Rheumatic fever

It has been known since the 1920s that there is a genetic element in the incidence of rheumatic fever, in that the disease is more prevalent in individuals having blood groups A and B than in those with blood group O, and Glynn has pointed out that this observation has been made in many different countries.

Rheumatic fever is a disease where the etiological mechanism has been worked out. Streptococcus pyogenes microorganisms infect the upper respiratory tract and, 2-3 weeks later, a generalized serum sickness-like disease develops, with fever, arthritis, sometimes chorea and carditis. Kaplan and Meyeser-ian demonstrated in 1962 that the damage is caused by crossreactive antibodies, which attack the cardiac valves, because self antigens in cardiac tissues resemble the antigens found in S. pyogenes. So here is an example of an autoimmune disease that has been triggered by an infection, because there is molecular mimicry between the human host and the bacterial infectious agent.

All blood groups have a common precursor, the H gene, which gives rise to the H substance, individuals with blood group O express in their red cell membrane the H substance, which has a terminal carbohydrate residue (L)-fucose. Watkins, in 1966, showed that individuals with blood group A have another gene, whose gene product is a glycosyl-transferase, which adds N-acety1-(D)-galactosamine to the preterminal galactose of the H substance. Thus individuals with blood group A have two terminal residues, N-acetyl-(D)-galactosamine and (L)-fucose. Blood group B individuals have a gene which adds (D)-galactose to the preterminal galactose of H substance, giving rise to two terminal residues, (D)-gal-actose and (L)-fucose. In examining the Haworth formulae of these sugars, the substitutions at every carbon atom are different between (L)-fucose and N-acetyl-(D)-glactosamine, except for the connecting first carbon atom. Heymann and colleagues showed in 1964 that the terminal sugar residue in streptococci is N-acetyl-(D)-glucosamine, which is attached to the backbone of a rhamnose polymer. The only difference between N-acetyl-(D)-glucosamine and N-acetyl-(D)-galactosamine is the hydroxyl group, which is in a different orientation on the C-4 atom of galactose. Thus, other things being equal, blood group A resembles the streptococcal antigen more than blood group O. Similarly with blood group B, where (D)-glactose is structurally closer to N-acetyl-(D)-glucosamine of S. pyogenes than (L)-fucose of blood group O. Therefore any antibodies produced in blood group A individuals, following infection with S. pyogenes, will bind to tissue antigens containing blood group A substance and cause reactive inflammation.

Goldstein and coworkers showed in 1969 that cardiac tissue contains molecular groups similar to blood group A substance. Thus antistreptococcal antibodies should bind to such crossreacting antigens, explaining the higher frequency of rheumatic fever in individuals possessing such blood groups. It would appear that molecular mimicry provides an explanation for the higher frequency of rheumatic fever in individuals with blood groups A and B compared with individuals with blood group O. Zabris-kic and colleagues have extended this concept and showed that the chorea of rheumatic fever can also be explained by a molecular mimicry model between streptococcal antigens and basal ganglia.

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