On 2016 Jun 25, Donald Forsdyke commented:

HISTORY OF LECTIN PATHWAY RESEARCH

The history of this field has recently been reviewed (1,2).

1 Forsdyke DR (2016) Microbes & Infection 18, 450-459. Almroth Wright, opsonins, innate immunity and the lectin pathway of complement activation: a historical perspective. Forsdyke DR, 2016

2 Sims RB, Schwaeble W, Fujita T (2016) Complement research in the 18th-21st centuries: progress comes with new technology. Immunobiology 221:1037-1045 Sim RB, 2016

On 2015 Nov 16, Donald Forsdyke commented:

COMPLEMENT ACTIVATION BY PLANT AND ANIMAL LECTINS - THE LECTIN PATHWAY

The “proof-of-principle” that “lectins can be made more selective through molecular engineering” was demonstrated with the plant mannose-binding lectin Concanavalin-A in the 1970s (1). The functions then studied were mitogenicity, complement activation, and serum-binding activity. The dimeric form was found to retain mitogenicity without complement activation. The tetrameric form retained both activities (2).

The discovery that plant lectins activate the mammalian complement system (1) was initially attributed to a single antibody-independent “alternative” pathway of complement activation (3). However, subsequently the observation was extended to animal mannose-binding lectins and a second “alternative” pathways was characterized (4). This was named the “lectin pathway” and the other retained the “alternative pathway” name. Thus, there are three complement activation pathways – the classical, the lectin and the alternative.

In this light there are caveats regarding the proposed topical application of lectins to prevent HIV infection.

(i) There is suggestive evidence that lectins can cross mucous membranes, thus accessing body fluids and exerting toxic, perhaps complement-mediated, effects (5). While the elegant studies of Swanson et al. (6) show how mitogenic effects might be avoided, the possibility of toxic effects has not been excluded.

(ii) Reaction of soluble lectins with targets can be extensively buffered by competing lectin-binding activities, both associated with cell surfaces and in body fluids. When HIV buds from infected cells its envelope includes normal cell surface components that bind lectin. Furthermore, when plant lectins activate lymphocytes cultured in serum-containing medium, doubling the serum concentration doubles the lectin requirement (7). Thus, very high lectin concentrations may be needed for in vivo microbicidal effects. Is in vitro BanLec mitogenicity dependent on the BanLec/serum ratio? If so, is molecular engineering able to decrease competitive binding by serum and natural secretions?

(iii) While avoidance of initial HIV infection is important, use of lectins has not been thought promising in this respect. Hopefully the lectin work is not diverting resources from studies of the “shock-and-kill” approach that promises complete HIV eradication (8)?

(1) Milthorp P, Forsdyke DR (1970) Inhibition of lymphocyte activation at high ratios of concanavalin A to serum depends on complement. Nature 227:1351-1352. Milthorp P, 1970

(2) Forsdyke DR (1977) Role of receptor aggregation in complement-dependent inhibition of lymphocytes by high concentrations of concanavalin-A. Nature 267:358-360. Forsdyke DR, 1977

(3) Eidinger D, Gery I, Elleman C (1977) The inhibition of murine lymphocyte mitotic responses by human and mouse sera. 1. Evidence for a role of antibody-independent activation of the alternative complement pathway. Cellular Immunology 30:82-91. Eidinger D, 1977

(4) Degn SE, et al. (2014) Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Proc. Natl. Acad. Sci. USA 111:13445-13450. Degn SE, 2014

(5) Forsdyke DR (1978) Role of complement in the toxicity of dietary legumes. Medical Hypothesis 4:97-100. Forsdyke DR, 1978

(6) Swanson MD, et al. (2015) Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. Cell 163:746-758. Swanson MD, 2015

(7) Forsdyke DR (1967) Quantitative nucleic acid changes during PHA-induced lymphocyte transformation in vitro: dependence of the response on the PHA/serum ratio. Biochemical Journal 105:679-684. Forsdyke DR, 1967

(8) Forsdyke DR (1991) Programmed activation of T-lymphocytes. A theoretical basis for short term treatment of AIDS with azidothymidine. Medical Hypothesis 34:24-27. Forsdyke DR, 1991

On 2015 Nov 16, Donald Forsdyke commented:

COMPLEMENT ACTIVATION BY PLANT AND ANIMAL LECTINS - THE LECTIN PATHWAY

The “proof-of-principle” that “lectins can be made more selective through molecular engineering” was demonstrated with the plant mannose-binding lectin Concanavalin-A in the 1970s (1). The functions then studied were mitogenicity, complement activation, and serum-binding activity. The dimeric form was found to retain mitogenicity without complement activation. The tetrameric form retained both activities (2).

