Natural killer cells (NK cells)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Immune System has 2 arms:

- Innate immune system
- Adaptive immune system


The 2 arms of the immune system: innate immunity and adaptive immunity (click to enlarge the image).

NK Cells

NK
Natural Killers, "born to kill"
Not lymphocytes

NK cells are CD45+ CD3- CD16+ or CD56+.

NKT cells are CD45+ CD3+ CD16+ or CD56+.

NK are "born to kill," they are natural killers because they do not need a stimulus to kill affected cells. In a sense, NK are "hyperactive" and potenially, the most dangerous cells in the human body.

MHC I
I
Inhibits cell killing by NK

Viruses inhibit MHC I expression which leads to killing by NK cells.

IL 15
Increases number of NK cells
IL 12 stimulation
INF gamma stimulation of NK cells

NK cells (not T-lymphocytes) are different from NKT cells. NKT cells are T-lymphocytes.

NK cells are CD45+ CD3- CD16+ or CD56+.

NKT cells are CD45+ CD3+ CD16+ or CD56+.

The mnemonic for different T-cell subtypes is FERMNN G ("pheromon G"):

Four, CD4, helper cells (Th1 and Th2)
Eight, CD8, killer cells
Regulatory, formerly known as suppressors
Memory
Naïve T cells
Natural Killer T cells (NKT)

Gamma/delta T cells (γδ)


Mind map of the 7 different T-cell subtypes remembered by the mnemonic FERMNN G (click to enlarge the image).

Published: 12/05/2007
Updated: 09/05/2010

Immunosuppressive drugs: Mycophenolate (CellCept)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Mycophenolate (CellCept) is often used as an alternative to azathioprine.

Mycophenolic acid. Image source: Wikipedia, public domain.

Mycophenolate mofetil is increasingly being used in place of azathioprine in organ transplantation, as it is associated with less bone marrow suppression, fewer opportunistic infections, and a lower incidence of acute rejection.

Mycophenolic acid is commonly marketed under the trade names CellCept (mycophenolate mofetil; Roche) and Myfortic (mycophenolate sodium; Novartis).

Mycophenolate is derived from the fungus Penicillium stoloniferum.

Mycophenolate blocks lymphocyte proliferation by inhibiting guanine nucleotide synthesis in lymphocytes. Mycophenolate affects purine nucleotide synthesis and metabolism. It is used in organ transplantation and is available in oral and intravenous form.

Mycophenolate was shown to be effective in severe atopic dermatitis, with some responders

showing lasting remission.

What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?

(A) NFkB

(B) calcium

(C) ipraimmunophilin

(D) NFAT

(E) calcineurin

(F) calmodulin

(G) AP-1

Answer: E.

References

Immunosuppressive drugs. Wikipedia.
Abbas' Immunology, edition 6, 2009.
Mycophenolic acid. Wikipedia.

Published: 05/20/2009
Updated: 08/20/2010

Defects in T cells - part of severe combined immunodeficiencies (SCID)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Severe combined immunodeficiencies (SCIDs) represent a heterogeneous group of disorders. The most common SCID is X-linked and, therefore, most cases are diagnosed in male infants.

Defects in T cells

- CD8 lymphopenia can be caused by BLS1 (MHC1 deficiency) and ZAP70 deficiency

- CD4 lymphopenia can be caused by BLS2 (MHCII deficiency), p56lck deficiency,

and HIV infection
- see more examples in the figure below

When diagnosing SCID, focus on B and NK phenotype because T cells are aslmost always absent/deficient with few exceptions.

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

Receptors for each of the following cytokines share the common gamma chain except which one?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: E.

Lack of a signal through which cytokine receptor accounts for the lack of T cell maturation in X-linked SCID?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: B.

Lack of a signal through which cytokine receptor accounts for the lack of NK cell maturation in X-linked SCID?

A. IL-2

B. IL-7

C. IL-9

D. IL-15

E. IL-5

Answer: D.

References

Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005 May;94(5 Suppl 1):S1-63.

Algorithm 1: General Approach for the Diagnosis of Primary Immunodeficiency

Algorithm 2: Diagnosis of Humoral Immunodeficiency

Algorithm 3: Diagnosis of Cellular and Combined Immunodeficiencies

Algorithm 4: Diagnosis of Phagocyte Defects

Algorithm 5: Diagnosis of Complement Deficiency

Algorithm 6: General Considerations for Therapy of Primary Immunodeficiency

Published: 09/10/2010
Updated: 09/12/2010

Defects in T cells - part of severe combined immunodeficiencies (SCID)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Severe combined immunodeficiencies (SCIDs) represent a heterogeneous group of disorders. The most common SCID is X-linked and, therefore, most cases are diagnosed in male infants.

Defects in T cells

- CD8 lymphopenia can be caused by BLS1 (MHC1 deficiency) and ZAP70 deficiency

- CD4 lymphopenia can be caused by BLS2 (MHCII deficiency), p56lck deficiency,

and HIV infection
- see more examples in the figure below

When diagnosing SCID, focus on B and NK phenotype because T cells are aslmost always absent/deficient with few exceptions.

Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).

References

Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol 2005 May;94(5 Suppl 1):S1-63.

Algorithm 1: General Approach for the Diagnosis of Primary Immunodeficiency

Algorithm 2: Diagnosis of Humoral Immunodeficiency

Algorithm 3: Diagnosis of Cellular and Combined Immunodeficiencies

Algorithm 4: Diagnosis of Phagocyte Defects

Algorithm 5: Diagnosis of Complement Deficiency

Algorithm 6: General Considerations for Therapy of Primary Immunodeficiency

Published: 09/10/2010
Updated: 09/12/2010

Allergic fungal sinusitis (AFS)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Allergic fungal sinusitis is a chronic hyperplastic sinusitis with eosinophilic inflammation. It is associated with fungal allergens. The pathologic features are similar to allergic bronchopulmonary aspergillosis (ABPA). 5%-10% of patients with chronic rhinosinusitis who require surgery have AFS.

