Phagocytes

Farhad Ravandi and Ronald Hoffman

Introduction, 277

Mechanisms of phagocyte function, 277

Locomotion, 277 Phagocyte receptors, 279 Phagocytic signalling, 281 Degranulation and secretion, 281

Phagocytic killing - the respiratory burst, 282 Phagocytic killing - nitric oxide, 282 Phagocytic killing - antimicrobial proteins, 283 Production, structure and dysfunction of phagocytes, 284

Neutrophils, 285 Eosinophils, 293 Basophils and mast cells, 296 Monocytes and macrophages, 298 Suggested bibliography, 301

Introduction

White blood cells have fundamental roles in defence against invading micro-organisms and the recognition and destruction of neoplastic cells as well as their role in acute inflammatory reactions. Furthermore, through their phagocytic function, white blood cells are influential in clearing senescent and apoptotic cells, hence allowing tissue repair and remodelling. Production of various cytokines by white blood cells influences the functions of other cells and affects processes such as cellular and humoral immunity, and allergic phenomena. The phagocytic actions of white blood cells can cause damage to the host tissue, leading to inflammation. This occurs either as a by-product of their microbial killing actions or as a direct attack on the host in autoimmune disorders.

Normal haemopoiesis, including generation of appropriate white blood cell number and constellation, is dependent upon intricately regulated signalling cascades that are mediated by cytokines and their receptors. Orderly function of these pathways leads to the generation of the normal constellation of haemo-poietic cells, and their abnormal activation results in impaired apoptosis, uncontrolled proliferation and neoplastic transformation. Cytokines function in a redundant and pleiotropic manner; different cytokines can exert similar effects on the same cell type and any particular cytokine can have several differing biological functions. This complexity of function is a result of shared receptor subunits as well as overlapping downstream pathways, culminating in transcription of similar genes. Increased understanding of the role of cytokines and other growth factors in the control of normal haemopoiesis has led to better delineation of the pathogenetic events that affect the function and number of these cells.

In this chapter, we consider the normal production and function of white blood cells involved in phagocytosis and describe various disorders causing their altered number and activity.

Mechanisms of phagocyte function Locomotion

Phagocytes are an important part of the innate host defence system, performing their function either as resident cells in tissues (e.g. macrophages) or as circulating defenders (e.g. neutrophils, eosinophils and monocytes). Phagocytosis of invading microorganisms by both types of defender involves the synthesis of highly toxic derivatives of molecular oxygen by the respiratory burst NADPH oxidases and the delivery of stored antimicrobial proteases into the vacuoles containing microbes.

Circulating phagocytes such as neutrophils respond to spatial gradients of chemotaxin and move by alternating the extrusion and retraction of broad frontal lamellipodia that determine the direction of movement. As a result, the cell body elongates along the axis defined by the lamellar protrusion. As little as a 2% change in the concentration of the chemoattractant can be recognized by neutrophils. The signals generated by such gradients activate the cytoplasm of the cell for propulsive and retractive events. Movement of neutrophils is achieved by the contraction of an actin filamentous network in the cortical gel at the leading front. This dynamic network provides strength for the forming protrusions and serves as an anchor for adhesion molecules. ATP provides the energy for the movement of the cell.

Phagocytic cells possess a number of cell-cell adhesion receptors and ligands, which mediate their recruitment, migration and interaction with other immune cells (Table 17.1). These include members of the integrins, the immunoglobulin super-family and the selectins. Migration of macrophages involves their adhesion to endothelial surfaces and their extravasation through to the extravascular space. This process is mediated by cytokine-regulated expression of intercellular adhesion molecules (ICAMs) on the surface of both phagocytes and endothelial cell. ICAMs share similar structure to the immunoglobulin (Ig)

Table 17.1 Phagocytic cell adhesion molecules.

Adhesion molecule

CD number

Cellular distribution

Ligand

Function

Integrin family

Very late-acting antigens

ajPj (VLA-1)

CD49a/29

Mo, EC

Collagen I, IV, laminin

Cell adherence to ECM

a2Pj (VLA-2)

CD49b/29

Mo, EC, platelets

Collagen I, IV, laminin

a3Pi (VLA-3)

CD49c/29

Mo

Collagen I, laminin, fibronectin

Cell adherence to ECM

a.P1 (VLA-4)

CD49d/29

Mo, eos, bas

Fibronectin, VCAM-1

Cell adherence to ECM and

cell-cell adhesion matrix

a5P1 (VLA-5)

CD49e/29

Mo, neut, EC

Fibronectin

Cell adherence to ECM

a6Pi (VLA-6)

CD49f/29

Mo

Laminin

Cell adherence to ECM

Leucocyte integrins(LFA-1 family)

aDP2

-/18

Ma

?

aLP2 (LFA-1)

CD11a/18

Mo, Ma, granulocytes

ICAM-1, ICAM-2, ICAM-3

Cell-cell adhesion and

cell-matrix adhesion

aMP2 (CR3, Mac-1)

CD11b/18

Mo, Ma, granulocytes

ICAM-1, C3bi, fibronectin,

Endothelium adherence/

factor X, microbial antigens

extravasation

aXP2 (p150,95)

CD11c/18

Mo, Ma, granulocytes

C3bi, fibronectin

Adhesion during

inflammatory response

Cytoadhesins

aVP3 (vitronectin receptor)

CD51/61

Mo, EC

Vitronectin, fibronectin, collagen,

Cell adherence to ECM

thrombospondin, vWF

aRP3 (leucocyte response integrin)

Mo, granulocytes

Vitronectin, fibronectin, collagen,

Cell adherence to ECM

thrombospondin, vWF

«VP5

CD51/-

Mo

Vitronectin, fibronectin

Cell adherence to ECM

ŒvP7

CD51/-

Ma

?

