The immune system is designed to recognise, detect and clear harmful pathogens from the body, but autoimmunity arises when an immune response is mounted against the host’s own tissues.  To prevent this from occurring, there are mechanisms to ensure that lymphocytes capable of recognising host tissues are destroyed. These mechanisms are known as central and peripheral tolerance.


Central tolerance is the process by which self-reactive lymphocytes are destroyed in central lymphoid organs, the thymus and bone marrow. T and B cells are produced in the bone marrow, whilst their development occurs in the thymus and bone marrow respectively.

These cells possess T and B cell receptors, each with its unique ability to bind particular molecular motifs, such as a peptide on a bacterial cell wall. These motifs are known as antigens and are “presented” to lymphocytes on major histocompatibility complex (MHC) proteins on the surface of antigen presenting cells (APCs) such as dendritic cells. If a lymphocyte’s receptor binds to the antigen with a strong enough affinity, it will become activated. Danger arises therefore, when the MHC protein and the T/B cell receptor has a high affinity for host tissue antigens.

So let’s consider how these T and B cell receptors are generated in the first place. In the thymus, T cell receptors are generated by V, D and J gene segments. During T cell development, these genes are randomly rearranged, in the absence of an antigen, producing a vast array of T cell receptors each with its unique specificity. This is really important, as it ensures there is a large source of T cells with the capability of recognising whatever intruders may attack the body. It does of course also mean, that a population of T cells exist with self-reactive T cell receptors.

In the bone marrow, a similar process occurs with B cells. Random rearrangements of V, D and J gene segments creates a diverse range of IgD proteins that are the B cell receptors on immature B lymphocytes, again producing a diverse repertoire of B cell receptor specificity, but also some self-reactive B lymphocytes.

So how do we filter out these self-reactive lymphocytes? This is where central tolerance comes into play.

Once T cells have been confirmed to recognise either MHC I or MHC II depending on whether they express CD8 or CD4 co-receptors, they are presented to self-antigen in the thymus. If the T cell binds to self-antigen with high affinity, it is apoptosed (known as negative selection), whilst those that have weak affinity for self-antigen mature into natural T regulatory cells (nTreg) which we will discuss later. Of course, T cells with no affinity for self-antigen are allowed to mature and circulate in the body.


You may be wondering how self-antigens from the whole body are presented to immature T cells when they only develop in the thymus. This is achieved through thymic stromal cells, specialist antigen-presenting cells. They express the AIRE (autoimmune regulator) gene, which allows them to express genes for extra-thymic proteins. For example, whilst kidney cells may only express parts fo the genome that encode for kidney proteins, AIRE allows the expression of genes across the whole genome. This enables peptides from all over the body to be presented to developing lymphocytes and allows a wide range of antigen presentation.

Immature B cells initially possess IgD B cell receptors on their surface. If this recognises self-antigen it is apoptosed. B cell receptors with mild affinity for self-antigen undergo light chain receptor editing. The B cell receptor consists of heavy and light chains which contain immune cell binding (constant) and antigen binding (variable) regions. Receptor editing basically means that the receptor is altered, so that it can recognise different antigens. This effectively gives the B cell another chance to survive central tolerance mechanisms. Again, B cells possessing B cell receptors that have no affinity for self-antigen are allowed to mature. It is also worth mentioning that the AIRE gene mentioned above is not used for the development of B cells.



Despite these mechanisms, some self-reactive lymphocytes will manage to slip through the net and avoid negative selection. This will arise when an antigen has not been presented to a developing T cell and it is easy to appreciate that thymic stromal will not be able to produce every possible antigen that has affinity for every developing T cell at any one time. Because of this, a second safety mechanism is needed, peripheral tolerance.


Peripheral tolerance involves numerous mechanisms by which self-reactive lymphocytes are destroyed or made harmless in secondary lymphoid organs including the lymph nodes and spleen.

–          Induction of tolerance by dendritic cells – Immature dendritic cells can present self-antigen from apoptotic cells to naive T cells in secondary lymphoid organs. They do not express co-stimulatory molecules required for the activation of T cells at this stage, so upon antigen presentation, the T cell either undergoes apoptosis, or is induced into becoming a Treg cell.

–          Immunoprivileged organs – Certain tissues are not accessible by lymphocytes due to anatomical barriers, preventing self-reactive T and B cells from mounting an immune response to these tissues. These include the eye and testis.

