Systemic autoimmunity

Immunosuppressive agents are indicated for the therapy of systemic autoimmune diseases (e.g., systemic lupus... 

Kouskoff V, Korganow AS, Duchatelle V, Degott C, Benoist C, Mathis D. Organ-specific disease provoked by systemic autoimmunity. Cell 1996 87(5) 811—822. 

It has been well documented that the anaemia of chronic disease, ACD, results in a lowering of various haematological parameters. Several mediators are involved, among them histamine, serotonin, bradykinin, prostaglandins and, as found more recently, cytokines and nitric oxide. ACD is a parameter of systemic autoimmune disorders. The severe inflammatory stimuli lead to several systemic changes, mediated by inflammation-associated cytokines, e.g. IL-6, IL-1 TNFa, TGF beta that regulate hepatic synthesis of the acute phase proteins. 

Pollard, K.M. et al., Costimulation requirements of induced murine systemic autoimmune disease, J. Immunol., 173, 5880, 2004. 

Occupational exposure to silica dust has been identified as a risk factor for several systemic autoimmune diseases. This literature dates back almost 100 years, to the description by Bramwell of diffuse scleroderma in stone masons.26 Rheumatoid arthritis and scleroderma in miners were described in the 1950s, and more formal cohort studies of miners and of granite workers were conducted in the 1980s. Other studies focusing on silicosis patients, and several case-control studies of these diseases and of Wegner... 

Kubicka-Muranyi, M. et al., Murine systemic autoimmune disease induced by mercuric chloride T helper cells reacting to self proteins. Int. Arch. Allergy Immunol., 109, 11, 1996. 

Pollard, K.M., Pearson, D.L., Flultman, P., Flildebrandt, B. and Kono, D.Fl. (1999) Lupus-prone mice as models to study xenobiotic-induced acceleration of systemic autoimmunity. Environmental Health Perspectives, 107, 729-735. 

Klinman, D. M., and Steinberg, A. D., Systemic autoimmune disease arises from polyclonal B cell activation. J. Exp. Med. 165,1755-1760 (1987). 

A low titer of circulating IgG anti-insulin antibodies that neutralize the action of insulin to a negligible extent develops in most insulin-treated patients. Rarely, the titer of insulin antibodies leads to insulin resistance and may be associated with other systemic autoimmune processes such as lupus erythematosus. 

SLE is a systemic autoimmune disorder characterized by the activation of T and polyclonal B lymphocytes, production of autoantibodies, and formation of immune complexes causing tissue and organ damage (A9). Abnormal Th cytokines are involved in the pathogenesis of autoimmune diseases (H15). Recent reports indicated that peripheral blood mononuclear cells of SLE patients show decreased in vitro production of Thl cytokines IL-2, IFN-y (F8), TNF-a (H14), and IL-12 (H13, L14, L15) with upregulation of Th2 cytokine IL-4 (F8) and IL-10 (L14). Such an imbalance of Th cytokines may account for the polyclonal B cell activation observed in SLE. An earlier report suggested that there was no relationship between in vitro production of Thl and Th2 cytokines and disease activity (B4), whereas other studies demonstrated that serum concentrations of Thl cytokines IL-12 (T6), TNF-a (D4), and IFN-y (A6) are significantly elevated in SLE patients. 

SLE is the prototype systemic autoimmune disease, with a hallmark of autoantibody production. The mechanism leading to loss of self-tolerance and production of autoantibodies is discussed in Section 2. 

Pao, L. I., K. P. Lam, J. M. Henderson, J. L. Kutok, M. Alimzhanov, L. Nitschke, M. L. Thomas, B. G. Neel, and K. Rajewsky. 2007. B cell-specific deletion of protein-tyrosine phosphatase shpl promotes B-la cell development and causes systemic autoimmunity. Immunity 27 35-48. 

Autoimmune diseases have been reported to be more frequent in human subjects treated with several recombinant cytokines [38], For instance, increased titers or the new occurrence of autoantibodies have been observed in hepatitis C patients treated with the recombinant interferons-alpha (IFNa). Quite a few clinical case reports describe the development of organ-specific as well as systemic autoimmune diseases including systemic lupus erythematosus, insulin-dependent type I diabetes mellitus, autoimmune thrombocytopenia, autoimmune hemolytic anemia, myasthenia gravis, and autoimmune thyroiditis in patients under IFNa therapy. Although the mechanism involved is not fully elucidated, the available data support the pathogenic potential of IFNa in autoimmunity [31]. In contrast, autoimmune effects associated with IFNp therapy are thought to be of lesser concern based on the current clinical evidence [38], Thyroid autoimmunity in contrast to other autoimmune diseases is frequent in patients treated with recombinant interleukin-2 (rIL-2). Thus, among 281 previously euthyroid cancer patients treated with rIL-2, up to 41%... 

Figure 15.5 Examples of organ-specific and systemic autoimmune disease.

---