How does immune tolerance prevent autoimmunity?

The basic function of the immune system is to protect the organism from pathogenic microbes (bacteria, viruses, etc.) and foreign, harmful substances. In case of contact with foreign antigens, the mechanisms of innate and adaptive immunity are activated, which destroy pathogenic microbes, neutralize toxins or remove harmful substances.

The immune system has the ability to distinguish its self tissue antigens from foreign antigens. The self antigens do not trigger the activation of the cells of the immune system and this is called “immune tolerance”.

Immune tolerance represents complex mechanisms that prevent the immune response from being triggered by self antigens, cells and tissues.

The break of immune tolerance results in autoimmune reactions and autoimmune diseases. Understanding the pathogenesis of autoimmune diseases is still incomplete despite the fact that a large number of molecules and intracellular signaling pathways have been elucidated, as well as immune cells that play a role in autoimmunity.

1. Why do autoimmune diseases occur?

Autoimmunity is an immune response to self antigens, self cells and tissues, which can result in altered function or destruction of cells and tissues. If the disease is the result of such altered immune reactivity, it is called an autoimmune disease.

The true cause of autoimmune diseases is unknown. For most autoimmune diseases, predisposing factors are genetic and environmental factors. Environmental factors, including infections, medications, hormones, diet, disbiosis, xenobiotics, and others, can be triggers for autoimmunity. However, the triggers of the disease usually remain unknown, as well as the reason why some people get autoimmune diseases and others do not.

The most common triggers of autoimmunity are considered to be infections. Infectious agents can trigger an autoimmune response either by inducing inflammation in tissues when unwanted activation of autoreactive T cells (bystander activation) can occur or when T lymphocytes are activated by contact with microbial antigens and then cross-react with their self antigens, known as molecular mimicry (cross-reactivity).

2. Some examples of autoimmune diseases

To date, there are more than 80 clinically distinct diseases that are classified as autoimmune diseases. Autoimmune diseases occur in 3-5% of the population and vary in severity, from mild to life-threatening, and some of them lead to significant disability with great socioeconomic consequences.

Autoimmune diseases can be systemic or organ-specific when the immune response is directed to autoantigens localized in a particular organ.

Some typical examples of autoimmune diseases and their main clinical manifestations are:

  • Rheumatoid arthritis – inflammation in several joints (arthritis) that are swollen, stiff and painful; inflammation may also exist in other organs (such as the lungs or eyes)
  • Systemic lupus erythematosus (SLE) – inflammation in several organ systems, especially in the joints, skin, lungs and kidneys
  • Sjögren’s syndrome – dry eyes and mouth due to inflammation in the salivary and lacrimal glands; arthritis, inflammation in other organs is common (lungs)
  • Vasculitis – inflammation of blood vessels; includes several forms of this disease that lead to symptoms and organ damage
  • Multiple sclerosis – an immune response to myelin, the sheath of nerve cell axons that leads to impaired movement, balance, vision and other disorders.
  • Celiac disease – gluten consumption leads to an immune reaction that damages the small intestine and disrupts normal digestion, and can develop a rash, joint pain and fatigue
  • Type 1 diabetes – immune reaction damages insulin-producing beta cells of the pancreas, leading to disorders of blood sugar regulation and energy metabolism followed by organ damage (blood vessels, kidneys, eyes)
  • Alopecia areata – a skin disease in which an immune attack on hair follicles leads to uneven hair loss, especially on the scalp
  • Hashimoto’s thyroiditis – an immune response to thyroid tissue that results in tissue destruction and decreased thyroid hormone levels (hypothyroidism)

3. What are the mechanisms of immune tolerance

Under physiological conditions, there is an immune tolerance to one’s own antigens, which is achieved by the mechanisms of central and peripheral tolerance.

4. Mechanisms of central tolerance

Central tolerance is a process in which immature T and B lymphocytes with receptors specific for self antigens encounter their autoantigens in the primary lymphoid organs, and then consequently die or become unreactive. Central tolerance takes place in the early phase of lymphoid cell development.

Central tolerance implies negative selection of autoreactive T and B lymphocytes.

Negative selection of autoreactive T lymphocytes – Central tolerance of T lymphocytes takes place in the thymus. T lymphocytes in the thymus (thymocytes) interact with mTEC (medullary cells of the thymic epithelium) and DC (dendritic cells) of the thymus, which express and present TSA (tissue-specific antigens of self tissues). Autoreactive T cells, which recognize and bind TSA with high affinity, are removed by the so-called clonal deletion and functional inactivation. The mechanisms leading to the expression of self tissue antigens at TEC have not been fully elucidated. One of the key molecules is the transcriptional regulator AIRE (autoimmune regulator), which regulates the expression of many peripheral tissue antigens, including insulin, IRBP (a retinoid-binding protein; also known as RBP3), and others. Mutation of the AIRE gene in humans causes autoimmune polyendocrine syndrome type-1 (APS-1).

