Genetics, autoimmune diseases

Bogdanos DP, Smyk DS, Rigopoulou El, et al. Twin studies in autoimmune disease genetics, gender and environment. / Autoimmun. 2012 38(2-3) J156-J169. 

The development of autoimmune disease depends on a combination of genetic and environmental factors (Figure 24.1).3-5-28 Most autoimmune diseases are thought to be polygenic, involving more than one gene, and depend on the accretion of a number of genetic traits.5-10... 

FIGURE 24.1 The development of autoimmune disease depends on a combination of genetic and environmental factors. 

Rioux, J.D. and Abbus, A.K., Paths to understanding the genetic basis of autoimmune disease, Nature, 435, 584, 2005. 

Wanstrat, A. and Wakeland, E., The genetics of complex autoimmune diseases Non-MHC susceptibility genes, Nature Immunol., 2, 802, 2001. 

Cooper, G.S., Miller, F.W., and Pandey, J.P., The Role of Genetic Factors in Autoimmune Disease Implications for Environmental Research, Environ. Health Perspect., 107, 693, 1999. 

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]. 

The mechanisms of autoimmunity may also entail interaction with MHC structures determined by the HLA alleles. Individuals carrying certain HLA alleles have been shown to be predisposed to certain autoimmune diseases, which may account in part for the genetic variability of autoimmunity. In addition, metabolites of a particular drug may vary between individuals to confound the development of drug-induced autoimmunity. Dendritic cells, such as the Langerhans cells of the skin and B lymphocytes that function to present antigens to Th cells, express class-II... 

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. 

The etiologies of the autoimmune inflammatory diseases, OA, osteoporosis and crystal-deposition disease are still not known in exact details. This is in contrast with impressive molecular insights gained recently. However, there is consensus that manifestations of autoimmune diseases are precipitated by either acute and/or chronic interactions of genetic and environmental risk factors. 

Gibofsky, A., Khanna, A., Suh, E., and Zabriskie, J.B. (1991) The genetics of rheumatic fever relationship to streptococcal infection and autoimmune disease. / Rheumatol (Suppl 30) 18 1-5. 

In summary, genetically modified animals are instrumental in understanding complex in vivo interactions, in the normal and the pathological forms. This knowledge is indispensable for the identification of drug targets for the intervention with not yet understood processes as well as with diseases with undefined onset and slow progression, as for instance autoimmune diseases or Alzheimer s disease. 

A patient developed atorvastatin-induced severe autoimmune hepatitis and a lupus-like syndrome. Although the drug was immediately withdrawn, the disease persisted and deteriorated to a fulminant form with acute hepatic failure. There was no response to conventional immunosuppression with glucocorticoids and azathioprine. Only the introduction of intense immunosuppressive therapy, as used in solid organ transplantation, led to a complete and sustained recovery. The patient had the HLA haplotypcs DR3 and DR4, which are well-known genetic factors associated with autoimmune diseases. 

Inbred strains could be chosen on the basis of availability, knowledge of strain characteristics and absence of any biological properties which would preclude use of the strain, such as autoimmune disease or cancer. Strains which are genetically dissimilar could be chosen in order to maximise the chance of choosing at least one susceptible strain. For example inbred mouse strains have been classified into seven major families, based on the analysis... 

Petkova, S. B., Akilesh, S., Sproule, T. J., Christianson, G. J., A1 Khabbaz, H., Brown, A. C., et al. (2006) Enhanced half-life of genetically engineered human IgGl antibodies in a humanized FcRn mouse model potential application in Immorally mediated autoimmune disease. Int Immunol 18,1759-1769. 

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