User:Immcarle64/sandbox

Central Tolerance DRAFT
Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation (and central tolerance) 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.

Central tolerance is not perfect, so peripheral tolerance exists as a secondary mechanism to ensure that T and B cells are not self-reactive once they leave primary lymphoid organs. Peripheral tolerance is distinct from central tolerance in that it occurs once developing immune cells exit primary lymphoid organs (the thymus and bone-marrow), prior to their export into the periphery.

Function of central tolerance
Central tolerance is essential to proper immune cell functioning because it helps ensure that mature B cells and T cells do not recognize self antigens as foreign microbes. More specifically, central tolerance is necessary because T cell receptors (TCRs) and B cell receptors (BCRs) are made by cells through random somatic rearrangement.[1] This process, known as V(D)J recombination, is important because it increases the receptor diversity which increases the likelihood that B cells and T cells will have receptors for novel antigens.[1] Junctional diversity occurs during recombination and serves to further increase the diversity of BCRs and TCRs. The production of random TCRs and BCRs is an important method of defense against microbes due to their high mutation rate. This process also plays an important role in promoting the survival of a species because there will be a variety of receptor rearrangement within a species meaning that there is a very high chance of at least one member of the species having receptors for a novel antigen.

While the process of somatic recombination is essential to a successful immune defense, it can lead to autoreactivity. For example, lack of functional RAG1/2, enzymes necessary for somatic recombination, has been linked to development of immune cytopenias in which antibodies are produced against the patient’s blood cells. Due to the nature of a random receptor recombination, there will be some BCRs and TCRs produced that recognize self antigens as foreign. This is problematic since these B and T cells would, if activated, mount an immune system attack against self if not killed or inactivated by central tolerance mechanisms.[2] Therefore, without central tolerance, the immune system could attack self, which is not sustainable and could result in an autoimmune disorder.[2]

Mechanisms of central tolerance
The end result of tolerance is a population of lymphocytes that are not reactive to self-antigens, but may be able to recognize foreign, non-self antigens depending on the randomly arranged receptor. Importantly, lymphocytes can only develop tolerance towards antigens that are present in the bone marrow (for B cells) and thymus (for T cells).

B cell tolerance
Immature B cells in the bone marrow undergo negative selection when they bind self peptides.

Properly functioning B cell receptors recognize non-self antigen or pathogen associated molecular proteins (PAMPs).

Main outcomes of autoreactivity of BCRs
 * 1) Apoptosis (clonal deletion)
 * 2) Receptor editing: the self-reactive B cell changes specificity by rearranging genes and develops a new BCR that does not respond to self. This process gives the B cell a chance for editing the BCR before it is signaled to apoptose or become anergic.
 * 3) Induction of anergy (a state of non-reactivity)

T cell tolerance
T cell central tolerance occurs in the thymus. T cells undergo positive and negative selection.

T cell receptors must have the ability to recognize self major histocompatibility complex (MHC) molecules with bound non-self peptide.

Steps of T cell tolerance
 * 1) During positive selection, T cells are checked for their ability to bind peptide-MHC complexes with affinity. If the T cell cannot bind the MHC class I or MHC class II complex, it does not receive survival signals, so it dies via apoptosis. T cell receptors with sufficient affinity for peptide-MHC complexes are selected for survival.
 * 2) * Depending on whether the T cell binds MHC I or II, it will become a CD8+ or CD4+ T cell, respectively.
 * 3) * Positive selection occurs in the thymic cortex with the help of thymic epithelial cells that contain surface MHC I and MHC II molecules.
 * 4) During negative selection, T cells are tested for their affinity to self. If they bind a self peptide, then they are signaled to apoptose (process of clonal deletion).
 * 5) * The thymic epithelial cells display self antigen to the T cells to test their affinity for self.
 * 6) * Transcriptional regulators AIRE and Fezf2 play important roles in the expression of self tissue antigens on the thymic epithelial cells in the thymus.
 * 7) * Negative selection occurs in the cortico-medullary junction and in the thymic medulla.
 * 8) The T cells that do not bind self, but do recognize antigen/ MHC complexes, and are either CD4+ or CD8+, migrate to secondary lymphoid organs as mature naïve T cells.

The first use of central tolerance was by Ray Owen in 1945 when he noticed that dizygotic twin cattle did not produce antibodies when one of the twins was injected with the others blood. His findings were confirmed by later experiments by Hasek and Billingham. The results were explained by Buret’s clonal selection hypothesis. Burnet and Medawar won the Nobel Prize in 1960 for their work in explaining how immune tolerance worked.

Article Evaluation
What have I learned from the Wiki training?

- Wiki articles should have a neutral point of view.

- Finding good sources is essential to writing a strong Wiki article.

-- Make sure these sources are verifiable and the information is up to date.

- Topics should be notable.

