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
Deficiencies of almost all complement components have been reported but most are very uncommon. C2 deficiency is most common, at 1:10,000.
Complement deficiencies (click to enlarge the image).
What is CH50?
All 9 components of classical pathway (C1-C9) are required for a normal CH50 value, which is 150 to 250 units/mL.
CH50 of 200 units/mL means that a serum sample diluted 1:200 lysed 50% of the antibody-coated sheep erythrocytes in the test mixture.
SLE
SLE is seen much more frequently with deficiency of C1q than any other complement
deficiency
Terminal Complement Deficiency
Terminal complement deficiency is associated with disseminated Neisseria infections and may be associated with various autoimmune diseases. Lysis, not merely opsonization, is required to clear Neisseria infection. These patients have normal C3 levels.
Related Reading
Chapter 6: The Complement System, Part 1 and Part 2. Allergy and Immunology Review Corner: Chapter 6, Part 1 of Middleton’s Allergy Principles and Practice, 7th Edition, edited by N. Franklin Adkinson, et al. FIT Corner Q&A. Mnemonics: Complement
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
Phagocyte immunodeficiencies (click to enlarge the image).
Hyper-IgE syndrome (HIES) is a complex primary immunodeficiency characterized by atopic dermatitis associated with extremely high serum IgE levels and susceptibility to infections of the lung and skin with extracellular bacteria.
HIES is associated with heterozygous dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) and severe reductions of T(H)17 cells.
Genetic basis:
- Dominant-negative mutations in the signal transducer and activator of transcription 3 (STAT3) gene result in the classical multisystem form of HIES - A null mutation in the tyrosine kinase 2 (TYK2) gene causes an autosomal recessive HIES associated with viral and mycobacterial infections
Signal transduction for multiple cytokines, including IL-6 and IL-23, is was defective, resulting in impaired TH17 function.
Clinical features of HIES
- Recurrent infections of the lower respiratory system and skin - Chronic eczema - Extremely elevated IgE levels - Eosinophilia
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 patients with HIES are not neutropenic. Neutrophils engulf and kill bacteria normally but they do have intermittent chemotactic defects in 80% of cases. Inflammatory cytokine production is impaired and inflammation is minimal leading to cold (non inflamed) abscesses.
Nonimmunological abnormalities include:
- distinctive facial appearance - fracture following minor trauma - scoliosis - hyperextensive joints - retention of deciduous teeth
In HIES, there is hypertelorism, prominent mandible, broad nasal bridge, wide nasal tip, and increased interalar distance (a larger distance between alae nasi) ("boxer's nose").
In HIES, lung abscesses are almost always staphylococcal. A pneumatocele often develops, and becomes a substrate for superinfections with Aspergillus and Pseudomonas.
Patients with HIES characteristically will have a pneumatocele on chest X-ray.
Laboratory findings in HIES
- IgE is usually above 2000 IU/ml - T cell dysfunction may underlie the excessive production of IgE - IgG is normal - Antibody responses to polysaccharide and protein antigens are abnormal - Eosinophilia is common
A combination of 5 clinical features predicted STAT3 mutations with 85% accuracy.
Diagnostic guidelines for STAT3-deficient HIES:
- Possible: IgE greater than 1000 IU/mL plus a weighted score of clinical features greater than 30 based on recurrent pneumonia, newborn rash, pathologic bone fractures, characteristic face, and high palate.
- Probable: These characteristics plus lack of T(H)17 cells or a family history for definitive HIES.
- Definitive: These characteristics plus a dominant-negative heterozygous mutation in STAT3.
How to make the diagnosis of HIES from a practical point of view?
A clinical diagnosis is made based on the classic manifestations and laboratory tests such as elevated IgE levels and hypereosinophilia. A specific confirmatory diagnosis would require demonstration of one of the following genetic defects:
- dominant mutations in signal transducer and activator of transcription 3 (STAT3)
- mutations in the tyrosine-kinase 2 gene (Tyk2)
- autosomal recessive mutations in DOC8
However, no commercial labs are offering these tests as of year 2010. Research laboratories might be willing to perform the assays.
Treatment of HIES
Anti-staphylococcal antibiotics long-term. The prognosis is generally good for those who undergo treatment.
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
Hyper-IgE syndrome. Yoshiyuki Minegishia. Current Opinion in Immunology, 2009. doi:10.1016/j.coi.2009.07.013
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
Phagocyte immunodeficiencies (click to enlarge the image).
In leukocyte adhesion deficiency type III, there is a normal expression, but defective activation of β1, β2, and β3 integrins suggesting defect in one or more intracellular signaling molecules.
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
Phagocyte immunodeficiencies (click to enlarge the image).
There is inability to put sialyl-LewisX cap on leukocytes. Sialyl LewisX (SLeX) is a tetrasaccharide carbohydrate attached to O-glycans on the surface of the cells that plays a vital role in cell-cell recognition processes. Sialyl Lewis X is also a blood group antigen.
Sialyl LewisX. Image source: Wikipedia, public domain.
Sialyl Lewis X determinant, E-selectin ligand carbohydrate structure, is expressed on granulocytes and monocytes and mediates extravasation. Defective synthesis of Sialyl Lewis X can be caused by defects in fucose metabolsims.
Fucose is a hexose deoxy sugar. Image source: Wikipedia, GNU Free Documentation License.
CD15 F Fifteen Fucose, Sialyl LewisX (SLeX) FucT-1 gene
LAD 2 is a rare, AR disease due to an absence of fucosylated carbohydrate ligands that leads to a defective rolling of hematopoietic cells.
Glycans that incorporate fucose - SLex (CD15a) and H antigen (Bombay) are not expressed on cells.
