During Tolerizing Apoptosis

The noninflammatory, tolerance-inducing forms of apoptosis that typify developmental and homeostatic situations generate a highly stereotyped form of death, both morphologically and biochemically (Hengartner 2000). This final common death pathway in this form of tolerance-inducing death is mediated by a family of highly specific death proteases (caspases), which operate in an autoamplifying cascade that can be activated by numerous upstream signals (Thornberry and Lazebnik 1998). Recent studies have stressed that distinct autoantigen structures can be generated when this default caspase-dependent pathway is inhibited or bypassed (Andrade et al. 1998, Casciola-Rosen et al. 1999, Odin et al. 2001). Numerous factors have now been demonstrated to be relevant in the inhibition of caspase-mediated death of ker-atinocytes, including expression of antiapoptotic Bcl-2 family members, expression of high levels of heat shock proteins, and potentially direct endogenous or viral protease inhibitors of the caspases. Several alternate pathways that are of particular relevance in the skin are discussed below.

Generation of Unique Autoantigen Cleavage Fragments During Cytotoxic Lymphocyte Granule-Induced Death

The cytotoxic lymphocyte granule pathway is expressed in cytotoxic T lymphocytes and natural killer cells, which are active in target cell killing of infected, stressed, transformed, or antibody-coated cells. Recent studies from our laboratory have demonstrated that numerous SLE ribonucleoprotein autoantigens (e.g., U1-70 kDa, La/SSB) are directly and efficiently cleaved by the cytotoxic lymphocyte granule protease granzyme B (Andrade et al. 1998, Casciola-Rosen et al. 1999). The fragments generated by such cleavage are distinct from those generated by caspases in other forms of cell death. We proposed that such unique autoantigen fragments may expose cryptic epitopes in these self-antigens, which have not previously been tolerized, and activate autoreactive T cells. Exposure to altered forms of self-antigens may play an important role in the initiation of immune responses to the highly select group of autoantigens targeted in this group of diseases. Because the granule pathway may also play an important role in inducing cytotoxicity of antibody-coated target cells, it may also be involved in the propagation/amplification phases of disease. It is of interest that granzyme B expression in inflamed epidermis has previously been demonstrated (Berthou et al. 1997).

Generation of Unique UV-Induced Photoproducts During Irradiation of the Skin

Although many autoantigens targeted in SLE are redistributed in cells dying by apop-tosis, only ribonucleoprotein complexes containing La/SSB, Ro/SSA, Sm, and U1-70 kDa have been implicated in the pathogenesis of experimental photo-induced epidermal damage. It has been proposed that a pathologic immune response develops in patients with lupus against one or more of the photoproducts found in normal skin after UV irradiation, raising the possibility that these ribonucleoprotein complexes themselves (unlike other autoantigens) might be lupus chromophores. It is also possible that photoproducts that present in normal skin after UV irradiation might be metabolized abnormally in patients with lupus owing to genetic polymorphisms, predisposing to an exaggerated autoimmune response against these photo-products. The resulting immune response is directed against the UVB-induced complexes and subsequently spreads to individual component molecules (RNA and protein), generating an autoamplifying injury characteristic of these self-sustaining diseases (Fig. 17.2). Our laboratory recently demonstrated that such covalent RNA-

Apoptosis Lupus

Fig. 17.2. Model of photo-induced epidermal damage (Buyon 1996). UVB irradiation generates novel autoantigen photoproducts by inducing RNA/protein cross-linked complexes (Sontheimer 1989). In the irradiated cells dying by apoptosis, these novel photoproducts are concentrated in apoptotic surface blebs (Orteu et al. 2001). In genetically susceptible individuals, an exaggerated autoimmune response against these photoproducts might result in an immune response initially directed against the UVB-induced complexes and could subsequently spread to monomeric molecules (RNA and protein) (Simmons-O'Brian et al. 1995).Autoantibody binding to UV-exposed antigens might induce lysis of keratinocytes by antibody-dependent cellular cytotoxicity and subsequent epidermal damage. The initial antibody-dependent cellular cyto-toxicity against keratinocytes might spread the immune response to other autoantigens (via granzyme B autoantigen cleavage), resulting in systemic disease flares (Provost and Reichlin 1988). Autoantibody binding to apoptotic surface blebs might also enhance their capture and presentation by Fc receptor-expressing antigen-presenting cells, favoring spreading of the immune response to other modified autoantigens in the blebs

Fig. 17.2. Model of photo-induced epidermal damage (Buyon 1996). UVB irradiation generates novel autoantigen photoproducts by inducing RNA/protein cross-linked complexes (Sontheimer 1989). In the irradiated cells dying by apoptosis, these novel photoproducts are concentrated in apoptotic surface blebs (Orteu et al. 2001). In genetically susceptible individuals, an exaggerated autoimmune response against these photoproducts might result in an immune response initially directed against the UVB-induced complexes and could subsequently spread to monomeric molecules (RNA and protein) (Simmons-O'Brian et al. 1995).Autoantibody binding to UV-exposed antigens might induce lysis of keratinocytes by antibody-dependent cellular cytotoxicity and subsequent epidermal damage. The initial antibody-dependent cellular cyto-toxicity against keratinocytes might spread the immune response to other autoantigens (via granzyme B autoantigen cleavage), resulting in systemic disease flares (Provost and Reichlin 1988). Autoantibody binding to apoptotic surface blebs might also enhance their capture and presentation by Fc receptor-expressing antigen-presenting cells, favoring spreading of the immune response to other modified autoantigens in the blebs autoantigen complexes are indeed generated in keratinocytes after UV irradiation (Andrade et al. 2001). Studies to define the immune response to the biochemically unique antigen forms and the clearance of such complexes in patients with SLE are currently under way.

The generation of these autoantibodies might have important consequences in the propagation and amplification of the autoimmune response to apoptotic cells in several ways: (a) antibody binding to UV-exposed autoantigens might induce kera-tinocyte lysis by antibody-dependent cellular cytotoxicity; (b) antibody binding to apoptotic keratinocytes might enhance the capture and presentation of apoptotic surface blebs by B cells, favoring spreading of the immune response to other modified autoantigens in the blebs; (c) antibodies are likely to change the nature of the response upon phagocytosis from noninflamatory to inflammatory; and (d) antibodies might themselves induce cell damage and death and thereby autoamplify any injury.

How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment