Immune tolerance

Immune tolerance, or immunological tolerance, refers to a state of unresponsiveness of the immune system to substances or tissue that usually  have the capacity to elicit an immune response.

Immune tolerance is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens.

Immune tolerance is classified into central tolerance or peripheral tolerance.

Thymus and bone marrow are central and other tissues and lymph nodes are helpful to establish peripheral immune tolerance.

It is important for normal physiology. 

Central tolerance is the main way the immune system learns to discriminate self from non-self. 

Peripheral tolerance is key to preventing over-reactivity of the immune system to various environmental entities such as allergens, or gut microbes.

While an efficient thymus helps eliminate self reactive cells, many self reactive T cells escape thymic negative selection leading to the need for peripheral mechanisms to ensure that self tolerance is maintained.

When a deficit in central or peripheral tolerance exists it can cause autoimmune diseases: systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS-1),and immunodysregulation polyendocrinopathy enteropathy X-linked syndrome, and potentially contribute to asthma, allergy, and inflammatory bowel disease.

Immune tolerance in pregnancy allows a mother to develop a genetically distinct offspring with an alloimmune response muted enough to prevent miscarriage.

Immune tolerance  negatively allows some pathogenic microbes to successfully infect a host and avoid elimination.

Similarly, peripheral tolerance in the local microenvironment is a common survival strategy for a number of cancers that prevent  their elimination by the host immune system.

Immune tolerance is a state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response.

Immune tolerance reduces or eliminates an immune response to particular agents. 

Immune tolerance  is the phenomenon underlying discrimination of self from non-self, suppressing allergic responses, allowing chronic infection instead of rejection and elimination, and preventing attack of fetuses by the maternal immune system. 

Tolerance does not refer to the change in the underlying pathogen, but is used to describe the changes in the host’s physiology.

Immune tolerance also does not usually refer to exogenous artificially induced immunosuppression:  corticosteroids, immunosuppressive chemotherapy or irradiation.

Immune tolerance is not comparable to 

immunological paralysis, where immune actions are limited but not fundamentally changed.

The human immune system typically produces both T cells and B cells that are capable of being reactive with self-antigens.

With immune tolerance these self-reactive cells are usually either killed prior to becoming active within the immune system, placed into a state of anergy or removed from their role within the immune system by regulatory cells. 

Immune tolerance is differentiated into central or peripheral.

Central tolerance is established by deleting lymphocyte clones to self-antigens before they develop into fully immunocompetent cells. 

Central immune tolerance occurs during lymphocyte development in the thymus and bone marrow for T and B lymphocytes, respectively. 

In the thymus and bone marrow maturing lymphocytes are exposed to self-antigens presented by medullary thymic epithelial cells and thymic dendritic cells, or bone marrow cells. 

Self-antigens are present due to endogenous expression, importation of antigen from peripheral sites via circulating blood.

In thymic stromal cells, expression of proteins of other non-thymic tissues occurs by the action of the transcription factor AIRE.

Lymphocytes with receptors that bind strongly to self-antigens are removed by induction of apoptosis of the autoreactive cells, or by induction of anergy, a state of non-activity.

Weakly autoreactive B cells may also remain in a state where they simply do not respond to stimulation of their B cell receptor. 

Some weakly self-recognizing T cells are alternatively differentiated into natural regulatory T cells (nTreg cells).

Because T cells alone can cause direct tissue damage the ability for the deletion threshold is much more stringent for T cells than for B cells.

It is more advantageous for B cells recognize a wider variety of antigens so it can produce antibodies against a greater diversity of pathogens. 

B cells are fully activated after confirmation by more self-restricted T cells.

When T cells and B cells  recognize the same antigen, autoreactivity is held in check.

Negative selection ensures that T and B cells can initiate a potent immune response to the host’s own tissues are eliminated while preserving the ability to recognize foreign antigens. 

Lymphocyte development is most active in fetal development but continues throughout life as immature lymphocytes are generated, slowing as the thymus degenerates and the bone marrow shrinks in adult life.

Peripheral tolerance develops following  T and B cells maturity, and after they enter the peripheral tissues and lymph nodes.

The T cells that leave the thymus are relatively, but not,  fully safe from self-antigen reactivity, as some will have receptors (TCRs) that can respond to self-antigens.

Some T cells that leave the thymus 

are present in such high concentration outside the thymus that they can bind to weak receptors.

Such self-reactive T cells that escape intrathymic negative selection in the thymus can inflict cell injury unless they are deleted or effectively impaired  in the peripheral tissue, chiefly by nTreg cells.

Reaction to certain antigens can also be diminished by induction of tolerance after repeated exposures.

With induction of tolerance there is a differentiation of naïve CD4+ helper T cells into induced Treg cells.

Treg cells mediate peripheral tolerance,and other regulatory immune T cell subsets similar to but phenotypically distinct including TR1 cells help establish a local tolerant environment.

B cells also express CD22, a non-specific inhibitor receptor that decreases B cell receptor activation. 

T and B cells are the hallmark of the antigen-specific adaptive immune system.

T-cells orchestrate immune responses both indirectly by providing soluble and membrane associated signals that promote the survival, expansion, and differentiation of B cells which create antibodies that support humoral immunity, and indirectly by killing foreign  and infected tissues through cellular and soluble mediators.

T-cells recognize foreign antigens through a set of T-cell receptors (TCR ‘s) designed to mediate immunity without the collateral damage of destroying native tissues.

Regulatory T cells (Tregs) recognize self peptides and when activated control self reactive pathogenic T cells.

The  amino acid tryptophan needed by T cells to proliferate.

Dendritic cells have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels.

Treg cells are characterized by the expression of the Foxp3 transcription factor, which is responsible for the suppressive phenotype of these cells.

