Immunosuppressive drugs: Azathioprine

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

(This article is based in large part on Wikipedia articles that were reviewed for accuracy, please see the reference links).

Azathioprine is an immunosuppressant pro-drug, converted in the body to the active metabolites 6-mercaptopurine and 6-thioinosinic acid. It is a purine synthesis inhibitor. Azathioprine is available in oral form.


Azathioprine. Image source: Wikipedia, public domain.

For many years, dual therapy with azathioprine and steroids was the standard anti-rejection regimen, until cyclosporine was introduced into clinical practice in 1978.

Azathioprine is a purine synthesis inhibitor, inhibiting the proliferation of cells, especially leukocytes. Azathioprine suppresses the bone marrow and CBC should be monitored. Caution should be exercised when it is used in conjunction with purine analogues such as allopurinol.


Metabolic pathway for azathioprine. Image source: Wikipedia, GNU Free Documentation License.

Azathioprine may be used in severe atopic dermatitis. It has a slow onset of action and needs a trial for several months to see an improvement.

Mycophenolate (CellCept) - 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.

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.
Azathioprine. Wikipedia.
Mycophenolic acid. Wikipedia.

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

Drugs acting on immunophilins: Cyclosporine, Tacrolimus, Sirolimus

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

(This article is based in large part on Wikipedia articles that were reviewed for accuracy, please see the reference links).

Cyclosporine A and tacrolimus were isolated from soil organisms inhibit T-helper functions. They are structurally different but a similar mechanism of action. Cyclosporine and tacrolimus are available in oral and intravenous form. Topical tacrolimus and pimecrolimus are approved for atopic dermatitis. Cyclosporine was ineffective in topical form.

Cyclosporine

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


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

Together with tacrolimus, cyclosporine is a calcineurin inhibitor (CNI). It has been in use since 1983 and is one of the most widely used immunosuppressive drugs. Initially isolated from a Norwegian soil sample, Ciclosporin A, the main form of the drug, is a cyclic peptide of 11 amino acids produced by the fungus Beauveria nivea.

The immuno-suppressive effect of cyclosporin was discovered on January 31, 1972, by employees of Sandoz (now Novartis) in Basel, Switzerland. The success of Cyclosporin A in preventing organ rejection was shown in liver transplants performed by Dr. Thomas Starzl at the University of Pittsburgh Hospital. The first patient, on March 9, 1980, was a 28-year-old woman. Cyclosporin was subsequently approved for use in 1983.


Cyclophilin. Image source: Wikipedia, public domain.

Cyclosporin is thought to bind to the cytosolic protein cyclophilin (an immunophilin) of lymphocytes, especially T-cells. This complex of cyclosporin and cyclophilin inhibits calcineurin, which under normally induces the transcription of interleukin-2.

Cyclosporin has been increasingly substituted with newer, and less nephrotoxic, immunosuppressants such as tacrolimus (Prograf) (see below).

Tacrolimus

Tacrolimus is a 23-member macrolide produced by Streptomyces tsukubaensis. The name tacrolimus is derived by taking the "t" for Mount Tsukuba (where the organism was discovered), "acrol" for macrolide and "imus" for immunosuppressant. It is also referred to as FK506, its research compound designation.

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.

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.


Tacrolimus. Image source: Wikipedia, public domain.

Tacrolimus is a 23-membered macrolide lactone discovered in 1984 from the fermentation broth of a Japanese soil sample that contained the bacteria Streptomyces tsukubaensis.

Tacrolimus was among the first macrolide immunosuppressants discovered, preceded by the discovery of rapamycin (sirolimus) on Rapa Nui (Easter Island) in 1975.

Like cyclosporin, it was found in a soil fungus, although it is produced by a type of bacterium, Streptomyces tsukubaensis. The name tacrolimus is derived from 'Tsukuba macrolide immunosuppressant'.

The drug is owned by Astellas Pharma Inc., and is sold under the tradenames Prograf, Advagraf, and Protopic. It is sometimes referred to as FK-506 (Fermentek catalogue number 506). It was first approved by the Food and Drug Administration (FDA) in 1994 for use in liver transplantation.

