B cell repertoire development in normal physiology and autoimmune disease
1993 (English)Doctoral thesis, comprehensive summary (Other academic)
The B cell repertoire in the neonatal immune system (IS) is characterised by reactivity towards self-components, including other immunoglobulin (Ig) V-regions. These properties have been suggested to be a requirement for the development of a normal immune system. DNA sequencing of two interacting Ig idiotypes, derived from neonatal, preimmune mice, demonstrated that such idiotypic connectivity is germ- line encoded and devoid of VDJ junctional diversity. The serum levels of the same Ig idiotypes were studied in normal mice and demonstrated that the expression in serum fluctuated over time in a pattern compatible with a complex dynamic system. In contrast, similar analyses in autoimmune mice or humans demonstrated fluctuations in Ig titers that differed significantly from the healthy individuals. These findings suggested that pathological autoimmunity may be associated with fundamental alterations in the dynamics of natural antibody (ab) expression. This was further investigated in the nonobese diabetic (NOD) mouse, an animal model for human Type I diabetes. Suppression of the early B cell development in the NOD mouse prevented the development of diabetes, suggesting a role for B cells/Igs in the development of diabetes in these mice. Furthermore, neonatal injections of polyclonal Ig preparations or single, monoclonal natural abs inhibited disease induction. The prevention of diabetes development by one such natural ab was demonstrated to be dependent on both the dose injected and the timing of administration. Studies of the B cell repertoire development in NOD mice, compared to normal mice, by DNA-sequence analyses of IgVH rearrangements utilising genes from the most D-proximal Vh family, Vh7183, supported the idea of an aberrant B cell repertoire in this mouse model. Thus, the adult NOD mouse retained a neonatal pattern of Vh7183 rearrangements. This pattern could, however, be "normalised" by neonatal injection of a natural antibody, previously demonstrated to prevent the development of T cell dependent autoimmunity in the NOD mouse.
Place, publisher, year, edition, pages
Umeå: Umeå universitet , 1993. , 72 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 376
B cell repertoire, connectivity, natural antibodies, non-obese diabetic (NOD), Ig therapy, Vh7183 gene family
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:umu:diva-101767ISBN: 91-7174-798-2OAI: oai:DiVA.org:umu-101767DiVA: diva2:802109
1993-06-04, Föreläsningssalen, Institutionen för Mikrobiologi, Umeå Universitet, Umeå, 09:30
Diss. (sammanfattning) Umeå : Umeå universitet, 1993, härtill 6 uppsatser2015-04-202015-04-102015-04-20Bibliographically approved