B

Fig. 2. Organization of the Fc receptor gene cluster and the structure of Fc7 receptors. A. The Fc receptor genes, the so-called Fc receptor cluster (FRC), are located on human chromosom 1q21-24 region. The FRC gene for Fc^RI is located proximal to the centromeric end, while the Fc^RII/III gene is located near the telomeric end of FRC. B. The Fc^RI consists of a chain and a dimer of the 7 chain. The Fc^RIIIA consists of a chain and mainly 7 chain dimer except for natural killer cell, where the Fc7RIIIA contains £ chain dimer. The Fc7RIIB, inhibitory Fc7 receptor, has a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), while Fc7RI, Fc7RIIA and Fc7RIIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) on their cytoplasmic domains. Black circles indicate three principal polymorphism sites on Fc7RIIA, Fc7RIIIA, and Fc7RIIIB. (Reprinted after modification from Journal of Allergy and Clinical Immunology, Vol 111, Binstadt BA, Geha RS, and Bonila FA., IgG Fc receptor polymorphisms in human disease: Implications for intravenous immunoglobulin therapy, 697-703 (2003) with permission from the American Academy of Allergy, Asthma, and Immunology).

FcyRI FcyRlla/c FcyRllla FcyRllb FcyRIlIb

Fig. 2. Organization of the Fc receptor gene cluster and the structure of Fc7 receptors. A. The Fc receptor genes, the so-called Fc receptor cluster (FRC), are located on human chromosom 1q21-24 region. The FRC gene for Fc^RI is located proximal to the centromeric end, while the Fc^RII/III gene is located near the telomeric end of FRC. B. The Fc^RI consists of a chain and a dimer of the 7 chain. The Fc^RIIIA consists of a chain and mainly 7 chain dimer except for natural killer cell, where the Fc7RIIIA contains £ chain dimer. The Fc7RIIB, inhibitory Fc7 receptor, has a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), while Fc7RI, Fc7RIIA and Fc7RIIIA contains an immunoreceptor tyrosine-based activation motif (ITAM) on their cytoplasmic domains. Black circles indicate three principal polymorphism sites on Fc7RIIA, Fc7RIIIA, and Fc7RIIIB. (Reprinted after modification from Journal of Allergy and Clinical Immunology, Vol 111, Binstadt BA, Geha RS, and Bonila FA., IgG Fc receptor polymorphisms in human disease: Implications for intravenous immunoglobulin therapy, 697-703 (2003) with permission from the American Academy of Allergy, Asthma, and Immunology).

immunoglobulin for activation (Fig. 3). The binding of the C1q component to Fc portions of IgG or IgM triggers a proteolytic cascade. The C3b fragment, which is generated as a result of the cascade, not only acts as opsonins, but also binds to C3 convertase to form C5 convertase, thereby generating a membrane attack complex that disrupts the target cell membrane and results in cell death. In addition, binding of C3b to complement receptors expressed on effector cells such as NK cells, macrophages, or neutrophils induces phagocytosis or cell-mediated lysis—so-called complement-dependent cellular cytotoxicity (CDCC) (3,4).

In addition to the positive control for activation of complement lysis, complement inhibitory proteins such as CD55 or CD59 exert a negative control mechanism of complement lysis (3,4). Tumor cells over-expressing CD55 and CD59, such as CLL cells, are less likely to achieve a response to rituximab therapy. In other words, a blockade of CD55 and CD59 may enhance rituximab-mediated CDC.

Table 1

Properties and Distribution of Fc^ Receptors

Name

Structure

Alleles

IgG Subclass Specificity

Distribution

Mo/Mc NK

PMN B

DC

Mast Plt

Fc^RI (CD64)

IgG1=IgG3 >IgG4»IgG2

+ —

± —

+

± —

Fc^RII (CD32)

IgG1=IgG3»IgG2,IgG4

Fc^RIIA

a

R/H-131

R is lower affinity

+ —

+—

+

++

Fc^RIIB

a

+ —

— +

+

+ —

Fc^RIIC

a

— +

Fc^RIII (CD16)

IgG1, IgG3>>IgG2, IgG4

Fc^RIIIA

F/V-158

F is lower affinity

++

——

+

——

Fc^RIIIB

a (GPI)

NA1/NA2

NA2 is lower affinity

——

+—

——

Mo, monocytes; Mc, macrophage; NK, natural killer cell; PMN, polymorphonuclear leukocyte; B, B-cells; DC, dendritic cells; Plt, platelet; GPI, glycosylphosphatidylinositol-linked; NA, neutrophil antigen.

Reprinted after modification from Journal of Allergy and Clinical Immunology, Vol. 111, Binstadt BA, Geha RS, and Bonila FA, IgG Fc receptor polymorphisms in human disease: Implications for intravenous immunoglobulin therapy, 697-703 (2003) with permission from the American Academy of Allergy, Asthma, and Immunology.

^ Membrane

Attack Complex

Fig. 3. Mechanism of complement-dependent cytotoxicity. Binding of rituximab with the CD20 antigen leads to initiation of the classical pathway of complement activation. The binding of the Fc portions with C1q triggers a proteolytic cascade. The activated C1q subsequently activates C4 and C2. The complex of C1q, C4 and C2 subsequently forms the C3 convertase complex. The C3 con-vertase generates large amounts of C3b. The C3b molecule form C5 convertase after binding with C3 convertase. C5b, C6, C7, C8 and C9 associate to generate the membrane attack complex (MAC), which kills the target cells. The CD55 (decay accelerating factor, DAF), inhibits both C3 and C5 convertase, while CD59 (membrane inhibitor of reactive lysis) inhibits the activity of the MAC. In addition, released C3a and C5a molecules induce chemotaxis and the activation of immune cells.

Chemotaxis Immune activation

^ Membrane

Attack Complex

Fig. 3. Mechanism of complement-dependent cytotoxicity. Binding of rituximab with the CD20 antigen leads to initiation of the classical pathway of complement activation. The binding of the Fc portions with C1q triggers a proteolytic cascade. The activated C1q subsequently activates C4 and C2. The complex of C1q, C4 and C2 subsequently forms the C3 convertase complex. The C3 con-vertase generates large amounts of C3b. The C3b molecule form C5 convertase after binding with C3 convertase. C5b, C6, C7, C8 and C9 associate to generate the membrane attack complex (MAC), which kills the target cells. The CD55 (decay accelerating factor, DAF), inhibits both C3 and C5 convertase, while CD59 (membrane inhibitor of reactive lysis) inhibits the activity of the MAC. In addition, released C3a and C5a molecules induce chemotaxis and the activation of immune cells.

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