Treatment of LAD 2
Fucose supplementation - a trial recommended in all LAD 2 patients. Fucose has been only administered to a handful of patients with one successful case.
Adhesion Molecules
Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS.
LAD type 1 is a problem of PMNs binding to integrins (LAF-1). Integration (tight adhesion) is the second phase of the PMN recruitment (see the "SIP" mnemonic below). LAD type 2 is a problem of PMNs binding to selectins. Selection ("rolling") is the first phase of the PMN recruitment (see the "SIP" mnemonic below).
Neutrophils (PMN) are the most numerous among peripheral leukocytes (70%) and are the first line of defense against pathogens. PMN circulate in the blood for only 6 hours. PMN migration is regulated via adhesion molecules.
Recruitment of Leukocytes to Sites of Infection
SIP of wine: Selectins Integrins Penetration of BM by PMN
Selectins are first in the chain of events. They upregulate TNF and IL-1. Integrins cause release of VCAM and VLA.
Adhesion molecules, 3 groups = SIS Selectins Integrins Superfamily Ig
LAD type 1 is a problem of PMNs binding to integrins (LAF-1). Integration (tight adhesion) is the second phase of the PMN recruitment (see the "SIP" mnemonic above). LAD type 2 is a problem of PMNs binding to selectins. Selection ("rolling") is the first phase of the PMN recruitment (see the "SIP" mnemonic above).
Selectins
The name selectin comes from the words "selected" and "lectins." Selectins are a type of carbohydrate-recognizing proteins.
There are 3 groups of selectins = LEP L-selectins, CD62L Leukocytes
E-selectins, CD62E Endothelial cells
P-selectins, CD62P Platelets
Selectin E (endothelial adhesion molecule 1). Image source: Wikipedia.
CD62E - E-selectin is a cell adhesion molecule expressed only on endothelial cells activated by cytokines.
CD62L - L-selectin is a cell adhesion molecule found on leukocytes.
CD62P - P-selectin is a cell adhesion molecule (CAM) found in granules in endothelial cells (cells lining blood vessels) and activated platelets.
Leukocyte adhesion deficiency II (LAD2 ) is characterized by which of the following?
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
Phagocyte immunodeficiencies (click to enlarge the image).
First recognized as a distinct clinical entity in the 1970s. The classic descriptions of LAD included recurrent bacterial infections, defects in neutrophil adhesion, and a delay in umbilical cord sloughing. The defects in adhesion result in poor neutrophil chemotaxis and phagocytosis.
LAD 1
CD18 is a beta chain common to all members of beta 2 subclass of integrins.
CD11a, CD11b, and CD11c are alpha chains associated with LFA-1, Mac-1, and p150,95:
- Lymphocyte function associated antigen-1 (LFA-1, CD11a/CD18)
In LAD 1, there is a leukocytosis due to inability of neutrophils to marginate.
Clinical features of LAD 1:
Lack of pus formation at sites of infection Recurrent soft tissue infections Delayed umbilical cord separation Severe periodontal disease
LAD 1 diagnosis is by flow cytometry for CD18 and heterodimers CD11a/b/c.
Rolling Adhesion. This video describes the way in which leukocytes bind to the blood vessel endothelium. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
Leukocyte Extravasation. This video describes how a leukocyte moves out of the endothelium of a blood vessel. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.
CD18
The inherited molecular defect in patients with LAD is a defect in CD18. CD18 is the β2 chain (β-2 integrin subunit) common to LFA-1 and MAC-1.
CD18 is involved in making 3 proteins (LFA-1, Integrin alphaXbeta2, and MAC-1/CR3). The defect results in the lack of important molecules which help neutrophils make their way from the blood stream into the infected areas of the body.
CD18 is integrin, beta 2 (ITGB2) (complement component 3 receptor 3 and 4 subunit). Integrins are surface proteins composed of an alpha chain and a beta chain. A given chain may combine with multiple partners resulting in different integrins. For example, beta 2 combines with the alpha L chain to form the integrin LFA-1, and combines with the alpha M chain to form the integrin Mac-1.
CD18 is the beta subunit of 3 different structures (paired with CD11 a, b, c):
- LFA-1 (paired with CD11a) - Macrophage-1 antigen, MAC-1 (paired with CD11b) - Integrin alphaXbeta2 (paired with CD11c)
Lymphocyte function-associated antigen 1 (LFA-1) is found on leukocytes is involved in recruitment to the site of infection. It binds to ICAM-1 on antigen-presenting cells and functions as an adhesion molecule. LFA-1 is part of the family of leukocyte integrins which are recognised by their common β-chains (CD18). LFA-1 also has a distinct α-chain (CD11a).
Macrophage-1 antigen, MAC-1 (integrin alphaMbeta2) is a complement receptor (CR3) consisting of CD11b and CD18. It binds to C3b and C4b.
Integrin alphaXbeta2 (CR4) is a complement receptor composed of CD11c and CD18.
CD11 a, b, c
Integrin, alpha L (antigen CD11A, lymphocyte function-associated antigen 1) is also known as ITGAL or CD11a. CD11a is one of the two components, along with CD18, which form lymphocyte function-associated antigen-1. Efalizumab (Raptiva), used to treat psoriasis, is a recombinant humanized monoclonal antibody that binds to CD11a and acts as an immunosuppressant. Due to risk for progressive multifocal leukoencephalopathy (PML), Efalizumab (Raptiva) was withdrawn from the market in 2009.