Causative fungi include Bipolaris, Curvularia, Alternaria, Drechslera, Helminthosporium, Fusarium, and Aspergillus. The most common cause of AFS is Bipolaris.

Clinical features of AFS

The typical typical patient is a young adult with a history of allergic rhinitis/chronic sinusitis which is refractory to therapy. Nasal blockage becomes worse as nasal polyps enlarge. CT of sinuses shows extensive mucosal disease with complete sinus opacification. There may be blood eosinophilia and elevated serum IgE.

Diagnostic criteria for AFS:

1. chronic sinusitis of at least 6 months with CT or MRI findings
2. nasal polyps
3. typical allergic mucin found at sinus surgery, with absence of tissue invasion
4. fungus in allergic mucin - histopathology/culture

Allergic mucin is often described as "peanut butter".

Treatment of AFS

Treatment consists of of surgical debridement and oral steroids.

Oral corticosteroids are usually initiated before surgery and are for three to four weeks postoperatively.

Antifungal agents have not been shown to significantly modify clinical course.

AFS is a chronic condition that requires life-long therapy. AFS recurrence varies in the range of 10-90%.

Related reading

Atrophic Rhinosinusitis: Progress Toward Explanation of an Unsolved Medical Mystery. Medscape, 2011.

Published: 05/09/2010

Updated: 03/09/2011

Allergic Bronchopulmonary Aspergillosis (ABPA)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Pulmonary Infiltrates with Eosinophilia (PIE) Syndromes are a heterogeneous group of lung diseases.


Pulmonary Infiltrates with Eosinophilia (PIE) (click to enlarge the image).

Allergic Bronchopulmonary Aspergillosis (ABPA)

ABPA occurs in patients with severe asthma who are often steroid-dependent. It occurs in 10% of patients with cystic fibrosis according to some studies ABPA is caused by the spores of Aspergillus fumigatus and is characterized by peripheral eosinophilia and high IgE (greater than 1,000 ng/mL (417 IU/ml)). ABPA is due to fungal colonization, not to local invasion.

T cell predominance in lung diseases:

CD8: hypersensitivity pneumonitis (HP) and COPD

Th2, CD4: Asthma, ABPA, pulmonary eosinophilia

Th1, CD4: granulomatous TB, sarcoid, berylliosis

Allergic Bronchopulmonary Aspergillosis (ABPA) (click to enlarge the image).

ABPA occurs in 1-2% of patients with asthma and 1-15% of patients with cystic fibrosis (CF).

Untreated ABPA rapidly progresses to severe central bronchiectasis and pulmonary fibrosis.

A
ABPA
Asthma
Aspergillus

Diagnosis of ABPA

Essential diagnostic criteria for ABPA:

- asthma
- high IgE (greater than 1,000 ng/mL (417 IU/ml))
- immediate skin test reactivity to A. fumigatus (skin prick test)
- elevated specific IgE to A. fumigatus
- chest CT with central bronchiectasis

ABPA stages

Untreated ABPA evolves through 5 stages:

1. acute phase
2. remission
3. exacerbation
4. steroid-dependent asthma
5. pulmonary fibrosis

ABPA treatment

ABPA treatment is with oral corticosteroids (CS) long term. The typical dose is daily prednisone at 0.5-1 mg/kg until there is a clinical improvement and a resolution of infiltrates on CXR.

The antifungal medication itraconazole can be also be helpful.

The treatment goal is to prevent the development or progression of bronchiectasis and worsening of pulmonary function.

Monitoring of ABPA therapy

Rising IgE levels can predict an ABPA recurrence. Doubling of the baseline IgE often indicates an ABPA exacerbation.

References

Allergy and Immunology MKSAP, 3rd edition.
More Than Asthma: Allergic Bronchopulmonary Aspergillosis. NEJM Images in Clinical Medicine, 08/2008.
Allergic Bronchopulmonary Aspergillosis: Challenges in Diagnosis. Viswanath P. Kurup, PhD, Banani Banerjee, PhD, Paul A. Greenberger, MD, and Jordan N. Fink, MD. Medscape General Medicine, 12/23/1999.
Allergic Bronchopulmonary Aspergillosis. MK Cheezum, CJ Lettieri. Medscape Allergy & Clinical Immunology, 2008.
Allergic Bronchopulmonary Aspergillosis (ABPA). Russell Blair, MD; Jeremy S. Breit, MD; Stephen P. Peters, MD, PhD. Merck Manual, 2008
Allergic Bronchopulmonary Aspergillosis. Ritesh Agarwal. CHEST March 2009 vol. 135 no. 3 805-826.
Aspergillosis. NEJM, 04/2009.

Published: 02/08/2008
Updated: 08/22/2010

Vocal Cord Dysfunction (VCD): Brief Summary

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist, Fort Lauderdale, FL

Definition

Vocal cord dysfunction (VCD) is an upper airway obstruction caused by paradoxical adduction of the vocal cords on inspiration. VCD has also been misleadingly referred to as Munchausen stridor, episodic laryngeal dyskinesia, psychosomatic stridor, and emotional laryngeal asthma. VCD is more accurately described as paradoxical vocal fold motion.

Vocal cord dysfunction (VCD) is the paradoxical adduction of vocal cords during inspiration - normally, the vocal cords should abduct, or open during inspiration. VCD is often called an “asthma imitator” as these patients are often labeled as having a treatment-resistant asthma.

Laryngoscopic view of normal vocal folds. Image source: Wikipedia, Gray's Anatomy, public domain.

Etiology

The exact cause and pathogenesis of vocal cord dysfunction (VCD) remain unclear. Laryngeal hyperresponsiveness likely plays a role in a subset of patients. The origin and pathogenesis of VCD need to be better defined.

Symptoms of VCD

Vocal cord dysfunction (VCD) symptoms include:

- difficulty in breathing-in” - dyspnea on inspiration

- “fighting for breath”

- Wheezing, often inspiratory

- Stridor - inspiratory by definition
- Hoarse voice
- Dysphonia
- Chest or throat tightness
- Cough

Patients have described choking or stridor, and the stridorous sounds are loudest above the throat.

The typical patients with VCD is:

- Young female "overachiever" and/or athlete
- Middle-aged woman with some psychiatric history (anxiety or deppression) or occupation in health care

Diagnosis of VCD

Physical examination in VCD often shows inspiratory wheezing over larynx. Bronchodilators can paradoxically worsen the wheezing.

Spirometry not very helpful

Some findings on spirometry are often interpreted to suggest VCD, but recent studies have had varying results on how useful these are in the diagnosis of VCD. Spirometry may show reduced FEV1 and FVC with a preserved ratio and "blunted" inspiratory loop.

Rhinolaryngoscopy

The diagnosis is made with fiberoptic laryngoscopy while patient is symptomatic.

Diagnosis is made by direct visualization of the adduction of the vocal cords via rhinolaryngoscopy. However, the method used to provoke symptoms and adduction varies.

The standard for diagnosing VCD is to see adduction of the vocal cords during inspiration while the patient is having symptoms. This is done by flexible fiberoptic rhinolaryngoscopy. Seeing complete adduction of the vocal cords on inspiration with the formation of a small, posterior, diamond-shaped glottic chink is pathognomonic but seen in only 6% of cases.

Laryngoscopic evidence of VCD is found in 60% of patients during quiet respiration.

If vocal cords appear normal during laryngoscopy, several methods have been used to provoke symptoms:

- methacholine or histamine

- exercise

- breathing maneuvers (pant, breathe deeply, phonate, cough, sniffling)

Treatment of VCD

The early recognition and treatment of VCD are imperative to prevent the misdiagnosis and mismanagement of asthma. In addition, and confusingly, VCD and asthma can occur together.

Breathing exercises

Treatment ov VCD includes breathing exercises (pursed-lip breathing). Relaxation techniques, such as pursing lips, panting, and relaxing shoulders, should be implemented (see a list of VCD exercises from Medscape).

Speech therapy

Long-term therapy includes speech and behavioral treatment. In one study of adolescent female athletes, 95% were able to control their symptoms up to 6 months after speech therapy.

Other treatment options

Intermittent positive pressure ventilation (IPPV) may provide short term relief. Botulinum (Botox (R) injections the vocal cords have also been tried. Topical lidocaine spray is another option (aspiration due to decreased sensation may occur).

An anticholinergic inhaler was shown to be effective in some patients.

Long-term treatment of comorbid conditions (eg, proton pump inhibitors for GERD and laryngopharyngeal reflux) is also important.

References

Vocal cord dysfunction: an update. Leslie M. Gimenez, MD, Heidi Zafra, MD. Annals of Allergy, Asthma and Immunology, Volume 106, Issue 4, Pages 267-274 (April 2011).

VCD exercises. Medscape, 2011.

Use of videography in the diagnosis of exercise-induced vocal cord dysfunction: A case report with video clips. JACI, Volume 119, Issue 6, Pages 1329-1331 (June 2007)

Related reading

Olympic athlete hopeful improves her symptoms - and running time - after vocal training for vocal cord dysfunction. Daily Mail, 2011.

Video: Expiratory Vocal Cord Dysfunction and Laryngopharyngeal Reflux. CityAllergy: 62 yr old woman w/spasmodic coughing, wheezing and chronic dyspnea. Her PFTs showed a barely obstructive contour and she did not improve with inhaled or oral steroids. Her endoscopy showed evidence of LPR and posterior kinking of the larynx with expiration (classic VCD has inspiratory kinking).

Differential diagnosis of cough, a simple mnemonic is GREAT BAD CAT TOM. Click here to enlarge the image: (GERD (reflux), Laryngopharyngeal Reflux (LPR), Rhinitis (both allergic and non-allergic) with post-nasal drip (upper airway cough syndrome), Embolism, e.g. PE in adults, Asthma, TB (tuberculosis), Bronchitis, pneumonia, pertussis, Aspiration, e.g foreign body in children, Drugs, e.g. ACE inhibitor, CF in children, Cardiogenic, e.g. mitral stenosis in adults, Achalasia in adults, Thyroid enlargement, e.g. goiter, "Thoughts" (psychogenic), Other causes, Malignancy, e.g. lung cancer in adults).

Published: 05/09/2010

Updated: 01/09/2012

Mind Maps: Occupational Asthma

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology


Occupational Asthma (click to enlarge the image).


Agents associated with occupational asthma (click to enlarge the image).

Published: 05/09/2010
Updated: 09/09/2010

Monoclonal antibodies (mAb)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Monoclonal antibodies are produced by hybridomas. A hybridoma is a product of cell fusion between:

- normal antibody producing B cell (plasma cell)
- myeloma cell

Typically, spleen cells from an immunized mouse are fused with myeloma cells by using polyethylene glycol (PEG) to produce a hybrid cell line called a hybridoma.

Each hybridoma is descended from a single cell and all the antibodies produced by that cell are identical. These antibodies are called monoclonal antibodies (mAbs).

Monoclonal antibodies (mAbs) nomenclature related to sufix

-omab - murine, only of mouse origin. Murine component is 100%

-ximab - chimeric human/mouse. mAb combines murine mAb variable regions with the constant region of human antibody. Murine component is 30%

-zumab - humanized. mAb combines murine mAb variable regions with a portion of a human IgG molecule. Murine component is less than 10%

-umab - "fully" human mAb cloned into a bacteriophage

-cept - fusion of a receptor to the Fc part of human IgG1

Examples of monoclonal antibodies (mAb) in clinical practice

- Rituximab - against CD20. Used in autoimmune diseases, B cell lymphomas
- Anti-CD20 monoclonal antibody ocrelizumab helps patients with relapsing-remitting multiple sclerosis (MS) (Lancet, 2011).

