Antibody chemical reactivity: Beneficial and pathogenic roles

Antibodies (Abs) to autoantigens and foreign antigens (Ags) mediate, respectively, various pathogenic and beneficial effects. Abs express enzyme-like nucleophiles that react covalently with electrophiles. A subpopulation of nucleophilic Abs expresses proteolytic activity, which can inactivate the Ag permanently. This thesis shows how the nucleophilicity can be exploited to inhibit harmful Abs or potentially protect against a virus. Inactivation of pathogenic Abs from Hemophilia A (HA) patients by means of nucleophile-electrophile pairing was studied. Deficient factor VIII (FVIII) in HA subjects impairs blood coagulation. FVIII replacement therapy fails in 20-30% of HA patients due to production of anti-FVIII Abs. FVIII analogs containing electrophilic phosphonate group (E-FVIII and E-C2) were hypothesized to inactivate the Abs by reacting specifically and covalently with nucleophilic sites. Anti-FVIII IgGs from HA patients formed immune complexes with E-FVIII and E-C2 that remained irreversibly associated under conditions that disrupt noncovalent Ab-Ag complexes. The reaction induced irreversible loss of Ab anti-coagulant activity. E-FVIII alone displayed limited interference with coagulation. E-FVIII is a prototype reagent suitable for further development as a selective inactivator of pathogenic anti-FVIII Abs. The beneficial function of Abs to human immunodeficiency virus type 1 (HIV-1) was analyzed. HIV-1 eludes the immune system by rapidly changing its coat protein structure. IgAs from noninfected subjects hydrolyzed gp120 and neutralized HIV-1 with modest potency by recognizing the gp120 421-433 epitope, a conserved B cell superantigenic region that is also essential for HIV-1 attachment to host cell CD4 receptors. An adaptive immune response to superantigens is generally prohibited due to their ability to downregulate B cells. IgAs from subjects with prolonged HIV-1 infection displayed improved catalytic hydrolysis of gp120 and exceptionally potent and broad neutralization of diverse CCR5-dependent primary HIV isolates attributable to recognition of the 421-433 epitope. This indicates that slow immunological bypass of the superantigenic character of gp120 is possible, opening the path to effective HIV vaccination. My research reveals a novel route to inactivate pathogenic nucleophilic Abs using electrophilic antigens. Conversely, naturally occurring nucleophilic Abs may help impede HIV infection, and the Abs could be developed for passive immunotherapy of HIV infected subjects

Beneficial Catalytic Immunity to Aβ Peptide

We review attempts to treat Alzheimer disease with antibodies that bind amyloid β peptide (Aβ) and the feasibility of developing catalytic antibodies for this purpose. Naturally occurring immunoglobulin M (IgM) class antibodies that hydrolyze Aβ and inhibit Aβ aggregation were identified. The production of these antibodies increases as a function of age, ostensibly reflecting an attempt by the immune system to protect against the deleterious effect of Aβ accumulation in old age. A search for catalytic antibodies in a library of human immunoglobulins variable (IgV) domains yielded catalysts that hydrolyzed Aβ specifically at exceptionally rapid rates. The catalytic IgVs contained the light-chain variable domains within scaffolds that are structurally reminiscent of phylogenetically ancient antibodies. Inclusion of the heavy-chain variable domain in the IgV constructs resulted in reduced catalysis. We present our view that catalytic antibodies are likely to emerge as more efficacious and safer immunotherapy reagents compared to traditional Aβ-binding antibodies

Autoantibodies to the epidermal growth factor receptor in systemic sclerosis, lupus and atoimmune mice

NRC publication: Ye

Building ecological-economic models and scenarios of marine resource systems: Workshop report

As part of the ecosystem approach to managing fisheries and other uses of marine ecosystems, there has been a growing call for the development of integrated assessment tools to support the provision of both tactical and strategic management advice. Of particular importance in this domain is the development of models that capture the dynamic interactions between social and economic systems, and marine ecosystems. In February 2013, a workshop jointly organised by the ICES working group on Integrative, Physical–biological and Ecosystem Modelling and researchers attending the “Mathematics of Bio-economics” initiative, a contribution to the international event “Mathematics of Planet Earth 2013”, brought together experts to discuss recent advances and key methodological challenges posed by this field of research. The manuscript provides a brief report of the key points discussed during the workshop, including identification of the research which may help progress both the development of these modelling approaches and their application to actual management decision problems