TOLERANCE AND AUTOIMMUNITY 1

TOLERANCE AND AUTOIMMUNITY
●Sometimes, the immune system fails to distinguish self from nonself and generate response against the self cells too. Such an inappropriate response of the immune system against the self cells is termed AUTOIMMUNITY.

●Autoimmunity leads to a number of chronic and acute autoimmune diseases namely; rheumatoid arthritis,  multiple sclerosis,  lupus erythematosis and certain types of diabetes.

●But then, there are a number of mechanisms that protect the host from potentially selfreactive  lymphocytes . These are given a general term TOLERANCE.

■tolerance is of 2 types:- central and peripheral
■central tolerance-  before maturation , T and B cells are exposed to a number of antigens including 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 recognising self antigens with a greater than threshold  affinity are deleted because if allowed to mature, they will act against self cells leading to autoimmunity.

■How central tolerance acts:  It deals with self reactive lymphocytes through clonal deletion ,apoptosis and receptor editing.

●Actually, maturation of lymphocytes to give rise to a functional TCR or Ig occur through a process in which any V-region gene can associate with any D or J segment ; and so generation of a V-region that reacts with a self antigen is possible and so it needs to be checked.
●For this reason, B cells and T cells specific for self antigens are negatively selected in bone marrow and thymus respectively.
self reactive B cells are deleted  by the induction of apoptosis and some undergo receptor editing in which the V region is edited and non-autoreactive B cells are released.
Similarly,  autoreactive T cells are deleted through apoptosis.

■peripheral tolerance - yet central tolerance fails because:
1)all self antigens are not expressed in the bone marrow and thymus.
2)there is a threshold affinity required between lymphocytes and self antigens to trigger clonal  deletion.

●Due to this,  weakly self reactive lymphocytes make way to periphery but here peripheral tolerance works to prevent autoimmunity from occurring.
Actually,  when in periphery; the B cells get to interact with self antigens; they are inactivated again to prevent them from reaching lymphoid follicles and germinal centers where they become plasma cells able to secrete antibodies .

●If still, they escape: then in the absence of help from T-helper cells which already have been negatively selected in the thymus,  they become unresponsive and anergic and never migrate to germinal centers.

●Similarly,  T cells in the absence of costimulatory signals cant be activated; Besides, recognition of antigen by TCR presented on MHC is needed.

●Additionally , CTLA-4 acts to inhibity costimulatory signal by binding with B7 and thus inhibiting T cell activation. When gene for CTLA-4 is deleted , the host exhibit autoimmunity .

■ROLE OF T-REGULATORY CELL-weakly self-recognizing T cells are alternatively differentiated into regulatory T cells (Treg cells), which act as sentinels in the periphery to calm down potential instances of T cell autoreactivity.


●T reg cells are a unique type of CD4+ cells that express high levels of the IL-2R alpha-chain (CD25).
Certain of these cells upregulate the  transcription  factor Foxp3 and then develop in to  Treg cells capable of suppressing reaction to self antigens.
Supression is regulated, atleast in part ,through the production of IL-10 and TGF-beta

●Cell death also plays an important role in maintaining tolerance.
Activated T cells express  increased levels of Fas and FasL ; In both B and T cells; engagement of fas by fas L leads to AICD ( activation induced cell death).

■NOTE-The deletion threshold is much more stringent for T cells than for B cells since T cells alone can cause direct tissue damage. Furthermore, it is more advantageous for the organism to let its B cells recognize a wider variety of antigen so it can produce antibodies against a greater diversity of pathogens. Since the B cells can only be fully activated after confirmation by more self-restricted T cells that recognize the same antigen, autoreactivity is held in check.

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