Tacrolimus is a macrolide. It binds to the immunophilin FKBP12 (FK506 binding protein) creating a new complex. This FKBP12-FK506 complex inhibits calcineurin thus inhibiting both T-lymphocyte signal transduction and IL-2 transcription. Although this activity is similar to cyclosporin, studies have shown that the incidence of acute rejection is reduced by tacrolimus use over cyclosporin.

As an ointment (Protopic) tacrolimus and pimecrolimus are used in the treatment of atopic dermatitis. It suppresses inflammation in a similar way to steroids, and is equally as effective as a mid-potency steroid. An important advantage of tacrolimus is that unlike steroids, it does not cause skin thinning (atrophy). It may therefore be applied to the thinner skin over the face and eyelids.


Pimecrolimus. Image source: Wikipedia, public domain.

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.

Sirolimus

Sirolimus (rapamycin, trade name Rapamune) is a macrolide lactone. Rapamycin blocks lymphocyte proliferation by inhibiting IL-2 signaling.

Sirolimus was first discovered as a product of the bacterium Streptomyces hygroscopicus in a soil sample from Easter Island — an island also known as "Rapa Nui", hence the name.

Sirolimus was originally developed as an antifungal agent. However, this was abandoned when it was discovered that it had potent immunosuppressive and antiproliferative properties.

Unlike the similarly-named tacrolimus, sirolimus is not a calcineurin inhibitor. However, it has a similar suppressive effect on the immune system. Sirolimus inhibits the response to interleukin-2 (IL-2). In contrast, tacrolimus inhibits the production of IL-2.

Contrary to ciclosporine and tacrolimus that affect the first phase of the T lymphocyte activation, sirolimus affects the second one, namely the signal transduction and their clonal proliferation.

The mode of action of Sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) in a manner similar to tacrolimus. However, unlike the tacrolimus-FKBP12 complex which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mammalian target of rapamycin (mTOR) pathway.

Therefore, sirolimus acts synergistically with ciclosporine and, in combination with other immunosuppressants, has few side-effects. Also, it indirectly inhibits several T lymphocyte kinases and phosphatases, preventing the transmission of signal into their activity and the transition of the cell cycle from G1 to S phase. In a similar manner, it prevents the B cell differentiation to the plasma cells, reducing production of IgM, IgG, and IgA antibodies.


Sirolimus. Image source: Wikipedia, public domain.


A plaque commemorating the discovery of sirolimus on Easter Island, near Rano Kau. Image source: Wikipedia, public domain.

References

Ciclosporin. Wikipedia.
Tacrolimus. Wikipedia.
Sirolimus. Wikipedia.
Immunosuppressive drugs. Wikipedia.

Tacrolimus Ointment (Protopic) for Atopic Dermatitis: Development and Mechanism of Action of Tacrolimus. Medscape.

Abbas' Immunology, edition 6, 2009.

Published: 05/18/2009
Updated: 09/08/2010

Tumor necrosis factor receptor superfamily (TNFRSF)

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

A tumor necrosis factor receptor (TNFR) is a cytokine receptor that binds tumor necrosis factors (TNF). There are many TNF receptors grouped in a "family" called tumor necrosis factor receptor superfamily or TNFRSF.

Some CDs are members of the TNFRSF:

CD27
CD30
CD40
FAS
CD120
CD134
CD137


This video describes the process by which apoptosis is activated by T cells. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

References

Cluster of differentiation (CD) of leukocytes
Tumor necrosis factor receptor. Wikipedia.

Published: 05/18/2009
Updated: 05/18/2009

CD127, IL-7 receptor alpha chain

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD127 is the IL-7 receptor alpha chain.