The discovery that plant lectins activate the mammalian complement system (1) was initially attributed to a single antibody-independent “alternative” pathway of complement activation (3). However, subsequently the observation was extended to animal mannose-binding lectins and a second “alternative” pathways was characterized (4). This was named the “lectin pathway” and the other retained the “alternative pathway” name. Thus, there are three complement activation pathways – the classical, the lectin and the alternative.

In this light there are caveats regarding the proposed topical application of lectins to prevent HIV infection.

(i) There is suggestive evidence that lectins can cross mucous membranes, thus accessing body fluids and exerting toxic, perhaps complement-mediated, effects (5). While the elegant studies of Swanson et al. (6) show how mitogenic effects might be avoided, the possibility of toxic effects has not been excluded.

(ii) Reaction of soluble lectins with targets can be extensively buffered by competing lectin-binding activities, both associated with cell surfaces and in body fluids. When HIV buds from infected cells its envelope includes normal cell surface components that bind lectin. Furthermore, when plant lectins activate lymphocytes cultured in serum-containing medium, doubling the serum concentration doubles the lectin requirement (7). Thus, very high lectin concentrations may be needed for in vivo microbicidal effects. Is in vitro BanLec mitogenicity dependent on the BanLec/serum ratio? If so, is molecular engineering able to decrease competitive binding by serum and natural secretions?

(iii) While avoidance of initial HIV infection is important, use of lectins has not been thought promising in this respect. Hopefully the lectin work is not diverting resources from studies of the “shock-and-kill” approach that promises complete HIV eradication (8)?

(1) Milthorp P, Forsdyke DR (1970) Inhibition of lymphocyte activation at high ratios of concanavalin A to serum depends on complement. Nature 227:1351-1352. Milthorp P, 1970

(2) Forsdyke DR (1977) Role of receptor aggregation in complement-dependent inhibition of lymphocytes by high concentrations of concanavalin-A. Nature 267:358-360. Forsdyke DR, 1977

(3) Eidinger D, Gery I, Elleman C (1977) The inhibition of murine lymphocyte mitotic responses by human and mouse sera. 1. Evidence for a role of antibody-independent activation of the alternative complement pathway. Cellular Immunology 30:82-91. Eidinger D, 1977

(4) Degn SE, et al. (2014) Complement activation by ligand-driven juxtaposition of discrete pattern recognition complexes. Proc. Natl. Acad. Sci. USA 111:13445-13450. Degn SE, 2014

(5) Forsdyke DR (1978) Role of complement in the toxicity of dietary legumes. Medical Hypothesis 4:97-100. Forsdyke DR, 1978

(6) Swanson MD, et al. (2015) Engineering a therapeutic lectin by uncoupling mitogenicity from antiviral activity. Cell 163:746-758. Swanson MD, 2015

(7) Forsdyke DR (1967) Quantitative nucleic acid changes during PHA-induced lymphocyte transformation in vitro: dependence of the response on the PHA/serum ratio. Biochemical Journal 105:679-684. Forsdyke DR, 1967

(8) Forsdyke DR (1991) Programmed activation of T-lymphocytes. A theoretical basis for short term treatment of AIDS with azidothymidine. Medical Hypothesis 34:24-27. Forsdyke DR, 1991

On 2016 Jun 25, Donald Forsdyke commented:

HISTORY OF LECTIN PATHWAY RESEARCH

The history of this field has recently been reviewed (1,2).

1 Forsdyke DR (2016) Microbes & Infection 18, 450-459. Almroth Wright, opsonins, innate immunity and the lectin pathway of complement activation: a historical perspective. Forsdyke DR, 2016

2 Sims RB, Schwaeble W, Fujita T (2016) Complement research in the 18th-21st centuries: progress comes with new technology. Immunobiology 221:1037-1045 Sim RB, 2016