«MtNr 
DEPARTMENT OF HEALTH. EDUCATION, AND WELFARE 
PUBLIC HEALTH SERVICE 
NATIONAL INSTITUTES OF HEALTH 
BETHESDA. MARYLAND 20014 
May 18, 1979 
Dr. Wallace Rowe 
Chief, Laboratory of Viral Diseases 
Building 5, Room 137 
National Institute of Allergy and 
Infectious Diseases 
Bethesda, Maryland 20205 
Dear Wally: 
The proposal that insertion into derivatives of E. coli K12 of 
genetic material coding for eukaryotic proteins potentially cross- 
reactive with a human protein might lead to the production of autoanti- 
bodies in a colonized individual and to subsequent immunopathology 
clearly requires careful consideration. It is well established in 
experimental animals that immunization with denatured, cross-reactive, 
or even native antigens can cause the production of autoantibodies 
and, in some cases, an immunopathologic state. Instances which are 
particularly well studied include responsiveness to thyroglobulin (1) , 
myelin basic protein (2,3) and the acetylcholine receptor (4). It is 
well established that humans treated with bovine or porcine insulin 
will often develop antibodies which bind to human insulin (5) . This 
may occur in individuals who were not hypoinsulinemic prior to 
treatment (6) . 
Furthermore, the association of a protein cross-reactive with a human 
protein with a gram negative bacterium might very well enhance the 
immunogenicity of that protein. Such organisms possess at least two 
classes of molecules which are potent polyclonal activators of B lympho- 
cytes (7,8), one of which (lipopolysaccharide) has well established 
adjuvant properties (9) . It is well known that conjugation of small 
molecules such as nitrophenyl groups (10) or relatively low molecular 
weight polysaccharides (11) to killed Brucella abortus organisms can 
create immunogens which cause powerful responses directed at the 
conjugated group. Furthermore, treatment with lipopolysaccharide 
alone, iji vitro, will often cause the production of antibodies directed 
at autologous antigens (11). These considerations make it clear that, 
theoretically at least, bacteria which express altered human proteins 
or proteins cross-reactive with those of humans could induce auto- 
antibody production if they gained access to the immune system under 
appropriate conditions. 
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