Some HA stem antibodies can be polyreactive [38], and it is possible that selection against B-cells specific for HA stem epitopes contributes to HA stem antibody immunosubdominance. head domain name can safeguard animals and humans from influenza computer virus infections [20]. The majority of these antibodies neutralize by blocking viral attachment to host cells, although other neutralization mechanisms might be in play MG-262 for some of these antibodies [1, 21]. Contamination and vaccination typically elicit strain-specific HA-head antibodies that are often long-lived [22], but MG-262 these antibodies can become ineffective when viruses acquire antigenic changes in the HA head. Such an example occurred during the 2014C2015 season when a new antigenically drifted H3N2 strain possessing a novel glycosylation site around the HA head caused dramatically reduced vaccine effectiveness [23, 24]. Although most antibodies against the HA head are directed against epitopes adjacent to the conserved HA RBS [25, 26], some antibodies are able to partially mimic the sialic acid receptor and bind to conserved residues within the HA RBS [13, 15, 16, 27, 28]. Hemagglutinin stem antibody responses constitute a small fraction of total MG-262 anti-influenza computer virus antibodies in most humans [29]. In contrast to most epitopes around the HA head, the HA stem is usually less tolerant of change [30C33] and is MG-262 much more highly conserved across subtypes. Although some anti-HA stem monoclonal antibodies can directly neutralize viruses through inhibiting HA proteolytic processing, pH-induced conformational changes, and viral egress [1, 21], many HA stem antibodies require Fc-mediated effector functions for in vivo protection [34]. HEMAGGLUTININ IMMUNODOMINANCE OF PRIMARY ANTIBODY RESPONSES Antibodies against highly exposed epitopes around the HA head usually dominate the primary responses against influenza viruses (Physique 1A). Primary H3N2 infections in ferrets elicit high levels of antibodies that are directed towards HA antigenic sites A and B [35, 36], which are located in close proximity to the HA RBS [25]. Likewise, H1N1-infected young children tend to mount antibody responses to epitopes in antigenic sites near the HA RBS [37]. Although steric hindrance or inaccessibility has been suggested to contribute to the immunosubdominance of HA stem antibodies [38], recombinant HA vaccines also fail to elicit high-titer HA stem responses [39]. In fact, cryoelectron tomography has shown that the majority of the HA on influenza virions are indeed available to bind to stem antibodies [40]. Some HA stem antibodies can be polyreactive [38], and it is possible that selection against B-cells specific for HA stem epitopes contributes to HA stem antibody immunosubdominance. Recent data suggest that the fine specificity of influenza computer virus antibody responses in mice changes over time [41]. Angeletti et al [41] found that (1) antibodies against epitopes near the top of the HA head dominate the early response and (2) antibodies against other epitopes increase later in the response. Given that most studies have only examined a limited range of timepoints, it is likely that shifts in antibody immunodominance dynamics have yet MG-262 to be fully explored. Open in a separate window Physique 1. Immunodominance of primary responses and recall responses against influenza hemagglutinin (HA). (A) The HA head domain (pink) is usually immunodominant in primary responses, whereas antibodies against the stem domain name (blue) are rare. (BCC) Antibodies against the HA head remain dominant after exposure to antigenically comparable (B) and antigenically drifted (C) seasonal viral strains. Antibodies elicited by antigenically drifted seasonal influenza computer virus strains often have high levels of somatic hypermutations that allow recognition of altered epitopes. (DCE) Antibodies against new pandemic viral strains tend to be more dominant initially against the (D) conserved HA stem, and (E) rare conserved epitopes, if any, in the HA head. Memory B cells producing antibodies against these conserved epitopes are preferentially boosted upon exposure to new pandemic viral strains. The color similarity of CCL2 the HA head domain name represents the similarity of the antigenicity in all physique panels. Almost all immunological studies of influenza computer virus have been carried out in organisms that make immunoglobulin (Ig)-based humoral responses. To test whether some features of immunodominance are antigen-intrinsic, Altman et al [42] studied immune responses in lampreys that were immunized with influenza computer virus. Lampreys, a jawless fish, lack Ig genes but encode variable lymphocyte receptors (VLRs), which are an entirely different system of humoral adaptive immunity based on Leu-rich repeats rather than Ig domains. Remarkably, lamprey VLR responses were found to be focused on the same HA epitopes as those that have been observed in mice [42]. The similarity of antibody and VLR responses against HA.