikipedia, public domain.

Chlorine and exercise do not affect markers of inflammation in the airway of swimmers

The prevalence of exercise-induced bronchoconstriction (EIB) is 10% in the general population, up to 90% of those with asthma, and 50% of those with allergic rhinitis.

Chlorine metabolites and training load may produce exercise-induced bronchospasm (EIB) in elite swimmers. The aim of this Scottish study was to assess the combined effects of chlorine and exercise on the unified airway of adolescent elite swimmers.

A squad were assessed during an indoor pool session. Athletes trained at least 8 hr per week and underwent pre and post a 2 hr session:

- tidal (TNO) and nasal (NNO) exhaled NO
- peak nasal inspiratory flow (PNIF)

22% of swimmers had known asthma; 36% had a positive exercise challenge; 50% complained of symptoms suggestive of EIB.

36% who did not have asthma were found to have a positive exercise challenge.

There was no significant association between reported exercise symptoms and positive exercise test.

There was no significant change in TNO or NNO for pre vs postexposure, irrespective of asthma diagnosis or AHR.

The authors concluded that combined exposure to chlorine and exercise did not affect surrogate markers of inflammation in the unified airway. There was a high prevalence of undiagnosed EIB.

Exercise-induced bronchospasm (EIB) (click to enlarge the image):



References:

Effects of chlorine and exercise on the unified airway in adolescent elite Scottish swimmers. K. L. Clearie, S. Vaidyanathan, P. A. Williamson, A. Goudie, P. Short, S. Schembri, B. J. Lipworth. Allergy. 2009.
Swimming may not increase the risk of asthma or allergic symptoms http://goo.gl/ZdiG5
High prevalence of asthma among elite swimmers http://goo.gl/Sm8Fo
Swimming in indoor chlorinated pools associated with airway changes similar to mild asthma, but w/o hyperresponsiveness. JACI, 2011.
Lung function declines in volunteers after exposure to trichloramine (NCl3) in indoor pool http://buff.ly/QjZiHE
Image source: Wikipedia, a Creative Commons License.

Urticaria guidelines by EAACI, EDF and WAO

Urticaria is a frequent disease with a life-time prevalence of 20%.

Chronic urticaria not only cause a decrease in quality of life, but also affect performance at work and school.

The recommended first line treatment is new generation, nonsedating H(1)-antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended.
For patients who do not respond to a four-fold increase in dosage of nonsedating H(1)-antihistamines, it is recommended that second-line therapies should be added.

Corticosteroids are not recommended for long-term treatment due to their unavoidable severe adverse effects. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).

References:
EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria.
EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria.
Zuberbier T, Asero R, Bindslev-Jensen C, Walter Canonica G, Church MK, Giménez-Arnau A, Grattan CE, Kapp A, Merk HF, Rogala B, Saini S, Sánchez-Borges M, Schmid-Grendelmeier P, Schünemann H, Staubach P, Vena GA, Wedi B, Maurer M. Allergy. 2009 Oct;64(10):1417-26.
Image source: Urticaria, Wikipedia, public domain.

"Outside-to-inside, back to outside" paradigm in atopic dermatitis focuses on skin barrier

Pathogenesis of atopic dermatitis includes:

- Th1/Th2 cell dysregulation
- abnormalities in IgE production and dendritic cell signaling
- mast cell hyperactivity

Current therapy has been largely directed towards ameliorating Th2-mediated inflammation and pruritus.

There is emerging evidence that atopic dermatitis results from inherited and acquired insults to the skin barrier,

There is a strong association between mutations in filaggrin and atopic dermatitis, particularly in Northern Europeans.

Sustained hapten access through a defective skin barrier stimulates a Th1 to Th2 shift in immunophenotype, which in turn further aggravates the barrier.

