Discussion

IFN-y is a cytokine released mainly by certain T cells and natural killer cells. It drives the immune response by directing CD4+ T cells toward a Th-1 phenotype, activating macrophages to kill pathogens, enhancing or inducing MHC class I and class II molecules and stimulating B cells to mature and secret antibodies (Snapper 1996). In many autoimmune diseases, IFN-y appears to play a key role in activating autoreactive T cells (Buntinx et al. 2002). Thus different clinical manifestations of these diseases may depend on the cell territory in which these cytokines are hyperproduced (Skurkovich et al. 1994). High levels of IFN-y or IFN-y-producing T cells compared to controls have been found in the disease sites of many Th-1 autoimmune diseases, such as in the synovial fluid in rheumatoid arthritis (Canete et al. 2000), in the cerebrospinal fluid and plaques in multiple sclerosis (Woodroofe and Cuzner 1993; Traugott and Lebon 1988), in the aqueous humor and corneal infiltrating cells in cases of corneal transplant rejection (Yamagami et al. 1998), in the islet ß cells in type I diabetes (von Herrath and Oldstone 1997), in the ocular cells in uveitis (Whitcup et al. 1992), and in the lesions of various autoimmune skin diseases, such as psoriasis (Barker et al. 1991), vitiligo (Grimes et al. 2004), and acne (Mouser et al. 2003). Though the exact mechanism of autoimmunity is not well understood, evidence is rapidly accumulating that IFN-y, IFN-a, and TNF-a may not only participate in the disease process but also directly increase disease progression. As mentioned, we first found circulating IFNs in patients with various autoimmune diseases (Skurkovich et al. 1975). In humans, IFN-y can, for example, trigger or exacerbate multiple sclerosis (Panitch et al. 1987), rheumatoid arthritis (Seitz et al. 1988), psoriasis (Fierlbeck et al. 1990), and others. IFN-a can also induce underlying autoimmune diseases, including autoimmune thyroid disease (Murakami et al. 1999), type I diabetes (Fabris et al. 1998), and rheumatoid arthritis (Pittau et al. 1997). In multiple sclerosis, evidence points to IFN-y as having a direct role in inducing central nervous system demyelination (Horwitz et al. 1997). IFN-y in chronic high levels may set in motion the autoimmune process. Some pathological action is mediated by the induction by IFN-y of nitric oxide synthetase, which produces nitric oxide (NO), which can cause neurodegeneration (Moncada et al. 1991). NO is produced in large amounts by activated macrophages in response to high levels of IFN-y acting synergistically with other cytokines such as TNF-a and IL-1, in whose induction IFN-y participates (Goodwin et al. 1995). NO damages melanocytes in vitiligo (Rocha and Guillo 2001) and P cells in diabetes (Thomas et al. 2002).

Certain endogenous and exogenous factors (genetic, viruses, bacteria, fungi, in some cases sex hormones, parasites, and others) may be involved in the initiation of autoimmune diseases and may induce IFN-y. Scientists have implicated Epstein-Barr virus, mycobacteria, Proteus, and Escheria coli, for example, in the pathogenesis of rheumatoid arthritis (Harrison and McColl 1998). Human endogenous retroviruses (HERV) have been found in patients with multiple sclerosis (Christensen et al. 2001) and schizophrenia (Karlsson et al. 2001). Coxsackie viruses may help bring about type I diabetes (Harrison and McColl 1998). Certain pediatric autoimmune neuropsychiatric diseases are associated with streptococcus (PANDAS), including obsessive-compulsive disorder and Tourette's syndrome (Snider and Swedo 2003). A protein of Group A P-hemolytic streptococci has been implicated in psoriasis (Prinz 1997). Certain other skin diseases also appear to be associated with particular viruses, bacteria, fungi, possibly parasites, and sex hormones that may induce Th-1 cytokines. As mentioned, IFN-y, TNF-a, and Th-1-positive cells or mRNA expression of IFN-y and other Th-1 cytokines are found in skin lesions of autoimmune skin diseases, such as alopecia, psoriasis, and vitiligo. P. acnes, implicated in acne, when injected into horses, increases IFN-y expression (Davis et al. 2003). Sex hormones also act in acne, possibly as inducers of IFN-y. Since estrogen upregu-lates IFN-y production (Karpuzoglu-Sahin et al. 2001), hormones may act together with P. acnes to increase IFN-y production. It is possible to consider acne a temporary autoimmune condition that may depend in part on the effects of high levels of sex hormones in such periods as adolescence, the premenstural period, and pregnancy. SD is associated with the fungus Pityrosporum ovale (Malassezia furfur) (Faergemann et al. 1996). IFN-y has been implicated in SD through the detection of IFN-y induced protein 10 (IP-10) in keratinocytes in biopsies of SD lesions (Smoller et al. 1990). Antimycotics or antibiotics are effective to some extent in SD (Reichrath 2004), possibly because by removing the fungus, one removes the possible inducer of proinflammatory cytokine production. IFN-y-positive cells are also present in the skin lesions of dermatophytosis (Koga et al. 2001), and in rosacea T-cell subsets in the dermal infiltrates of lesions are frequently associated with the parasite Demodex folliculorum (Rufli and Buchner 1984). Though there is little research on this parasite as an inducer of proinflammatory cytokines, chronic dermatitis was found associated with large numbers of Demodex ectoparasites, and pronounced CD4 and CD8 T-cell infiltrates in the dermis and lymphadenopathy associated with increased IFN-y and IL-12 expression were observed (Liu et al. 2004).