- Omalizumab - againts FcεRI (cε3). Used in asthma
- Adalimumab - against TNF-α. Used in rheumatoid arthritis
- Palivizumab - against RSV. Used to prevent RSV infection in infants with bronchopulmonary dysplasia
- Mepolizumab - against IL-5. Used in hypereosinophilic syndrome and patients with eosinophilic asthma
- Daclizumab - against IL-2 receptor α chain (CD25). Used to prevent renal allograft rejection
- Natalizumab - against α 4 chain of integrin molecule. Used in multiple sclerosis (MS)
- Abciximab - against integrin αIIβ3. Used in acute coronary syndromes (ACS)

Published: 08/12/2008
Updated: 08/25/2011

Neutrophils

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Neutrophils, also called polymorphonuclear leukocytes (PMNs), are the most abundant circulating WBCs. PMNs mediate the earliest phase of inflammatory response.

Granulocytes are CD45+ CD15+ cells.

PMNs migration to tissues

CXCL8 (IL-8) forms a chemotactic gradient that directs leukocytes towards site of tissue injury/infection. Neutrophils are activated by cytokines secreted by Th17 cells.

Neutrophils migrate into tissues via:

- IL-8
- LTB4

- IFNγ

- f-met-leu-phe (fMLP)

-C5a

- interactions between Sialyl-Lewis X, P-selectins and LFA-1/ICAM-1


Neutrophils extravasate from blood vessels to the site of tissue injury or infection during the innate immune response. Image source: Wikipedia, GNU Free Documentation License.

What is the PMN half-life?

6 hours. 100 trillion cells are produced every day by the BM.

What is the most important PMN enzyme?

Elastase.

PMNs do not stain either red (eosinophils) or blue (basophils).


Video: A neutrophil chasing bacteria, set to music.


Phagocyte immunodeficiencies (click to enlarge the image).

References

Phagocyte deficiencies

Published: 06/28/2010

Updated: 07/16/2010

Immunoglobulin E (IgE)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

IgE is involved in immediate hypersensitivity (allergy). It binds to allergens and triggers histamine release from mast cells. It has the lowest serum concentration (mcg rather than mg) and the shortest half-life (2 days) among Ig (GAMED).

Controls of Ig type switch

IgA switching: APRIL, BAFF, TGF-beta

IgE switching: IL-4

IgG switching: IFN-gamma

There are 5 immunoglobulin classes remembered by the mnemonic GAMED: Ig G, A, M, E, D. B-cells are the only cell types that synthesize antibody molecules.


Five immunoglobulin classes (mind map).

In order of their serum concentrations:

IgG 1000 mg/dL
IgA 200 mg/dL
IgM 150 mg/dL
IgD 4 mg/dL
IgE 0.005 mg/dL (extremely low serum concentration compared to other Ig in (GAMED)

Measurement of total IgE is expressed in 1 IU/mL = 2.44 ng/mL.

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.

Ig order of their serum half-life in days:

IgG 21
IgM 10
IgA 6
IgD 3
IgE 2 (shortest half-life among other Ig in GAMED)

Ig structures. Image source: Wikipedia.

Role of IgE and mast cells in allergy. Image source: Wikipedia.

Omalizumab binds to Cε3 region of IgE.

IL-4 and IL-13

IL-4 and IL-13 are cytokines produced by Th2 cells. They up-regulate IgE production and thus increase allergic inflammation. IL-4 is much more potent than IL-13.

I
IL-4
IL-13
Increase
IgE production
Inflammation promoters

Receptors for IgE

High-Affinity IgE Receptor (FcεRI)

The high affinity receptor for IgE (FcεRI) is expressed on mast cells (fixed in tissues) and basophils (circulating in blood). The level of FcεRI expression is regulated by levels of IgE. FcεRI molecule consists of 4 chains: alpha, beta and 2 gamma.

FcεRI is found in 2 forms:

- tetrameric form is composed of one α chain, one β chain, and two γ chains. It is found on mast cells, basophils, eosinophils.

- trimeric form is composed of one α chain and two γ chains. It is found on monocytes and dendritic cells (the β chain is absent).

Some patients with chronic urticaria have IgG directed against the α chain of FcεRI. IgE binds to FcεRI via the α chain.

Low-Affinity IgE Receptor (FcεRII, CD23)

CD23 is the low affinity IgE receptor (FceRII). CD21 (CR2) binds EBV, HHV8, C3d, and CD23 (low affinity IgE receptor (FceRII).

The role of FcεRII is not clear. Variations in the low-affinity IgE receptor gene (FCER2 or II) are associated with an increase in severe exacerbations in children with asthma. There are several reasons that a patient may not respond to inhaled corticosteroid therapy in asthma and genetics, including FCER2 variants, may be an important one.

Variations in some of the SNPs were associated with increased IgE levels and increased risk of severe exacerbations of asthma during inhaled corticosteroid treatment. Therefore, FCER2 variations may lead to asthma exacerbations despite inhaled steroids. Personalized medicine via pharmacogenetics can lead to genetic studies guiding therapeutic decisions in the future.

Anti-IgE (omalizumab, Xolair) is approved for treatment of severe persistent asthma. There are occasional case reports of anti-IgE (omalizumab) use as a new therapeutic approach for chronic rhinosinusitis. Omalizumab binds to Cε3 region of IgE.

There is a correlation between IgE titres and the severity of clinical reaction to egg after the diagnosis has been established. A cut-off level of 8.20 kU/l had a 90% probability of clinical reactivity. IgE titres may help determine which patients are at risk of a reaction to eggs.

Higher levels of IgE are associated with more severe asthma (the cut-off level is 100 IU/mL). IgE level is inversely correlated with baseline lung function and asthma severity.

ImmunoCAP Immunoassay

The ImmunoCAP method was developed by Phadia. It utilizes a “sandwich” ELISA technique:

1. The ImmunoCAP sponge has allergen bound to it and serves as the first piece of bread ("bottom half").

2. Patient serum is added and specifc IgE to that allergen binds to the allergen on the sponge - this is the "meat" of the ELISA sandwich.

3. All of the unbound protein is washed away abd anti-IgE is added - this binds to the sIgE that was captured by the sponge in step two. The anti-IgE conjugate is the "second piece of bread" ("top half").