Secondary Staphylococcus aureus colonization not amplifies inflammation and further stresses the barrier in atopic dermatitis. S. aureus (enterotoxins), M sympodialis, and allergens are trigger factors of atopic dermatitis - they stimulate dendritic cells (JACI, 2012).

There is a new 'outside-to-inside, back to outside' paradigm for the pathogenesis of atopic dermatitis. 'Barrier repair' therapies could be developed in the future.



Atopic Dermatitis Treatment - Illustrated (click here for full size image).

References:

Abnormal skin barrier in the etiopathogenesis of atopic dermatitis. Elias, Peter M; Schmuth, Matthias. Current Opinion in Allergy and Clinical Immunology, 2009.
Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation http://goo.gl/Evqr
Loss-of-function mutations in filaggrin gene are associated with atopic dermatitis, and now with peanut allergy too. JACI, 2011.
Early food sensitization and FLG mutation in infants with early eczema increase the risk for later asthma (JACI, 2011).
Staphylococcus aureus biofilm and and superantigens are associated with chronic sinusitis, cause T-helper 2 skewing http://bit.ly/ngnxBe
Image source: Skin layers. Wikipedia, public domain.

Related:

Sulfite (sulphite) hypersensitivity and "wine allergy"

Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries.

Sulfites (also sulphites) are compounds that contain the sulfite ion SO. Sulfites occur naturally in all wines to some extent. Sulfites are commonly introduced to arrest fermentation at a desired time, and may also be added to wine as preservatives to prevent spoilage and oxidation at several stages of the winemaking.

Sulphites can induce a range of adverse clinical effects in sensitive individuals:

- dermatitis
- urticaria
- flushing
- hypotension
- abdominal pain
- diarrhoea
- anaphylaxis
- asthmatic reactions

Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain them.

Studies report a 3-10% prevalence of sulphite sensitivity among asthmatic patients following ingestion.

The mechanisms underlying sulphite sensitivity remain unclear.


A 3-D model of the sulfite anion. Image source: Wikipedia, public domain.

References:
Clinical effects of sulphite additives. Vally H, Misso NL, Madan V. Clin Exp Allergy. 2009 Sep 22.
Sulfite. Wikipedia.

Related:
Allergy to Wine? Correct Diagnosis May be Wine-Induced Anaphylaxis and Sensitization to Hymenoptera Venom
Alcohol, allergies, histamines and sulfites – reactions from an allergist http://bit.ly/aJdjf2
Possible reaction to metabisulfite. AAAAI - Ask the Expert. http://goo.gl/Qaaij
Challenge test to metabisulfites - AAAAI Ask the Expert, 2011.
Alcohol allergy? 1. Prick-prick tests with suspected drinks. 2. If negative, oral challenge test with increasing doses of the drinks should be performed. http://buff.ly/16uHYbi
Image source: Wikipedia, Free Documentation License.

Risk factors and prevalence of asthma in schoolchildren

In 2002, a cross-sectional population-based study was carried out in Spain, following the International Study of Asthma and Allergies in Childhood (ISAAC) Phase III methodology.

Participation rate was 88 % (4492 of 4872 schoolchildren).

Prevalence of wheeze in the past year, asthma ever, and physician-diagnosed asthma were 8 %, 7 % and 6 %, respectively.

Risk factors independently associated with all three asthma case definitions were:

- history of bronchitis or pneumonia
- allergic rhinitis
- family members with atopic disease
- residing in an industrialised area

Risk factors for asthma:

- male sex
- atopic eczema
- dog at home

Exclusive breast-feeding and the presence of another animal (not a dog or cat) were protective factors.

Maternal age was inversely related to asthma. Residence in an area of heavy truck traffic and the father smoking at home were associated with asthma.

Risk factors for wheeze in the past year were low social class, history of sinusitis and the father smoking at home.

The authors concluded that environmental factors are related to the presence of asthma.
Preventive measures should be directed to improving air pollution, promoting breast-feeding and reducing smoking in the home.

