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, another type of IgG constant region receptor, 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. This signaling pathway involves the phosphorylation of specific amino acids within a sequence of proteins and eventually leads to elimination of opsonized immune complex. [9]

Related Research Articles

<span class="mw-page-title-main">Immune system</span> Biological system protecting an organism against disease

The immune system is a network of biological systems that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splinters, distinguishing them from the organism's own healthy tissue. Many species have two major subsystems of the immune system. The innate immune system provides a preconfigured response to broad groups of situations and stimuli. The adaptive immune system provides a tailored response to each stimulus by learning to recognize molecules it has previously encountered. Both use molecules and cells to perform their functions.

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">B cell</span> Type of white blood cell

B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody molecules which may be either secreted or inserted into the plasma membrane where they serve as a part of B-cell receptors. When a naïve or memory B cell is activated by an antigen, it proliferates and differentiates into an antibody-secreting effector cell, known as a plasmablast or plasma cell. In addition, B cells present antigens and secrete cytokines. In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the B stands for bursa and not bone marrow, as commonly believed.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

<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">Adaptive immune system</span> Subsystem of the immune system

The adaptive immune system, also known as the acquired immune system, or specific immune system is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired immune system is one of the two main immunity strategies found in vertebrates.

<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 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">Phagosome</span>

In cell biology, a phagosome is a vesicle formed around a particle engulfed by a phagocyte via phagocytosis. Professional phagocytes include macrophages, neutrophils, and dendritic cells (DCs).

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

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

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">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">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">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">Type III hypersensitivity</span> Type of allergic reaction

Type III hypersensitivity, in the Gell and Coombs classification of allergic reactions, occurs when there is accumulation of immune complexes that have not been adequately cleared by innate immune cells, giving rise to an inflammatory response and attraction of leukocytes. There are three steps that lead to this response. The first step is immune complex formation, which involves the binding of antigens to antibodies to form mobile immune complexes. The second step is immune complex deposition, during which the complexes leave the plasma and are deposited into tissues. Finally, the third step is the inflammatory reaction, during which the classical pathway is activated and macrophages and neutrophils are recruited to the affected tissues. Such reactions may progress to immune complex diseases.

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. The American Association of Immunologists. 123 (3): 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. 1 2 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.
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