Allergen-specific IgE levels are not comparable between different laboratory methods - for example, ImmunoCAP vs. DPC Immulite 2000. Predictive values of specific IgE levels published in the literature for management of food allergies are based on studies using the ImmunoCAP assay. These predictive values cannot be applied to specific IgE levels from other assay systems.

Conditions with elevated IgE

Atopic dermatitis, Asthma, ABPA, and allergic fungal sinusitis

Infections (parasites, HIV, TB, EBV, and CMV)

Malignancy (IgE myeloma and lymphoma)

Churg-Strauss syndrome

Kimura’s disease, painless, unilateral cervical lymphadenopathy or subcutaneous masses in the head or neck region

Immunodeficiency diseases with elevated IgE

Hyper IgE syndrome (HIES)

Wiskott-Aldrich syndrome (WAS)

Omenn syndrome

DiGeorge syndrome (DGS)

Netherton syndrome, form of ichthyosis associated with SPINK5

Nezelof syndrome, congenital hypoplasia of the thymus with retention of normal parathyroid function (in contrast to complete DiGeorge syndrome in which there is absence of the parathyroids)

References

Allergy blood testing: A practical guide for clinicians - CCJM review, 2011.

Published: 06/28/2010

Updated: 09/16/2011

Mononuclear Phagocytes (Monocytes)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Mononuclear phagocytes circulate in the blood as monocytes and reside in all tissues of the body as macrophages.

Macrophages differentiate into specialized forms in different tissues remembered by the mnemonic KOMA:

Kupffer cells (liver)
Osteoclasts (bone)
Microglia (CNS)
Alveolar macrophages (lung)

Monocytes turn into macrophages once they enter tissues. Dendritic cells are not the same as macrophages. Monoblasts give rise to both macrophages and dendritic cells.

Monocytes express CD14 and CD16. They migrate to peripheral tissues via VLA-4/VCAM-1 interactions. Monocytes express CD14, CD11b/CD18 (Mac-1), and CD36.

Monocytes are CD45+ CD14+ cells. Granulocytes are CD45+ CD15+ cells.

CD14 is present on macrophages. CD14 is the first described pattern recognition receptor (PAMP receptor) and it binds to bacterial LPS.

TLR4 (for LPS)

CD14

CD16 is FcγRIII, a low-affinity Fc receptor for IgG. CD16 is found on NK cells, macrophages, and neutrophils.

Fc gamma receptors for IgG are CD 16, 32, 64 (double). Fc gamma receptors for IgG (CD 16, 32, 64) are labeled in "reverse" order:

CD 16 - FcR III - low-affinity

CD 32 - FcR II - intermediate-affinity

CD 64 - FcR I - high-affinity

CD16 and CD56 are present on NK cells.

Fc II receptors:

CD 32 - Fc gamma II

CD 23 - Fc epsilon II, Fc receptors for IgE

Hemophagocytic lymphohistiocytosis (HLH)

Hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome is an uncontrolled activation of macrophages with increase in circulating cytokines. This potentially life-threatening disease is

characterized by fever, hepatosplenomegaly and high ferritin. Hemophagocytosis can often be seen on bone marrow

biopsy.

In boys with X-linked lymphoproliferative (XLP) syndrome (Duncan’s syndrome), HLH is often a fatal complication of Epstein-Barr virus (EBV) infection.

Related reading

Interferon regulatory factor 8 (IRF8) Mutations and Human Dendritic-Cell Immunodeficiency. NEJM, 2011.

Published: 05/18/2009

Updated: 09/20/2011

T Helper Cells

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

CD4 T cells make 60% of circulating T cells. CD4 T cells are cytokine-secreting helper cells. They recognize antigens only through MHC II -- the antigen has to be ingested and degraded by antigen-presenting cells (APC) and presented on the cell surface via MHC II molecules.


Schematic representation of MHC class II. Image source: Wikipedia.


MHC Class II Processing. This video describes the assembly of MHC Class II molecules. This video is from: Janeway's Immunobiology, 7th Edition, Murphy, Travers, & Walport. Source: Garland Science.

The CD4 molecule is a protein of the immunoglobulin superfamily. The HIV virus binds to CD4 via its gp120 and therefore is has a special predilection for infecting CD4 cells.


Diagram of HIV. Image source: Wikipedia.

CD4/CD8 ratio is a sensitive marker to predict HIV infection in infants. Shearer et al. analyzed HIV-exposed infants and found that a CD4/CD8 ratio of 1.8 or less at 3 months of age was more sensitive than CD4+ T-cell counts to predict HIV infection. This finding may be useful to help HIV diagnosis in poorer countries without access to virology laboratories.

Th1 and Th2 Cells

CD4 helpers are divided into Th1 and Th2 subsets. The differentiation into Th1 or Th2 is driven by cytokines (IL2, IL4) which upregulate STAT molecules (signal transducers and activators of transcription).

Th1

Th1 cells participate in cell-mediated immunity (delayed type hypersensitivity reactions and killing of intracellular
pathogens), autoimmune diseases (e.g. RA, MS).

Th2

Th2 cells participate in humoral immunity via activation of B cells. They play an important role in allergic inflammation (e.g. asthma, allergic rhinitis) via activation of mast cells andeosinophils. Th1/Th2 bias is a term which describes whether Th1 or Th2 response is predominant.

Th
I
Infection
Intracellular pathogens
Immune diseases, i.e. autoimmune diseases
Inflammatory bowel disease (IBD)

Th2
Antibodies, i.e. humoral immunity
Allergy
Asthma
Allergic rhinitis


Th1 and Th2 subsets (mind map)

Early childhood immunizations have been viewed as promoters of asthma by:

- stimulating a TH2-type immune response
- decreasing "microbial pressure," thus shifting the balance between TH1 and TH2 immunity

Number of CD4 T cells /mcL is different in children and adults

Adults, older than 18 years
More than 500

Children - depends on age

0-1 year
More than 1500

1-5 year
More than 1000

6-12 year
More than 500

The hygiene hypothesis

Decreased atopic sensitization associated with living in a farm was explored by studying bacteria found in cowsheds. Acinetobacter lwoffii and Lactococcus lactis shifted the immune response toward the secretion of TH1 cytokines in a murine model. One begins to wonder if biotherapy with bacterial extracts would be in the future of studies of allergy prevention.