- There should not be individual research published on Wiki.

- Make sure that you do not disobey copyright laws or plagiarize at all.

- Source editing reveals the Wikicode, but Visual editing is changing what is seen on the page to non editors.

- Make sure you link to other Wiki pages as appropriate.

Future Plans
- I would like to add citations throughout the article and remove any sentences that I can't find support for. I think one of the most prominent issues with the wiki page on central tolerance is that it lacks many necessary citations.

- I would also like to find a straight forward figure to outline the mechanism of central tolerance or make one of my own figures (ideally).

- I think the "requirement for central tolerance" requires the most work overall and I may end up splitting the large section into smaller, easier to process chunks.

- I would also like to organize/tidy the B and T cell tolerance sections since they are mostly large blocks of text with few words italicized/ bolded and lack subsections.

- With remaining time, I will look into any immunological diseases that may be caused by defects in central tolerance mechanisms or processes closely related to central tolerance.

Central Tolerance Outline
P1: Overview paragraph. Include important, broad facts about central tolerance; It should summarize, very briefly, what the rest of the article will say in detail.

- occurs in the bone marrow (B cells) and the thymus (T cells)

P2: Peripheral tolerance

P3/ P4: Gene rearrangement for BCR and TCR/ maturation

P5: Central tolerance more specific- locations, general mechanism that occurs for B and T cells

P6: Mechanisms of central tolerance- ensure that all information is correct and formatted in a logical way, and add citations P7: Genetic Defects
 * B cell tolerance
 * T cell tolerance

- add sentence about how successive/ parallel checkpoints provide back up mechanisms to ensure that no receptors reactive to self get by, but sometimes some forbidden receptors are able to bypass the many checkpoints in their way

P8: History

P9: References

Areas that need improvement
- Overview paragraph at the beginning (non existent)

- The requirement for central tolerance section is all over the place, so I will focus mostly on rewriting this section being sure to use citations!

- Citations throughout

Overview paragraph
Central tolerance is the process where the immune system eliminates or inactivates maturing T cells or B cells that are reactive to self. Elimination is achieved through clonal deletion whereas inactivation is accomplished through anergy (Back to cent tolerance). Central tolerance is essential to proper immune cell functioning because it ensures that B cells and T cells do not recognize 'self' antigens as foreign microbes.

More specifically, central tolerance is necessary because T cell receptors (TCRs) and B cell receptors (BCRs) are made through random somatic rearrangement. This process maximizes the diversity of the receptors which increases the likelihood that the B cells and T cells will have receptors for newly encountered antigens. However, due to the randomness of the process, there are some BCRs and TCRs made that recognize 'self' as foreign, and would mount an immune system attack against 'self' if not destroyed or inactivated by central tolerance mechanisms (CITE). Therefore, Without central tolerance, the immune system would constantly be attacking 'self' which is not sustainable and could lead to an autoimmune disorder (CITE).

As a result of central tolerance, maturing B cells and T cells that are reactive to self antigens are not able to leave the primary lymphoid organs (CITE). Lymphocyte maturation (and central tolerance) 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 (CITE).

Requirement for central tolerance section
** IN THE MIDDLE OF FIXING THIS SECTION**

- use Immunology textbook VDJ rearrangement section-

all T and B cell precursors have an identical genome

combination of the alpha- and beta-chain for the T cell receptor (TCR), or of the heavy and light chain for the B cell receptor (BCR), each encoded by 2 different gene copies - the unused copy gets inactivated.

T cell and B cell receptor genes contain multiple gene segments (the V, D, and J segments) which need to be physically rearranged by somatic gene rearrangement - called V(D)J-recombination - to make a functional BCR or TCR.

At the site of segment recombination, additional bases will be inserted, which results in additional diversity - called junctional diversity - and gives rise to the complementarity determining regions (CDR).

These random combinations and base insertions allow the creation of T cell receptors and antibodies against antigens which the host has never encountered during its evolutionary history, and is thus a powerful defense against rapidly evolving pathogens.

How self reactive BCRs and TCRs are created: Conversely, the random nature of junctional diversity creates, by chance, a population of T cells and B cells that are self-reactive (i.e., recognize an antigen which is a constituent component of the host).

In mammals, central tolerance is established in the thymus (T cells) and bone marrow (B cells). These are the two primary lymphoid organs where T cells and B cells mature.

During the maturation phases of both T cells and B cells, the cells are sensitive to self-antigens. The response to antigen at this stage depends on the properties of the antigen, the cell type, and the developmental stage, and can lead to the cell becoming non-responsive (anergic), undergoing directed suicide (negative selection), altering its antigen receptor (receptor editing), or entering a regulatory lineage.

As this tolerance is dependent on encountering self-antigens during maturation, lymphocytes can only develop central tolerance towards those antigens present in primary lymphoid organs.