–          nTreg suppression – natural T regulatory cells are produced from T cells which recognised self-antigen with low affinity. They suppress the activity of self-reactive Th1 cells and induce them into becoming induced Treg cells (iTreg), which promote a repair response rather than an aggressive inflammatory response.

Natural T regulatory cells (nTreg)
  • These cells recognise self-antigen a little during central tolerance
  • They contribute towards peripheral tolerance and regulate the function of Th cells
  • They have elevated FOXP3 transcription factor which causes the expression of anti-inflammatory cytokines (IL-10, TGF-b)
  • Cytokines released during inflammation promote up-regulation of co-stimulatory molecules, increasing the likelihood that self-reactive lymphocytes will be activated. The role of nTreg cells is to stop this happening!
nTreg cells have several ways in which they can inhibit the responses of aberrant Th1 cells:
(1) CTLA-4 on the nTreg binds to B71.2 on the DC and prevents it from binding to CD28. This stops co-stimulation of the Th1 cell.
(2) They can release perforin and granzymes which induce apoptosis of the Th1 cell.
(3) IL-10 produced following activation of the FOXP3 transcription factor outcompetes IL-12 and causes a shift from a Th1 – iTreg and a classically activated (M1) macrophage to an alternatively activated (M2) macrophage. This triggers a more reparative and less damaging immune response.
(4) Th1 cell normally produces IL-2 in response to co-stimulation and cytokine release from the DC. IL-2 however is taken up by CD25 on the nTreg, which is one chain of the IL-2 receptor. This prevents autocrine signalling to the Th1 cell and prevents proliferation, preventing a harmful immune response.


–          Anergy – in the absence of acute inflammation, APCs do not possess co-stimulatory molecules which are required for the activation of T lymphocytes. Therefore, self-reactive T cells that engage self-antigen on APCs in the absence of these co-stimulatory molecules undergo cell death, as there are insufficient signals to induce their differentiation into specific T cell types.

–          B cell regulation – If B cells encounter self-antigen in peripheral tissues in the absence of mature Th cells, they become unable to respond to further antigenic stimulation and destroyed.

We can see that many mechanisms exist to prevent self-reactive cells from reaching secondary lymphoid organs and mounting an immune response against host tissues. However, a number of autoimmune disease arise where these mechanisms have clearly failed.


There are many reasons for autoimmunity to develop.

HLA alleles may be implicated. Human Leukocyte Antigen alleles code for the MHC proteins we mentioned earlier (which bind to antigens and present them to T and B cell receptors). Certain HLA alleles may give rise to MHC proteins with a high affinity for self-antigen. As a result, people with these alleles may be at a higher risk of developing autoimmunity. Certain HLA alleles have been linked with conditions such as type 1 diabetes and Grave’s disease (hyperthyroidism).

Defects in apoptosis can give rise to autoimmunity. If self-reactive lymphocytes cannot undergo apoptosis, then they cannot be destroyed during negative selection. Additionally, apoptosis enables controlled cell death in which cellular contents remain membrane bound, preventing the leakage of potentially immunogenic self-peptides that may stimulate self-reactive lymphocytes. Therefore it is important that apoptotic mechanisms remain intact.

Epigenetics describes the modification of gene expression which can occur with ageing or environmental influences. Epigenetic changes to genes involved in lymphocyte development and activation may increase the risk of autoimmunity. For example, epigenetic changes may cause silencing of the CTLA-4 gene expressed by nTreg cells. As a result, these cells cannot suppress the activity of self-reactive Th1 cells thereby leading to an inflammatory response against host tissues. These events could relate to any gene involved in immune regulation.

Environmental factors are a massive influencing factor in the development of autoimmune disease. Early exposure to various microorganisms and potential allergens can help induce immune tolerance to these, preventing the initiation of an immune response against them in later life. Viral or bacterial infection may also trigger autoimmunity to arise due to molecular mimicry. This is the process by which host tissues may contain molecular motifs that resemble those of pathogenic antigens. Following an infection, lymphocytes may continue to mount an immune response against host tissues due to their similarity to the pathogen. Such events may be implicated in conditions such as multiple sclerosis following infection with the Epstein-Barr virus.

In reality, it is a combination of all these factors, and more, that culminates in autoimmune disease. For example, self-reactive HLA-alleles, self-reactive T lymphocytes which escape central tolerance mechanisms, epigenetic changes to the CTLA-4 gene and infection by EBV may all eventually culminate in autoimmune disease. You need a number of key players to line up in order for the domino effect to occur, so essentially autoimmunity results from rather unfortunate luck.