Interleukin 7 (IL-7)

Interleukin 7 (IL-7) is a hematopoietic growth factor secreted by the stromal cells of the bone marrow and thymus. IL-7 stimulates the differentiation of multipotent (pluripotent) hematopoietic stem cells into lymphoid progenitor cells (as opposed to myeloid progenitor cells where differentiation is stimulated by IL-3). IL-7 stimulates proliferation of all cells in the lymphoid lineage (B and T lymphocytes and NK cells). A defect in IL-7RA leads to SCID (T-/B+/NK+).

Interleukin-7 receptor (IL7R)

Interleukin 7 receptor (IL7R), also known as CD127 (Cluster of Differentiation 127), is a type I cytokine receptor. Type I cytokine receptors are transmembrane receptors expressed on the surface of cells that recognize and respond to cytokines with four α-helical strands.

Type I cytokine receptors are mediated through JAK/STAT and bind: IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, GM-CSF.


Key steps of the JAK-STAT pathway. Image source: Wikpedia, public domain.


Cytokine Signaling. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

IL7R plays a critical role in the V(D)J recombination during lymphocyte development. A defect in IL-7RA leads to SCID (T-/B+/NK+).

Thymic stromal lymphopoietin (TSLP)

Thymic stromal lymphopoietin (TSLP) signals through a heterodimeric receptor complex composed of the TSLP receptor and the IL-7R alpha chain. Some researchers have classified TSLP as a "master regulator" of the Th2 response due to overexpression of the cytokine in pulmonary tissue and skin cells result in Th2-induced asthma and dermatitis.

TSLP is produced mainly by non-hematopoietic cells as fibroblasts, epithelial cells and different types of stromal cells.

Anti-TSLP is a potential new therapeutic target in asthma.

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.


(click to enlarge the image)


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

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.

References

Cluster of differentiation, Wikipedia.
List of human clusters of differentiation (CD), Wikipedia.
TSLP calms inflammation. The Journal of Experimental Medicine, Vol. 206, No. 3, 493, 2009.
TSLP, Wikipedia.
Interleukin-7 receptor, Wikipedia.
Interleukin 7, Wikipedia.
Cluster of differentiation (CD) of leukocytes

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthmahttp://goo.gl/c0vzJ

Published: 05/18/2009
Updated: 01/18/2011

CD45, Protein tyrosine phosphatase, receptor type, C (PTPRC)

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD45, leukocyte common antigen (LCA), is a type I transmembrane protein present on all hemopoietic cells, except erythrocytes. CD45 is defective in T-B+NK+ SCID.

Type of cell	CD markers
stem cells	CD34+,CD31-
all leukocyte groups	CD45+
Granulocyte	CD45+,CD15+
Monocyte	CD45+,CD14+
T lymphocyte	CD45+,CD3+
T helper cell	CD45+,CD3+,CD4+
Cytotoxic T cell	CD45+,CD3+,CD8+
B lymphocyte	CD45+,CD19+ or CD45+,CD20+
Thrombocyte	CD45+,CD61+
Natural killer cell	CD16+,CD56+,CD3-

Protein tyrosine phosphatase, receptor type, C also known as PTPRC is an enzyme also known as CD45 antigen. CD45 was originally called leukocyte common antigen (LCA).

CD45 is a protein tyrosine phosphatase (PTP) and an essential regulator of T- and B-cell antigen receptor signaling. CD45 suppresses JAK kinases, and thus functions as a regulator of cytokine receptor signaling. CD45 activates various Src family kinases required for the antigen receptor signaling.


Key steps of the JAK-STAT pathway. Image source: Wikpedia, public domain.

Type I cytokine receptors are mediated through JAK/STAT and bind: IL-2, 3, 4, 5, 6, 7, 9, 10, 12, 13, 15, GM-CSF.

The first event following the TCR ligation (binding) is the activation of Src kinases - autoinhibitory loop.

CD45 phosphorylation in TCR signaling is of early and key importance. CD45 and ZAP70 defects cause SCID. ZAP-70 deficiency is a form of SCID with no CD8 cells and no T cell function, but with normal B and NK cells.

