Autoimmune disease systemic sclerosis

Myositis, autoimmune. Rare systemic inflammatory myopathies, including primary polymyositis, primary dermatomyositis, myositis associated with malignancy, childhood dermatomyositis, and myositis with multisystem autoimmune disease (e.g. mixed connective tissue disease, systemic sclerosis). Autoantibodies against aminoacyl-tRNA synthetases (e.g. anti-Jo-1), signal recognition particle (e.g. anti-SRP54), nuclear helicase (anti-Mi-2), tRNA and tRNA-protein complexes (e.g. anti-Mas), and translation factor (anti-KJ) have been described as myositis specific. 

A recent report by the National Institutes of Health estimated that at 14 to 22 million people in the United States are affected by an autoimmune disease.1 As a group, these diseases represent a leading cause of death among women under age 65, with systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes being the major sources of this impact on mortality.2 The autoimmune thyroid diseases, type 1 diabetes and rheumatoid arthritis are the most common of the autoimmune diseases (Table 25.1).3-5 Most autoimmune diseases disproportionately affect women. In the thyroid diseases, primary biliary cirrhosis, scleroderma, systemic lupus erythematosus, and Sjogren s syndrome, more than 85% of patients are female, but it is not known why the female predominance is so high in these specific diseases. 

For some autoimmune diseases, little is known about environmental factors involved in the initiation or progression of the disease. For other diseases, however, considerable research has been conducted on one or more types of exposures. Most epidemiologic studies of environmental influences have focused on multiple sclerosis, rheumatoid arthritis, scleroderma, systemic lupus erythematosus, and small vessel vasculitis, but experimental studies using murine models of these diseases is limited (Table 25.1). 

Strong mechanistic evidence from rodent models of autoimmune disease of viral or other infectious agents affecting autoimmunity or progression to overt disease, but harder to demonstrate in humans. Enterovirus (Coxsackie virus) focus of epidemiologic studies in type 1 diabetes, Epstein-Barr virus focus of epidemiologic studies in multiple sclerosis and systemic lupus erythematosus. 

Similarly, under certain disease conditions, altered NA innervation and/or AR signaling capacity impairs sympathetic communication with cells of the immune system, influencing disease progression. Altered catecholamine communication with the immune system is evident in autoimmune diseases such as arthritis and multiple sclerosis [5-7] and in infectious diseases, such as leprosy and a mouse model of acquired immunodeficiency syndrome [15, 43, 44], The impact of altered NA innervation of... 

Autoimmune disease—One of a number of illnesses caused by the immune system targeting the patient s own tissues for destruction, such as rheumatoid arthritis or multiple sclerosis. 

Interferons—Family of immune system signal proteins that interfere with the ability of viruses to infect cells. Interferons have been genetically engineered to provide treatments by weakening immune response in autoimmune disease such as multiple sclerosis, or by strengthening immune response in diseases like hepatitis C. 

Slow viruses are becoming increasingly suspect in the instances of much more common diseases, particularly the autoimmune diseases. An autoimmune disease may be defined as a disease wheiein the immune system of the body does not direct its attack on an invading foreign substance, but instead at the body s own tissue. Many authorities consider rheumatoid arthritis and multiple sclerosis as autoimmune diseases. The precise causes of these diseases have remained obscure. Multiple sclerosis is a demyelinating disease and has variously been described as an autoimmune disease, a viral disease, or an autoimmune disease provoked by a virus. Epidemiological studies indicate that from 3 to 23 years may elapse between the time of exposure to the virus and the onset of symptoms. Further evidence points to involvement of a myxovirus. Measles virus is of this kind. 

Clinical Use. Cyclophosphamide (Cytoxan, Neosar) is an anticancer alkylating agent that is commonly used in a variety of neoplastic disorders (see Chapter 36). This drug may also be helpful in suppressing the immune response in certain autoimmune diseases, such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis.12 43 High doses of cyclophosphamide are also used to prevent tissue rejection in patients receiving bone marrow transplants and other organ transplants. 

Cytokines are a potential way to modify the immune system in several situations because of their ability to act as immunoregulatory chemicals. For example, cytokines such as interferon-alpha and interleukin-2 can be administered to treat certain forms of cancer (see Chapter 36). Likewise, certain interferons can help control viral infections, and interferon-beta may be helpful in autoimmune diseases such as multiple sclerosis (see Chapter 34). Researchers continue to investigate how immune function can be manipulated to treat various diseases, and additional immune system modulators will almost certainly be forthcoming. 

Linomide (A/-phenylmethyl-l,2-dihydro-4-hydroxyl-l-methyl-2-oxo-qui-noline-3-carboxamide, structure given in Table 1) has been proven to be an immunomodulator [32], In clinical trials, it has been shown to be a potential treatment for autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosis and multiple sclerosis [37-39]. It has also been reported to possess antiangiogenic activity [33,40]. 

There is indirect evidence of sex differences in immunology. Women have a higher incidence of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. The influence of sex hormones on the immune system may provide insight into these immunological disorders. For example, estrogen stimulates both humoral and cell-mediated immunity, whereas testosterone has the opposite effect (126). Therefore, it is not surprising that there is sex-dependent variability in response to immunosuppressive agents. 

There are reports of correlations of defective or deficient NKT cells in a number of autoimmune diseases in mice and humans (Sumida et al., 1995 Baxter et al., 1997, Wilson et al., 1998 Hies et al., 2000 Mieza et al., 1996 Zeng et al., 2000 Shi et al., 2001 Nagane et al., 2001). In humans, diabetes, systemic sclerosis, myasthenia gravis, and multiple sclerosis and in mice, a lupus model, are associated with NKT cell deficiencies. It was demonstrated that the adoptive transfer of NKT cells prevented diabetes in NOD mice. However, it is not clear whether the effectiveness of this treatment was actually due to the establishment of immune deviation of Tr cell-mediated aedve tolerance. 

In contrast to T cells, in different immunopathologies, the brain provides a fostering envkonment to B cells. Primary central nervous system (CNS) lymphomas are usually of B cell origin. The cerebrospinal fluid (CSF) of patients with chronic infections and autoimmune diseases of the CNS typically contains remarkably stable oligoclonal Ig bands. In the CNS of multiple sclerosis patients, clonally expanded B cells and plasma cells persist. Ectopic B cell follicles develop in the meninges of patients with secondary progressive MS, and B cell differentiation may be recapitulated in the CNS of MS patients (Krumbholz et al., 2006) (see Chapters 18-24). 

Although CSA has been used for treatment of other autoimmune diseases such as atopic dermatitis, myasthenia gravis, systemic sclerosis and primary biliary cirrhosis, data about chronic structural injury in these situations are scarce. There are occasional reports of end stage renal failure or development of interstitial fibrosis in kidney biopsies in demyelinat-... 

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