The influence of natural antibody specificity on antigen immunogenicity

Benatuil, Lorenzo; Kaye, Joel; Rich, Robert F.; Fishman, Jay A.; Green, William R.; Iacomini, John

doi:10.1002/eji.200526146

Cited by 36 publications

(42 citation statements)

References 48 publications

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“…Finally, other investigators 50 have shown that conjugating a protein antigen to a foreign sugar can lead to enhanced production of antibodies against the protein itself, without the need for adjuvant. This response was dependent on the presence of antibodies against the foreign glycan, with the resulting immune complexes apparently acting as an adjuvant.…”

Section: Discussionmentioning

confidence: 99%

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Pham¹,

Gregg²,

Karp³

et al. 2009

Blood

112

138

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Humans are genetically unable to synthesize the common mammalian sialic acid N-glycolylneuraminic acid (Neu5Gc). However, Neu5Gc can be metabolically incorporated and covalently expressed on cultured human cell surfaces. Meanwhile, humans express varying and sometimes high titers of polyclonal anti-Neu5Gc antibodies. Here, a survey of human tissues by immunohistochemistry with both a monospecific chicken anti-Neu5Gc antibody and with affinity-purified human antiNeu5Gc antibodies demonstrates endothelial expression of Neu5Gc, likely originating from Neu5Gc-rich foods like red meats. We hypothesized that the combination of Neu5Gc incorporation and anti-Neu5Gc antibodies can induce endothelial activation. Indeed, the incubation of high-titer human sera with Neu5Gc-fed endothelial cells led to Neu5Gc-dependent antibody binding, complement deposition, endothelial activation, selectin expression, increased cytokine secretion, and monocyte binding. The proinflammatory cytokine tumor necrosis factor-␣ also selectively enhanced human anti-Neu5Gc antibody reactivity. AntiNeu5Gc antibodies affinity-purified from human serum also directed Neu5Gc-dependent complement deposition onto cultured endothelial cells. These data indicate a novel human-specific mechanism in which Neu5Gc-rich foods deliver immunogenic Neu5Gc to the endothelium, giving anti-Neu5Gc antibody-and complement-dependent activation, and potentially contributing to human vascular pathologies. In the case of atherosclerosis, Neu5Gc is present both in endothelium overlying plaques and in subendothelial regions, providing multiple pathways for accelerating inflammation in this disease.

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Section: Discussionmentioning

confidence: 99%

Evidence for a novel human-specific xeno-auto-antibody response against vascular endothelium

Pham¹,

Gregg²,

Karp³

et al. 2009

Blood

112

138

View full text Add to dashboard Cite

show abstract

“…We have recently demonstrated in KO mice a Ͼ100-fold increase in the immune response to the immunizing gp120 of HIV after the carbohydrate chains of gp120 were enzymatically modified to replace sialic acid residues with ␣-gal epitopes that form immune complexes with anti-Gal (35). Similarly, BSA with coupled synthetic ␣-gal epitopes was shown to be much more immunogenic than BSA with carbohydrate epitopes that do not bind anti-Gal (60).…”

Section: Discussionmentioning

confidence: 99%

Intratumoral Injection of α-gal Glycolipids Induces Xenograft-Like Destruction and Conversion of Lesions into Endogenous Vaccines

Galili

Wigglesworth²,

Abdel-Motal³

2007

The Journal of Immunology

134

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This study describes a novel cancer immunotherapy treatment that exploits the natural anti-Gal Ab to destroy tumor lesions and convert them into an endogenous vaccine targeted to APC via FcγR. Anti-Gal constitutes 1% of immunoglobulins in humans and interacts specifically with α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R). The binding of anti-Gal to α-gal epitopes on pig cells mediates xenograft rejection. The proposed method uses glycolipid micelles with multiple α-gal epitopes (α-gal glycolipids). These glycolipids are extracted from rabbit red cell membranes and are comprised of ceramides with carbohydrate chains containing 5–25 carbohydrates, all capped with α-gal epitopes. Efficacy of this treatment was demonstrated in α1,3-galactosyltransferase knockout mice producing anti-Gal and bearing B16 melanoma or B16/OVA producing OVA as a surrogate tumor Ag. These mice are unique among nonprimate mammals in that, similar to humans, they lack α-gal epitopes and can produce the anti-Gal Ab. Intratumoral injection of α-gal glycolipids results in local inflammation mediated by anti-Gal binding to the multiple α-gal epitopes and activation of complement. These glycolipids spontaneously insert into tumor cell membranes. The binding of anti-Gal to α-gal expressing tumor cells induces the destruction of treated lesions as in anti-Gal-mediated xenograft rejection. Anti-Gal further opsonizes tumor cells within the lesion and, thus, targets them for effective uptake by APC that transport the tumor Ags to draining lymph nodes. APC further cross-present immunogenic tumor Ag peptides and elicit a systemic anti-tumor immune response. Similar intratumoral injection of α-gal glycolipids in humans is likely to induce the destruction of treated lesions and elicit a protective immune response against micrometastases.

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“…Therefore, 143 further in vitro and in vivo validation is warranted to confirm the poten- individual T-cell repertoire specificity, in addition to antigen processing 340 may explain why some HLA binding peptide sequences do not induce T 341 cell activation in some individuals [58]. 342 It has recently been proposed that drug immunogenicity may be 343 affected by pre-existing antibodies, namely by the natural antibody 344 repertoire, although no definitive conclusions exist [59,60]. A fraction 345 of natural antibodies is conserved among different individuals [61,62].…”

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confidence: 99%