Fatty acids in breast milk, n-3 long-chain polyunsaturated fatty acids (LCPs), may have a protective role in the development of atopic disease.

References:
Risk factors and prevalence of asthma in schoolchildren in Castellon (Spain): a cross-sectional study. Arnedo-Pena A, Puig-Barberà J, Bellido-Blasco JB, Pac-Sa MR, Campos-Cruañes JB, Artero-Sivera A, Museros-Recatalá L. Allergol Immunopathol (Madr). 2009 May-Jun;37(3):135-42.
Image source: Wikipedia, public domain.

Hymenoptera venom immunotherapy is a safe and effective in pediatric patients

Hymenoptera venom allergy is a growing problem. A Spanish study analyzed 21 paediatric patients treated with venom immunotherapy. The maintenance dose administered was 100 mcg (the approximate amount of venom delivered during 2 honeybee stings).

Two systemic reactions (both with an Apis extract) were registered. Both the cutaneous test and specific IgE showed a reduction at the end of treatment.

Seven patients (33 %) suffered a spontaneous re-stung during the maintenance phase or after immunotherapy was completed. In 4 patients there was no allergic reaction and the other 3 children suffered a mild local reaction.

The authors concluded that venom immunotherapy is a safe and effective treatment in pediatric patients with hymenoptera venom allergy.

References:

Hymenoptera venom allergy: characteristics, tolerance and efficacy of immunotherapy in the paediatric population. Carballada González FJ, Crehuet Almirall M, Manjón Herrero A, De la Torre F, Boquete París M. Allergol Immunopathol (Madr). 2009 May-Jun;37(3):111-5.
Hymenoptera-Sting Hypersensitivity - NEJM review, 2014 http://buff.ly/1mEZX8z
Honeybee immunotherapy is less safe and less effective than for other flying Hymenoptera http://goo.gl/RgAjj
Images source: Wikipedia, Free Documentation License.

Case Report: Occupational Inhalant Allergy to Pork followed by Food Allergy to Pork and Chicken

Typically, animal-derived proteins are implicated in food allergies. However, animal proteins can play a role in inhalant allergies with secondary food allergy symptoms.

A 42-year-old female with a history of occupational inhalant allergy to pork reported rhinitis, asthma, dysphonia and conjunctivitis 30 minutes after ingestion of chicken.

Skin tests were positive to chicken meat.

Protein extracts were prepared from chicken meat and the patient showed specific IgE binding to chicken meat proteins. Inhibition studies with chicken and porcine hemoglobin as well as with serum albumins demonstrated cross-reactive IgE antibodies.

This is a case of confirmed occupational inhalant allergy due to pork followed by food allergy to pork and 3 years later by food allergy to chicken.

Porcine and chicken hemoglobin were found to be cross-reactive allergens.

Cross-reactivity between porcine and chicken serum albumin was possibly linked to a prior sensitization to cat serum albumin.

Most patients allergic to red meat are sensitized to gelatin. Alpha-Gal IgE might be the target of reactivity to gelatin (JACI, 2012).

References:

Occupational Inhalant Allergy to Pork followed by Food Allergy to Pork and Chicken: Sensitization to Hemoglobin and Serum Albumin. Hilger C, Swiontek K, Hentges F, Donnay C, de Blay F, Pauli G. Int Arch Allergy Immunol. 2009 Sep 15;151(2):173-178
Meat allergy
A small number of people who are allergic to cat may also get allergic reactions when eating pork http://goo.gl/zVSaN
Image source: Varieties of meat, Wikipedia, public domain.

What is Sidak correction?

From Wikipedia:

In statistics, the Bonferroni correction is a method used to address the problem of multiple comparisons.

The Bonferroni correction is derived by observing Boole's inequality

In probability theory, Boole's inequality, named after George Boole, (also known as the union bound) says that for any finite or countable set of events, the probability that at least one of the events happens is no greater than the sum of the probabilities of the individual events.

