Dependence of the adaptive immune response on innate immunity: Some questions answered but new paradoxes emerge

Abstract

Summary Recently a new model of vertebrate immunity has been gaining popularity. In this new model it is hypothesized that activation of innate immunity is a prerequisite for an adaptive immune response to an antigen. Following activation the innate system induces key costimulator molecules on APC, which are essential for antigen-driven clonal expansion of T and B cells. The model largely explains the need for adjuvants in the induction of adaptive immunity, provides a possible mechanism for the immune system to perceive the biological nature of a pathogen and thereby produce the most effective immune response, and transfers much of the onus of self-non-self discrimination from the adaptive to the innate immune system. In the present article we highlight two paradoxes raised by the new model. First, by linking adaptive immunity to innate recognition the immune system is unable to take full advantage of the genetic diversity of T and B cell antigen receptors. Thus, the abihty of the immune system to combat a pathogen is totally dependent on the efficiency of" recognition by the innate system and, therefore, the germ-line mutation rate of the genes involved in the innate response. Second, if signals from the innate system induce costimulatory molecules on APC, then one would expect the accidental clonal expansion of many autoreactive T and B cells. We suggest that one means of resolving the first paradox is to propose that the major reason for the evolution of adaptive immunity wa.s to provide, via immunological memory, resistance to reinfection, rather than simply to combat the primary infection by the pathogen. In the case of autoreactivity we suggest that autodestruction is prevented by immune responses being tightly regulated at the effector T cell level. Finally, we argue that the two paradoxes, rather than undermining the new model of immunity, highlight our lack of understanding of key element.s of the vertebrate immune system.

From Infection to Autoimmunity

“…NK cells also perform an important function in distinguishing between infectious non-self and non-infectious self early in innate immunity, which may significantly influence the later development of adaptive immunity [82]. Thus, the innate immune response appears not to be merely a vestige of an ancient antimicrobial system, but to critically influence the development of the acquired immune response [50,55] (Figure 5). …”

“…However, recent research indicates that innate immunity critically impacts the subsequent development of the adaptive immune response [51,[53][54][55]. How innate immunity controls the initiation of an adaptive immune response and the development of autoimmune disease is not well understood [50], and research in our laboratories is addressing this question. We will limit our discussion to three major agents of the innate immune response, complement, natural killer (NK) cells, and the early-acting, pro-inflammatory cytokines.…”

“…Other studies have shown that treatment of animals with CVF, which leads to complement depletion by activating the alternative pathway, suppresses antibody responses to both thymusdependent and thymus-independent antigens [86][87][88]. Many of the mediators associated with the innate immune response, particularly cytokines, can act in a long-range endocrine manner so that APC far removed from the site of infection can be activated to present either viral or auto-antigens to T and B cells [50,55,89]. Moreover, recent evidence suggests that a bidirectional relationship exists between innate and adaptive immunity [81,83,[90][91].…”

“…In the past, innate immunity has been considered only to provide rapid, but incomplete anti-microbial host defense until the slower, more definitive acquired immune response develops [50][51][52]. However, recent research indicates that innate immunity critically impacts the subsequent development of the adaptive immune response [51,[53][54][55].…”

Molecular mimicry may contribute to pathogenesis of ulcerative colitis

“…The antigen may be provided by a virus or a bacterium in molecular mimicry. Human populations that are exposed to high pathogen loads have a much lower incidence of autoimmunity than their Ôpathogen-freeÕ counterparts probably due to development of tolerance [25].…”