Evolution of sialic acids: Implications in xenotransplant biology

Abstract

All living cells are covered with a dense "sugar-coat" of carbohydrate chains (glycans) conjugated to proteins and lipids. The cell surface glycome is determined by a non-template driven process related to the collection of enzymes that assemble glycans in a sequential manner. In mammals, many of these glycans are topped with sialic acids (Sia), a large family of acidic sugars. The "Sialome" is highly diverse owing to various Sia types, linkage to underlying glycans, range of carriers, and complex spatial organization. Presented at the front of cells, Sia play a major role in immunity and recognition of "self" versus "non-self," largely mediated by the siglecs family of Sia-binding host receptors. Albeit many mammalian pathogens have evolved to hijack this recognition system to avoid host immune attack, presenting a fascinating host-pathogen evolutionary arms race. Similarly, cancer cells exploit Sia for their own survival and propagation. As part of this ongoing fitness, humans lost the ability to synthesize the Sia type N-glycolylneuraminic acid (Neu5Gc), in contrast to other mammals. While this loss had provided an advantage against certain pathogens, humans are continuously exposed to Neu5Gc through mammalian-derived diet (eg, red meat), consequently generating a complex immune response against it. Circulating anti-Neu5Gc antibodies together with Neu5Gc on some human tissues mediate chronic inflammation "xenosialitis" that exacerbate various human diseases (eg, cancer and atherosclerosis). Similarly, Neu5Gc-containing xenografts are exposed to human anti-Neu5Gc antibodies with implications to sustainability. This review aimed to provide a glimpse into the evolution of Sia and their implications to xenotransplantation.

Elicited and pre‐existing anti‐Neu5Gc antibodies differentially affect human endothelial cells transcriptome

“…The reason that elicited anti‐Neu5Gc Abs do not result in a clear inflammatory profiling of the EC transcriptome remains hypothetical. Circulating anti‐Neu5Gc Abs show extremely large differential reactivities with multiple Neu5Gc‐containing glycans in an array format . One can speculate that such a huge epitope conformational diversity may result in a low concentration of Abs for a given EC surface membrane target.…”

“…Circulating anti-Neu5Gc Abs show extremely large differential reactivities with multiple Neu5Gc-containing glycans in an array format. 44 One can speculate that such a huge epitope conformational diversity may result in a low concentration of Abs for a given EC surface membrane target. Such a situation combined with the yet unknown mechanisms shaped by evolution to cope with the condition resulting from the concomitant presence of natural anti-Neu5Gc…”

Blood-Borne ST6GAL1 Regulates Immunoglobulin Production in B Cells

“…By sequestration of CD22 away from the BCR, sialic acid in cis potentiates antigen-induced activation, marginal zone B cell development, as well as T-dependent and T-independent immune responses (25)(26)(27)(28). Conversely, engagement of CD22 by sialic acid in trans recruits CD22 to the immune synapse, enforcing tolerance to self-antigens (24,29). It has long been presumed that the synthesis of sialylated CD22 ligands is a direct result of the action of cell-intrinsic sialyltransferases within the ER-Golgi complex.…”

A Common Food Glycan, Pectin, Shares an Antigen with Streptococcus pneumoniae Capsule

“…Another example of a food antigen that interferes with immune responses in humans is the N-glycolylneuraminic acid present in red meat. Its ingestion creates the target for subtilase cytotoxin secreted by a pathogenic Escherichia coli strain (21) and may trigger chronic inflammation, termed "xenosialitis" (22).…”