Pattern recognition molecules and innate immunity to parasites

Recent pioneering advances in understanding how plants, insects and worms eliminate pathogens has led to the realization that innate immunity plays a vital role in protecting humans from infection. This comprehensive review examines the molecules involved in innate immune responses, how they act to control parasites and if their engagement can explain many immune features characteristic of parasitic infections

Pattern recognition molecules and innate immunity to parasites

Recent pioneering advances in understanding how plants, insects and worms eliminate pathogens has led to the realization that innate immunity plays a vital role in protecting humans from infection. This comprehensive review examines the molecules involved in innate immune responses, how they act to control parasites and if their engagement can explain many immune features characteristic of parasitic infections

Limited role of charge matching in the interaction of human immunoglobulin A with the immunoglobulin A Fc receptor (Fc alpha RI) CD89

Human immunoglobulin A (IgA) mediates protective effector mechanisms through interaction with specific cellular Fc receptors (Fc alpha RI). Two IgA Fc interdomain loops (Leu257-Leu258 in the CH2 domain and Pro440-Phe443 in the CH3 domain) have previously been identified as critical for binding to Fc alpha RI. On the receptor, the interaction site for IgA has been localized to the EC1 domain. The essential Fc alpha RI residues involved are Tyr35, Tyr81 and Arg82, with contributions also from Arg52 and to a lesser extent from His85 and Tyr86. The basic nature of the side chains of some of the receptor residues implicated in ligand binding suggested that charge matching might play some role in the interaction. To address this possibility, we have generated five IgA1 mutants with point substitutions in acidic residues lying close to the putative interaction site and assessed their abilities to bind Fc alpha RI on human neutrophils. Mutants E254A, E254L and E437A displayed affinities for Fc alpha RI comparable to that of wild-type IgA1, while mutants D255A and D255V had only slightly reduced affinities for the receptor. Therefore, electrostatic interactions appear unlikely to play a significant role in the IgA-Fc alpha RI interaction. Moreover, the lack of effect of mutations in residues adjacent to those previously implicated in binding, reaffirms the importance of the interdomain loops in Fc alpha RI binding

Limited role of charge matching in the interaction of human immunoglobulin A with the immunoglobulin A Fc receptor (FcαRI) CD89

Human immunoglobulin A (IgA) mediates protective effector mechanisms through interaction with specific cellular Fc receptors (FcαRI). Two IgA Fc interdomain loops (Leu257–Leu258 in the CH2 domain and Pro440–Phe443 in the CH3 domain) have previously been identified as critical for binding to FcαRI. On the receptor, the interaction site for IgA has been localized to the EC1 domain. The essential FcαRI residues involved are Tyr35, Tyr81 and Arg82, with contributions also from Arg52 and to a lesser extent from His85 and Tyr86. The basic nature of the side chains of some of the receptor residues implicated in ligand binding suggested that charge matching might play some role in the interaction. To address this possibility, we have generated five IgA1 mutants with point substitutions in acidic residues lying close to the putative interaction site and assessed their abilities to bind FcαRI on human neutrophils. Mutants E254A, E254L and E437A displayed affinities for FcαRI comparable to that of wild-type IgA1, while mutants D255A and D255V had only slightly reduced affinities for the receptor. Therefore, electrostatic interactions appear unlikely to play a significant role in the IgA–FcαRI interaction. Moreover, the lack of effect of mutations in residues adjacent to those previously implicated in binding, reaffirms the importance of the interdomain loops in FcαRI binding

The generation and evaluation of recombinant human IgA specific for Plasmodium falciparum merozoite surface protein 1-19 (PfMSP1(19))

BACKGROUND: Human immunoglobulin G (IgG) plays an important role in mediating protective immune responses to malaria. Although human serum immunoglobulin A (IgA) is the second most abundant class of antibody in the circulation, its contribution, if any, to protective responses against malaria is not clear. RESULTS: To explore the mechanism(s) by which IgA may mediate a protective effect, we generated fully human IgA specific for the C-terminal 19-kDa region of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19), a major target of protective immune responses. This novel human IgA bound antigen with an affinity comparable to that seen for an epitope-matched protective human IgG1. Furthermore, the human IgA induced significantly higher NADPH-mediated oxidative bursts and degranulation from human neutrophils than the epitope-matched human IgG1 from which it was derived. Despite showing efficacy in in vitro functional assays, the human IgA failed to protect against parasite challenge in vivo in mice transgenic for the human Fcα receptor (FcαRI/CD89). A minority of the animals treated with IgA, irrespective of FcαRI expression, showed elevated serum TNF-α levels and concomitant mouse anti-human antibody (MAHA) responses. CONCLUSIONS: The lack of protection afforded by MSP1 19-specific IgA against parasite challenge in mice transgenic for human FcαRI suggests that this antibody class does not play a major role in control of infection. However, we cannot exclude the possibility that protective capacity may have been compromised in this model due to rapid clearance and inappropriate bio-distribution of IgA, and differences in FcαRI expression profile between humans and transgenic mice

The generation and evaluation of recombinant human IgA specific for Plasmodium falciparum merozoite surface protein 1-19 (PfMSP1 19)

<h4>Background</h4>Human immunoglobulin G (IgG) plays an important role in mediating protective immune responses to malaria. Although human serum immunoglobulin A (IgA) is the second most abundant class of antibody in the circulation, its contribution, if any, to protective responses against malaria is not clear.<h4>Results</h4>To explore the mechanism(s) by which IgA may mediate a protective effect, we generated fully human IgA specific for the C-terminal 19-kDa region of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19), a major target of protective immune responses. This novel human IgA bound antigen with an affinity comparable to that seen for an epitope-matched protective human IgG1. Furthermore, the human IgA induced significantly higher NADPH-mediated oxidative bursts and degranulation from human neutrophils than the epitope-matched human IgG1 from which it was derived. Despite showing efficacy in in vitro functional assays, the human IgA failed to protect against parasite challenge in vivo in mice transgenic for the human Fcα receptor (FcαRI/CD89). A minority of the animals treated with IgA, irrespective of FcαRI expression, showed elevated serum TNF-α levels and concomitant mouse anti-human antibody (MAHA) responses.<h4>Conclusions</h4>The lack of protection afforded by MSP1 19-specific IgA against parasite challenge in mice transgenic for human FcαRI suggests that this antibody class does not play a major role in control of infection. However, we cannot exclude the possibility that protective capacity may have been compromised in this model due to rapid clearance and inappropriate bio-distribution of IgA, and differences in FcαRI expression profile between humans and transgenic mice