Integrin alpha M (ITGAM) is one protein subunit that forms the heterodimeric integrin alpha-M beta-2 (αMβ2) molecule, also known as macrophage-1 antigen (Mac-1) or complement receptor 3 (CR3) ITGAM is also known as CR3A, and cluster of differentiation molecule 11B (CD11B).
CD11c is also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX).
The integrin superfamily consists of 30 proteins that promote cell-cell or cell-matrix interactions. The name integrins derives from the idea that they coordinate (i.e., "integrate") signals.
All integrins are cell surface proteins composed of 2 polypeptide chains, α and β.
Integrins are classified into several subfamilies based on the β chains.
The β1-containing integrins are also called VLA molecules. VLA ("very late antigens") received their name because α1β1 and α2β1 were expressed on T cells 2 to 4 weeks after repetitive stimulation in vitro in the early experiments.
The β1 integrins are also called CD49a-fCD29. CD49a-f refers to different α chains (α1 to α6). CD29 refers to the common β1 subunit.
The β2 integrins are also known as the LFA-1 family or CD11a-cCD18. CD11 refers to different α chains and CD18 to the common β2 subunit. LFA-1 is also called CD11aCD18.
Other members of the LFA-1 family include CD11bCD18 (Mac-1 or CR3) and CD11cCD18 (p150,95 or CR4), both of which have the same β subunit as LFA-1.
Diagnosis
A WBC differential count reveals extremely elevated levels of neutrophils (on the order of 6-10x normal) because they are unable to leave the blood vessels. Specific diagnosis is made through monoclonal antibody testing for CR3, one of the three complete proteins which fail to form properly as a result of β-2 integrin subunit deficiency.
Treatment
Once the diagnosis of LAD is made, bone marrow transplantation is the current standard of care.
Adhesion molecules, 3 groups = SIS Selectins Integrins Superfamily Ig
Integrins
LFA (leukocyte function Ag), VLA (very late Ag). For example, LFA 1-3 bind to CD (cluster of differentiation) cell adhesion molecules on the surface of 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
Phagocyte immunodeficiencies (click to enlarge the image).
In Chediak-Higashi syndrome (CHS), there are giant abnormal granules in all granule-containing cells – including melanocytes. CHS patients are unable to form normal lysosomes and cytoplasmic granules.
Clinical features of Chediak-Higashi Syndrome (CHS)
- neutropenia
- recurrent pyogenic infections - partial oculocutaneous albinism - progressive neurologic abnormalities - mild coagulation defects - lymphoma-like accelerated phase which often leads to death
Less than 500 cases of CHS were reported worldwide in the past 20 years. Parental consanguinity is common. CHS is linked to a mutation at 1q42 leading to an absent CHS1/LYST protein, a lysosomal trafficking regulator.
CHS1/LYST is part of the BEACH family of vesicle trafficking regulatory proteins. BEACH is a family of vesicle trafficking regulatory proteins, BEACH domain (named after BEige And Chediak-Higashi), related to WD40 repeats (proteins in histone recognition).
Diagnosis of CHS
The diagnosis is usually made with the giant granules secondary to chemotactic defect, and mutations in LYST 1q42.
Prognosis of CHS
Only 10% of patients survive early childhood. Patients with CHS who do not die from infection, enter the "accelerated phase" of the disease. In the "accelerated phase" of CHS, a massive lymphohistiocytic infiltration affects all organ systems and even more profound immune deficiency takes place. This phase is usually lethal.
Author: V. Dimov, M.D., Allergist/Immunologist and Assistant Professor at University of Chicago Reviewer: S. Randhawa, M.D., Allergist/Immunologist
Phagocyte immunodeficiencies (click to enlarge the image).
There is a defective intracellular killing of bacteria (catalase positive) and fungi. CGD is X-linked (2/3) or autosomal recessive (1/3). The incidence of CGD is 1/100,000. There are defects in phagocyte NADPH oxidase (phox).
NADPH oxidase is a 5-protein complex:
- Membrane-bound cytochrome b-245/b588 = gp91phox and p22phox, embedded in walls of secondary granules - Proteins in cytosol - p47phox, p67phox, and p40phox
Mutations in 4 of the 5 genes (gp91phox, p47phox, p22phox, and p67phox) account for all known cases of CGD:
- gp91phox is encoded by CYBB, located at Xp21.1, 65-70% of cases
- p22phox is encoded by CYBA, located at chromosome 16q24
- cytosolic factor p47phox is encoded by NCF1, located at 7q11.23, 25% of cases.
- cytosolic factor p67phox is encoded by NCF2, located at chromosome 1q25
In CGD, phagocytic cells ingest but do not kill bacteria due to failure to form oxygen radicals.
PMN kills microbes by using 2 enzymes: ROS and NO. This "respiratory burst" is impaired in chronic granulomatous disease (CGD). In CGD, PMN function migration is normal bu there is no respiratory burst.
CGD was first described in 1957 as "a fatal granulomatosus of childhood". CGD is a diverse group of hereditary diseases in which PMN cannot form the reactive oxygen compounds (superoxide radicals) to kill ingested pathogens. This leads to the formation of granulomata in many organs, hence the name of the condition. CGD affects 1 in 200,000 people in the U.S. and 20 new cases are diagnosed each year.
Two neutrophils (PMN) among red blood cells. PMN are the type cells affected by chronic granulomatous disease. Image source: Wikipedia, GNU Free Documentation license.
Superoxide anion. Image source: Wikipedia, GNU Free Documentation license.
Phenotype expression in CGD
Infections caused by catalase-positive bacteria and fungi (Staph aureus, Burkholderia cepacia, Serratia marcescens, Aspergillus, and Nocardia) are common but not streptococcal infections. The granuloma formation is due to a lack of phagocytic activity, it commonly affects GI, GU, and liver. Common infections are pneumonia, lymphadenitis, liver abscess, skin abscess, perianal abscess, and osteomyelitis.