A related correction is called the Šidák correction. The Šidák correction is derived by assuming that the individual tests are independent. Since we are assuming that they are independent, the probability that all of them are not significant is the product of the probabilities that each of them are not significant.

The Šidák correction gives a stronger bound than the Bonferroni correction but requires the additional condition of independence. Because the Šidák correction requires calculating fractional powers, it is more complicated to do and the simpler Bonferroni correction is often preferred.

Nasal rinsing is effective treatment for pregnant women with allergic rhinitis

Nasal rinsing appears suitable for the management of pregnant women with seasonal allergic rhinitis since no deleterious effects on the fetus are to be expected.

Pregnant women with seasonal allergic rhinitis were randomized to intranasal lavage with hypertonic saline 3 times daily versus no local therapy during a 6-week pollen season. Patients kept a daily record of rhinitis symptoms.

An improvement in rhinitis score was observed in the study group during all weeks of therapy.

Antihistamines use was reduced and no adverse effect was reported in the active group.

The study authors concluded that nasal rinsing is a safe and effective treatment option in pregnant women with seasonal allergic rhinitis.



Mayo Clinic: What can you do about that runny nose and nasal congestion? Medications are one option, but so is nasal cleansing.



Treatment Options for Allergic Rhinitis (click to enlarge the image).



SinusRinse video (this post is not sponsored by any person or company).

 References:

Nasal Lavage in Pregnant Women with Seasonal Allergic Rhinitis: A Randomized Study. Garavello W, Somigliana E, Acaia B, Gaini L, Pignataro L, Gaini RM. Int Arch Allergy Immunol. 2009 Sep 15;151(2):137-141.
Video: How to do nasal irrigation Nasal Irrigation with Saline Solution May be Better Than Saline Sprays for Chronic Rhinitis
Nasal Irrigation as part of daily hygiene routine? "They brush their teeth, they wash their face, they rinse their nose" http://goo.gl/F0N11
Is Rinsing Your Sinuses Safe? FDA replies: http://goo.gl/XL5bJ

What is Bioconductor and R statistical environment?

What is Bioconductor?

Bioconductor is a free, open source and open development software project for the analysis and comprehension of genomic data generated by lab experiments in molecular biology.

What is R statistical environment?

R Project for Statistical Computing or "R" is an open source language and environment for statistical computing and graphics.

R was created by Ross Ihaka and Robert Gentleman at the University of Auckland, New Zealand, and is now developed by the R Development Core Team. It is named partly after the first names of the first two R authors (Robert Gentleman and Ross Ihaka), and partly as a play on the name of S.

S is a statistical programming language developed primarily by Bell Laboratories.

R provides a wide variety of statistical (linear and nonlinear modeling, classical statistical tests, time-series analysis, classification, clustering, and others) and graphical techniques. R, like S, is designed around a true computer language, and it allows users to add additional functionality by defining new functions.

The Bioconductor project, which started in the fall of 2001, provides R packages for the analysis of genomic data.

CD28(null) T Cells Infiltrate Muscles of Patients with Dermatomyositis and Polymyositis

Dermatomyositis and polymyositis are disabling rheumatic diseases characterized by T cells infiltrating muscle tissue.

Patients with dermatomyositis and polymyositis were screened for frequency of CD4(+)CD28(null) and CD8(+)CD28(null) T cells in peripheral blood by flow cytometry.

Presence of these cells in inflamed muscle tissue from 13 of these patients was analyzed by three-color immunofluorescence microscopy.

Muscle-infiltrating T cells were predominantly CD4(+)CD28(null) and CD8(+)CD28(null) T cells in patients with dermatomyositis and polymyositis.

