Thymus and its role in protecting body against overactive immune system

Summary

Thymus is involved in removing T cells that may attack body and if it fails then it may cause wide range of autoimmune disorders where T cells may potentially kill any cells type. T cells are produced in way which makes it possible for majority of them to attack body and this is checked in thymus as thymus produces any protein any other tissue produces including neural tissue. Immature T cells which don't have neither CD4 or CD8 receptors are not active but they get activated within thymus. In thymus large "nurse" cells swallow these T cells inside them (and after filling would not take in other T cells until old ones get removed) where they mature by getting one of those 2 receptor types. Those with CD8 would become T killer cells that attack damaged cells including cancers and those with CD4 become T helper cells which help at finding targets for T killer cells. Less commonly those with CD4 become regulatory T cells that inhibit immune system and these cells may form other T cells in case of chronic inflammation. If those large cells detect that T cells are likely to attack body or just malformed then they cause death of these T cells. About 95% of T cells get killed in thymus because they were not formed correctly or they showed potential to attack body. While T cells have lifespan lasting about weeks they may become memory cells if they they are needed during infection after which they may become T memory cells that survive about decade in bone marrow, spleen and lymphoid tissue.
Thymus produces all those different proteins mainly with few proteins. One such is AIRE (autoimmune regulatory element) which binds to silenced DNA regions which happen to have positively charged side-chains that stick to negatively charged DNA. AIRE is attached to several proteins (common to proteins involved in gene regulation) among which is CREB that adds negatively charged parts to histones which then come loose from DNA and allow RNA polymerase to express that gene. Usually AIRE causes 1 cell to express one cluster of genes and neighboring cell may produce different cluster of cells (~10% of thymic cells express neural genes including oxytocin and nerve growth factor genes). If AIRE is mutated seriously enough then this T cell selection may not happen. Similar things may happen if thymus gets removed if having heart surgery on small kids (removed because it gets in the way) and sometime tumors in thymus if cells that don't express AIRE form the tumor. AIRE has less known roles in other organs as young embryos, all internal organs from heart, liver, spleen, testis, ovaries to bone marrow and muscles produce AIRE as well although they don't have such control over immune system as thymus.

Citations and additions

Type I is autoimmune disorder where T cells cause death of insulin containing cells during childhood and at least in some cases it is associated with thymus not producing insulin within itself so cells that produce it elsewhere are attacked by T cells.

Example of APECED progression on 39 year old woman. At age 3 she developed chronic candidiasis (white fungal infection in mouth and mucus membranes) which usually starts within first few years of someone with APECED. At age 11 she got hypoparathyroidism which slows metabolism. At 23 she got diagnosed with chronic hepatitis. Addison’s disease (low adrenaline gland activity) and type 1 diabetes at 27 and in her 30s her muscles started weakening that made her bedridden by 39. This one was more rare APECED type which shows if 1 allele is mutated but most APECED cases happen if both parents had mutated version of AIRE.

Thymus grows after castration or adrenalectomy. Thymus and hypothalamus/pituitary gland seem to mutually regulate each other. Females tend to have more antibodies of all classes than men and estrogen increases levels of circulating antibodies. Estrogen also shortens time to organ rejection after transplantation. Estrogens reduce activities of natural killer and T-cells as well as release of thymic hormones. Growth hormone increases size of thymus and circulating naive T-cells in HIV patients.

Loss of AIRE is common causes for infertility in at least women as part of APECED. Alopecia is possible symptom. Some of the antigens AIRE produces in thymus are antigens that ovaries produce. Mice with AIRE knockout had delayed puberty but all had puberty.

Only 50% were able to have at least 1 litter and 16% gave birth to second litter. 83% of previously bred mice had lost all ovarian follicular reserves.  Among virgin females 25% lost follicules by week 8 and by 20th week 50-60% had lost follicules. Their ovulation and fertilization rates were normal. Autoimmunity may also cause miscarriages.  Follicle loss was associated with increased (~5 times) serum follicle-stimulating hormone levels and ovarian invasion by CD3+ T-cells. About third of those who reach menopause before 40 had autoimmunity as cause.  Part of thymic work happens through MHC I and II proteins present on surface of thymic cells and white blood cells. If T-cell show autoimmune effect then they get disabled in thymus before they could activate and cause autoimmunity.