Mnemonic

J
JAK3 defect causes a form of SCID.
Janus
"Just fine" B cells (T-/B+/NK-)


This video describes the cellular signaling that takes place with the T cell receptor. This video is from: Janeway's Immunobiology, 7th Edition Murphy, Travers, & Walport. Source: Garland Science.

Various isoforms of CD45 exist:

- CD45RA
- CD45RO
- CD45RB
- CD45RC
- CD45RAB
- CD45RAC
- CD45RBC
- CD45R (ABC)

CD45 is a highly glycosylated and a very long protein.

Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. CD45RA cells contain TRECs. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45RO. CD45RA is large and it shortens as the cell matures.

The cytoplasmic domain of CD45 is one of the largest known and it has an intrinsic phosphatase activity that removes an inhibitory phosphate group on a tyrosine kinase called Lck (in T cells) or Lyn/Fyn/Lck (in B cells) and activates it.

Memory T cells

- Central memory TCM cells express L-selectin and the chemokine receptor CCR7, they secrete IL-2, but not IFNγ or IL-4.

- Effector memory TEM cells produce IFNγ and IL-4.

CD markers for central vs. effector memory T cells:

Central memory T cells: CD45RO+, CCR7+, CD62L+

Effector memory T cells: CD45RO+, CCR7-, CD62L-

Memory B cells have CD27.

CD45 is expressed in lymphomas, B-cell CLL, hairy cell leukemia, and acute nonlymphocytic leukemia.


T and B Cells - Naive and Memory Cell Markers (click to enlarge the image).

CD44

CD44
CD45 - leukocyte common antigen, present on all hemopoietic cells except erythrocytes

CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. PMN adhesion to the endothelium is mediated through CD44.


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.

CD44 expression is an indicative marker for effector-memory T-cells.

CD44
CD99
Both participate in leukocyte migration.

What CD marker correlates well with T cell receptor excision circles (TRECs)?

(A) CD19

(B) CD45RO

(C) CD27

(D) CD45RA

(E) CD18

(F) CD15

A: D. Naive T lymphocytes express large CD45 isoforms and are usually positive for CD45RA. CD45RA cells contain TRECs. Activated and memory T lymphocytes express the shortest CD45 isoform, CD45RO. CD45RA is large and it shortens as the cell matures.

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

References

Cluster of differentiation (CD) of leukocytes
CD44, Wikipedia.
PTPRC. Wikipedia.
Memory T cell. Wikipedia.

Published: 05/18/2009
Updated: 08/18/2010

CD15, Sialyl LewisX (SLeX)

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

Sialyl LewisX (SLeX, CD15) 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. CD15 is a carbohydrate adhesion molecule (not a protein) that mediates phagocytosis and chemotaxis.

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


Sialyl LewisX (SLeX). 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.


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.

LAD type 2

There is inability to put sialyl-LewisX (SLeX) cap on leukocytes. CD15 (SLeX) is found on neutrophils; expressed in patients with Hodgkin disease, some B-cell CLL, ALL, and most AML.

LAD type 2

CD15
F
Fifteen
Fucose, Sialyl LewisX (SLeX)
FucT-1 gene

CD18

CD18 helps neutrophils make their way from the blood stream into the infected areas of the body.


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.

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)

CD11a - Subunit of LFA-1, a membrane glycoprotein that provides cell-cell adhesion by interaction with ICAM-1. Lymphocyte function-associated antigen 1 (LFA-1) consists of an alpha-chain (CD11a) and beta-chain (CD18).

CD11b - Subunit of MAC-1, a complement receptor (CR3). MAC-1 consists of an alpha-chain (CD11b) and beta-chain (CD18).

CD11c - Integrin alphaXbeta2 is a subunit of the complement receptor CR4. CR4 consists of an alpha-chain (CD11c) and beta-chain (CD18). CD11c is expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell CLL. CD11c is one of the defining markers for dendritic cells.

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.

LAD type 1

First recognized as a distinct clinical entity in the 1970s. The inherited molecular defect in patients with LAD type 1 is a defect in CD18. CD18 is the β2 chain (β-2 integrin subunit) common to LFA-1 and MAC-1.