References:
T Cell Infiltrates in the Muscles of Patients with Dermatomyositis and Polymyositis Are Dominated by CD28null T Cells. Authors: Fasth AE, Dastmalchi M, Rahbar A, Salomonsson S, Pandya JM, Lindroos E, Nennesmo I, Malmberg KJ, Söderberg-Nauclér C, Trollmo C, Lundberg IE, Malmström V. J Immunol. 2009 Sep 14.
Image source: X-Ray of the knee in a patient with dermatomyositis. Wikipedia,
Mrich, Creative Commons Attribution ShareAlike 1.0 License.

Total IgE level predicts asthma only among atopic subjects

The level of IgE increases during childhood until about 10 years of age. At age 10, the total IgE reaches a value that is typically maintained throughout adult life.

The National Health and Nutrition Examination Survey 2005-2006 examined a representative sample of the US population 6 years of age and older.

The median total IgE level was 40.8 kU/L. Omalizumab binds to Cε3 region of IgE.

The prevalence of current asthma was 8.8%.

The prevalence of atopy was 42%, as defined by 15 specific IgEs.


Immunoglobulin structures. Image source: Wikipedia, public domain.

The odds ratio (OR) for asthma with a 10-fold increase in total IgE level was 2.18. Total IgE level predicted asthma only among atopic subjects and not among nonatopic subjects. Among atopic subjects, the association between total IgE level and asthma became stronger as the number of positive specific IgE test results increased.

92% of atopic subjects were identified by 6 specific IgEs, but to increase the identification to more than 99% required 11 specific IgEs.

The authors concluded that total IgE levels are associated with asthma only among persons who have positive results for at least 1 allergen-specific IgE.

References:
Total IgE levels and asthma prevalence in the US population: Results from the National Health and Nutrition Examination Survey 2005-2006. Gergen PJ, Arbes SJ Jr, Calatroni A, Mitchell HE, Zeldin DC. J Allergy Clin Immunol. 2009 Jul 31. [Epub ahead of print].

Senicapoc, a novel Gardos channel inhibitor, reduced asthmatic response to inhaled allergen

Gardos channel is a protein "pump" that expels intracellular potassium when activated by calcium. Gardos channel causes dehydration of sickle erythrocytes, its inhibition may serve as an antisickling strategy. http://bit.ly/O15MF

Oral senicapoc, Gardos channel inhibitor, reduced the late asthmatic response to a challenge of inhaled allergen http://bit.ly/JuvyG

However, on 10/26/2009, Icagen Inc. said senicapoc failed the main goals of a midstage study, and it does not plan to keep developing the drug.

Icagen said that in the study of 69 patients randomly receiving either 40 mg of senicapoc daily or a placebo, the drug didn't improve the patients' exercise-induced asthma symptoms.

References:
Icagen asthma drug senicapoc trial fails. Yahoo Finance, 2009.
Image source: Senicapoc. Wikipedia, public domain.

Updated: 10/27/2009

Antimicrobial peptides and atopic dermatitis

Our skin is constantly challenged by microbes but is rarely infected.

How is that possible?

Cutaneous production of antimicrobial peptides (AMPs) is a primary system for protection. Antimicrobial peptides (AMP) are ubiquitous cationic proteins that play a role in innate immunity.

Cathelicidins are unique AMPs that protect the skin through 2 pathways:

- antimicrobial activity
- cytokine release, inflammation, angiogenesis, and reepithelialization

Cathelicidin dysfunction may be a central factor in the pathogenesis of several cutaneous diseases:

- atopic dermatitis - cathelicidin is suppressed. AMPs are decreased under the influence of TH2 cells. Atopic dermatitis patients are susceptible to Staphylococcus aureus due to a decrease in AMP. S. aureus (enterotoxins), M sympodialis, and allergens are trigger factors of atopic dermatitis - they stimulate dendritic cells (JACI, 2012).

- rosacea - cathelicidin is abnormally processed to induce inflammation

- psoriasis - cathelicidin converts self-DNA to stimulate an autoinflammatory cascade

Vitamin D3 is as a major factor involved in the regulation of cathelicidin.

