Autoreactive Lymphocytes

DEPAP, but not aniline or other 3-(A-phenylamino)- 1,2-propanediol derivatives, induced both apoptosis and necrosis in human peripheral blood lymphocytes in vitro in a time- and concentration-dependent fashion. In short-term cell cultures, possibly representative of the toxic oil syndrome acute phase, DNA degradation occurred rapidly. Apoptosis preceded membrane damage. In longer-term cultures, cytotoxicity was characterized by necrosis. As the cells die, abnormal forms of autoantigens are released, activating autoreactive lymphocytes, which could ultimately initiate autoimmune disease (Gallardo et al., 1997 Lahoz et al., 1997). 

Part of these T-lymphocytes transform into memory cells. These cells are different from their ancestors in that they are activated by a much lower antigen binding strength and also much less depend on signal 2. Now self-antigens can activate these T-lymphocytes. As during activation continuously new memory cells are formed, autoreactivity is sustained and autoimmune disease follows (Fig. 2). 

Autoimmune Disease. Figure 2 Generation of autoreactivity. APC, antigen presenting cell IFN, interferon LPS, lipopolysaccharide MHC, major histocompatibility complex T, T-lymphocyte TCR, Tcell (antigen) receptor TLR, toll like receptors. For details see text. 

Yung, R. et al., Mechanisms of drug-induced lupus. II. T cells overexpressing lymphocyte function-associated antigen 1 become autoreactive and cause a lupuslike disease in syngeneic mice, J. Clin. Invest., 97, 2866, 1996. 

Programmed cell death plays an important role during lymphocyte development, by eliminating autoreactive cells, as well as in the effector phase of the immune response, when antigen induced cell death halt cell activation. Several groups have been studied the function of PTEN in the immune response. PTEN heterozygous (PTEN+/-) mutants develop a lethal polyclonal autoimmune disorder with features reminiscent of those observed in Fas-deficient mutants. Fas-mediated apoptosis was impaired in Pten+/-mice, and T lymphocytes from these mice show reduced activation-induced cell death and increased proliferation upon activation. PI3-K inhibitors restored Fas responsiveness in PTEN+/- cells. These results indicate that PTEN is an essential mediator of the Fas response and a repressor of autoimmunity, thus implicate the P13-Kinase/Akt pathway in Fas-mediated apoptosis (DiCristofano et al, 1999)... 

Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP, et al Synergism of cytotoxic T lymphocyte-associated antigen-4 blockade and depletion of CD25 + regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte responses. 

Elimination of autoreactive B- or T-lymphocytes, natural selection and elimination of cells in the thymus 95 % of T cells that migrate to the thymus are eliminated by apoptotis. 

The current concept of autoimmune diabetes is that pancreas islet P cells are destroyed by an autoimmune response mediated by T lymphocytes that react specifically to one or more P cell proteins (Bach, 1994). Figure 25.1 shows the pathogenesis of type 1 diabetes. This concept gave rise to the idea that auto-immune diabetes can be prevented by the manipulation of autoreactive T cells or... 

Bystander activation activation of autoreactive cells through nonspecific inflammation and induction of inflammatory cytokines and chemokines is also of pathological consequence in MS. It has been suggested that bystander activation, induced by persistent virus infection or primed by molecular mimicry may activate autoreactive T-cells specific for the CNS (McCoy et al., 2006). Einally, cryptic antigens may also play a role in immune activation. In other immune-mediated diseases such as Chronic Lymphocytic Thyroiditis and Chagas Heart Disease, exposure of cryptic epitopes leads to the activation of autoimmune cells and further contributes to... 

Richardson B, Powers D, Hooper F, Yung RL, O Rourke K Lymphocyte function-associated antigen 1 overexpression and cell autoreactivity. Arthritis Rheum 1994 37 1363-72. 

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