Perpetuation of immunological memory: a relay hypothesis

Abstract

SUMMARYA mechanism is proposed which explains the perpetuation of B-cell immunological memory inde®nitely without requiring the presence of long-living memory cells or persisting antigen. The salient feature of this model is that immunological memory can be perpetuated inde®nitely through the mutual interaction of idiotypic and anti-idiotypic B cells. These cells mutually stimulate and clonally expand with either speci®c or bystander T-cell help. Because B cells can present antigen, they present`apparently foreign' idiopeptides to T cells. The idiopeptides of de novo synthesized antibody is presented to CD8 + T cells that recognize the idiopeptide-presenting cell as targets and regulate their population. The recycling of immunoglobulins from surface to endosomal compartment of B cells leads to the presentation of idiopeptides by major histocompatibility complex (MHC) class II to CD4 + T cells. Even if the majority of the clonally expanded cells die because of lack of stimulation, cytotoxic T lymphocyte (CTL) lysis or for other reasons, the surviving cells will be able to carry forward the memory. This mechanism also provides a means for af®nity maturation through idiotypic selection of somatically mutated high af®nity cells or those from the nai È ve pool. We have termed these two types of complementary B cells as Burnet B cells: those which recognize the antigen or antigen mimic, and Jerne B cells, which can recognize the idiotypes of antibody and carry antigen mimics. The proposed hypothesis can explain differential duration of memory for different antigens, the shelf space paradox, af®nity maturation, repertoire shift, etc.

An Ag-Dependent Approach Based on Adaptive Mechanisms for Investigating the Regulation of the Memory B Cell Reservoir

“…9 and 10 suggest that the homeostatic turnover of a memory B cell depends on the antigen type and also on their mutation(s). Thus, our model aligns best with the earlier work of Nayak et al(2001) and Matzinger et al (1995), and it also aligns to some extent with the work of Tarlinton et al, specifically with respect to storage capacity (homeostatic turnover). However, our results do not line up with a hypothesis of randomness (stochastically) for the kinetics of immune memory, as inferred by Choo et al…”

“…8 indicate, in part, an alignment with the work of Choo et al(2010) and with that of Tarlinton et al, because some populations were "forgotten" so that others could be "memorized", thereby complying with the principle of homeostatic turnover. However, Tarlinton et al(2008) [49] and Choo et al (2010) [57] suggest that the mechanism for achieving homeostasis is stochastic, contrary to earlier work of Matzinger (1995) [50] and Nayak et al (2001) [19], who indicated that the durability of memory depends on the antigen type.…”

“…The epitopes [1,8,[17][18][19], which are portions of an antigen that can be connected by the B cell receptor (BCR), are also represented by bit-strings. The antibodies have receptors (paratopes) [1,8,[17][18][19] that are represented by the same bit-string models as the BCR B cell that produced them. Thus, the new dynamic equations that describe the behavior of the adaptive immune system, taking into account the inclusion of antibody populations, are the following:…”

“…Twenty years ago, Farmer, Packard, and Perelson presented an elegant dynamical model [1] to study Idiotype Network theory [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19], in which they showed that every molecular and cellular binding site (cell receptor) can be modeled by binary bit-strings of length ℓ. In such a model, an antibody molecule can always recognize an antigen when there is complementarity between their bit-strings.…”

The lack of anti-idiotypic antibodies, not the presence of the corresponding autoantibodies to glutamate decarboxylase, defines type 1 diabetes

“…We speculate that an antigen-independent memory could be generated by the interaction of GAD65Ab-specific B cells with complementary B cells that produce anti-Id (for review see ref. 44). Moreover, the anti-Ids explain previous evidence of a serum factor preventing the binding of autoantibodies to GAD65 observed by Brown and Christie (45).…”