Diagnosis of CGD
There are 2 tests to diagnose CGD. The diagnosis of CGD is based on flow cytometry (dihydro-rhodamine 123 assay) (DHR) or nitroblue tetrazolium dye test (NBT).
NBT test (classic test) in CGD - interpretation:
- Normal PMNs stimulated with phorbol esters or calcium ionophore, phagocytose and reduce NBT. There are large cells with blue cytoplasm (NBT).
- Unstimulated PMNs or stimulated PMNs derived from a CGD patient do not reduce NBT. There are small cells with colorless (or slightly yellow) cytoplasm.
The original test for diagnosis of CGD from a historical perpsective is nitroblue-tetrazolium (NBT). NBT test depends on the direct reduction of NBT by superoxide free radical to form an insoluble formazan. NBT is a simple rapid test but is only a "yes/no" test (qualitative test) which detects whether or not there is a problem with the oxidative enzymes. It cannot provide information on how much the enzymes are affected, i.e. NBT is not a quantitative test. DHR test is preferred because it is a quantitative assay.
In recent years, there has been a shift in the diagnostic paradigm for evaluation of male patients with CGD, based on the rhodamine assay. Rhodamine dyes fluoresce and can be detected easily with fluorometers. Rhodamine takes up SOD and its level is measured by flow cytometry, thus providing information about how much superoxide a patient's phagocytes can produce.
A Rhodamine 6G-based dye laser. The dye solution is the orange fluid in the tubes. Image source: Wikipedia, GNU Free Documentation license.
CGD diagnostic tests
Dihydrorhodamine 123 (DHR) test
Non-fluorescent rhodamine derivative, DHR, is taken up by phagocytes and oxidized to a green fluorescent by products of the NADPH oxidase.
DHR flow cytometry quantifies neutrophil oxidative capacity. This is the most sensitive option and the most commonly used test. Phagocytic cells reduce DHR to rhodamine.
Immunoblot can be used to confirm CGD: Failure to detect p47phox or p67phox.
Treatment of CGD
Antimicrobial prophylaxis in CGD relies on a triad of therapies:
Prophylactic TMP-SMX reduces frequency of staphylococcal infections, but does not affect fungal infections. Long-term itraconazole or voriconazole reduces Aspergillus and Candida infections. IFN-gamma 3x weekly also reduces infections.
BMT is with variable success in CGD since patients develop bacterial and fungal infections during chemoablation. Gene therapy is not successful in humans due to vector issues. A 2011 study reported excellent survival after stem cell transplantation for chronic granulomatous disease (CGD) (JACI, 2011).
The median survival is 38 years for X-linked CGD and 50 years for AR CGD.
All patients with CGD should receive lifelong antifungal plus antibacterial prophylaxis with or without immunomodulatory therapy (INF-gamma).
The 3 types of interferons, remembered by the mnemonic ABG: alpha, beta, gamma (click to enlarge the image).
Interferons bind to membrane receptors, which initiate the activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT)-signaling pathways. This leads to gene transcription.
Various interferons have been approved for clinical use:
IFN-γ 1b (Actimmune)
Used in chronic granulomatous disease (CGD).
Recombinant IFN-α-2a (Roferon-A)
Used in chronic hepatitis C, hairy cell leukemia, chronic myeloid leukemia (CML).
Recombinant IFN-α-2b (Intron-A)
Used in Kaposi’s sarcoma, chronic hepatitis B or C, malignant melanoma, follicular lymphoma, and condylomata acuminate.
IFN-α -n3 (Alferon-N)
Used for treatment of genital warts.
Pegylated IFN-α-2a (Pegasys)
Used in chronic hepatitis B or C.
IFN-β-1a (Avonex/Rebif)
Used in relapsing multiple sclerosis (MS).
IFN-β-1b (Betaseron)
Used in early or relapsing multiple sclerosis (MS).
The most common cause of chronic granulomatous disease (CGD) is:
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
Phagocyte immunodeficiencies (click to enlarge the image).
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
T-cell Immunodeficiencies (click to enlarge the image).
Bare lymphocyte syndromes include MHC class I and MHC class II deficiencies. These are primary immune deficiency disorders (PIDD) due to a lack of expression of either MHC I or MHC II.
Screening Tests for T-cell Immunodeficiency
Absolute lymphocyte count
Chest X-ray for thymus shadow in the newborn period
Delayed skin hypersensitivity to recall antigens
Quantitation of T-cell subsets
Candida (most cost effective), MMR, Histoplasma, Diphtheria
One-test sensitivity ~ 65%
Three tests ~ 96%
In the past: dinitrochlorobenzene (DNCB) 2.5% followed in 3-4 weeks by 0.1% to see if “sensitized”
Delayed-type hypersensitivity (DTH) response
The standardized DTH test includes Candida, tetanus, mumps, and TB. Trichophyton is also commonly used. However, the only FDA-approved reagents for DTH are PPD, Candida and mumps.
Advanced T-cell testing
Lymphocyte proliferative response to mitogens, Ag, and allogenic cells
Lymphocyte mediated cytotoxicity – NK and ADCC activity
Production of cytokines, TH2/TH1 and functional response to cytokines
Signal transduction studies
Northern blot analysis for mRNA
TREC
Formation of TRECs
During their passage through the thymus, T-cell precursors rearrange their TCR genes. There are excisions of segments of DNA, the ends are ligated to form small circles called T-cell receptor excision circles (TRECs).