Adhesion Molecules


Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS.

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

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.

CD markers for central vs. effector memory T cells:

Central memory T cells: CD45RA-, CD27+, CCR7+, CD62L+

Effector memory T cells: CD45RA-, CD27-, CCR7-, CD62L-

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).

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.

Ig Superfamily = cell adhesion molecules (CAM)

VIP:
VCAM (vascular cell adhesion molecule)
ICAM (intercellular adhesion molecule)
PECAM (platelet-endothelial cell adhesion molecule)


Intercellular adhesion molecule 2 (ICAM 2). Image source: Wikipedia.

Leukocyte adhesion deficiency II (LAD2 ) is characterized by which of the following?

(A) X-linked inheritance

(B) neutropenia

(C) hypogammaglobulinemia

(D) severe mental retardation

(E) autosomal recessive inheritance

(F) CD18 defect

(G) Sialyl LewisX-related defect

Answers: D, E, G. LAD1 is related to CD18 defect.

References

Leukocyte adhesion deficiency. Wikipedia.
CD18. Wikipedia.
Sialyl Lewis X. Wikipedia.

Published: 05/18/2009
Updated: 08/18/2010

CD11

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology


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 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)

CD11a - Subunit of LFA-1, a membrane glycoprotein that provides cell-cell adhesion by interaction with ICAM-1. Lymphocyte function-associated antigen 1 (LFA-1) consists of an alpha-chain (CD11a) and beta-chain (CD18).

CD11b - Subunit of MAC-1, a complement receptor (CR3). MAC-1 consists of an alpha-chain (CD11b) and beta-chain (CD18).

CD11c - Integrin alphaXbeta2 is a subunit of the complement receptor CR4. CR4 consists of an alpha-chain (CD11c) and beta-chain (CD18). CD11c is expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell CLL. CD11c is one of the defining markers for dendritic cells.

CD11a


CD11a. Image source: Wikipedia, public domain.

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).

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.

CD11b


CD11b. Image source: Wikipedia, public domain.

Macrophage-1 antigen, MAC-1 (integrin alphaMbeta2) is a complement receptor (CR3) consisting of CD11b and CD18. It binds to C3b and C4b. 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


CD11b. Image source: Wikipedia, public domain.

Integrin alphaXbeta2 (CR4) is a complement receptor composed of CD11c and CD18. CD11c is also known as Integrin, alpha X (complement component 3 receptor 4 subunit) (ITGAX).


Complement receptors (click to enlarge the image).

CD18

CD18 helps neutrophils make their way from the blood stream into the infected areas of the body.


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.

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.

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.

LAD type 1

First recognized as a distinct clinical entity in the 1970s. The inherited molecular defect in patients with LAD type 1 is a defect in CD18. CD18 is the β2 chain (β-2 integrin subunit) common to LFA-1 and MAC-1.

LAD type 2

There is inability to put sialyl-LewisX cap on leukocytes. Sialyl LewisX (SLeX, CD15) 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.

LAD type 2

CD15
F
Fifteen
Fucose, Sialyl LewisX (SLeX)
FucT-1 gene

Adhesion Molecules


Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS.

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

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.

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).

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.

Ig Superfamily = cell adhesion molecules (CAM)

VIP:
VCAM (vascular cell adhesion molecule)
ICAM (intercellular adhesion molecule)
PECAM (platelet-endothelial cell adhesion molecule)


Intercellular adhesion molecule 2 (ICAM 2). Image source: Wikipedia.

References

Leukocyte adhesion deficiency. Wikipedia.
CD18. Wikipedia.
Sialyl Lewis X. Wikipedia.

Published: 05/18/2009
Updated: 06/18/2010

CD18

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD18 is involved in making 3 proteins (LFA-1, Integrin alphaXbeta2, and MAC-1/CR3).


CD18. Image source: Wikipedia, public domain.

CD18 helps neutrophils make their way from the blood stream into the infected areas of the body.


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.