Immunoglobulin superfamily

ICAM-1

CD54

Mo, EC

aLß2, aMß2

Cell-cell adhesion

ICAM-2

CD102

Mo, EC

aLß2

Cell-cell adhesion

ICAM-3

CD50

Mo, granulocytes

aLß2

Cell-cell adhesion

VCAM-1

CD106

Ma, EC, dendritic cells

a4ß1

Recruitment

PECAM-1

CD31

Mo, EC, platelets

CD31, aVß3

Transmigration

HCAM

CD44

Ubiquitous

Collagen I, IV, fibronectin

Extravasation

Selectin family

L-selectin

CD62L

Mo, granulocytes

Carbohydrate determinants

Migration, rolling on

on EC

vessel wall

E-selectin

CD62E

Neutrophil, EC

Mo, neut, eos

Migration, rolling on

vessel wall

P-selectin

CD62P

EC, platelets

Mo, neut, eos

Adhesion to activated

platelets and EC

Bas, basophil; cd, cluster of differentiation; EC, endothelial cell; eos, eosinophil; ICAM, intercellular adhesion molecule; Mo, monocyte; Ma, macrophage; neut, neutrophil.

family and other Ig-like adhesion molecules such as VCAM-1, and serve as ligands for the ß2-integrins. The distribution and regulation of the three members of the ICAM family is different. ICAM-1 is expressed at a low level on endothelial cells; its expression is enhanced by the inflammatory cytokines such as interleukin 1 (IL-1), interferon-a (IFN-a) and IFN-y. ICAM-2 is constitutively expressed on endothelial cells, with no response to the inflammatory cytokines. ICAM-3 is expressed by neu-

Table 17.2 Opsonic receptors mediating phagocytosis.

Receptor

Marker

Opsonic ligand

Binding affinity (Ka)

Cell type

Function

FcyRI

CD64

IgG1

High (50 nmol/L)

Monocytes, Macrophages, Neutrophils (after IFN-y exposure)

Phagocytosis, Respiratory burst

FcyRII

CD32

IgG1 = IgG3> IgG4 = IgG2

Low (1 ^M)

Neutrophils, monocytes, macrophages

Phagocytosis, Respiratory burst

FcyRIII

IgG1 = IgG3

Low (110 nmol/L)

Neutrophils, monocytes, macrophages

IIIB - Phagocytosis (requires CR1 or FcyRII)

IIIA

CD16a, 1 allotype NA1

Low (470 nmol/L)

IIIB

CD16b, 2 allotypes NA1 and NA2

FcaR

CD89 My43 IgM

IgA1, IgA2, secretory IgA1 and IgA2

Neutrophils, monocytes, macrophages, T- and B-cell subsets, NK cells, erythrocytes

Phagocytosis, Respiratory burst, Bacterial killing

CR1

CD35 4 alleles

C3b and C4b dimers

High (0.5 nmol/L)

All phagocytes, some T lymphocytes

Phagocytosis

CR3

CD11b/CD18 Mac1

C3bi

High (0.5 nmol/L)

All phagocytes, NK cells, yS-T cells

Phagocytosis, Respiratory burst

CR, complement receptor; NK, natural killer.

CR, complement receptor; NK, natural killer.

trophils, monocytes and lymphocytes. Another member of the endothelial Ig superfamily, PECAM-1 (CD31), serves an important role in transmigration of neutrophils into mucosal or other body tissues.

The ß2-integrin family consists of three leucocyte restricted integrins, LFA-1 (CD11a/CD18), CR3 (MAC-1, CD11b/CD18) and p150/95 (CD11c/CD18). They share a common ß-subunit, CD18, and three unique a-subunits, CD11a, CD11b, and CD 11c. LFA-1 and ICAM-1 are both present on monocytes and mediate their attachment to endothelial cells and to lymphocytes bearing the corresponding receptor/ligand, thereby facilitating antigen presentation. Leucocyte adhesion deficiency (LAD) type I, described later in the chapter, is caused by the genetic deficiency of all three CD18 integrins. LAD-I neutrophils bind poorly to IL-1-stimulated endothelial cells and do not undergo transendothelial migration.

Selectins are expressed on all leucocytes (L-selectins) as well as post-capillary endothelial surfaces (E-selectins) and in platelet a-granules and endothelial cell Weibel-Palade bodies (P-selectins). Neutrophils, eosinophils, monocytes and macrophages constitutively express L-selectin. E- and P-selectins recognize oligosaccharide ligands on macrophages. Selectins are implicated in the early interactions of phagocytes and endothelium. The interaction of E- and P-selectins on cytokine-activated endothelial cells, and L-selectins on macrophages with their appropriate ligands, targets phagocytic cells to the endothelium at sites of vascular injury and initiates the rolling movement of leucocytes along the vessel wall. The ligands for selectins have a similar structure containing carbohydrate groups typically as terminal structures of glycoproteins and glycolipids. A major selectin ligand, a sialylated and fucosylated tetrasaccharide related to the sialylated Lewis X blood group, is heavily expressed on quiescent neutrophils and monocytes.

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