T-cell receptor excision circles (TRECs) can be used as a routine newborn screening protocol for SCID. DNA was extracted from DBSs NBS cards, and real-time quantitative PCR determined the number of TRECs (dried blood spots (DBSs), newborn screening (NBS) cards). No TRECs were detected in either the SCID or naive T-cell-depleted samples.
Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).
Treatment
In SCID, the younger the age of the patient at the time of transplantation, the better the prognosis. There is a 95% survival rate in an infant who undergoes a transplant before 3 months of age. After six months, the survival rate decreases dramatically, to 50%.
References
Screening for T-cell lymphopenia and SCID recommended as an addition to the newborn screening programs in all states. Expert Rev Clin Immunol. 2011 Nov;7(6):761-8.
The state of Wisconsin approach to newborn screening for SCID: 5 infants with SCID detected in 3 years. JACI, 2012.
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
T-cell immunodeficiency (click to enlarge the image).
ALPS is due to defects in Fas, Fas Ligand, caspases 8 or 10 which interfere with apoptosis, leading to failure to delete autoreactive clones.
Mutations in FAS or caspase 10 manifest as autoimmune lymphoproliferative syndrome (ALPS). In ALPS, lymphocytes do not get a signal to "die" and they accumulate in the lymphoid organs.
There is lymphadenopathy, splenomegaly, autoimmune anemia, and thrombocytopenia. There is an increased number of double negative (CD4-CD8-) alpha/beta T cells.
Abnormal apoptosis is a cardinal feature of the rare autosomal dominant condition autoimmune lymphoproliferative syndrome (ALPS).
ALPS manifests in early childhood with: - lymphadenopathy - hepatosplenomegaly - autoimmune diseases such as hemolytic anemia, thrombocytopenia, and autoimmune neutropenia, often in combination (ie, Evans syndrome)
ALPS patients have inactivating mutations in: - FasL (type Ib) - Fas (type Ia) - caspase-8 or caspase-10 (type II)
Mutations in Fas or FasL interfere with the elimination of activated lymphocytes following an infection.
The persistence of these cells leads to an expanded populations of lymphocytes and predisposes to autoimmune disease and lymphomas.
IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X linked) syndrome
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
T-cell Immunodeficiencies (click to enlarge the image).
IPEX is an acronym for: Immunodysregulation Polyendocrinopathy - DM1, thyroiditis Enteropathy - Life-threatening chronic diarrhea X-linked
The dermatitis is usually eczematous.
IPEX is rare, often fatal, X-linked disorder, first described in 1982. The first genetic mutations in FOXP3 were identified in 2000, Xp11.23. In normal circumstances, CD4 Treg cells are 5-10% of CD4 T cells. Symptoms in IPEX are similar to Omenn syndrome SCID (RAG enzyme defect).
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
T-cell Immunodeficiencies (click to enlarge the image).
CMCC can start in childhood or adulthood. Serum Ig’s are usually normal. Ab to Candida are normal but the skin reactivity is delayed. There is a decreased in vitro lymphoproliferative response. CMCC is associated with endocrinopathies.
CMCC is a collection of immunodeficiency syndromes. Skin, nails and mucous membranes are infected with Candida, thick hyperkeratotic nails are pathognomonic.
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
Combined Immunodeficiencies (click to enlarge the image).
AT is associated with neurologic abnormalities resulting in progressive ataxia. There are telangiectasias of the eyes and skin. There is a variable humoral and cellular immunity. In A-T, there is a predisposition to certain malignancies, especially lymphomas and leukemias.
The ATM gene is on 11q22.3. The ATM gene product has one region similar phosphatidylinositol (PI)-3 kinases and another similar to DNA repair/cell checkpoint genes. ATM is expressed in all tissues in the body.
ATM stands for AT Mutated. The ATM kinase is a part of a surveillance mechanism that finds DNA damage and stalls the progression of the cell cycle.
ATM phosphorylates:
- tumor suppressor BRCA1
- c-abl tyrosine kinase and the Nbs1 (Nijmegen breakage syndrome) protein involved in DNA repair in response to ionizing radiation
- eIF-4E-binding protein 1 – insulin resistance
A-T occurs in 1 in 20,000 to 100,000 live births, 1.4-2.0% of Caucasians in the U.S. carry one defective AT gene. Heterozygotes have none of AT sx but higher incidence of malignancy at a younger age and CAD.
A-T is AR, oculocutaneous telangiectasias are charecteristic. There is a progressive cerebellar ataxia with Purkinje cell degeneration. In AT, there is DNA fragility with abnormal chromosome translocation in lymphocytes. There are low IgA, IgE, and IgG2 with moderately reduced T cell production and functionality.
Sinopulmonary infections are the most common infections in A-T. Opportunistic infections are uncommon . Radiation hypersensitivity results in an extremely high rate of cancer. Ataxia manifests when the child learns to walk, telangiectasias develop by age 3-6. Age at death is 25 years.
Morbidity and mortality from ataxia-telangiectasia are associated with ATM genotype. Among patients with A-T, the Kaplan-Meier 20-year survival rate was 53.4%; the prognosis for these patients has not changed since 1954 (http://goo.gl/VMR27).
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
Combined Immunodeficiencies (click to enlarge the image).
WAS is X-linked recessive.
WAS features
Eczema, thrombocytopenic purpura, immunodeficiency Normal megakaryocytes but small defective platelets Presentation is usually in infancy: prolonged bleeding from circumcision, hematochezia, or excessive bruising
WAS is due to mutations in WAS protein (WASP). WAS maps to Xp11.22-11.23. WASP expression is limited to lymphocytic and megakaryocytic lineages. WASP participates in actin polymerization. There is an isolated X-linked thrombocytopenia (only) due to WAS mutations.
