Self-protein

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Self-protein refers to all proteins endogenously produced by DNA-level transcription and translation within an organism of interest. This does not include proteins synthesized due to viral infection, but may include those synthesized by commensal bacteria within the intestines. Proteins that are not created within the body of the organism of interest, but nevertheless enter through the bloodstream, a breach in the skin, or a mucous membrane, may be designated as “non-self” and subsequently targeted and attacked by the immune system. Tolerance to self-protein is crucial for overall wellbeing; when the body erroneously identifies self-proteins as “non-self”, the subsequent immune response against endogenous proteins may lead to the development of an autoimmune disease. [1] [2]

Contents

Examples

Proteins targeted by the immune systemResulting autoimmune disease
Thyroid stimulating hormone receptor Graves' disease [3]
Pancreatic beta-cell proteins Type 1 diabetes mellitus [4]
Nuclear and cell membrane phospholipids Lupus [5]
Tissue transglutaminase Celiac disease [6]

Of note, the list provided above is not exhaustive; the list does not mention all possible proteins targeted by the provided autoimmune diseases.

Identification by the immune system

Autoimmune responses and diseases are primarily instigated by T lymphocytes that are incorrectly screened for reactivity to self-protein during cell development.[ citation needed ]

During T-cell development, early T-cell progenitors first move via chemokine gradients from the bone marrow into the thymus, where T-cell receptors are randomly rearranged at the gene level to allow for T-cell receptor generation. [7] These T-cells have the potential to bind to anything, including self-proteins.[ citation needed ]

The immune system must differentiate the T-cells that have receptors capable of binding to self versus non-self proteins; T-cells that can bind to self-proteins must be destroyed to prevent development of an autoimmune disorder. In a process known as “Central Tolerance”, T-cells are exposed to cortical epithelial cells that express a variety of different major histocompatibility complexes (MHC) of both class 1 and class 2, which have the ability to bind to T-cell receptors of CD8+ cytotoxic T-cells, and CD4+ helper T-cells, respectively. The T-cells that display affinity for these MHC are positively selected to continue to the second stage of development, while those that cannot bind to MHC undergo apoptosis. [8] In the second stage, immature T-cells are exposed to a variety of macrophages, dendritic cells, and medullary epithelial cells that express self-protein on MHC class 1 and class 2. These epithelial cells also express the transcription factor labelled autoimmune regulator (AIRE) – this crucial transcription factor allows the medullary epithelial cells of the thymus to express proteins would normally be present in peripheral tissue rather than in an epithelial cell, such as insulin-like peptides, myelin-like peptides, and more. [9] As these epithelial cells now present a large variety of self-proteins that could be encountered across the body, the immature T-cells are tested for affinity to self-protein and self-MHC. If any T-cell has strong affinity for self-protein and self-MHC, the cell undergoes apoptosis to prevent autoimmune function. [8] T-cells that display low/medium affinity are allowed to leave the thymus and circulate throughout the body to react to novel non-self antigen. In this manner, the body attempts to systematically destroy T-cells that could lead to autoimmunity.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

<span class="mw-page-title-main">Thymus</span> Endocrine gland

The thymus is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells mature. T cells are critical to the adaptive immune system, where the body adapts to specific foreign invaders. The thymus is located in the upper front part of the chest, in the anterior superior mediastinum, behind the sternum, and in front of the heart. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura (HSP), systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<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.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

In immunology, central tolerance is the process of eliminating any developing T or B lymphocytes that are autoreactive, i.e. reactive to the body itself. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissues that would otherwise have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of several peptide sequences which can be both foreign and self in nature, just a few crucial residues can activate a single antibody or TCR. This highlights the importance of structural homology in the theory of molecular mimicry. Upon activation, these "peptide mimic" specific T or B cells can cross-react with self-epitopes, thus leading to tissue pathology (autoimmunity). Molecular mimicry is one of several ways in which autoimmunity can be evoked. A molecular mimicking event is more than an epiphenomenon despite its low probability, and these events have serious implications in the onset of many human autoimmune disorders.

A thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

<span class="mw-page-title-main">Autoimmune regulator</span> Immune system protein

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

In immunology, clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Short Course Immune Induction Therapy or SCIIT, is a therapeutic strategy employing rapid, specific, short term-modulation of the immune system using a therapeutic agent to induce T-cell non-responsiveness, also known as operational tolerance. As an alternative strategy to immunosuppression and antigen-specific tolerance inducing therapies, the primary goal of SCIIT is to re-establish or induce peripheral immune tolerance in the context of autoimmune disease and transplant rejection through the use of biological agents. In recent years, SCIIT has received increasing attention in clinical and research settings as an alternative to immunosuppressive drugs currently used in the clinic, drugs which put the patients at risk of developing infection, cancer, and cardiovascular disease.

<span class="mw-page-title-main">Medullary thymic epithelial cells</span>

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic antigen-presenting cells which contributes to the establishment of T cell central tolerance.

<span class="mw-page-title-main">Cortical thymic epithelial cells</span>

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the outer layer (epithelium) of the thymic stroma. The thymus, as a primary lymphoid organ, mediates T cell development and maturation. The thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production of functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.

References

  1. ↑ Rosenblum MD, Remedios KA, Abbas AK (June 2015). "Mechanisms of human autoimmunity". The Journal of Clinical Investigation. 125 (6): 2228–33. doi:10.1172/JCI78088. PMC   4518692 . PMID   25893595.
  2. ↑ Devarapu SK, Lorenz G, Kulkarni OP, Anders HJ, Mulay SR (2017). "Cellular and Molecular Mechanisms of Autoimmunity and Lupus Nephritis". International Review of Cell and Molecular Biology. Elsevier. 332: 43–154. doi:10.1016/bs.ircmb.2016.12.001. ISBN   978-0-12-812471-0. PMID   28526137.
  3. ↑ Morshed SA, Davies TF (September 2015). "Graves' Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies". Hormone and Metabolic Research. 47 (10): 727–34. doi: 10.1055/s-0035-1559633 . PMC   5047290 . PMID   26361259.
  4. ↑ Roep BO, Peakman M (April 2012). "Antigen targets of type 1 diabetes autoimmunity". Cold Spring Harbor Perspectives in Medicine. 2 (4): a007781. doi: 10.1101/cshperspect.a007781 . PMC   3312399 . PMID   22474615.
  5. ↑ Riemekasten G, Hahn BH (August 2005). "Key autoantigens in SLE". Rheumatology. 44 (8): 975–82. doi:10.1093/rheumatology/keh688. PMID   15901907.
  6. ↑ Caja S, Mäki M, Kaukinen K, Lindfors K (March 2011). "Antibodies in celiac disease: implications beyond diagnostics". Cellular & Molecular Immunology. 8 (2): 103–9. doi:10.1038/cmi.2010.65. PMC   4003135 . PMID   21278768.
  7. ↑ Sambandam A, Bell JJ, Schwarz BA, Zediak VP, Chi AW, Zlotoff DA, et al. (2008-09-16). "Progenitor migration to the thymus and T cell lineage commitment". Immunologic Research. 42 (1–3): 65–74. doi:10.1007/s12026-008-8035-z. PMID   18827982. S2CID   43186901.
  8. 1 2 Xing Y, Hogquist KA (June 2012). "T-cell tolerance: central and peripheral". Cold Spring Harbor Perspectives in Biology. 4 (6): a006957. doi:10.1101/cshperspect.a006957. PMC   3367546 . PMID   22661634.
  9. ↑ Anderson MS, Su MA (April 2011). "Aire and T cell development". Current Opinion in Immunology. 23 (2): 198–206. doi:10.1016/j.coi.2010.11.007. PMC   3073725 . PMID   21163636.
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