Absence of Mucosal Immunity in the Human Upper Respiratory Tract to the Commensal Bacteria Neisseria lactamica but Not Pathogenic Neisseria meningitidis during the Peak Age of Nasopharyngeal Carriage

Abstract

The normal flora that colonizes the mucosal epithelia has evolved diverse strategies to evade, modulate, or suppress the immune system and avoid clearance. Neisseria lactamica and Neisseria meningitidis are closely related obligate inhabitants of the human upper respiratory tract. N. lactamica is a commensal but N. meningitidis is an opportunistic pathogen that occasionally causes invasive disease such as meningitis and septicemia. We demonstrate that unlike N. meningitidis, N. lactamica does not prime the development of mucosal T or B cell memory during the peak period of colonization. This cannot be explained by the induction of peripheral tolerance or regulatory CD4+CD25+ T cell activity. Instead, N. lactamica mediates a B cell-dependent mitogenic proliferative response that is absent to N. meningitidis. This mitogenic response is associated with the production of T cell-independent polyclonal IgM that we propose functions by shielding colonizing N. lactamica from the adaptive immune system, maintaining immunological ignorance in the host. We conclude that, in contrast to N. meningitidis, N. lactamica maintains a commensal relationship with the host in the absence of an adaptive immune response. This may prolong the period of susceptibility to colonization by both pathogenic and nonpathogenic Neisseria species.

Neisseria lactamicaSelectively Induces Mitogenic Proliferation of the Naive B Cell Pool via Cell Surface Ig

“…Carriage of N. meningitidis is also associated with mucosal regulatory T cell activity, which may prevent immunopathology and promote continued carriage (8). Conversely, although carriage of N. lactamica has been associated with increased titers of antimeningococcal Ig in the periphery during the peak period of nasopharyngeal carriage (17), N. lactamica appears to evade the adaptive immune system in the URT mucosa, failing to prime the development of immunological memory (9). T cell responses only become detectable to N. lactamica Ags in older individuals, presumably as a result of cross-reactivity with N. meningitidis proteins or to other commensal Neisseria species to which they develop memory following carriage (9).…”

“…Conversely, although carriage of N. lactamica has been associated with increased titers of antimeningococcal Ig in the periphery during the peak period of nasopharyngeal carriage (17), N. lactamica appears to evade the adaptive immune system in the URT mucosa, failing to prime the development of immunological memory (9). T cell responses only become detectable to N. lactamica Ags in older individuals, presumably as a result of cross-reactivity with N. meningitidis proteins or to other commensal Neisseria species to which they develop memory following carriage (9). Although N. lactamica evades priming immunological memory, we have also shown that outer membrane vesicles (OMVs) prepared from this bacteria stimulate a potent proliferative response in tonsillar mononuclear cell (TMNC) cultures from young children and adults that is absent in response to N. meningitidis.…”

“…This proliferative response is dependent upon the presence of CD19 + B cells and is associated with the production of T cellindependent polyclonal IgM that resembles natural Ab. The production of natural Ab may be one mechanism by which N. lactamica maintains immunological ignorance in the host, shielding it from the adaptive immune system, promoting continued carriage (9). In addition, due to its polyclonal reactivity, this Ig may crossreact with colonizing N. meningitidis on the nasopharyngeal epithelium and thus offer some protection against invasive meningococcal disease.…”

“…Carriage studies have revealed that individual strains of N. meningitidis and N. lactamica can colonize the host for months at a time (14) without causing immunopathology. In previous investigations, we have demonstrated that N. meningitidis and N. lactamica interact with the mucosal immune system in very different ways (9,15). N. meningitidis primes an adaptive immune response rapidly upon the onset of carriage (16), generating both T cell (15) and B cell (9) memory in the local mucosa.…”

“…Commensal colonizers at other mucosal sites, such as the upper respiratory tract (URT), have also evolved mechanisms to circumvent clearance by the host immune system (8,9). The genus Neisseria is a group of Gram-negative, mostly diplococcus bacteria, the majority of which are obligate colonizers of the human URT (10).…”