WAS presentation
Prolonged bleeding from circumcision site Bloody diarrhea Excessive bruising Atopic derm Asthma Recurrent infection pneumococci
WAS is associated with small platelets – this is unusual because most bleeding disorders stimulate BM and often produce larger platelets.
Infections usually develops within the first year of life. WAS is associated with early infection with encapsulated organisms followed by opportunistic pathogens later in life. Survival beyond teens is rare. Infections and bleeding are usual causes of death. There is a 12% incidence of fatal malignancy.
Treatment and prognosis of WAS
BM transplant is the only definitive treatment option in WAS. Without transplant, patients with clinically severe WAS die in childhood. Splenectomy performed in the context of IVIG treatment and prophylactic antibiotics has proven beneficial if a BM donor is not available. The most common cause of death is EBV-induced lymphoreticular malignancy.
Successful Stem-Cell Gene Therapy for the Wiskott–Aldrich Syndrome was reported in the NEJM in 2010. This German study included 2 two patients who had this disorder and were treated with a transfusion of autologous, genetically modified hematopoietic stem cells (HSC).
There was a sustained expression of WAS protein expression in HSC, lymphoid and myeloid cells, and platelets after gene therapy. T and B cells, natural killer (NK) cells, and monocytes were functionally corrected.
After treatment, the patients' clinical condition markedly improved, with resolution of hemorrhagic diathesis, eczema, autoimmunity, and predisposition to severe infection.
Comprehensive insertion-site analysis showed vector integration that targeted multiple genes controlling growth and immunologic responses in a persistently polyclonal hematopoiesis.
Lentiviral vectors are expected to improve efficacy and safety of gene therapy for the Wiskott–Aldrich syndrome (http://goo.gl/gCH2P).
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)
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
Combined Immunodeficiencies (click to enlarge the image).
Deletion of 22q11.2 is the cause of DGS in 90% of cases. Hypocalcemia that results from the hypoparathyroidism can result in seizures. There are wide clinical variations of DGS.
DGS is due to dysmorphogenesis of the 3rd and 4th pharyngeal pouches which leads to thymic and parathyroid aplasia or hypoplasia . DGS can be partial or complete, depending on the degree of thymic hypo/aplasia . Microdeletions at 22q11.2 are the most common cause. DGS is rarely familial.
The lack of thymus in DGS leads to a lack of T-cell differentiation. DGS manifests with decreased cellular immunity which leads to an increased susceptibility to certain fungal, viral and bacterial infections. The B-cell function is also affected due to the lack of helper cells.
Features of complete DGS
Micrognathia Hypertelorism Low-set malformed ears Short Philtrum Fish shaped mouth Thymic aplasia or hypoplasia, congenital heart disease, hypoparathyroidism Absent thymus shadow
DiGeorge syndrome: part of CATCH 22
DiGeorge syndrome (DGS) comprises thymic hypoplasia, hypocalcaemia, outflow tract defects of the heart, and dysmorphic facies. It results in almost all cases from a deletion within chromosome 22q11.
DiGeorge syndrome should be seen as the severe end of the clinical spectrum embraced by the acronym CATCH 22 syndrome:
Patients with complete DiGeorge syndrome typically do not have a thymic shadow on chest X-ray.
Treatment of DiGeorge Syndrome
No treatment is needed for children with the partial form. DGS has a generally good prognosis if there are no major cardiac anomalies.
The transplant of thymic epithelial explants from HLA-matched donors has reconstituted immune function in some patients with complete DiGeorge syndrome.
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)
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
10 Warning Signs of Primary Immunodeficiency in Children
1. Four or more new ear infections within one year.
2. Two or more sinus infections within one year, or chronic sinusitis.
3. Two or more months on antibiotics with little effect.
4. Two or more pneumonias within one year, or pneumonia twice over any time.
5. Failure of an infant to gain weight or grow normally.
6. Recurrent, deep skin or organ abscesses.
7. Persistent thrush in mouth or fungal infection on skin.
8. Need for intravenous antibiotics to clear infection.
9. Two or more deep-seated infections including septicemia .
10. A family history of primary immunodeficiency.
10 Warning Signs of Primary Immunodeficiency in Adults
1. Two or more new ear infections within one year.
2. Two or more serious sinus infections within one year, in the absence of an allergy; or chronic sinusitis.
3. One pneumonia per year for more than one year, or pneumonia twice over any time.
Definition of PIDD: Genetically determined immunodeficiency.
The World Health Organization recognizes more than 100 PIDD. Most of PIDD are rare but selective IgA deficiency is relatively common, prevalence 1:500.
Humoral immunodeficiency (click to enlarge the image).
B and T cells "talk" constantly in T-dependent immune responses where a host of enzymes are involved in class switching - AICD, UNG, CD40, CD40L - if there is a defect in any of these enzymes, B cells cannot class switch - Ig gets "stuck" at IgM level and hyper-IgM immonodeficiency develops.
T-cell Immunodeficiencies (click to enlarge the image).
The autoimmune regulatory gene (AIRE) is expressed in the thymus. AIRE promotes expression of non-thymic tissue antigens in the thymus - a key part of the thymic education of T cells.
Mutation in the AIRE gene produces disorders such as autoimmune polyglandular syndrome or autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED). In this syndrome, T cells do not develop tolerance to self-antigens. The endocrine organs are attacked by autoreactive T cells. The AIRE mutation was the first report of a single-gene defect causing a systemic human autoimmune disease.
Mutations in FAS or caspase 10 manifest as autoimmune lymphoproliferative syndrome (ALPS). In ALPS, lymphocytes do not get a signal to "die" and they accumulate in the lymphoid organs.