T helper cells (click to enlarge the image).


Regulatory T cells - 6 groups have been described as of year 2010 (click to enlarge the image).

Published: 06/28/2010
Updated: 08/16/2010

Pathogen-associated molecular patterns (PAMPs) and receptors (PRRs)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Pathogen-associated molecular patterns (PAMPs)

Microbial products which stimulate innate immunity are called pathogen-associated molecular patterns (PAMPs). Pathogen-associated molecular patterns (PAMPs) are on bacteria - they bind to receptors called pattern recognition receptors.

Innate immunity reacts to these common bacterial structures - PAMPs, pathogen-associated molecular patterns. PAMPs are produced only by the bacterial invader and not by the host. If it were the other way around, innate immunity would get "confused" and attack the host instantly and immediately as it is typical of its nature.

PAMPs include:

- lipopolysaccharides (LPS) on Gram-negative bacteria
- lipoteichoic acid on Gram-positive bacteria

- peptidoglycans
- mannan
- bacterial RNA and DNA
- glucan

Receptors that bind these PAMPs are called pattern recognition receptors (PRRs). PAMPs are unique to microbes. Mammalian cells do not have PAMPs and this one of the reasons why there is no autoimmune disease caused by innate immunity.

For example, human cells do not have mannose - bacteria do. Receptors recognize mannose on bacteria - and this starts the mannose-lectin complement pathway.

Mannose is one of the PAMPs. TLRs are pattern recognition receptors.

Example of a match: ligand-receptor: mannose (bacteria)-mannose-binding lectin (MBL) (soluble recognition molecule in humans)

Mannose-binding lectin (MBL) starts the third complement pathway. MBL is plasma protein that functions as an opsonin.

APC (macrophages) have PAMPs-recognition receptors, called pattern-recognition receptors in short.

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

PAMPs Recognition Receptors (PRR)

There are 4 PAMPs receptors remembered by the mnemonic: T-CNS

Toll-like receptors (TLR)
C-type lectin receptors (CLR)
N-formyl Met-Leu-Phe receptors (fMLP)
Scavenger receptors

Caspase activation and recruitment domains (CARD)
Nucleotide-binding oligomerization domains (NODs) (NLR or NACT-LRR)

Pattern-recognition receptors (PRR) (molecules) are divided into 3 groups: SES

Secreted
Endocytic
Signaling

C-type lectins

C-type lectins are calcium-dependent carbohydrate-binding molecules expressed on the plasma membranes of macrophages and other cells.

The best known C-type lectin is the mannose receptor. Mannose-binding receptor binds to bacterial carbohydrates. It activates the 3rd complement pathway.

Another C-type lectin is Dectin1.

C
C-type lectins
Calcium-dependent
Carbohydrate-binding molecules

C-type lectins:

- Mannose-binding
- Dectin

Secreted pattern-recognition molecules bind to microbes (opsonization) and make them "tastier" to phagocytes. An example of secreted pattern-recognition molecules is a mannose-binding protein (lecithin). These molecules are associated with serine proteases MASP (mannose-binding lectin-associated serine proteases).

Scavenger receptors

One scavenger receptor, SRB1, is involved in atherogenesis. Scavenger receptors mediate the uptake of oxidized lipoproteins into cells.

NF MLP

N-formyl Met-Leu-Phe (NF MLP) receptors are the most chemoattractive (chemotactic) receptors for PMNs.

N
NF MLP
Neutrophil chemoattractant

All chemokines are proteins.
All chemokines are chemoattractants but not all chemoattractants are chemokines. For example PGD-6 is a chemoattractant but not a chemokine, it is a prostaglandin not a protein.

NLRs

NLRs (NACHT-LRRs) are a family of cytoplasmic molecules.

CARD

Caspase activation and recruitment domain (CARD)-containing proteins. Homozygous mutations in the CARD9 gene are associated with chronic mucocutaneous candidiasis. Dysfunction of CARD9 impairs the innate signaling of dectin-1, an antifungal pattern-recognition receptor (NEJM, 10/2009).

Related reading

Immunodeficiency and Genetic Defects of Pattern-Recognition Receptors. Mihai G. Netea, M.D., Ph.D., and Jos W.M. van der Meer, M.D., Ph.D. N Engl J Med 2011; 364:60-70, January 6, 2011.

Published: 06/28/2010

Updated: 01/08/2011

Organ Transplantation

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago

Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Transplant rejection - reaction types

- Hyperacute rejection is due to deposition of neutrophils, endothelial damage, and thrombosis. It is mediated by preformed ABO natural antibodies, HLA antibodies, and complement. It occurs within minutes to hours within the first day of transplantation.

- Accelerated rejection is due to vascular disruption and hemorrhage. It is mediated by non-complement fixing antibodies, NK cells, and monocytes. It occurs over the course of 3-5 days after transplantation.

- Acute rejection is due to tubulitis (in kidney transplants), interstitial inflammation, parenchymal
cell damage, and endovasculitis. It is mediated by T cells and antibodies.

- Chronic rejection is due to intimal proliferation and vessel occlusion. It is mediated by antibodies. It takes place over months to years.

High risk groups for hyperacute and accelerated rejection:

- multiparous women
- recipients of multiple blood transfusions

Stimulation of CD4+ T cells through antigen receptor is not sufficient to initiate activation. Activation of CD4+ T lymphocytes needs co-stimulation via the APC.

T cell vs. ligand combinations for activation of CD4+ T cells

CD40L -- CD40
CD28 -- CD80 or CD86

Medications

Cyclosporine and tacrolimus interfere with activating process involving T cell receptors and costimulatory molecules CD28 and CD80 or CD86. Together with tacrolimus, cyclosporine is a calcineurin inhibitor (CNI).

