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.
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)
- Mac-1 (CD11b/CD18) and
- gp 150/95 (CD11c/CD18)
Complement receptors (click to enlarge the image).
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.
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.
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.
Once the diagnosis of LAD is made, bone marrow transplantation is the current standard of care.
Adhesion molecules, 3 groups = SIS
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)
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
(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).