Combined Immunodeficiencies (click to enlarge the image).
Bare lymphocyte syndromes include MHC class I and MHC class II deficiencies. These are primary immune deficiency disorders (PIDD) due to a lack of expression of either MHC I or MHC II. MHC class I deficiency leads to CD8 lymphopenia. MHC class II deficiency leads to CD4 lymphopenia.
Severe Combined Immunodeficiency (SCID) (click to enlarge the image).
In SCID, the younger the age of the patient at the time of transplantation, the better the prognosis. There is a 95% survival rate in an infant who undergoes a transplant before 3 months of age. After six months, the survival rate decreases dramatically, to 50%.
Receptor editing reactivates RAG-1 and RAG-2 when a high affinity self-antigen is recognized by a B cell receptor (BCR). RAG-1 and RAG-2 defects lead to Omenn syndrome, a form of SCID.
Severe combined immunodeficiency (SCID) - 4 groups according to T/B/NK cells (click to enlarge the image).
Receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 contain γ chain, which is affected in X-linked 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
Interleukins are a group of cytokines (signaling molecules) that were first found to be expressed by white blood cells (leukocytes). The name is a misnomer since interleukins are produced by a wide variety of body cells, not only leukocytes.
Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology
IL-18 is a proinflammatory cytokine. IL-18 works together with IL-12 to induce cell-mediated immunity following infection with microbial products like lipopolysaccharide (LPS)
IL-18 belongs to the interleukin-1 superfamily.
Interleukin-1 superfamily
Interleukin-1 superfamily includes:
- IL-1α - IL-1β and IL-1RA - IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, and IL1F10 - IL-33 - IL-18
IL-1α, IL-1β, and IL-1RA have been renamed IL-1F1, IL-1F2, and IL-1F3. IL-33 is also called IL-1F11.
IL-18 and IL-12 inhibit IL-4 dependent IgE and IgG1 production, and enhance IgG2a production in B cells.
IL-18 binding protein (IL18BP) binds and blocks IL-18.
Whereas IL-1 and IL-18 promote proinflammatory and TH1-associated responses, IL-33 induces the production of TH2-associated cytokines.
Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology
Interleukin-1 (IL-1) is one of the first cytokines ever described. Since IL-1 can induce fever, affect lymphocytes, increase the number of bone marrow cells and cause degeneration of bone joints, several names were coined including endogenous pyrogen, lymphocyte activating factor, haemopoetin-1 and mononuclear cell factor.
IL-1 exists in two forms: IL-1α and IL-1β.
Source: monocytes, PMNs, epithelial cells;
Receptor: IL-1 binds to type I IL-1 receptor, this leads to MyD88 recruitment, activation of protein kinases (IRAK4, IRAK1 and TRAF6), and then activation of NFκB.
TLR3 signaling is mediated by toll-interleukin-1-receptor domain containing adapter inducing interferon β (TRIF) and is MyD88-independent.
Effects: IL-1 mediates local inflammation, induces fever and synthesis of acute phase reactants by the liver (via IL-6 production)
IL-1 is composed of 2 distinct proteins called IL-1α and IL-1β.
Interleukin-1 superfamily
IL-1 Receptor antagonist (IL-1RA) competes for receptor binding with IL-1α and IL-1β, blocking their role in immune activation.
Interleukin-1 superfamily includes:
- IL-1α
- IL-1β and IL-1RA
- IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, and IL1F10
- IL-33
- IL-18
IL-1α, IL-1β, and IL-1RA have been renamed IL-1F1, IL-1F2, and IL-1F3.
IL-33 is also called IL-1F11.
IL-1 family nomenclature
Newly cloned interleukin 1 (IL-1) family members1, 2, 3 were originally given an IL-1 family (IL-1F) designation, but as functions have now been elucidated for several of these, some researchers have proposed that each now be assigned an individual interleukin designation. IL-1F6, IL-1F8 and IL-1F9 are encoded by distinct genes but use the same receptor complex (IL-1Rrp2 and AcP), are proinflammatory and deliver nearly identical signals (http://goo.gl/X7ai).
IL-18
IL-18 is a proinflammatory cytokine. IL-18 works together with IL-12 to induce cell-mediated immunity following infection with microbial products like lipopolysaccharide (LPS)
IL-18 and IL-12 inhibit IL-4 dependent IgE and IgG1 production, and enhance IgG2a production in B cells.
IL-18 binding protein (IL18BP) binds and blocks IL-18.
Whereas IL-1 and IL-18 promote proinflammatory and TH1-associated responses, IL-33 induces the production of TH2-associated cytokines.
Medications
Treatment of CAPS
Anakinra (IL-1RA) is an IL-1 receptor antagonist that inhibits IL-1. Recombinant IL-1Ra or Anakinra (Kineret) is available commercially to treat systemic juvenile rheumatoid arthritis (JRA). Live vaccines should not be given concurrently with Anakinra.
Canakinumab is a human anti–interleukin-1β monoclonal antibody. Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.
Rilonacept (Arcalyst), is a dimeric fusion protein. IL-1 Trap or Rilonacept (Arcalyst) is used for management of cryopyrin-associated periodic syndromes (CAPS). Patients must me evaluated for latent TB before initiating therapy. Live vaccines should not be given concurrently. Taking rilonacept with TNF inhibitors is not recommended and may increase the risk of serious infections.
Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology
Interleukin 33 (IL-33) is a cytokine belonging to the IL-1 superfamily, it induces cells to produce type 2 cytokines.
