T activation

T activation is the earliest known and the most common form of polyagglutination, a group of conditions characterized by alterations in red blood cell (RBC) membrane glycoprotein structure in certain pathological states, resulting in the agglutination of such transformed cells in the presence of most ABO compatible adult sera. In vitro polyagglutination was first described by HuÈ bener (1925) and then by Thomsen (1927), but it was Thomsen's graduate student, Friedenreich (1930), who elucidated the underlying mechanism and named it T haemagglutination, after his mentor. The alteration of red-cell membrane structure is simply the removal of N-acetyl neuraminic acid residues from the normally disialylated tetrasaccharides of the MN, Ss and other RBC membrane sialoglycoproteins by the enzymatic action of bacterial neuraminidase. Cleavage of the neuraminic acid residues exposes the hidden beta-linked galactosyl residue (Gal-b(1±3)-GalNAc), the T cryptantigen (Fig 1). The unmasked T antigen binds with the anti-T IgM antibodies that are normally present in human adult plasma, resulting in agglutination in vitro and possible haemolysis in vivo. The phenomenon is usually transient, often lasting only a few days or weeks, rarely persisting for months (Obeid et al, 1977). Other variants of T activation secondary to bacterial enzyme action on red-cell antigens are less common. Th transformation is considered to be an incomplete or intermediate form of T activation, as further action by stronger neuraminidases results in the classic T activation. Tk polyagglutination is as a result of microbial bgalactosidases that cleave a galactose residue from paragloboside, exposing N-acetylglucosamine, the Tk receptor. Transient Tx activation has been described in children with pneumococcal infection and also in a child with acute haemolytic anaemia, but no identifiable infection, but the molecular mechanism of this condition has not been clarified (Wolach et al, 1987). Tn activation is different from other forms of T activation in that it is persistent and is not associated with microbial enzyme action, but is the result of mutation in a clone of red cells, with the abnormal cells containing a cryptantigen with only one acetylated galactose residue without the beta-linkage, secondary to the absence of the enzyme 3-bgalactosyltransferase (Cartron et al, 1978). Tn polyagglutination has been associated with myelodysplastic syndromes and acute leukaemia in adults (Ness et al, 1979). In newborn infants, however, transient Tn polyagglutination has been described, often associated with an antenatal flu± like illness in the mother, and is probably as a result of delayed maturation or temporary deficiency of b-3-galactosyltransferase in the fetus (Rose et al, 1983). Variants of T activation and polyagglutination because of congenital or acquired alterations in non-T RBC surface antigens (Cad, VA, acquired B, haemoglobin M-Hyde Park, etc.) are not discussed further in this review (Horn, 1999). In clinical practice, T-antigen exposure is most often associated with neuraminidase-producing organisms, particularly with Clostridium perfringens and Streptococcus pneumoniae. Other organisms implicated include Bacteroides, Escherichia coli and other gram-negative bacilli, such as Actinomyces and influenza virus. Vibrio Cholerae produces neuraminidase and T activation in vitro; in vivo T activation secondary to this organism has not been reported in the English literature. The degree of T activation of red cells may be influenced by the amount of neuraminidase in the circulation and is probably mitigated in part by serum neuraminidase inhibitors. T-transformed red cells may be destroyed quickly by immune-mediated intravascular haemolysis, secondary to complement-fixing anti-T IgM antibodies. In addition, the T-activated red cells may be cleared more rapidly from the circulation because of a paucity of membrane sialic acid residues (Durocher et al, 1975). Anti-T IgM antibodies are absent at birth and in early infancy, but are present in most adults. The formation of these antibodies has been attributed to antigenic stimulation by intestinal flora that possess antigens similar to T antigens, analogous to the development of ABO antibodies secondary to environmental antigenic stimuli (Springer & Tegtmeyer, 1981). Contrary to earlier haemagglutination methods that failed to detect any anti-T activity in umbilical cord sera, sensitive radioimmunoassay techniques have been able to demonstrate the presence of small quantities of anti-T antibodies of the non-agglutinating IgG class in cord sera, probably of maternal origin (Kim, 1980). The ubiquitous nature of anti-T antibodies in adults would suggest that exposure of the T antigen would result in autoagglutination and haemolysis, but this has been rarely demonstrated (Moores et al, 1975), and indeed, most reports on T activation do not indicate whether anti-T antibody is present in the patient's serum during the acute disease. The absence of anti-T in the plasma of adults with T-activated red cells has been variously attributed to adsorption of antibody to the red cells or to immune tolerance or immune paralysis (Issit, 1985). There are isolated case reports of