Therapies targeting cathelicidin and other AMPs might be beneficial in inflammatory skin diseases.



Atopic Dermatitis Treatment - Illustrated (click here for full size image).

References:

Antimicrobial peptides and the skin immune defense system. Schauber J, Gallo RL. J Allergy Clin Immunol. 2009 Sep;124(3S2):R13-R18.
Extracellular vesicles derived from Staphylococcus aureus induce atopic dermatitis-like skin inflammation http://goo.gl/Evqr
Image source: The modes of action by Antimicrobial peptides. Wikipedia, Ymahn, Creative Commons Attribution-ShareAlike 3.0 License.

5% of packaged foods with an advisory label had detectable levels of allergens

Tips for managing food allergy (MJA, 2004):

- Always carry an EpiPen 2-Pak
- Always read food labels
- Ask questions about food preparation (be aware of the risk of cross-contamination)
- No label/no eat
- No EpiPen/no eat
- Tell friends about a serious food allergy
- Tell friends if feeling unwell, especially after eating.


Some of the "culprits" in food allergy. Image source: Mcclatchy-Tribune.

From The Great Falls Tribune:

5% of packaged foods with an advisory label had detectable levels of several common allergens.

2% of packaged foods without warning labels contained an allergen.

3 of the most commonly used terms to label food allergens and what they really mean:

"May Contain"

No allergen in the product's ingredients. There may be small amounts present because of cross-contamination — sharing a production facility with a product that contains allergens.

"Manufactured on the Same Line As"

The food was produced in machines used to make other products containing an allergen, such as peanuts. Major food companies tend to have better allergy controls in place than smaller companies.

"Gluten-Free"

These products shouldn't contain gluten, a main component of wheat, but some have low levels. The FDA is working to develop standards for this label.

Anaphylaxis Canada's video on how to read a food label:



References

"May contain traces of . . .”: hidden food allergens. MJA, 2004.
Confusion: 69% of UK cereals labelled as containing traces of nuts, despite none listing nuts as an ingredient - BMJ, 2011.
Food-allergy lingo. Great Falls Tribune.

Allergy to preservatives in topical ophthalmic therapies

Ocular hypersensitivity reactions to ophthalmic preservatives are:

- IgE-mast cell mediated
- cell mediated
- irritant (toxic)

Quaternary ammoniums (benzalkonium chloride) are most commonly associated with irritant toxic reactions (8% of cases).

Organomercurials (thimerosal) and alcohols (chlorobutanol) have the highest association with allergic responses.

References:
Allergy to ophthalmic preservatives. Hong, Jison; Bielory, Leonard. Current Opinion in Allergy and Clinical Immunology: October 2009 - Volume 9 - Issue 5 - p 447-453.
Image source: Benzalkonium chloride, Wikipedia, public domain.

Early colonization with gut microbes may be associated with fewer allergies

Among sensitized infants, those with high salivary secretory IgA (SIgA) are less likely to develop allergic symptoms.

Early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development.

Infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of Toll-like receptor 4 (TLR4) mRNA. Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system.

This 2012 study found beneficial effects: Protective effect of Lactobacillus probiotic against eczema in infants persists up to age 4, including for rhinitis.

References:

Influence of early gut microbiota on the maturation of childhood mucosal and systemic immune responses. Y. M. Sjögren, S. Tomicic, A. Lundberg, M. F. Böttcher, B. Björkstén, E. Sverremark-Ekström, M. C. Jenmalm. Clinical & Experimental Allergy.
Toll-like receptors (TLRs)
Probiotics may down modulate key parameters of allergic rhinitis. Clin Exp Allergy 2011.
Image source: Bifidobacterium adolescentis. Wikipedia, GNU Free Documentation License.

Allergic sensitization in early life through TLR7 activation (in mice)

Children hospitalized in early life with severe infections are significantly more likely to develop recurrent wheezing and asthma.

