Breaking T and B Cell Tolerance

Experiments with transgenic or non- transgenic mice have shown that, in principle, tolerant T and B cells can be reactivated by infectious agents. Infections are capable of restoring in silenced T cells the capacity to produce cytokines (Rocken et al. 1992; Racke et al. 1994). This phenomenon was extended to the situation of transplantation induced tolerance (Ehl et al. 1998). Similarly, reactivity and immunoglobulin production by B cells that were silenced either by exogenous or transgenic endogenous antigens can be restored with mitogens, including bacteria derived lipopolisacchrides (Louis et al. 1973; Goodnow et al. 1991). Even though these experiments have shown that infectious agents can abolish solid T and B cell tolerance there are little data showing that this reactivation of tolerant T and B cells can also lead to autoimmune disease. One first example suggesting such a situation is given by double transgenic mice that bear a TCR recognizing a transgenic self-antigen expressed by hepatocytes. Injection of bacterial DNA motifs that activate DC and promote DC1-development by these activated DC did also induce transient liver damage, as evidenced by an increase of transaminases. However, this phenomenon was short lived and no data are available proving that autoimmune disease can be the direct consequence of polyclonal T cell activation (Limmer et al. 1998). In small animal models, induction of autoimmune disease by bacterial DNA motifs or more complex bacterial lysates such as complete Freund's adjuvans required, in addition, always immunization with an antigen that mimics peptide motifs of the targeted self antigen (Bachmaier et al. 1999). Thus, in normal mice bacterial DNA motifs triggered the myocarditis only when co-administered with an altered self-peptide, derived from chlamydia.

These data suggest that immunization against antigens that are structurally related to self-antigens are essential for the induction of autoimmunity. This concept is further supported by functional and structural analysis of T cell epitopes of infectious agents and potential self-antigens. Chlamydia peptides can share functional similarities with peptides expressed by mammalian heart muscle, while other infectious agents share important peptide sequences with potential self-antigens such as myelin basic protein. This aspect is especially significant since molecular mimicry does not require molecular identity. Studies with altered peptide ligands have shown that induction of cytokine production or T cell proliferation requires only poor structural relation as long as important anchor positions are conserved (Gautam et al. 1994; Wucherpfennig and Strominger 1995). Various examples suggest that this may be of relevance for autoimmune diseases of the skin. Thus, the first eruption of the juvenile type of psoriasis is preceded by streptococcal infections in most patients (Prinz 1999) and lichen planus is associated in a large number of patients with an acute or chronic liver disease (Chuang et al. 1999). In some patients lichen planus may even be provoked by active or even passive vaccination against hepatitis (Tessari et al. 1996; Degitz and Röcken 1997).

Despite the experimental prove for both, re-activation of tolerant T cells and for molecular mimicry, the exact role of infections in the pathogenesis of autoimmune diseases remains open. One important alternative would be the direct infection and molecular alteration through infectious disease. One important example is chronic active hepatitis, where relatively weak immune responses follow the slowly progressing wave of infected hepatocytes and thus slowly destroy the liver. In this situation, activation of the T cell mediated immune responses, associated with a short aggravation of the hepatitis may lead to reduction and control of the viral load and cure from chronic progressive hepatitis (Berg et al. 1997; Gerlach et al. 1999; Moradpour and Blum 1999). In the skin a very similar phenomenon is visible during fungal infections. The border, the clinically manifest eczema, reflects the immune reaction against a large burden of fungi. Inside the inflammatory margin, the eczema and the fungal load are significantly milder. In the case of fast growing fungi, the eczema may present as a policyclic disease (Fig. 4).

A third level where infections could directly interfere with autoreactive T cells is the pattern of cytokines that T cells produce. Thus, infection with the nematode nippostrongylus brasiliensis can not only restore reactivity in silenced CD4+ T cells but also induce IL-4 production by these silenced T cells (Rocken et al. 1992; Rocken et al. 1994; Rocken et al. 1996).

In conclusion, increasing understanding of the TLR-mediated activation if innate immune cells and their link to adaptive immunity has helped to create a concept that also applies to the activation of autoreactive T and B cells.

Fig. 4. Waves of inflammation as reflected by the migrating margins of eczema found during tinea infection

Thus in a series of models, activating innate immunity via TLR has turned on or increased the adaptive immune response. These data emphasize the power of infectious diseases in mounting immune responses and in modulating the cytokine phenotype of established immune responses. PAMPs binding to TLR and regulating the transcription of pro-inflammatory genes through NFkB are the basis for this new understanding. Thus, PAMPs like immunostimulatory DNA binding TLR9, like lipopolysachharides binding TLR4 and others are capable of activating DC, B cells, and probably also T cells. Instructing IL-12 producing DC via TLR9 can be achieved by injection of TLR9 ligands into mice. Using the model of progressive, Th2-mediated leishmaniasis infection in susceptible BALB/c mice, Zimmermann et al. showed that immunostimula-tory DNA motifs are capable of reverting even fully established type 2 immune responses into IFNy dominated type 1 immune responses and DTHR (Zimmermann et al. 1998). Thus, injection of immunostimulatory DNA motifs and triggering TLR9 overcame the tolerance towards the parasite and restored control over Leishmania major in animals with a large parasite burden. In view of such a powerful Thl-inducing capacity, it was likely that similar immunostimulatory motifs are also capable of breaking self-tolerance and induce autoreactive Thl/Tcl cells that cause inflammatory tissue destruction. Indeed, it was shown very recently that viruses provide TLR signals required for bypassing regulatory T cell-mediated tolerance (Yang et al. 2004). PAMPs may therefore be considered as the leading group of danger signals that nature provides and that may also lead to activation of autoreactive T and B cells.

In addition to PAMPs derived from microbes, there is increasing evidence suggesting that endogenous ligands can also trigger TLR and activate autoreactive lymphocytes (Ulevitch 2004). Systemic lupus erythematosus is characterized by the production of autoantibodies against nucleic-acid-containing macromolecules such as chromatin or ribonucleoprotein particles. DC and B cells are effectively activated by immune complexes containing chromatin, a process that involves TLR9. This activation leads to proliferation of autoreac-tive T and B cells providing direct evidence for TLR promoted autoimmunity mediated by endogeneous ligands (Leadbetter et al. 2002; Boulé et al. 2004).

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