Negative selection of autoreactive B lymphocytes – B lymphocytes are formed in the bone marrow (BM). Random recombination of the V(D)J gene in B lymphocyte precursors within BM creates a population of newly formed B cells with very diverse BCR (B cell receptor), but also generates a large number of potentially harmful B cells that express autoreactive BCRs. The majority (55–75%) of all antibodies in early immature B lymphocytes show autoreactivity, of polyreactive and antinuclear specificity. Most autoreactive B cells are removed or inactivated by central and peripheral tolerance mechanisms.

In the bone marrow, polyreactive and autoreactive immature B cells are eliminated by apoptosis or induction of anergy before they leave the BM and go to the peripheral secondary lymphoid organs. Mature B cells exhibit IgM and IgD and are able to be activated in contact with a foreign antigen and to produce high-affinity antibodies. Peripheral tolerance mechanisms include anergy induction and antigen receptor desensitization.

The greatest evidence for the essential role of B cells in autoimmunity is that immunotherapies that eliminate B lymphocytes are effective in many systemic autoimmune diseases, such as rheumatoid arthritis and SLE (systemic lupus erythematosus).

5. Mechanisms of peripheral tolerance – the role of regulatory cells

Peripheral tolerance implies mechanisms of tolerance towards mature lymphocytes in secondary lymphoid organs that have avoided negative selection during ontogenesis, i.e. during central tolerance.

Autoreactive lymphocytes with pathogenic potential can avoid regulatory processes of central tolerance and exist in the peripheral organs of healthy individuals. Autoimmunity exists in every person: from the basic physiological level during lymphocyte selection and in maintaining immune homeostasis, to the middle level in which low autoantibody titers and a small number of autoreactive T cells circulate, and finally to the pathogenic level in which autoimmunity causes tissue injury and disease.

Peripheral tolerance is achieved through three main mechanisms:

  1. Induction of anergy (a state of inactivation in which lymphocytes remain alive but are unable to respond to autoantigen)
  2. Deletion of autoreactive T cells by apoptosis
  3. Development of “induced” regulatory T cells (iTreg)

Regulatory lymphocytes play a key role in suppressing the immune response to self antigens during peripheral tolerance.

FoxP3+ regulatory T lymphocytes (Treg) – Treg cells have the greatest ability to regulate innate and adaptive immunity in preventing autoimmunity. The Treg cells that develop in the thymus are called tTreg (Treg from the thymus) or nTreg (natural Treg) cells. Treg can be induced by the cytokines TGF-β (transforming growth factor-β) and Interleukin-2 (IL-2) and are then called iTreg (induced Treg) or pTreg (peripheral Treg). The Treg cell phenotype is CD4+ FoxP3+ CD25hi.

Treg cells prevent autoimmunity by contact with autoreactive lymphocytes or through the production of immunosuppressive cytokines such as IL-10 and TGF-β.

Regulatory B lymphocytes (Breg) – Breg cells prevent autoimmunity through the production of the immunosuppressive cytokine IL-10. Recently, a new population of B lymphocytes containing granzyme B has been discovered, which negatively regulates proinflammatory Th1 and Th17 cells, which play a key role in autoimmune diseases.

CD8+ Treg – in addition to CD4+ Treg, CD8+ Treg cells play a significant role in maintaining tolerance and preventing autoimmune diseases.

Mesenchymal stromal cells (MSCs) – in addition to regulatory T and B lymphocytes, non-hematopoietic, multipotent mesenchymal stromal cells that exist in most tissues participate in suppressing the immune response and preventing autoimmunity. MSCs directly prevent T lymphocyte activation/proliferation and induce T lymphocyte apoptosis through several mechanisms involved: NO (nitric oxide), IDO (indoleamine 2,3-dioxygenase), PD-L1 (programmed cell death ligand 1) or FasL (which by binding to its Fas receptor induces apoptosis).

immune tolerance

Nature Reviews Genetics 7, 917-928, 2006.

The next posts will discuss the mechanisms of suppression of the immune response during peripheral tolerance.

If you have questions, comments and suggestions for topics I will be happy to answer.

Literature

Yang SH, Gao CY, Li L, Chang C, Leung PSC, Gershwin ME, Lian ZX. The molecular basis of immune regulation in autoimmunity. Clin Sci (Lond). 2018 Jan 5;132(1):43-67. doi: 10.1042/CS20171154. PMID: 29305419.

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