Immune complex

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Immune complex diseases

An immune complex, sometimes called an antigen-antibody complex or antigen-bound antibody, is a molecule formed from the binding of multiple antigens to antibodies. [1] The bound antigen and antibody act as a unitary object, effectively an antigen of its own with a specific epitope. After an antigen-antibody reaction, the immune complexes can be subject to any of a number of responses, including complement deposition, opsonization, [2] phagocytosis, or processing by proteases. Red blood cells carrying CR1-receptors on their surface may bind C3b-coated immune complexes and transport them to phagocytes, mostly in liver and spleen, and return to the general circulation.

Contents

The ratio of antigen to antibody determines size and shape of immune complex. [3] This, in turn, determines the effect of the immune complex. Many innate immune cells have FcRs, which are membrane-bound receptors that bind the constant regions of antibodies. Most FcRs on innate immune cells have low affinity for a singular antibody, and instead need to bind to an immune complex containing multiple antibodies in order to begin their intracellular signaling pathway and pass along a message from outside to inside of the cell. [3] Additionally, the grouping and binding together of multiple immune complexes allows for an increase in the avidity, or strength of binding, of the FcRs. This allows innate immune cells to get multiple inputs at once and prevents them from being activated early. [3]

Immune complexes may themselves cause illness when they are deposited in organs, for example, in certain forms of vasculitis. This is the third form of hypersensitivity in the Gell-Coombs classification, called type III hypersensitivity. [4] Such hypersensitivity progressing to disease states produces the immune complex diseases.

Immune complex deposition is a prominent feature of several autoimmune diseases, including rheumatoid arthritis, scleroderma and Sjögren's syndrome. [5] [6] An inability to degrade immune complexes in the lysosome and subsequent accumulation on the surface of immune cells has been associated with systemic lupus erythematosus. [7] [8]

Functions

Regulation of antibody production

Immune complexes can also play a role in the regulation of antibody production. B cells express B-cell receptors (BCRs) on their surfaces and antigen binding to these receptors begins a signaling cascade that leads to activation. B cells also express FcγRIIb, low affinity receptors specific to the constant region of IgG, on their surfaces. IgG immune complexes are the ligand for these receptors and immune complex binding to these receptors induces apoptosis, or cell death. After B cells are activated, they differentiate into plasma cells and cease to express BCR but continue to express FcγRIIb, which allows IgG immune complexes to regulate IgG production via negative feedback and prevent uncontrolled IgG production. [9]

Activation of dendritic cells and macrophages

Immune complexes, particularly those made of IgG, also play a variety of roles in the activation and regulation of phagocytes, which include dendritic cells (DCs) and macrophages. Immune complexes are better at inducing DC maturation than an antigen on its own. [10] Again, the low affinity of many FcγR for IgG means that only immune complexes, not single antibodies, can induce the FcγR’s signaling cascade. When compared to single antibodies binding to FcγRs, immune complexes binding to FcγRs cause significant changes in internalization and processing of antigen, maturation of the vesicles containing the internalized antigen, and activation in DCs and macrophages. [11] There are multiple classes of macrophages and DCs that express different FcγRs, which have differing affinities for single antibodies and immune complexes. [11] This allows the response of the DC or macrophage to be tuned precisely, subsequently tuning the level of IgG. These diverse FcγRs cause different responses in their DCs or macrophages by initiating different signaling pathways that can either activate or inhibit cellular functions. [11] The binding of the immune complex to the DC’s membrane-bound receptor and internalization of the immune complex and receptor begins the process of antigen presentation, which allows the DC to activate T cells. Via this process, immune complexes cause enhanced T cell activation. [11]

Elimination of opsonized immune complexes

Type I FcγRs activation begins a cascade of reactions to eliminate the IgG-opsonized target. Type I FcγRs is another type of IgG constant region receptor, which can bind to IgG immune complexes and lead to the elimination of the opsonized complex. Immune complexes bind to multiple type I FcγRs, which cluster on the cell surface and begin the ITAM signaling pathway. Although both activating and inhibitory Type I FcγRs can mediate phagocytosis, but the internalization of IgG-opsonized targets through activating FcγRs is more effective for response. Immune complexes bind to multiple type I FcγRs, which cluster on the cell surface and begin the Immunoreceptor Tyrosine-Based Activation Motif (ITAM) signaling pathway. [12] ITAM is composed of tyrosine which is separated from a leucine or isoleucine by two other amino acids and is located in the cytoplasmic tail of the molecule. Following the clustering by IgG complexes, ITAM is phosphorylated by FcγRs crosslinking. This phosphorylation of the ITAM leads to pro-inflammatory signaling that mediates cellular activation which will induce a signaling cascade and eventually leads to elimination of opsonized immune complex. [13]

Related Research Articles

An immune response is a physiological reaction which occurs within an organism in the context of inflammation for the purpose of defending against exogenous factors. These include a wide variety of different toxins, viruses, intra- and extracellular bacteria, protozoa, helminths, and fungi which could cause serious problems to the health of the host organism if not cleared from the body.

