Spontaneous autoimmune disease

In the case of spontaneous autoimmune diseases mice are the most frequently used animal model. With the advent of transgenic and genetically modified (knockout, KO) mice, the number of genetically predisposed autoimmune models has substantially increased. Other species that have been useful include rats, monkeys, cats, dogs, rabbits, and chickens for some specific forms of autoimmune diseases [4, 5]. 

Bolland, S., and J. V. Ravetch. 2000. Spontaneous autoimmune disease in Fc(gamma)RIIB-defrcient mice results from strain-specific epistasis. Immunity 13 277-285. 

The most common cause of hypothyroidism is failure of the thyroid gland this is known as primary hypothyroidism. In adults, the cause of primary hypothyroidism is often spontaneous autoimmune disease (e.g., Hashimoto s thyroiditis) or destructive therapy for hyperthyroid states... 

Izui, S., McConahey, P.J. and Dixon, F.J. (1978). Increased spontaneous polyclonal activation of B lymphocytes in mice with spontaneous autoimmune disease. J. Immunol, 121, 2213-2219... 

Autoimmune diseases may have an acute or a chronic insidious onset with a chronic progressive course with varying periods of severe or mild disease activity and spontaneous remissions in a minority of patients. Inherent to the initially chronic progression, reversible autoimmune inflammation and disability are susceptible to effective therapy when still no irreversible organ damage has occurred. Nowadays these reversible joint or organ changes in autoimmune arthritis and autoimmune nephritis can be normalized with novel treatment modalities. 

Administration of a cocktail containing eicosapentenoic acid and docosahexenoic acid to volunteers for up to 6 weeks, resulted in a significant depression in IL-1J3 (61%), IL-1 a (39%), and TNF (40%) synthesis. These levels returned to normal after a few weeks [99]. In vitro studies indicate that Pentoxifylline can block the effects of IL-1 and TNF on neutrophils [100]. It is a phosphodiesterase (PDE) inhibitor that causes increased capillary blood flow by decreasing blood viscocity and is used clinically in chronic occlusive arterial disease of the limbs with intermittent claudication. Denbufylline, a closely related xanthine, has been patented as a functional inhibitor of cytokines and exhibits a similar profile to Pentoxifylline [101]. Romazarit (Ro-31-3948) derived from oxazole and isoxazole propionic acids has been shown to block IL- 1-induced activation of human fibroblasts in vitro and in animal models reduces inflammation [102,103,104]. By using a spontaneous autoimmune MRL/lpr mouse model, a significant efficacy was shown [105]. Two-dimensional structures of some of these molecules are shown in Figure 14. 

Spontaneous human autoimmunity seems to be almost entirely restricted to the autoantibody responses produced by B-lymphocytes. Loss of tolerance by T-ceUs has been extremely hard to demonstrate, and where there is evidence for an abnormal T-ceU response it is usually not to the antigen recognised by the autoantibody. This disparity has led to the idea that human autoimmune disease is in most cases (with probable exceptions including type I diabetes) based on a loss of B-cell tolerance, which makes use of normal T-cell responses to foreign antigens in a variety of aberrant ways. 

Spontaneous ectopic germinal-center formation has long been recognized to occur in human autoimmune diseases and is a source of somatically mutated high-affinity autoandbodies. 

A 54-year-old man received interferon alfa-2a, 9 MU/ day, for chronic hepatitis C. He developed an asymptomatic right pleural effusion after 14 days. Although his serum titer of antinuclear antibodies was slightly increased, a more complete screening for autoimmune disease was negative. An infectious origin was also ruled out. The pleural effusion spontaneously disappeared after interferon alfa withdrawal and did not recur. 

The NOD mouse strain is an excellent model of autoimmune disease and an important tool for dissecting tolerance mechanisms. The peculiarity of this mouse strain is that it develops spontaneous autoimmune diabetes, which shares many similarities to autoimmune or type la diabetes (TID) in humans, including the presence of pancreatic islet-specific autoantibodies, and autoreactive CD4 and CD8 T cells. 

Similar to mercury and cadmium, lead has the potential to accelerate expression of autoimmune predisposition lead accelerated the death of male, but not female, NZB/NZW mice due to spontaneously developing autoantibodies and glomerulonephritis (Lawrence et al., 1987) and exacerbated the susceptibility of NZ mixed strains to develop lupus-type nephritis (Hudson et al., 2003). This potential contribution of lead to autoimmune disease remains a valid concern. 

Examples of spontaneous models of autoimmune disease are the BB rat (Mordes et al., 1987 Prins et al., 1991) and the NOD mouse (McDevitt et al., 1996), which develop autoimmune pancreatitis and subsequently diabetes, or the NZBxNZW/Fl or MRL/lpr mouse (Pollard et al., 1999 Shaheen et al., 1999), which spontaneously develop systemic lupus erythematosus-like disease. 

Antiphospholipid syndrome (APS). One of the most common autoimmune diseases, characterized by thrombosis, recurrent spontaneous abortions, and the presence of antiphospholipid antibodies. Antiphospholipd syndrome may occur as an isolated disease... 

CD4+CD25+ T cells. Subtype of regulatory CD4+ T cells with potential role in the regulation of the immune homeostasis. Seems to be important in preventing the development of autoimmune diseases (depletion leads to the spontaneous development of various autoimmune diseases in genetically susceptible animals transfer prevents the development of organ-specific autoimmunity). 

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