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.
Fucose, Sialyl LewisX (SLeX)
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.
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:
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
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).
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
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?
(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.