Mice sensitized to endotoxinlow ovalbumin (OVA) at birth in the presence of ssRNA or lipoteichoic acid, but not flagellin, showed an increase in:

- airway and tissue eosinophils
- mucus producing cells
- IL-13

TLR7 is an abbreviation for Toll-like receptor 7.

Mnemonic:

s
ssRNA
seven - TLR7


Pathogen Recognition Receptors, TLRs. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

References:
Allergic sensitization is enhanced in early life through toll-like receptor 7 activation. Phipps, N. Hansbro, C. E. Lam, S. Y. Foo, K. I. Matthaei, P. S. Foster. Clinical & Experimental Allergy.
Toll-like receptors (TLRs)

Oral challenge necessary for diagnosis of fluoroquinolone allergy, skin/in vitro tests not enough

Fluoroquinolone antibiotics are widely used for several reasons:

- broad antibacterial activity in the gram-negative and gram-positive spectrum
- high oral bioavailability
- good tissue penetration

Fluoroquinolones may cause hypersensitivity reactions.

101 patients with a history of immediate or delayed hypersensitivity in temporal relation to fluoroquinolones were assesed with skin testing, followed by oral challenges.

Patients with anaphylaxis symptoms were further evaluated with in vitro tests.

Fluoroquinolone hypersensitivity was excluded in 71 patients by tolerated oral challenge tests.

During positive challenge tests, 6 patients (3 with positive and 3 with negative skin prick tests) developed anaphylaxis. However, IgE-mediated mechanism could not be confirmed by in vitro tests.

Patch testing was negative. History alone leads clearly to a considerable over-estimation of fluoroquinolone hypersensitivity.

Skin or in vitro tests do not seem to be very useful in identifying hypersensitive patients.

Challenge tests appear to be necessary for definitely confirming or ruling out fluoroquinolone hypersensitivity.

Mnemonic for diagnosis of drug allergy

HASTA la vista (Spanish, See you later)

History
Assemble a list of drugs and rank them
Stop all drug candidates
Test
Administer - dose escalation or desensitization

References:
Diagnostic testing in suspected fluoroquinolone hypersensitivity. C. S. Seitz, E. B. Bröcker, A. Trautmann. Clinical & Experimental Allergy.
Basophil activation test for evaluation of IgE-mediated hypersensitivity reactions to quinolones http://goo.gl/LFEf
Mnemonics: Drug Allergy
Image source: Essential structure of all quinolone antibiotics: the blue drawn remainder of R is usually piperazine; if the connection contains fluorine (red), it is a fluoroquinolone. Wikipedia, public domain.

Available again: PRE-PEN is the only FDA approved skin test for penicillin allergy

From pre-pen.com:

In 2009, ALK-Abelló and AllerQuest, LLC announced the return of PRE-PEN® to the market. PRE-PEN is penicilloyl-polylysine (PPL).

ALK is the exclusive distributor of PRE-PEN® which received FDA approval on September 18, 2009. Manufacturing began in October 2009 at AllerQuest's dedicated penicillin production facility in Plainville, CT.

PRE-PEN® is the only commercially available FDA approved skin test for the detection of penicillin allergy.

PRE-PEN® is a clear, colorless, sterile solution supplied in 0.25mL sealed glass ampules. Each ampule is sufficient to evaluate one patient by skin prick test and intradermal test, in duplicate.

PRE-PEN® is sold in boxes of 5 ampules intended for single patient use only.

Over 30 million Americans are suspected to be allergic to penicillin, but most of these people may be able to be treated safely with penicillin and related antibiotics. In past years, in the absence of a penicillin test, allergy specialists were unable to test patients for penicillin sensitivity. ALK and AllerQuest are bringing this product back into the US market and are re-launching of PRE-PEN®."

