Are polysaccharide antibody responses independent: the T cell enigma?

Abstract

The molecular basis of immune responses to polysaccharide antigens is the least well understood of all antibody reactions, yet clinically, deficient responses have the most profound consequences for patients. Mice and men are competent to make antibodies to so called T cell-dependent (TD) protein and lipopolysaccharide (LPS)-based antigens more or less from birth, whereas the response to thymus-independent type 2 (TI-2) antigens such as pneumococcal and Haemophilus influenzae type B polysaccharides is delayed in humans until the second year of life. Consequently there is an increased risk from overwhelming sepsis with these bacteria during this period [1].A model encompassing the physiological and molecular interactions which generate TI-2 antibodies takes into account both the microenvironment and the accessory signals between lymphocytes and antigen-presenting cells, that are required to initiate and sustain these important responses. Most of what is known at present comes from the study of rodents, which we assume resemble humans in the basic mechanisms.Mice have a large pool of stable peripheral B cells with a lifespan of weeks to months, and a smaller pool with rapid turnover (days) [2]. Most of the latter come from the primary B cell pool in the bone marrow, which exports a large repertoire of short-lived antigen-naive B cells to the periphery. The responses of these B cells to protein TD and polysaccharide TI-2 antigens are different. Primary T cell-dependent antibody responses are initiated in the T zones of secondary lymphoid organs, where T cells primed by antigen presented on dendritic cells activate newly formed naive or peripheral antigen-specific B cells migrating through the T cell region [3]. Activated B cells differentiate either locally to antibody-producing cells (primary response) or migrate into B cell follicles where they proliferate and form germinal centres. 'Memory' B cells are exported from germinal centres to the recirculating pool, but also to non-recirculating B cell areas (the marginal zone of the spleen and the interfollicular areas of lymph nodes lining the lymphoid sinuses) [4,5]. Memory B cells reactivated by antigen migrate, proliferate, and differentiate in the outer T zone. The dominant feature of T cell-dependent responses to protein antigens is that individual B cells undergo clonal amplification with selection of high-affinity somatic mutants, many of which subsequently class switch.Antigen-specific B cells responding to TI-2 antigens also proliferate in the outer T zones and differentiate to antibodyproducing cells [6]. These antigens localize well on follicular dendritic cells in follicles, but unlike the case with protein antigens, in the absence of T cell help there is little evidence of B cell proliferation at this site. Mice which lack T cells can make TI-2 responses. However, some TI-2 antigens can elicit typical germinal centre reactions, and this may reflect the fact that some TI-2 antigens evoke T cell help [7]. Recently it has become clear that some T cells, par...

Understanding thymus‐independent antigen‐induced reduction of thymus‐dependent immune responses

“…Mice and humans are competent to make antibodies against TD antigens more or less from birth, whereas the response to TI-2 antigens such as pneumococcal and Haemophilus influenzae type B polysaccharides is delayed in humans until the second year of life. 28 This is also the case with the polysaccharide Dx B512. In mice, the response to Dx is only fully developed by 3 months of age, which is well into adulthood.…”

“…Though deficiencies in immune responses against polysaccharides can have important consequences for patients, the molecular basis for this type of immune reactions remains largely unknown. Mice and humans are competent to make antibodies against TD antigens more or less from birth, whereas the response to TI‐2 antigens such as pneumococcal and Haemophilus influenzae type B polysaccharides is delayed in humans until the second year of life 28 . This is also the case with the polysaccharide Dx B512.…”