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

CD11a - Subunit of LFA-1, a membrane glycoprotein that provides cell-cell adhesion by interaction with ICAM-1. Lymphocyte function-associated antigen 1 (LFA-1) consists of an alpha-chain (CD11a) and beta-chain (CD18).

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.

CD11b - Subunit of MAC-1, a complement receptor (CR3). MAC-1 consists of an alpha-chain (CD11b) and beta-chain (CD18).

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 - Integrin alphaXbeta2 is a subunit of the complement receptor CR4. CR4 consists of an alpha-chain (CD11c) and beta-chain (CD18). CD11c is expressed in hairy cell leukemias, acute nonlymphocytic leukemias, and some B-cell CLL. CD11c is one of the defining markers for dendritic cells.

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.


Complement receptors (click to enlarge the image).

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.

LAD type 1

First recognized as a distinct clinical entity in the 1970s. 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.

LAD type 2

There is inability to put sialyl-LewisX cap on leukocytes. Sialyl LewisX (SLeX, CD15) 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.

LAD type 2

CD15
F
Fifteen
Fucose, Sialyl LewisX (SLeX)
FucT-1 gene

Adhesion Molecules


Overview of adhesion molecules, 3 groups remembered by the mnemonic SIS.

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

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.

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).

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.

Ig Superfamily = cell adhesion molecules (CAM)

VIP:
VCAM (vascular cell adhesion molecule)
ICAM (intercellular adhesion molecule)
PECAM (platelet-endothelial cell adhesion molecule)


Intercellular adhesion molecule 2 (ICAM 2). Image source: Wikipedia.

References

Leukocyte adhesion deficiency. Wikipedia.
CD18. Wikipedia.
Sialyl Lewis X. Wikipedia.

Published: 05/18/2009
Updated: 06/18/2010

Leukocyte adhesion deficiency (LAD)

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).

Leukocyte adhesion deficiency (abbreviated LAD) is an immunodeficiency resulting in recurrent infections.

There are several types:

LAD I - beta 2-integrin family is deficient or defective.
LAD II - fucosylated carbohydrate ligands for selectins are absent, fewer infections but more developmental delay as compared to LAD I.
LAD III - activation of all beta–integrins (1, 2, and 3) is defective.

Leukocyte adhesion deficiency II (LAD2 ) is characterized by which of the following?

(A) X-linked inheritance

(B) neutropenia

(C) hypogammaglobulinemia

(D) severe mental retardation

(E) autosomal recessive inheritance

(F) CD18 defect

(G) Sialyl LewisX-related defect

Answers: D, E, G. LAD1 is related to CD18 defect (not LAD2).

Related reading

Leukocyte adhesion deficiency type I (LAD I)
Leukocyte adhesion deficiency type II (LAD II)
Leukocyte adhesion deficiency type III (LAD III)

References

ABAI Board Review, 2008.
Adhesion Molecules
Leukocyte adhesion deficiency. Wikipedia.
CD18. Wikipedia.
Sialyl Lewis X. Wikipedia.

Published: 05/18/2009
Updated: 08/19/2010

Chemokines

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

What is a chemokine?

Chemokines are a family of small cytokines (proteins) secreted by cells. All chemokines share similar characteristics such as small size (8-10 kilodaltons in size), and the presence of 4 cysteine residues that are key to forming their 3-dimensional shape. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines.

Classification

More than 50 chemokines interacting with 20 receptors have been described (52 chemokines as of 2010).

The chemokine receptors are part of the G-protein coupled receptors (7-membrane domain, snake-like structures).

The position of cysteine residues (C) in the chain subdivides chemokines into 4 structural families.

Members of the chemokine family are categorized into 4 groups depending on the spacing of their first 2 cysteine residues:

- C chemokines (2 members)
- CC chemokines (31 members)
- CXC chemokines (18 members)
- CX3C chemokines (1 member)


Chemokine structures. Image source: Wikipedia, GNU Free Documentation License.


All chemokines share a typical key structure that is stabilized by disulfide bonds between cysteine residues. Image source: Wikipedia, GNU Free Documentation License.