Interleukin-1 superfamily
Interleukin-1 superfamily includes:
- IL-1α
- IL-1β and IL-1RA
- IL1F5, IL1F6, IL1F7, IL1F8, IL1F9, and IL1F10
- IL-33
- IL-18
IL-1α, IL-1β, and IL-1RA have been renamed IL-1F1, IL-1F2, and IL-1F3. IL-33 is also called IL-1F11.
Whereas IL-1 and IL-18 promote proinflammatory and TH1-associated responses, IL-33 induces the production of TH2-associated cytokines.
IL-33 was previously named NF-HEV nuclear factor (NF) in high endothelial venules (HEVs) since it was originally identified in this location. IL-33 is also called IL-1F11 to note its place as a member of IL-1 superfamily (IL-1F11).
IL-33 binds to its receptors triggering NF-κB and MAP kinase signaling pathways that drive production of type 2 cytokines (IL-5 and IL-13) from Th2 cells.
Receptors for IL-33
IL-33 binds to 2 receptors:
- ST2 (IL1RL1)
- IL-1 Receptor Accessory Protein (IL1RAP)
ST2 (IL1RL1)
IL1RL1 stands for IL-1 receptor-like 1 protein. Mutations in the gene for IL1RL1 (ST2) have been linked to atopic dermatitis and asthma.
ST2 is also called IL1RL1, T1, DER4 and Fit-2. ST2 is highly expressed on mast cells and on TH2 cells.
The ST2 gene encodes two isoforms of ST2 proteins:
- ST2L, a transmembrane form
- soluble ST2 (sST2), a secreted form that can serve as a decoy receptor of IL-33
High levels of sST2 has been found in the sera of patients with acute asthma.
IL-33 is markedly elevated in the serum of patients during an anaphylactic shock and in atopic human tissue.
Phospholipase D1 (PLD1) catalyzes the hydrolysis of phosphatidylcholine (PC) to produce phosphatidic acid and choline. PC-specific PLD1 affects numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis.
Sphingosine-1-phosphate (S1P) and Sphingosine kinase 1 (SPHK1)
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid. Various stimuli increase cellular levels of S1P by activation of sphingosine kinase (SPHK), the enzyme that catalyzes the phosphorylation of sphingosine.
S1P regulates angiogenesis, vascular stability and permeability.
S1P is a major regulator of trafficking of T- and B-cells. S1P interaction with its receptor S1PR1 is needed for the egress of immune cells from the lymphoiod organs (such as thymus and lymph nodes). Some immunosuppessants such as FTY720 do not let lymphocytes leave the lymph nodes through blockage of S1PR.
In the presence of IgE, IL-33 activates mast cell degranulation through phospholipase
D1 and sphingosine kinase-1.
IL-33 expression is increased in patients with anaphylaxis and atopic dermatitis.
IL-33 is a potential therapeutic target against allergy. IL-33/ST2 pathway may provide new therapeutic targets for allergic rhinitis and asthma (http://goo.gl/3utyB).
NFkB dependent and independent cytokines and chemokines
It has been suggested that whilst the production of pro-inflammatory cytokines in mast
cells is NFkB dependent, the induction of Th2 cytokines is NFkB independent.
For example, IL-1, IL-3, IL-6, TNF-alpha, MIP-2, MCP-1, and MIP-1 syntheses are dependent on NF-kB activity. IL-5, IL-13, Eotaxin-2, RANTES or TARC syntheses are are independent of the NF-kB pathway.
Abbreviations
Chemokine (C-X-C motif) ligand 2 (CXCL2) is a small cytokine belonging to the CXC chemokine family that is also called macrophage inflammatory protein 2-alpha (MIP2-alpha), Growth-regulated protein beta (Gro-beta) and Gro oncogene-2 (Gro-2).
Chemokine (C-C motif) ligand 2 (CCL2) is a small cytokine belonging to the CC chemokine family that is also known as monocyte chemotactic protein-1 (MCP-1).
Chemokine (C-C motif) ligand 4 is also known as CCL4 and MIP-1.
Chemokine (C-C motif) ligand 24 (CCL24) is a small cytokine belonging to the CC chemokine family that is also known as Myeloid progenitor inhibitory factor 2 (MPIF-2) and Eosinophil chemotactic protein 2 (Eotaxin-2). CCL24 interacts with chemokine receptor CCR3 to induce chemotaxis in eosinophils.
Chemokine (C-C motif) ligand 5 also known as CCL5 or RANTES. CCL5 was earlier called Regulated upon Activation, Normal T-cell Expressed, and Secreted, abbreviated RANTES.
Chemokine (C-C motif) ligand 17 (CCL17) is a small cytokine belonging to the CC chemokine family that is also known as thymus and activation regulated chemokine (TARC).
IL-33 role in anaphylaxis
In the presence of IgE, IL-33 induces anaphylactic shock by rapidly activating mast cell degranulation. Although mast cell activation and degranulation by IL-33 is independent of the presence of T or B cells, the presence of preformed IgE is critical. In vitro the IgE sensitization need to be for at least 16 hours, and shorter sensitization durations failed to primed the mast cells for IL-33–mediated degranulation.
What is the most potent chemokine (chemoattractant) for eosinophils?
(A) IL-5
(B) IL-8
(C) LTB4
(D) eotaxin
(E) IL-4
(F) IL-13
Answer: D.
Eosinophil chemotactic protein 2 (Eotaxin-2) is the most potent chemoattractant for eosinophils but IL-5 is the most specific stimulant of their production.
Chapter 57: Drug Allergy. Allergy and Immunology Review Corner: Chapter 57 of Pediatric Allergy: Principles & Practices, edited by Donald Y.M. Leung, et al.
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