Dynamics and selection of many-strain pathogens. B cells encounter the exact same antigen in a subsequent infection C a major benefit of immunological memory (Ahmed and Gray 1996), provided the parasites are identical to those previously encountered. When subsequently infected with antigenically different parasites, however, those same antibodies can actually promote parasite replication. These apparent failures of specificity can have health consequences. A classic case is the enhancement of dengue virus replication by cross-reactive antibodies, alluded to above. Antigen-specific antibodies provide long-lasting protection against reinfection with the same serotype (Sabin 1952, cited by Goncalvez et al. 2007), but cross-reactive antibodies are associated with dengue hemorrhagic fever during subsequent infection with a different serotype, and the severity of disease varies with the combination and order of appearance of serotypes (Endy et al. 2004; Rothman 2004). Unable to neutralize the virus, the cross-reactive antibodies instead facilitate viral uptake to cells (Goncalvez et al. 2007). The antibodies are specific enough to bind but not to kill parasites. Costs of cross-reactive responses are also observed across parasite species. For instance, cross-reactive responses induced by influenza A exacerbate liver disease due to hepatitis C virus (Urbani et al. 2005). Balanced against these benefits of specificity and costs of cross-reactivity, it is apparent that cross-reactive immune responses can, in some contexts, simultaneously protect hosts against a wide array of parasites, a possibility that has not been lost on vaccinologists Caspase-3/7 Inhibitor I (Nagy et al. Caspase-3/7 Inhibitor I 2008). Indeed, cross-reactive antibodies induced by infection or immunization can protect hosts against other infections. For example, mice experimentally infected with a single malaria clone make cross-reactive antibodies that can bind to antigens of other parasite clones (displayed on the surface of infected red blood cells) and lead to their phagocytosis by macrophages (Mota et al. 2001). Similarly, cross-reactive antibodies from a person infected with can inhibit the growth of (Nagao et al. 2008). More importantly, cross-reactive antibodies benefit human hosts living in areas of multi-strain or multi-species malaria transmission in nature (Fesel et al. 2005; Haghdoost and Alexander 2007). Benefits of cross-reactive antibodies are also observed amongst flaviviruses: St. Louis encephalitis virus and Japanese encephalitis (JE) vaccine both induce cross-reactive antibodies to Caspase-3/7 Inhibitor I Caspase-3/7 Inhibitor I West Nile virus that ameliorate the disease in hamsters (Tesh et al. 2002). The induction of cross-reactive antibodies to West Nile by JE vaccine was corroborated in humans (Yamshchikov et al. 2005), though whether the antibodies are protective remains to be seen. In the case of influenza, cross-reactive responses induced by immunization with one virus can protect hosts against other viral genotypes (Sandbulte et al. 2007; Levie et al. 2008; Quan et al. 2008). Cross-reactive antibodies have also been implicated in protection against fungal infection (Casadevall and Caspase-3/7 Inhibitor I Pirofski 2007). Imprecision of antibody responses can therefore benefit the host in some contexts. Ideally, the degree of cross-reactivity would match the infections at hand (see Fig. 2; Scherer et al. 2004; van den Berg and Rand 2007). Variation in the activation thresholds of individual cells (van den Berg and Rand 2007) or tuning mechanisms such as the immunomodulatory molecules employed by regulatory T cells (Carneiro et al. 2005) should allow precise targeting when needed and cross-reactivity when needed. Recognizing need, however, would require lymphocytes to gather information on the relatedness of parasite antigens C e.g., during co-infections, or Rabbit Polyclonal to MAPKAPK2 (phospho-Thr334) comparing remembered to current antigens C to generate the optimal imprecision for a given context. The likelihood of such additional information processing ability is unclear, but even if the immune system could not manage by itself, biomedicine could potentially promote cross-reactive responses (i.e., help the immune system to see two parasites as related), if the context were right. Predicting when imprecisely targeted immune responses will occur, and when they will be to the detriment or benefit of hosts, is therefore of clear biomedical relevance, for vaccination programs and other medical interventions. Outlook Why, then, do adaptive immune responses cross-react? While we cannot give a definitive answer to this question, we suggest that the answer is likely to depend on context. In.