52 chemokines from 4 families have been described. They interact with 20 receptors (click here for a larger image).

C chemokines

C chemokines (γ chemokines) are unlike all other chemokines in that they have only two cysteines; one N-terminal cysteine and one cysteine downstream. Only 2 chemokines have been described for this subgroup and are called XCL1 (lymphotactin-α) and XCL2 (lymphotactin-ß). These chemokines attract T cell precursors to the thymus.

CC chemokines

The CC chemokines (ß-chemokines) have two adjacent cysteines near their amino terminus. This is the largest group with 31 members.

CCL5 (or RANTES) attracts cells such as T cells, eosinophils and basophils that express the receptor CCR5.

HIV (syncitia-inducing (SI) strains) uses the chemokine receptor CXCR4 to enter CD4 T-cells.

CCR5
CXCR4 (CD4)

F
Five - CCR5
Four - CXCR4 (CD4) - also involved in WHIM syndrome (PIDD)
Foray of HIV into the CD4 T-cells

CCL5 or RANTES - HIV-suppressive factor released from CD8+ T cells

A mutation of CXCR4 causes a phagocytic defect called WHIM syndrome (Warts, Hypogammaglobulinemia, Infection, and Myelokathexis). Myelokathexis refers to retention (kathexis) of neutrophils in the bone marrow (myelo). Myelokathexis causes severe chronic leukopenia and neutropenia. CXCR4 antagonist plerixafor corrects panleukopenia in patients with WHIM syndrome (http://goo.gl/Xxbyt).

F
Five - CCL5
Fights HIV

CCL17 and CCL22

CCL17 and CCL22 both use the CCR4 receptor and are related to inflammation. Chemokine (C-C motif) ligand 17 is considered a new asthma biomarker.

CCL19 and CCL21

CCL19 and CCL21 together organize B and T cell areas of secondary lymphoid organs (lymph nodes) and aid in the recruitment and interaction of lymphocytes and APCs. CCL21 is strongly expressed on high endothelial venules (HEVs). HEVs are found in all secondary lymphoid organs, with the exception of spleen.

CCL11 is eotaxin.

CXC chemokines

The two N-terminal cysteines of CXC chemokines (α-chemokines) are separated by one amino acid, represented in this name with an "X". There are 18 CXC chemokines.

CXC chemokines are subdivided into 2 categories:

- those with a specific amino acid sequence (or motif) of glutamic acid-leucine-arginine (or ELR for short) immediately before the first cysteine of the CXC motif (ELR-positive)

- those without an ELR motif (ELR-negative)

ELR-positive CXC chemokines induce the migration of neutrophils, and interact with chemokine receptors CXCR1 and CXCR2. An example of an ELR-positive CXC chemokine is interleukin-8 (IL-8), which induces neutrophils (PMN) to leave the bloodstream and enter into the surrounding tissue.

Mnemonic:

P
Positive ELR (glutamic acid-leucine-arginine) chemokine CXC
PMN migration


Interleukin-8, a chemokine of the CXC subfamily. CXCL8 (IL-8) forms a chemotactic gradient that directs leukocytes (mostly PMNs) towards site of tissue injury/infection. Image source: Wikipedia, public domain.


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.

CXC chemokines dominate neutrophil recruitment through binding to receptor CXCR2

CXCL1 binds to CXCR2

CXCL2 binds to CXCR2

CXCL3 binds to CXCR2

CXCL5 binds to CXCR2

CXCL6 binds to CXCR1 and CXCR2

CXCL7 binds to CXCR2

CXCL8 (IL-8) binds to CXCR1 and CXCR2

Chemokines that guide T and B cell migration within lymph nodes

CXCL13 (BCA-1) - binds to CXCR5 - causes B cell migration into follicles

CCL19 (MIP-3β/ELC) and CCL21 (SLC) - both bind to CCR7 - cause T cell and dendritic cell migration into parafollicular zones of lymph nodes

