Of the five immunoglobulin isotypes, Immunoglobulin G (IgG) is most abundant in human serum. The four subclasses, IgG1, IgG2, IgG3 and IgG4 which are highly conserved, differ in their constant region, particularly in their hinges and upper CH2 domains. These regions are involved in binding to both IgG-Fc receptor (FcγR) and C1q. As a result, the different subclasses have different effector functions, both in terms of triggering FcγR-expressing cells, resulting in phagocytosis or Antibody-dependent cell-mediated cytotoxicity (ADCC), and activating complement. The Fc-regions also contain a binding epitope for the neonatal Fc-receptor (FcRn), responsible for the extended half-life, placental transport, and bidirectional transport of IgG to mucosal surfaces. However, FcRn is also expressed in myeloid cells, where it participates in both phagocytosis and antigen presentation together with classical FcγR and complement. How these properties, IgG-polymorphisms and post-translational modification of the antibodies in the form of glycosylation, affect IgG-function, will be the focus of the current review.

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IgG subclasses and allotypes: from structure to effector functions.

The present invention concerns polypeptides comprising a variant Fc region. More particularly, the present invention concerns Fc region-containing polypeptides that have altered effector function as a consequence of one or more amino acid modifications in the Fc region thereof.

Polypeptide variants with altered effector function

https://www.cell.com/immunology/pdf/0167-5699(93)90166-I.pdf

Human IgG Fc receptor heterogeneity: molecular aspects and clinical implications.

The process of engulfing a foreign particle - phagocytosis - is of fundamental importance for a wide diversity of organisms. From simple unicellular organisms that use phagocytosis to obtain their next meal, to complex metazoans in which phagocytic cells represent an essential branch of the immune system, evolution has armed cells with a fantastic repertoire of molecules that serve to bring about this complex event. Regardless of the organism or specific molecules concerned, however, all phagocytic processes are driven by a finely controlled rearrangement of the actin cytoskeleton. A variety of signals can converge to locally reorganise the actin cytoskeleton at a phagosome, and there are significant similarities and differences between different organisms and between different engulfment processes within the same organism. Recent advances have demonstrated the complexity of phagocytic signalling, such as the involvement of phosphoinostide lipids and multicomponent signalling complexes in transducing signals from phagocytic receptors to the cytoskeleton. Similarly, a wide diversity of 'effector molecules' are now implicated in actin-remodelling downstream of these receptors.

Phagocytosis and the actin cytoskeleton

Publisher Summary This chapter focuses on studies of the murine and human leukocyte FcγR and FCɛR I, with particular reference to the structural characterization of these receptors, the molecular nature of their interaction with immunoglobulin (Ig), and their mechanisms of signal transduction. In addition, the chapter also reviews different aspects of FcμR, FcαR, the poly Ig receptor, the receptor for the transport of Ig in neonatal gut, and receptors for IgD. The characterization of the proteins, transcripts, and genes of the different classes of both these FcR families— FcγR and FCɛR I—has largely been completed and those for IgM, IgD, and IgA receptors still to be completed. Attention is now turning to understanding the nature of the mechanisms by which these receptors and their subunits are able to mediate their functions. The structural analysis of the functional basis of FcγR and FCɛR signaling is beginning to shed some light on the way these receptors trigger biological responses, and the molecular dissection of the pathways involved in signaling is also underway. The understanding of these interactions may provide the means to devise strategies to inhibit pathophysiological effects of FcR function that would have far reaching implications in the treatment of antibody induced hypersensitivity.

Molecular basis of Fc receptor function.

A heterogeneous group of receptors binding the Fc region of Ig, Fc receptors, provides important links between the cellular and humoral branches ofthe immune system. The members of this receptor group, specific for essentially all the Ig isotypes, are expressed on a variety of cells and mediate multiple important functions. Receptors for IgG (Fc’yR) , a subgroup within the larger group of FcR, were recently shown to belong to the Ig supergene family . Three major classes of leukocyte Fc R are currently recognized, all of which contain several members. Although rapid progress has been made in elucidating the structure of Fc’yR and organization of their genes [see 107] , many questions about the functions of these Fc’yR remain unanswered. In this review we focus on the various biological functions mediated by the different human Fc’yR. We utilize a new nomenclature for these receptors recently proposed by other workers (Kinet, J.-P. and Ravetch, J. , personal communication).

Biology of human immunoglobulin G Fc receptors.

We have tested the possible physical interactions between the iC3b receptor (CR3), lymphocyte function-associated Ag-1, and class III Fc gamma receptor (Fc gamma RIII) at neutrophil surfaces. Cells were labeled using fluorochrome-conjugated Fab or F(ab')2 fragments of antireceptor mAb. Labeled receptors were capped using second-step F(ab')2 fragments of goat anti-mouse Fab antiserum. After 20 min at 37 degrees C, 68% of the cells capped the anti-CR3 plus second-step complex. Capping was time, temperature, and cytochalasin B sensitive. When capped cells were probed with Fab' or F(ab')2 fragments of anti-Fc gamma RIII labeled with a distinct fluorochrome, 41% of the cells cocapped Fc gamma RIII. Indistinguishable results were obtained when potential antibody combining sites within caps were blocked with a large excess of Fab or F(ab')2 fragments. When Fc gamma RIII was capped, 49% of the cells cocapped CR3. Similarly, LFA-1 cocapped with both CR3 and Fc gamma RIII. Importantly, other membrane components including HLA class I, Mo5, CD13, CR type 1, and IL-8 receptors and N-4-nitrobenzo-2-oxa-1, 3-diszole L-alpha-dimyristoyl phosphatidylethanolamine did not cocap with CR3. However, the positive control Con A did cocap with CR3 and Fc gamma RIII. We next evaluated the effect of saccharides on CR3-Fc gamma RIII cocapping and found that 0.15 M N-acetyl-D-glucosamine (NADG), alpha-methyl-D-mannoside, and D-mannose significantly inhibited cocapping by 70, 58, and 48%, respectively. No inhibition was obtained using glucose, galactose, N-acetyl-neuraminic acid, fucose, sorbitol, fructose, or sucrose. Similarly, Fc gamma RIII-lymphocyte function-associated-1 cocapping was inhibited by NADG. However, the cocapping of CR3 with lymphocyte function-associated-1 or Con A were not affected by 0.15 M NADG, which suggests that NADG inhibition of leukoadhesin-Fc gamma RIII cocapping is not due to a general effect of NADG on capping. Inasmuch as Fc gamma RIII is a glycophospholipid-linked membrane protein, we speculate that it interacts with CR3 and/or lymphocyte function-associated-1 via lectin-like interactions.

Cocapping of the leukoadhesin molecules complement receptor type 3 and lymphocyte function-associated antigen-1 with Fc gamma receptor III on human neutrophils. Possible role of lectin-like interactions.

J. G. J. Van De Winkel

Papers

Biology of human immunoglobulin G Fc receptors.

Cocapping of the leukoadhesin molecules complement receptor type 3 and lymphocyte function-associated antigen-1 with Fc gamma receptor III on human neutrophils. Possible role of lectin-like interactions.

The human low affinity immunoglobulin G Fc receptor IIC gene is a result of an unequal crossover event.

Three genes for the human high affinity Fc receptor for IgG (Fc gamma RI) encode four distinct transcription products.

Gene organization of the human high affinity receptor for IgG, Fc gamma RI (CD64). Characterization and evidence for a second gene.