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Intravenous Immunoglobulin

Overview

Immune globulin products from human plasma were first used in 1952 to treat primary immune deficiency. Intravenous immunoglobulin (IVIG) contains the pooled immunoglobulin G (IgG) immunoglobulins from the plasma of approximately a thousand or more blood donors.

IVIGs are sterile, purified IgG products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG, which has intact Fc-dependent effector functions and only trace amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM).
Initially, immune globulin products were administered by intramuscular injection. One of biggest advances with IVIG in recent years has been the use of sorbitol-based formulations as opposed to sucrose-based formulations which allow for IV administration with less reactions.
. IVIG was initially shown to be effective in immune thrombocytopenic purpura (ITP) in 1981.
There are now multiple alternative IVIG preparations available for intravenous administration that have been approved by the Food and Drug Administration (FDA) for the treatment of primary humoral immunodeficiencies and chronic immune thrombocytopenic purpura.  Also, a liquid, pasteurized, 10% concentrated intravenous gammaglobulin preparation is as effective as a 5% concentrated preparation, making the concentrated versions more convenient to administer.

The image below is a schematic representation of an immunoglobulin G molecule.

Schematic representation of an immunoglobulin G mo

Schematic representation of an immunoglobulin G molecule. CH indicates constant region of heavy chain; CL, constant region of light chain; VH, variable region of heavy chain; and VL, variable region of light chain.

IVIG is an immunomodulating agent that has multiple activities. These include modulation of complement activation; suppression of idiotypic antibodies; saturation of Fc receptors on macrophages; and suppression of various inflammatory mediators, including cytokines, chemokines, and metalloproteinases.
Fc receptors are a class of receptors on immune cells that bind to the Fc (constant region) portion of an antibody. The Fc region of IgG facilitates interaction with and signaling through Fc receptors on antigen presenting cells such as phagocytes, B cells, and other cells and with Fc-binding plasma proteins (eg, components of the complement system).

Blockade of macrophage Fc receptors is considered the primary mechanism of action of immune globulin in persons with ITP and other autoantibody-mediated cytopenias. In persons with Kawasaki disease and dermatomyositis, IVIG is thought to inhibit the generation of membrane attack complexes (C5b-C9) and subsequent complement-mediated tissue damage by binding the activated components C3b and C4b, thus preventing their deposition on target surfaces. In persons with dermatomyositis, IVIG induces a decrease in the plasma levels of membrane attack complex and a substantial decrease in the amounts of C3b and membrane attack complex deposited in endomysial capillaries. The high content of anti-idiotypes against autoantibodies in IVIG facilitates its ability to neutralize autoantibodies, as is shown in patients with acquired hemophilia due to autoantibodies against factor VIII.

IVIG also has effects on the clearance of opsonized cells. The results of in vitro C3 uptake studies evaluating the effect of IVIG on the clearance of pre-opsonized cells suggest that IVIG produces a kinetic depression of C3 uptake and modifies the process of complement fragment deposition on erythrocytes.

IVIG also contains Natural Antibodies. Normal serum contains IgG, IgM, and IgA antibodies, which are referred to as natural antibodies because they are induced without deliberate immunization and are independent of antigenic exposure. They are considered key to the immunoregulatory effects of immune globulin in immune-mediated disorders.
Natural autoantibodies appear to be more polyreactive than immune antibodies; natural antibodies can frequently bind to different antigens.
Natural autoantibodies can (1) bind to pathogens; (2) help remove senescent or altered molecules, cells, and tumors; (3) induce remyelination; and (4) inhibit the growth of autoreactive B-cell clones. In the multifocal motor neuropathy disease state, IVIG intercedes to stop complement deposition that is triggered by anti-GM1 antibodies.
The effect of IVIG could also relate to the presence of natural antibodies. IVIG also contains cytokines, and perhaps neutralizing antibodies; interestingly, antibodies against granulocyte macrophage colony-stimulating factor, interferon, interleukin 1, and interleukin 6 in immune globulin have biologic activity in vivo.

The broad range of applications of IVIG shows the importance of immunoglobulins in the immune homeostasis in healthy people.

Noteworthy to remember is that while IVIG replacement prevents severe and lower respiratory tract infections, it does not prevent upper respiratory tract and non-respiratory infections in persons with common variable immune deficiency.
  The largest challenge faced in 2018 is identifying those persons with specific diseases who will respond to IVIG and what biomarkers might inform apposite therapy.

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