Drugs that have some positive effect in certain skin diseases inhibit proinflammatory cytokines IFN-y and/or TNF-a, which may be behind the effective action of these drugs. Acne and psoriasis respond to vitamin A, which inhibits IFN-y release by peripheral blood mononuclear cells (Wauben-Penris et al. 1998). The drug pimecrolimus, used to treat atopic dermatitis and psoriasis, also inhibits synthesis of IFN-y and TNF-a (Wolff and Stuetz 2004). Topical tacrolimus, effective in bringing about repigmentation in vitiligo, appears to work by suppressing TNF-a production (Grimes et al. 2004). In a psoriasis mouse model, mechlorethamine, a drug that inhibits IFN-y, TNF-a/p, and IL-12, inhibited psoriasis (Tang et al. 2003). Certain natural factors may help to stabilize IFN-y production, such as vitamins A and D (Cippitelli and Santoni 1998; Muller and Bendtzen 1996). This action of vitamin D may be an important factor in multiple sclerosis, in which a gradient of increasing prevalence with increasing latitude has been observed; the lower prevalence in southern climates is attributed to an ultra-violet radiation-induced increase in serum vitamin D levels, which may have a protective effect (Ponsonby et al. 2002). Normal intake of vitamins, minerals and microelements from food possibly helps maintain the balance between Th-1 and Th-2 cytokine production - possibly one of the functions of vitamins in the human and other living organisms (Albers et al. 2003). This suggests specific targeting of IFN-y or TNF-a, and IL-1 may have an even stronger, positive effect in treating these diseases.

Thus, IFN-y plays a fundamental role in the regulation of the metabolism and immunological status of cells in a healthy state. A disturbed IFN-y production with hyperproduced IFN-y is found in different sites in the organism and can bring many somatic and neuropsychiatric diseases. In healthy people, IFN-y is not found in the blood. The disturbance of IFN-a production in addition to other pathological actions may, as we have hypothesized before (Skurkovich et al. 1993, 1994, 1998, 2002d), also play a key role in the development of the autoantigen and the autoantigen complex. We have proposed that possibly, besides IFN-a, IFN-y may play a similar role (Skurkovich et al. 2002d). There may exist more than one type of IFN connected with antigen stimulation, as was suggested before (Skurkovich et al. 1998). Possibly some groups of autoimmune diseases are connected with a special or defective type of IFN-y or an altered IFN-y pathway. There may also be cases in which cytokines are hypoproduced, which could also lead to disturbances in health. Every change in the production of IFN-y and other cytokines can lead to pathology, but in particular to autoimmune conditions, including a temporary autoimmune condition. The main goal for rational treatment of Th-1-, Th-2-, and combined Th-1/Th-2-mediated diseases is to return the organism to homeostasis or a Th-1-Th-2 balance by suppressing or removing the hyperproduced cytokines with the help of antibodies, soluble receptors, vitamins, minerals and microelements, and different agents that suppress cytokine synthesis.

In conclusion, Th-1-mediated autoimmune diseases share certain characteristics. First, anti-IFN-y or anti-TNF-a may generally be universal treatments for Th-1 autoimmune diseases, particularly skin diseases. Second, every Th-1 autoimmune disease develops through a pathological immune cascade. In general, removing one member of the cascade can have some therapeutic effect. Third, all autoimmune diseases develop with a reduced ability of the mononuclear cells to induce in vitro IFN-y in response to stimulation. Fourth, deficiencies in natural killer cells are associated with autoimmune disease (Oikawa et al. 2003; Baxter and Smyth 2002). Fifth, in general autoimmune diseases are chronic, but in some cases can be temporary.

In autoimmune diseases, cytokines are often hyperproduced at the pathological site and then circulate in the blood, though finding cytokines in the blood is not always possible.

According to our investigations, anticytokine therapy holds great promise for treating many diseases, especially skin diseases. As described, we had good, sometimes striking, results with anti-IFN-Y and will continue testing this approach with other skin diseases. In our opinion, most skin diseases have a Th-1, Th-2, or Th-1/Th-2 genesis, and we feel our research, which introduced anticytokine therapy in 1974 (Skurkovich et al. 1974,1989), will contribute to the understanding and treatment of these diseases. In this article, we have not discussed other cytokines besides IFN-y, TNF-a, and IL-1 because of limited space and because we think these cytokines are most involved in the development of Th-1 autoimmune diseases.

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