Immune tolerance

State of unresponsiveness of the immune system

Immune tolerance, also known as immunological tolerance or immunotolerance, refers to the immune system's state of unresponsiveness to substances or tissues that would otherwise trigger an immune response. It arises from prior exposure to a specific antigen and contrasts the immune system's conventional role in eliminating foreign antigens. Depending on the site of induction, tolerance is categorized as either central tolerance, occurring in the thymus and bone marrow, or peripheral tolerance, taking place in other tissues and lymph nodes. Although the mechanisms establishing central and peripheral tolerance differ, their outcomes are analogous, ensuring immune system modulation. Immune tolerance is important for normal physiology and homeostasis. Central tolerance is crucial for enabling the immune system to differentiate between self and non self antigens, thereby preventing autoimmunity. Peripheral tolerance plays a significant role in preventing excessive immune reactions to environmental agents, including allergens and gut microbiota. Deficiencies in either central or peripheral tolerance mechanisms can lead to autoimmune diseases, with conditions such as systemic lupus erythematosus, rheumatoid arthritis, type 1 diabetes, autoimmune polyendocrine syndrome type 1 (APS 1), and immunodysregulation polyendocrinopathy enteropathy X linked syndrome (IPEX) as examples. Furthermore, disruptions in immune tolerance are implicated in the development of asthma, atopy, and inflammatory bowel disease. Additionally, the induction of peripheral tolerance within the local microenvironment is a strategy employed by many cancers to avoid detection and destruction by the host's immune system.

The phenomenon of immune tolerance was first described by Ray D. Owen in 1945, who noted that dizygotic twin cattle sharing a common placenta also shared a stable mixture of each other's red blood cells (though not necessarily 50/50), and retained that mixture throughout life. Burnet and Medawar were ultimately credited for "the discovery of acquired immune tolerance" and shared the Nobel Prize in Physiology or Medicine in 1960. tolerance does not refer to the change in the pathogen but can be used to describe the changes in host physiology. Immune tolerance also does not usually refer to artificially induced immunosuppression by corticosteroids, lymphotoxic chemotherapy agents, sublethal irradiation, etc. Nor does it refer to other types of non reactivity such as immunological paralysis. In the latter two cases, the host's physiology is handicapped but not fundamentally changed. Immune tolerance is formally differentiated into central or peripheral; These two methods of categorization are sometimes confused, but are not equivalent—central or peripheral tolerance may be present naturally or induced experimentally. This difference is important to keep in mind.

Central tolerance refers to the tolerance established by deleting autoreactive lymphocyte clones before they develop into fully immunocompetent cells. It occurs during lymphocyte development in the thymus and bone marrow for T and B lymphocytes, respectively. In these tissues, 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, and in the case of thymic stromal cells, expression of proteins of other non thymic tissues by the action of the transcription factor AIRE. Those lymphocytes that have 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 of immunological ignorance 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), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity (see peripheral tolerance below). B cells also express CD22, a non specific inhibitor receptor that dampens B cell receptor activation. A subset of B regulatory cells that makes IL 10 and TGF β also exists. Some DCs can make Indoleamine 2,3 dioxygenase (IDO) that depletes the amino acid tryptophan needed by T cells to proliferate and thus reduce responsiveness. DCs also have the capacity to directly induce anergy in T cells that recognize antigen expressed at high levels and thus presented at steady state by DCs. In addition, FasL expression by immune privileged tissues can result in activation induced cell death of T cells.

The skin and digestive tract of humans and many other organisms is colonized with an ecosystem of microorganisms that is referred to as the microbiome. Though in mammals a number of defenses exist to keep the microbiota at a safe distance, including a constant sampling and presentation of microbial antigens by local DCs, most organisms do not react against commensal microorganisms and tolerate their presence. Reactions are mounted, however, to pathogenic microbes and microbes that breach physiological barriers(epithelium barriers). Peripheral mucosal immune tolerance, in particular, mediated by iTreg cells and tolerogenic antigen presenting cells, is thought to be responsible for this phenomenon. In particular, specialized gut CD103+ DCs that produce both TGF β and retinoic acid efficiently promotes the differentiation of iTreg cells in the gut lymphoid tissue. Oral tolerance may have evolved to prevent hypersensitivity reactions to food proteins.

The soluble antigens in the lumen of intestine are transported to dendritic cells in the lamina propria. After receiving an antigen these dendritic cells migrate to the mesenteric lymph nodes. Here they interact with naïve T cells and induce differentiation into regulatory T cells. The newly differentiated regulatory T cells travel to the lamina propria, where they suppress the immune reaction against the recognized antigens.

Dendritic cells play a crucial role in establishing oral tolerance for food antigens. The dendritic cells in the intestines cannot directly sample the antigens, as they are located behind the epithelial wall. There are different mechanisms in which the dendritic cells come in contact with the food antigens
Dissolved antigens can be taken up by enterocytes. The antigens are then partially degraded in the lysosomes. The partially degraded antigens are presented on MHCII after lysosome merging with MHCII carrying endosomes. The MHCII carrying vesicles are released on the basolateral surface of the enterocytes. Here dendritic cells can interact with the presented antigens. Another pathway of soluble antigen transport occurs through goblet cells. Goblet cell associated antigen passages (GAP) transfer low molecular weight soluble antigens to CD103+ dendritic cells. CD103+ dendritic cells are associated with tolerance induction. CX3CR1+ macrophages extend in between enterocytes and directly take up antigens form the intestinal lumen. These macrophages are not capable of traveling to the mesenteric lymph nodes. They form gap junctions with CD103+ dendritic cells and transfer antigens to the dendritic cells.

After antigen interaction the CD103+ dendritic cells travel to the mesenteric lymph nodes where they interact with their T cell population. Within the mesenteric lymph nodes the CD103+ dendritic cells will induce differentiation of the naïve T cell population into Foxp3+ regulatory T cells (iTregs). It is important to note that under inflammatory conditions CD103+ dendritic cells will induce Th1 cells instead. The local microenvironment determines if CD103+ dendritic cells act tolerogenic or immunogenic. The differentiation into regulatory T cells is dependent on TGFβ and retinoic acid. Retinoic acid is also programming the T cells to stay in the gut environment by inducing CCR9 and α4β7 expression. The mesenteric lymph node stromal cells also release retinoic acid and are required for gut localisation of the mesenteric lymph node T cell population. The differentiated regulatory T cells subsequently migrate to the lamina propria, where they multiply. CX3CR1+ macrophages present in this environment secrete IL 10, which is required for the expansion of the regulatory T cell population. In the lamina propria the regulatory T cell population creates a tolerogenic environment to food antigens. It is known that tolerance to food antigens is systemic. The mechanism that establishes this systemic tolerance is not yet fully understood.

The hypo responsiveness induced by oral exposure is systemic and can reduce hypersensitivity reactions in certain cases. Records from 1829 indicate that American Indians would reduce contact hypersensitivity from poison ivy by consuming leaves of related Rhus species; however, contemporary attempts to use oral tolerance to ameliorate autoimmune diseases like rheumatoid arthritis and other hypersensitivity reactions have been mixed. The same probably occurs for cells mediating mucosal immune tolerance. Allergy and hypersensitivity reactions in general are traditionally thought of as misguided or excessive reactions by the immune system, possibly due to broken or underdeveloped mechanisms of peripheral tolerance. Usually, 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 localization to mucosa have been implicated in asthma and atopic dermatitis. Attempts have been made to reduce hypersensitivity reactions by oral tolerance and other means of repeated exposure. Repeated administration of the 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 is an important means by which growing tumors, which have mutated proteins and altered antigen expression, prevent elimination by the host immune system. It is well recognized that tumors are a complex and dynamic population of cells composed of transformed cells as well as stromal cells, blood vessels, tissue macrophages, and other immune infiltrates. These cells and their interactions all contribute to the changing tumor microenvironment, which the tumor largely manipulates to be immunotolerant so as to avoid elimination. There is an accumulation of metabolic enzymes that suppress T cell proliferation and activation, including IDO and arginase, and high expression of tolerance inducing ligands like FasL, PD 1, CTLA 4, and B7. Tumor derived vesicles known as exosomes have also been implicated promoting differentiation of iTreg cells and myeloid derived suppressor cells (MDSCs), which also induce peripheral tolerance. In addition to promoting immune tolerance, other aspects of the microenvironment aid in immune evasion and induction of tumor promoting inflammation.

Though the exact evolutionary rationale behind the development of immunological tolerance is not completely known, it is thought to allow organisms to adapt to antigenic stimuli that will consistently be present instead of expending considerable resources fighting it off repeatedly. Tolerance in general can be thought of as an alternative defense strategy that focuses on minimizing impact of an invader on host fitness, instead of on destroying and eliminating the invader. Such efforts may have a prohibitive cost on host fitness. In plants, where the concept was originally used, tolerance is defined as a reaction norm of host fitness over a range of parasite burdens, and can be measured from the slope of the line fitting these data. Immune tolerance may constitute one aspect of this defense strategy, though other types of tissue tolerance have been described. The injection of Treg cells specific for a tumor antigen also can reverse experimentally mediated tumor rejection based on that same antigen. The prior existence of immune tolerance mechanisms due to selection for its fitness benefits facilitates its utilization in tumor growth.

Immune tolerance contrasts with resistance. Upon exposure to a foreign antigen, either the antigen is eliminated by the standard immune response (resistance), or the immune system adapts to the pathogen, promoting immune tolerance instead. Resistance typically protects the host at the expense of the parasite, while tolerance reduces harm to the host without having any direct negative effects on the parasite. Patients with autoimmune diseases also often have a unique gene signature and certain environmental risk factors that predispose them to disease. This may have implications for current efforts to identify why certain individuals may be disposed to or protected against autoimmunity, allergy, inflammatory bowel disease, and other such diseases.