PRE-PEN® is available in single unit ampules. A puncture (prick) skin test is read in 15 minutes. A positive result requires a wheal of 5mm in diameter. If the SPT is negative (a wheal of 4 mm or less), an intradermal test is placed in duplicate (raising a bleb of  3 mm). A positive result is at least a 5 mm wheal after 20 minutes.

Download PrePen Package Insert (PDF).



Official video by the manufacturer, ALK-Abello: Penicillin Allergy Skin Testing with PRE-PEN® for Allergists.

References:

Drug Allergy
Skin testing to penicillin. Ask the expert. AAAAI, 2009.
Non IgE-mediated reaction to penicillin - AAAAI - Ask the Expert, 2011.
Image source: Penicillin core structure, in 3D. Purple is variable group. Wikipedia, public domain.

Some statistical methods used in allergy and immunology research

Example: Clinical efficacy and immune regulation with peanut oral immunotherapy. Jones SM et al. J Allergy Clin Immunol. 2009 Jul 2.

ANOVA shows if the means of several groups are all equal, generalizes Student's 2-sample t-test to more than 2 groups http://bit.ly/17ELj0

Factorial ANOVA is used when the experimenter wants to study the effects of two or more treatment variables http://bit.ly/17ELj0

In mixed-design ANOVA, one factor is a between-subjects variable and the other is within-subjects variable http://bit.ly/17ELj0

A mixed model is a statistical model containing both fixed effects and random effects. http://bit.ly/uvAQ8

Restricted maximum likelihood is a method for fitting linear mixed models http://bit.ly/3V9wn

Wilcoxon signed-rank test is a non-parametric test for 2 related samples or repeated measurements on a single sample http://bit.ly/4EXqZU

Wilcoxon signed-rank test can be used as alternative to paired Student's t-test when population cannot be assumed to be normally distributed. Mann-Whitney-Wilcoxon is a variant of Wilcoxon signed-rank test for 2 independent samples http://bit.ly/CnATg

LABA plus LAMA combination products for COPD and asthma

COPD is a large and fast expanding market estimated to be worth $6 billion (2007) and expected to double by 2011. The LAMA tiotropium (Spiriva) recorded sales of $2.77 billion in 2008. http://bit.ly/StieC

Once-daily beta2-agonists or ultra long-acting beta2-agonists (LABAs) are under development for asthma and COPD.
Ultra-LABAs include carmoterol, indacaterol, and several GSK molecules that are under development for treatment of asthma and COPD. Arcapta Neohaler (indacaterol) is the only once-daily ultra-LABA approved for COPD maintenance (http://goo.gl/3RJyu).

New long-acting antimuscarinic agents (LAMAs): aclidinium, LAS-35201, 2 GSK products, NVA-237 (glycopyrrolate), and OrM3.

Several options for once-daily dual-action ultra LABA plus LAMA combination products are currently being evaluated.
Dimer molecule in which both LABA and LAMA are present is called M3 antagonist-beta2 agonist (MABA) bronchodilators http://bit.ly/8behH

NVA237 is an anti-muscarinic agent glycopyrronium bromide which is currently registered for IV use during surgery. Dry-powder inhaler device with NVA237 produced a bronchodilation that was maintained for at least 32 hour. NVA237 demonstrated a 24-hour bronchodilation efficacy comparable to tiotropium and potentially faster onset of action http://bit.ly/StieC

QVA149 is an inhaled fixed dose combination of NVA237 (LAMA) and indacaterol (LABA) for the treatment of COPD http://bit.ly/1M92hI

References:


Anticholinergic (Tiotropium) Plus a Low-Dose Glucocorticoid May Effectively Control Asthma http://goo.gl/OGEr
QVA149 (LABA plus LAMA) demonstrates superior bronchodilation compared with indacaterol in COPD - Thorax http://goo.gl/OHSW0
The Risks and Benefits of Indacaterol - NEJM review and 16-min podcast. NEJM, 2011.