<span class="mw-page-title-main">Phagocytosis</span> Process by which a cell uses its plasma membrane to engulf a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

Humoral immunity is the aspect of immunity that is mediated by macromolecules – including secreted antibodies, complement proteins, and certain antimicrobial peptides – located in extracellular fluids. Humoral immunity is named so because it involves substances found in the humors, or body fluids. It contrasts with cell-mediated immunity. Humoral immunity is also referred to as antibody-mediated immunity.

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

<span class="mw-page-title-main">Antigen-presenting cell</span> Cell that displays antigen bound by MHC proteins on its surface

An antigen-presenting cell (APC) or accessory cell is a cell that displays an antigen bound by major histocompatibility complex (MHC) proteins on its surface; this process is known as antigen presentation. T cells may recognize these complexes using their T cell receptors (TCRs). APCs process antigens and present them to T cells.

<span class="mw-page-title-main">T-cell receptor</span> Protein complex on the surface of T cells that recognizes antigens

The T-cell receptor (TCR) is a protein complex found on the surface of T cells, or T lymphocytes, that is responsible for recognizing fragments of antigen as peptides bound to major histocompatibility complex (MHC) molecules. The binding between TCR and antigen peptides is of relatively low affinity and is degenerate: that is, many TCRs recognize the same antigen peptide and many antigen peptides are recognized by the same TCR.

<span class="mw-page-title-main">CD40 (protein)</span> Mammalian protein found in humans

Cluster of differentiation 40, CD40 is a type I transmembrane protein found on antigen-presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates antigen presenting cells and induces a variety of downstream effects.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

In immunology, an Fc receptor is a protein found on the surface of certain cells – including, among others, B lymphocytes, follicular dendritic cells, natural killer cells, macrophages, neutrophils, eosinophils, basophils, human platelets, and mast cells – that contribute to the protective functions of the immune system. Its name is derived from its binding specificity for a part of an antibody known as the Fc region. Fc receptors bind to antibodies that are attached to infected cells or invading pathogens. Their activity stimulates phagocytic or cytotoxic cells to destroy microbes, or infected cells by antibody-mediated phagocytosis or antibody-dependent cell-mediated cytotoxicity. Some viruses such as flaviviruses use Fc receptors to help them infect cells, by a mechanism known as antibody-dependent enhancement of infection.

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">B-cell receptor</span> Transmembrane protein on the surface of a B cell

The B-cell receptor (BCR) is a transmembrane protein on the surface of a B cell. A B-cell receptor is composed of a membrane-bound immunoglobulin molecule and a signal transduction moiety. The former forms a type 1 transmembrane receptor protein, and is typically located on the outer surface of these lymphocyte cells. Through biochemical signaling and by physically acquiring antigens from the immune synapses, the BCR controls the activation of the B cell. B cells are able to gather and grab antigens by engaging biochemical modules for receptor clustering, cell spreading, generation of pulling forces, and receptor transport, which eventually culminates in endocytosis and antigen presentation. B cells' mechanical activity adheres to a pattern of negative and positive feedbacks that regulate the quantity of removed antigen by manipulating the dynamic of BCR–antigen bonds directly. Particularly, grouping and spreading increase the relation of antigen with BCR, thereby proving sensitivity and amplification. On the other hand, pulling forces delinks the antigen from the BCR, thus testing the quality of antigen binding.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

<span class="mw-page-title-main">Alveolar macrophage</span>

An alveolar macrophage, pulmonary macrophage, is a type of macrophage, a professional phagocyte, found in the airways and at the level of the alveoli in the lungs, but separated from their walls.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Antibody-dependent enhancement</span> Antibodies rarely making an infection worse instead of better

Antibody-dependent enhancement (ADE), sometimes less precisely called immune enhancement or disease enhancement, is a phenomenon in which binding of a virus to suboptimal antibodies enhances its entry into host cells, followed by its replication. The suboptimal antibodies can result from natural infection or from vaccination. ADE may cause enhanced respiratory disease, but is not limited to respiratory disease. It has been observed in HIV, RSV virus and Dengue virus and is monitored for in vaccine development.

<span class="mw-page-title-main">FCRL3</span> Protein-coding gene in the species Homo sapiens

Fc receptor-like protein 3 is a protein that in humans is encoded by the FCRL3 gene.

<span class="mw-page-title-main">FCGR2B</span>

Fc fragment of IgG receptor IIb is a low affinity inhibitory receptor for the Fc region of immunoglobulin gamma (IgG). FCGR2B participates in the phagocytosis of immune complexes and in the regulation of antibody production by B lymphocytes.

<span class="mw-page-title-main">FCAR</span> Mammalian protein found in Homo sapiens

Fc fragment of IgA receptor (FCAR) is a human gene that codes for the transmembrane receptor FcαRI, also known as CD89. FcαRI binds the heavy-chain constant region of Immunoglobulin A (IgA) antibodies. FcαRI is present on the cell surface of myeloid lineage cells, including neutrophils, monocytes, macrophages, and eosinophils, though it is notably absent from intestinal macrophages and does not appear on mast cells. FcαRI plays a role in both pro- and anti-inflammatory responses depending on the state of IgA bound. Inside-out signaling primes FcαRI in order for it to bind its ligand, while outside-in signaling caused by ligand binding depends on FcαRI association with the Fc receptor gamma chain.