Cyclosporine binds to the cytosolic protein cyclophilin (an immunophilin) of lymphocytes, especially T-lymphocytes. This complex of cyclosporin and cyclophilin inhibits calcineurin, which normally induces the transcription of interleukin-2.


Ciclosporin (INN), cyclosporine (USAN) or cyclosporin (former BAN). Image source: Wikipedia, public domain.

Cyclosporine and FK-506 block T cell cytokine production by inhibiting activation of the NFAT transcription factor (note: different from NFkB).

Tacrolimus (FK-506 or Fujimycin, trade name Prograf) is a product of the fungus Streptomyces tsukubaensis. It is a macrolide lactone and acts by inhibiting calcineurin.


Tacrolimus. Image source: Wikipedia, public domain.

It binds to the immunophilin FKBP1A, followed by the binding of the complex to calcineurin and the inhibition of its phosphatase activity. In this way, it prevents the cell from transitioning from the G0 into G1 phase of the cell cycle. Tacrolimus is more potent than cyclosporine and has less pronounced side-effects.

What is the molecule that tacrolimus binds to in order to exert its therapeutic effect?

(A) NFkB

(B) calcium

(C) ipraimmunophilin

(D) NFAT

(E) calcineurin

(F) calmodulin

(G) AP-1

Answer: E.

Acute rejection typically occurs after:

A. minutes to hours

B. 3 months

C. one week

D. after long-term follow-up

Answer: C.

Related reading

Desensitization protocols may overcome incompatibility barriers in renal transplantation, NEJM, 2011.

Published: 06/28/2010

Updated: 07/16/2011

Food Protein Induced Enterocolitis Syndrome (FPIES)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor, University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist, Fort Lauderdale, FL

Food Protein Induced Enterocolitis Syndrome (FPIES) is a non-IgE mediated immune reaction in the gastrointestinal system to one or more specific foods, commonly characterized by profuse vomiting and diarrhea. Poor growth may occur with continual ingestion of the offending foods. Upon removing the problem food, all FPIES symptoms generally subside.

Pathology

Mediators released by T lymphocytes result in inflammation and vascular leakage in this non-IgE-mediated reaction. TNFα has also been implicated in food protein-induced enterocolitis (FPIES).

Adult non-IgE reactions to shellfish may be the same process as pediatric FPIES. Milk protein enteropathy looks similar to celiac disease, but it usually self-limiting.

Deficit in TGF-beta (and its receptors) may be important in development of FPIES. Increased TNF-alpha also seems to be important for FPIES.

Clinical features

FPIES presents with vomiting and diarrhea, and may progress to shock. It starts early in infancy.

In a large birth cohort from Israel, the cumulative incidence for FPIES was 0.34%.

The most common symptoms were:

- recurrent vomiting (100%)

- lethargy (77%)

- diarrhea (25%)

- pallor (14%)

- bloody diarrhea (4.5%).

All patients had FPIES within the first 6 months of life.

By the age of 3 years, 90% of the patients had recovered. There is 50% resolution per year for milk-induced FPIES.

There were no concomitant reaction to soy.

The prevalence of FPIES is significant, and its clinical presentation is distinct from that of IgE-cow's milk allergy (CMA).

Most patients with FPIES recover, although a proportion might convert to IgE-CMA. The likelihood for a cross-reactivity to soy in this population was less than previously estimated.

References

FPIES: Food Protein Induced Enterocolitis Syndrome. Patient Information: http://bit.ly/qad8q

The prevalence and natural course of food protein-induced enterocolitis syndrome to cow's milk:

A large-scale, prospective population-based study. J Allergy Clin Immunol. 2011 Mar;127(3):647-653.e3.

Related reading

Understanding FPIES Through Moms Sharing Their Stories. Nutricia Neocate blog, 2011.
International Association for Food Protein Enterocolitis (IAFFPE)

Published: 06/28/2010
Updated: 01/16/2012

Regulatory T cells

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

These cells were formerly known as suppressor T cells. The "classic" T regulatory cells (T-regs) express CD4, CD25 and FOXP3.

FOXP3 (forkhead box P3) functions as the master regulator in the development and function of regulatory T cells. FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. The fork head domain is a type of protein domain which is often found in transcription factors and whose purpose is to bind DNA.

CD25 is interleukin-2 receptor alpha chain (IL-2Ra). The IL-2 receptor (IL-2R) was the first interleukin receptor to be described and characterized. Daclizumab (Zenapax) is a humanized monoclonal antibody to the alpha subunit of the IL-2 receptor of T cells (anti-IL2Ra). It is used to prevent rejection in organ transplantation, especially in kidney transplants.

Regulatory T cells - 5 groups have been described as of year 2010:

- CD4+CD25+ regulatory T cells ("classic" T regs)
- TR1 cells, CD4 cells that secrete IL-10

- Th3 cells, a subset of CD4+ cells that secrete TGF-b
- CD8+ suppressor T cells
- γ/δ T cells


Regulatory T cells - 6 groups have been described as of year 2010 (click to enlarge the image).

Related reading

Redirecting T Cells - NEJM, 2011.

Published: 06/28/2010
Updated: 07/16/2011

Interleukin-3 (IL-3)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: CD4 T cells.

Receptors: Type I cytokine receptor family. Signal transduction involves Jak-STAT.

Erythropoietin (Epo) is produced in the kidney in response to low oxygen tension. Epo works through a type I cytokine receptor that signals through Jak2-STAT5.


(click to enlarge the image)

IL-3 effects: IL-3 promotes the growth and development of mast cells from bone marrow.

IL-3 is a basophil differentiating cytokine vs. stem cell factor (c-Kit ligand) which is a mast cell growth factor.

Published: 04/09/2010
Updated: 08/09/2010

Severe asthma in children - differential diagnosis and management

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Asthma is the most common chronic respiratory disease, affecting up to 10% of adults and 30% of children (JACI, 2011).



Severe asthma - differential diagnosis and management (click to enlarge the image). Related: Common Asthma-related Comorbidities. Medscape, 2011, (figure).

