Regeneration of Natural Antibody Repertoire After Massive Ablation of Lymphoid System: Robust Selection Mechanisms Preserve Antigen Binding Specificities

Abstract

Natural Abs (NAbs) are Igs present in the serum and body fluids of healthy vertebrate animals, without any previous intentional immunization. NAbs often exhibit autoreactivity but also play an essential role in immunity, being a first line of defense against infectious microorganisms. We have previously analyzed the natural serum IgM Ab repertoire of normal mice, characterizing their reactivity with hundreds/thousands of self Ags; a significant similarity among different individuals was observed, and it was found that many reactivities of NAbs stably kept during adulthood were established early in life, implicating that period as a critical time window in the physiology of NAb repertoire selection. In the work reported here, experiments were conducted to address the role of normal lymphocyte ontogeny to the formation and stability of adult NAb repertoire. The massive destruction of the lymphoid system was promoted in adult mice with gamma-irradiation, and regeneration of hemopoietic tissues was granted by bone marrow or fetal liver inoculum. NAb repertoire regeneration was followed for 60 days after gamma-irradiation in bone marrow or fetal liver chimeric animals. The analysis of serum IgM reactivity with hundreds/thousands of self Ags showed that the NAb repertoire regenerated most of its original format after massive destruction of lymphoid compartments, characterizing autoreactive repertoire selection as a robust biological process. The data also show that regeneration of the NAb repertoire occurred similarly in fetal liver and bone marrow chimeras, although the latter animals poorly reconstituted their CD5+ B1 cell compartment, suggesting that B1 cells are not essential for natural Ab regeneration.

B Cells Expressing a Natural Polyreactive Autoantibody Have a Distinct Phenotype and Are Overrepresented in Immunoglobulin Heavy Chain Transgenic Mice

“…There are reports indicating that NAA can be produced by MZ or B2 cells in mice (24,73). Bone marrow reconstitution studies have shown that B1 cells are not essential for NAA regeneration (74). These studies indicate that B cells other than B1 can contribute to the production of NAAs.…”

Evolution and conservation of immunological activity

“…Nevertheless, a significant number of observations on the production of natural plasma immunoglobulins, i.e., those appearing in healthy organisms without artificial immunization, has shown that, early in ontogeny, their reactivity is spontaneously organized in patterns (15) that are influenced by genes important for immunological activity (16) but, surprisingly, not by contact with environmental antigens, such as those derived from food and flora (17), and are robustly conserved throughout healthy living (18). In other words, these observations point to mechanisms of organization in the immune system which are immanent to its operation.…”

Visita à imunologia

“…Thus, although not having a topology, a reasonably permanent map of intercellular connections such as that presented by neurons in the nervous system, the lymphocytes also organize as a web, or a network of invariant organization 25 . This robust characteristic of the lymphocyte web of interactions may be accessed with measures of "global" reactivity of circulating immunoglobulins, mainly IgM, obtained using modified immunoblot techniques 25 .…”

“…This robust characteristic of the lymphocyte web of interactions may be accessed with measures of "global" reactivity of circulating immunoglobulins, mainly IgM, obtained using modified immunoblot techniques 25 .…”

“…The remaining activity is considered subsidiary or regulatory. Other immunologists argue that immune specificity is degenerate, loose, ample 9 ; that the same immune activity patterns occur in animals deprived of antigenic exposure 23 and regenerate when the system is destroyed, for instance, by lethal radiation 25 ; that there are many lymphocytes that react with other lymphocytes and with organism components 11 , and finally, that there is a steadiness in the immune activity that would not exist if the immune system activity were stimulated by antigenic contacts.…”