Treg cells originally characterized as  dependent on the neonatal thymus, these cells were thymically derived.

The conversion of naïve CD4+ T cells to Treg cells outside of the thymus, is defined as induced or iTreg cells to contrast them with thymus-derived nTreg cells. 

Both types of Treg cells quiete autoreactive T cell signaling and proliferation by cell-contact-dependent and -independent mechanisms.

nTreg cells develop in the thymus.

iTreg cells develop outside the thymus in chronically inflamed tissue, lymph nodes, spleen, and gut-associated lymphoid tissue.

nTreg cells develop from Foxp3- CD25+ CD4+ cells.

 iTreg cells develop from Foxp3+ CD25- CD4- cells.

 nTreg cells, require CD28 costimulation with activation 

iTreg cells require CTLA-4 costimulation.

nTreg cells are specific, for self-antigens.

iTreg cells recognize allergens, bacteria, tumor antigens, alloantigens, and self-antigens in inflamed tissue.

The ability of immune recognition of non-self-antigens complicates transplantation and engrafting of foreign tissue from another person and results in graft reaction. 

A few patients can develop allograft tolerance upon cessation of all exogenous immunosuppressive therapy, operational tolerance.

CD4+ Foxp3+ Treg cells, as well as CD8+ CD28- regulatory T cells dampen cytotoxic responses to grafted organs.

A fetus has a different genetic makeup than the mother.

A fetus also has  its father’s genes, and is thus perceived as foreign by the maternal immune system. 

Women who have borne multiple children by the same father typically have antibodies against the father’s red blood cell and major histocompatibility complex (MHC) proteins: the fetus usually is not rejected by the mother, making it essentially a physiologically tolerated allograft. 

Placental tissues interfacing with maternal tissues try to escape immunological recognition by downregulating identifying MHC proteins but also actively induce a marked peripheral tolerance. 

Placental trophoblast cells express a Human Leukocyte Antigen (HLA-G) that inhibits attack by maternal NK cells.

Placental trophoblast  cells also repress maternal T cell responses by amino acid starvation. 

Maternal T cells specific for paternal antigens are also suppressed by tolerant DCs and activated iTregs or cross-reacting nTregs.

Some maternal Treg cells also release soluble fibrinogen-like proteins 2, which suppresses the function of dendritic cells and macrophages involved in inflammation and antigen presentation to reactive T cells.

These mechanisms establish an immune-privileged state in the placenta that protects the fetus. 

Dysfunction in this peripheral tolerance results in miscarriage and fetal loss.

The skin and digestive tract of humans s colonized with an ecosystem of microorganisms that is referred to as the microbiome. 

We do not react against commensal microorganisms and tolerate their presence. 

Reactions to pathogenic microbes and microbes that breach physiological barriers occur.

Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen-presenting cells, is thought to be responsible for this phenomenon. 

Gut CD103+ DCs that produce both TGF-β and retinoic acid promote the differentiation of iTreg cells in the gut lymphoid tissue.

Foxp3- TR1 cells that make IL-10 are also enriched in the intestinal lining.

A break in this tolerance is thought to underlie the pathogenesis of inflammatory bowel diseases like Crohn’s disease and ulcerative colitis.

Oral immune tolerance refers to a specific type of tolerance induced by antigens given by mouth and exposed to the gut mucosa and its associated lymphoid tissues.

Oral immune tolerance systemic effects are explained by the extensive recirculation of immune cells to other  mucosal tissues.

Oral tolerance limit inflammation to bacterial antigens in the microbiome, and to prevent hypersensitivity reactions to food proteins.

Oral tolerance is a continuous natural immunologic event driven by exogenous antigen.

Allergy and hypersensitivity reactions  are thought to be excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. 

Treg cells, TR1, and Th3 cells at mucosal surfaces suppress type 2 CD4 helper cells, mast cells, and eosinophils, which mediate allergic response. 

Deficits in Treg cells or their limitation  to mucosa have been implicated in asthma and atopic dermatitis.

The repeated administration an allergen in slowly increasing doses, subcutaneously or sublingually appears to be effective for allergic rhinitis.

Repeated administration of antibiotics, which can form haptens to cause allergic reactions, can also reduce antibiotic allergies in children.

Immune tolerance occurs in  growing tumors, which have mutated proteins and altered antigen expression, preventing  elimination by the host’s immune system.

Tumors  have a complex and dynamic population of cells: transformed cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates.

A changing tumor microenvironment, manipulates to be immunotolerant so as to avoid elimination. 

There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, and high expression of tolerance-inducing ligands like FasL, PD-1, CTLA-4, and B7.

Exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which induce peripheral tolerance.

Other aspects of the microenvironment aid in immune evasion and induction of tumor-promoting inflammation.

Immune tolerance is thought to be an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader.

The existence of tolerance is mostly adaptive, allowing an adjustment of the immune response to a level appropriate for the given stressor.

Disadvantages in the immune system occurs when existing mechanisms of tolerance avoids detection and/or elimination of invading organisms by the host immune system. 

Induction of regulatory T cells, has been noted in infections with Helicobacter pylori, Listeria monocytogenes, Brugia malayi, and other worms and parasites.

The  existence of tolerance may lead to susceptibility to cancer progression. 

Treg cells can inhibit anti-tumor NK cells, and can facilitate tumor growth.

With an exposure to a foreign antigen, the antigen is eliminated by the standard immune response or the immune system adapts to the pathogen, promoting immune tolerance instead.

Resistance typically protects the host at the expense of the pathogen, while tolerance reduces harm to the host without having any direct negative effects on the pathogen.

Patients with autoimmune diseases often genetic, and certain environmental risk factors that predispose them to disease.


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