If asthma treatment is not working, check DAT:

- Diagnosis - not asthma at all (VCD, CF, FBA), asthma plus AR, GERD

- Adherence - compliance with medication - 24% of asthma exacerbations are attributable to ICS medication nonadherence (http://goo.gl/1i8ET). Poor adherence to asthma medications (less than 80%) was seen in 75% of children (JACI, 2011).

- Technique - NEB, HFA with spacer, DPI, etc.

3 C's of care - communication, continuity, concordance (finding common ground) are critical for asthma management (http://goo.gl/8gJM6).

Children who are referred to specialist care with asthma that does not respond to treatment (problematic severe asthma) are a heterogeneous group.

In many children with severe asthma, the diagnosis is wrong or adherence to treatment is poor. Therefore, the first step is a detailed diagnostic assessment to exclude an alternative diagnosis (“not asthma at all”), followed by a multidisciplinary approach to exclude comorbidities (“asthma plus”) and to assess whether the child has difficult asthma (improves when the basic management needs, such as adherence and inhaler technique, are corrected) or true, therapy-resistant asthma (still symptomatic even when the basic management needs are resolved). In particular, environmental causes of secondary steroid resistance should be identified.

Licensed therapeutic approaches include:

- high-dose inhaled steroids and LABA

- Symbicort maintenance and reliever (SMART) regimen (with budesonide and formoterol fumarate)

- anti-IgE therapy

Unlicensed treatments include methotrexate, azathioprine, ciclosporin, and subcutaneous terbutaline infusions.

Pediatric data are needed on cytokine-specific monoclonal antibody therapies and bronchial thermoplasty.


Asthma Inhalers (click to enlarge the image).

Inhaled corticosteroid (ICS)

Relative binding affinity for glucocorticoid receptor (GR): mometasone > fluticasone > budesonide > triamcinolone.

Relative anti-inflammatory potency: mometasone = fluticasone > budesonide = beclomethasone > triamcinolone.

References

Management of severe asthma in children. Prof Andrew Bush MD, Sejal Saglani MD. The Lancet, Volume 376, Issue 9743, Pages 814 - 825, 4 September 2010.

Evidence-based asthma management in children — what’s new? MJA 2011; 194 (8): 383-384.
One in 20 children has severe asthma that doesn't respond to standard therapies. http://goo.gl/omDI

An approach to recalcitrant, severe asthma - AAAAI Ask the Expert, 2011.

Common Asthma-related Comorbidities. Medscape, 2011, (figure) http://j.mp/qJqwNY and http://j.mp/omHVc6
24% of asthma exacerbations are attributable to ICS medication nonadherence (http://goo.gl/1i8ET)
Single inhaler therapy in asthma (SMART) linked to poor day-to-day control of symptoms and increasing inflammation. Clin Exp Allergy. 2012 Jan 18.

Published: 09/03/2010

Updated: 01/08/2012

Mind Maps: Atopic Dermatitis

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist

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

Allergic (atopic) march (click here to enlarge the image).

Related reading:

Adult atopic eczema - from patient's and doctor's practical point of view - BMJ, 2011.

Published: 01/24/2010
Updated: 10/03/2011

Interleukin-6 (IL-6)

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Source: monocytes, endothelial cells, fibroblasts. IL-6 is produced in response to IL-1 and TNF.

Receptor: IL-6 binds to a type I cytokine receptor and the signaling pathway involves Jak1 and STAT3 activation.

Cytokine receptors (click to enlarge the image).

IL-6 effects

IL-6 (and IL-1 via IL-6) stimulates synthesis of acute phase protein by the liver (CRP, etc.)

IL-6 and IL-1 stimulate production of neutrophils (PMNs) by the bone marrow. IL-6 is a growth factor for plasma cells in myeloma.

Medications

Humanized IL-6Ra or tocilizumab (Actemra) is used for treatment of rheumatoid arthritis and Castleman’s disease. Castleman's disease is an uncommon lymphoproliferative disorder defined as angiofollicular lymph node hyperplasia.

IL6R and chromosome 11q13.5 have been identified as risk loci for asthma, and an IL6R antagonist (tocilizumab) may be effective therapy (Lancet, 2011).

References

Cytokine Receptors

Published: 04/09/2010
Updated: 08/09/2011

SYK tyrosine kinase

Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago
Reviewer: S. Randhawa, M.D., Allergist/Immunologist and Assistant Professor at LSU (Shreveport) Department of Allergy and Immunology

Spleen tyrosine kinase (SYK) is known to have a crucial role in adaptive immune receptor signalling. Syk is the ZAP-70 analog in B cells.

However, recent reports indicate that SYK also mediates other, unexpectedly diverse biological functions, including cellular adhesion, innate immune recognition, osteoclast maturation, platelet activation and vascular development. SYK is activated by C-type lectins and integrins, and activates new targets, including the CARD9–BCL-10–MALT1 pathway and the NLRP3 inflammasome.

There is an evolutionarily ancient origin of SYK-mediated signalling. Moreover, SYK has a crucial role in autoimmune diseases and haematological malignancies.

The SYK tyrosine kinase is an evolutionarily ancient crucial player in diverse biological functions.

T cell activation involves all of the following steps EXCEPT:

A. RAS- MAPK pathway

B. activation of Syk

C. activation of NFAT

D. activation of Protein Kinase C

Answer: B. Syk is part of the B cell activation. ZAP-70 is its equivalent in T cells.

References

The SYK tyrosine kinase: a crucial player in diverse biological functions. Nature Reviews Immunology 10, 387-402 | doi:10.1038/nri2765

Published: 08/29/2009
Updated: 08/29/2010

Mnemonics

Mnemonics are memory tools, for example, medications for acute management of anaphylaxis can be remembered by the mnemonic EASI:

Epinephrine
Antihistamines
Steroids
Inhaled b2-agonists, if wheezing. IV fluids, if hypotensive.

Click here to see the full list of mnemonics in allergy and immunology.