CD markers for central vs. effector memory T cells:

Central memory T cells: CD45RA-, CD27+, CCR7+, CD62L+

Effector memory T cells: CD45RA-, CD27-, CCR7-, CD62L-

Mnemonic

CXCL13 binds to CXCR5 - causes B cell migration into follicles

1 + 3 = 4, 5 (binds to CXCR5)

CCL19 and CCL21 bind to CCR7 - cause T cell cell migration into parafollicular zones of lymph nodes

9 - 2 = 7 (bind to CCR7)

CX3C chemokines

There is only one CX3C chemokine - it has 3 amino acids between the 2 cysteines (d-chemokine). The only CX3C chemokine discovered to date is called fractalkine (or CX3CL1). It serves as both a chemoattractant and as an adhesion molecule.

Chemokine/receptor defects and diseases

CCR5/CCL3L1, CXCR4
HIV/AIDS

DARC
P. vivax malaria

CXCR4
HIV/AIDS
WHIM’s syndrome

CXCL4
Heparin-induced thrombocytopenia

CX3CR1, CCL5
Atheroslcerosis

CCL2, 5, 7, 11, CXCL8
Asthma/Allergies

CXCL12/CXCR4
Cancer metastases


(Click to enlarge the image).


Chemokine Signaling. This video describes the process of chemokine signaling. This video is from: Janeway's Immunobiology, 7th Edition, Murphy, Travers, & Walport. Source: Garland Science.

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.

There is more than one eotaxin:

CCL11 - Eotaxin

CCL24 - Eotaxin-2

CCL26 - Eotaxin-3

All of them bind to CCR3 - recruit eosinophils, basophils, and TH2 cells.

What chemokine attracts naïve B cells to lymph nodes?

CXCR5. CXCL13 binds to CXCR5.

What chemokine attracts naïve T cells to lymph nodes?

CCR7. CCL19 and CCL21 bind to CCR7.

References

Chemokine, Wikipedia.

(This article is based in large part on Wikipedia articles that were reviewed for accuracy, please see the reference links).
Mnemonics: Human immunodeficiency virus (HIV)
New biomarkers in asthma: chemokines and chitinase-like proteins

Published: 05/18/2009
Updated: 12/20/2010

CD99

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD44
CD99
Both participate in leukocyte migration.


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.

CD99 (Cluster of Differentiation 99) is also known as MIC2 or single-chain type-1 glycoprotein. CD99 is expressed on all leukocytes but highest on thymocytes and augments T-cell adhesion, apoptosis of double positive T cells, and participates in migration and activation.

CD44
CD45 - leukocyte common antigen, present on all hemopoietic cells except erythrocytes

CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. PMN adhesion to the endothelium is mediated through CD44.

References

Cluster of differentiation (CD) of leukocytes
CD99, Wikipedia.

Published: 05/18/2009
Updated: 05/18/2009

CD44

Author: V. Dimov, M.D., Fellow, Creighton University Division of Allergy & Immunology
Reviewer: S. Randhawa, M.D., Fellow, LSU (Shreveport) Department of Allergy & Immunology

CD44
CD45 - leukocyte common antigen, present on all hemopoietic cells except erythrocytes

CD44 is a cell-surface glycoprotein involved in cell-cell interactions, cell adhesion and migration. PMN adhesion to the endothelium is mediated through CD44.


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.

CD44 is a receptor for hyaluronic acid. A specialized sialofucosylated glycoform of CD44 called HCELL is found natively on human hematopoietic stem cells, and is a highly potent E-selectin and L-selectin ligand. HCELL functions as a "bone homing receptor", directing migration of human hematopoietic stem cells and mesenchymal stem cells to bone marrow.

CD44 expression is an indicative marker for effector-memory T-cells.

CD44
CD99
Both participate in leukocyte migration.


T and B Cells - Naive and Memory Cell Markers (click to enlarge the image).

References

Cluster of differentiation (CD) of leukocytes
CD44, Wikipedia.

Published: 05/18/2009
Updated: 05/18/2009