Development of T-cells is supervised by 2 cell types. In thymus they get engulfed by epithelial “nurse cells” (located from medulla to cortex) that remove ~95% of immature T-cells for having autoimmune potential or which are not developed enough. Outside thymus regulatory cells would restrict T-cell activity to reduce damage to healthy cells. If thymus fills with immature T-cells then new ones can’t enter until old ones get removed or leave. T-cells are guided by chemokines and held by adhesion molecules like selectins and integrins. Adhesion molecules may be expressed partially by oxytocin, androgens, estrogens, vasopressin, neurotensin, insulin growth factor 2, glucocorticoids, acetylcholine, histamine and serotonin. Thymus in mammals starts to lose mass during puberty and it can speed up with stress or steroid hormones. Castration can reduce loss of T-cell function during aging as testosterone causes apoptosis in thymus through TNF. Nurse cells release thymic hormone thymulin which is needed to produce Th1 cytokines IL-2 and interferon-gamma in tyhmus. Thymulin can be released when thymic cells are exposed to endorphins and enkephalins.  Adenosine and its receptors seem needed or causing apoptosis in T-cells. Regulatory T-cells (Treg) exit thymus similarly to other T-cells but Treg cells reduce inflammation. GABA agonists can increase weight of thymus and they increase cell division in thymus. Inducible Treg cells are formed outside of thymus commonly during chronic infections or towards antigens produced by unharmful bacteria in intestines. Glucocorticoids and nicotine stimulate activity of Treg cells.

Thymic epithelial cells (TEC) are one of two cell types that help against self immunity. TEC produce almost every hormone and substance body  produces. ~10% of TEC produce most of neural hormones and other neural proteins/peptides.

AIRE binds with all transcription sites that have RNA polymerase II. Without AIRE these RNA polymerases near un-methylated histones may have produced short RNA molecules with length of 50-100 base pairs but AIRE is needed for rest of the gene.

Thymus seems to protect from autoimmunity throughout lifespan as in case a 67 year old woman with thymic tumor got APECED type autoimmune disorders. Her tumor happened to have cells that didn’t express AIRE while her AIRE gene didn’t seem mutated.

RegulatoryT cells (containing CD25 and CD4 receptors) can suppress immune responses and they can be found in many types of cancers. T killer cells can attack damaged cells, including cancer cells, unless immunosuppressive interference keeps them from attacking cancer or other abnormal cells. In case ovarian cancer their proportion kept increasing as cancer progressed (from 0,3% in early stages to 2,5% in late stage cancer). Proportion of regulatory T cells increased twofold compared to T killer cells in that time. Loss of regulatory T cells did slow growth of tumors by up to ~80% but they still grew.

Lack of regulatory T cells seems to be involved among causes or symptoms of multiple sclerosis. Tregs produce anti-inflammatory cytokines to reduce or stop excessive inflammation.

Skin problems that ~25-40% people with APECED get include patchy hair loss, wider alopecia (hair loss) and loss of skin pigment which may turn skin black people white in patches. AIRE is produced also in urinary tract, genitals, gastrointestinal tract, respiratory tract, thyroid glands, adrenal glands and brain.AIRE production can be caused by TNF (tumor necrosis factor). TNF is relatively intensely produced in thymus and in in adults it’s mainly produced in medullary thymic cells.

TNF levelsincrease during infections. Excessive TNF can cause some thymic atrophy. After infection TNF levels rise in blood in 7 days and in thymus in ~14 days. Glucocorticoid hormones during intense stress promote apoptosis of more mature T cells in thymus. Infections stimulate movements of white blood cells from thymus to other organ like spleen and lymphoid organs several times which can be amplified by additional injection of TNF. Immature T cells are also more likely to leave thymus due to effects of TNF. TNF may act as stop signal to white blood cells as it is concentrated in place of inflammation where it binds with fibronectin that itself is involved in wound healing.