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• Thus, the immunological tolerance mechanisms have evolved to prevent harmful autoimmunity.
Central Tolerance:
• Whilst T-cells are developing in the thymus and B-cells are developing in the bone marrow, they can undergo
central tolerance.
• Central tolerance involves the primary lymphoid organs (thymus, bone marrow)
• Recognition of self antigen in these primary lymphoid organs can lead to apoptotic cell death, with deletion of
those particular cells.
• Or in the case of B-cells, there is also the possibility for the B-cell to change the specificity of its antigen
receptor & this is referred to as receptor editing.
• Regulatory lymphocytes can develop that can suppress unwanted autoimmune responses.
• Central tolerance is not 100% efficient, so it is backed up with a number of peripheral tolerance mechanisms.
Peripheral tolerance:
• These can involve the induction of anergy, non-responsiveness in lymphocytes when antigen is seen in the
absence of co-stimulation.
• Usually during an infection, co-stimulatory molecules such as CD80 and CD86 are up-regulated on dendritic
cells BUT when autoantigens are being shown to lymphocytes by dendritic cells, there is no co-stimulation and
this results in anergy.
• In the thymus, there is a transcription factor called the autoimmune regulator (AIRE).
• The function of AIRE, the autoimmune regulator is to cause expression of what are normally tissue-restricted
antigens so that these antigens are also expressed in the thymus to facilitate tolerance.
• There will be negative selection of the self-reactive T-cells and apoptotic cell death leading to deletion of those
autoreactive T-cells.
• In the absence of AIRE which can occur due to mutations, individuals will fail to delete tissue specific T-cells
resulting in autoimmunity and this can lead to pathology - autoimmune disease.
• So why is it that in around about 5% of individuals, this normal autoimmunity becomes pathogenic?
◦ It’s a mixture of genetic factors, environmental factors such as infections and other environmental factors
such as diet and stress and so forth, that lead to a breakdown of tolerance which affects the T-cells and B-
cells that are potentially pathogenic.
◦ That breakdown in tolerance affecting those particular clones of T and B-cells can precipitate the
development of autoimmune disease.