The following outline is provided as an overview of and topical guide to immunology:

References

  1. ↑ Cush, John; Kavanaugh, Arthur; Stein, Charles (2005). Rheumatology: Diagnosis and Therapeutics. Lippincott Williams & Wilkins. p. 78. ISBN   9780781757324.
  2. ↑ Goldsby, Richard (2002). Immunology . Macmillan. p.  381. ISBN   9780716749479.
  3. 1 2 3 Lu, Lenette L.; Suscovich, Todd J.; Fortune, Sarah M.; Alter, Galit (January 2018). "Beyond binding: antibody effector functions in infectious diseases". Nature Reviews Immunology. 18 (1): 46–61. doi:10.1038/nri.2017.106. ISSN   1474-1733. PMC   6369690 . PMID   29063907.
  4. ↑ Barret, James (1980). Basic Immunology and its Medical Application (2 ed.). St.Louis: The C.V. Mosby Company. ISBN   0-8016-0495-8.
  5. ↑ Lawley, Thomas; Moustopoulos, Haralampos (1979). "Demonstration of Circulating Immune Complexes in Sjögren's Syndrome". Journal of Immunology. 123 (3). The American Association of Immunologists: 1382–7. doi: 10.4049/jimmunol.123.3.1382 . PMID   469255. S2CID   31511399.
  6. ↑ Wallace, Daniel, ed. (2004). The New Sjogren's Syndrome Handbook. Oxford University Press. p. 68. ISBN   9780198038481.
  7. ↑ Monteith, Andrew J.; Kang, SunAh; Scott, Eric; Hillman, Kai; Rajfur, Zenon; Jacobson, Ken; Costello, M. Joseph; Vilen, Barbara J. (2016-04-12). "Defects in lysosomal maturation facilitate the activation of innate sensors in systemic lupus erythematosus". Proceedings of the National Academy of Sciences. 113 (15): E2142–E2151. Bibcode:2016PNAS..113E2142M. doi: 10.1073/pnas.1513943113 . ISSN   0027-8424. PMC   4839468 . PMID   27035940.
  8. ↑ Kang, SunAh; Rogers, Jennifer L.; Monteith, Andrew J.; Jiang, Chuancang; Schmitz, John; Clarke, Stephen H.; Tarrant, Teresa K.; Truong, Young K.; Diaz, Marilyn; Fedoriw, Yuri; Vilen, Barbara J. (2016-05-15). "Apoptotic Debris Accumulates on Hematopoietic Cells and Promotes Disease in Murine and Human Systemic Lupus Erythematosus". The Journal of Immunology. 196 (10): 4030–4039. doi: 10.4049/jimmunol.1500418 . ISSN   0022-1767. PMC   4868781 . PMID   27059595.
  9. ↑ Bournazos, Stylianos; Wang, Taia T.; Dahan, Rony; Maamary, Jad; Ravetch, Jeffrey V. (2017-04-26). "Signaling by Antibodies: Recent Progress". Annual Review of Immunology. 35 (1): 285–311. doi:10.1146/annurev-immunol-051116-052433. ISSN   0732-0582. PMC   5613280 . PMID   28446061.
  10. ↑ Nelson, Nicole L.J.; Zajd, Cheryl M.; Lennartz, Michelle R.; Gosselin, Edmund J. (November 2019). "Fcγ receptors and toll-like receptor 9 synergize to drive immune complex-induced dendritic cell maturation". Cellular Immunology. 345: 103962. doi:10.1016/j.cellimm.2019.103962. PMC   6892604 . PMID   31582169.
  11. 1 2 3 4 Guilliams, Martin; Bruhns, Pierre; Saeys, Yvan; Hammad, Hamida; Lambrecht, Bart N. (February 2014). "The function of Fcγ receptors in dendritic cells and macrophages". Nature Reviews Immunology. 14 (2): 94–108. doi:10.1038/nri3582. ISSN   1474-1733. PMID   24445665. S2CID   11733324.
  12. ↑ Getahun, A (2015). "Of ITIMs, ITAMs, and ITAMis: revisiting immunoglobulin Fc receptor signaling". Immunological reviews. 268 (1): 66–73. doi:10.1111/imr.12336. PMC   4621791 . PMID   26497513 . Retrieved May 2, 2024.
  13. ↑ Bournazos, Stylianos; Wang, Taia T.; Dahan, Rony; Maamary, Jad; Ravetch, Jeffrey V. (2017-04-26). "Signaling by Antibodies: Recent Progress". Annual Review of Immunology. 35 (1): 285–311. doi:10.1146/annurev-immunol-051116-052433. ISSN   0732-0582. PMC   5613280 . PMID   28446061.
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