Watching Immune System Molecules in Action

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Watching Immune System Molecules in Action

February 2, 2011

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Like a blood-borne army, immunoglobulin G belongs to a class of antibodies that

binds to viruses, fungi, bacteria and other foreign particles to initiate their

destruction. It does this by attaching to unique features on the invader's cell

surface and signaling their presence to defensive cells. Precisely how this

latter step happens is not entirely clear to scientists. However, finding how

this happens could lead to the development of ways to boost weakened immune

systems and treat such diseases as rheumatoid arthritis.

Now, using a technique called solution nuclear magnetic resonance (NMR)

spectroscopy, along with enzymology, a team at the Univ. of Georgia has

uncovered new knowledge about how immunoglobulin G (known as IgG and part of a

larger, better-known gamma globulin family) is recognized by the body, and in

particular, how sugar molecules, or " glycans " that are part of IgG may mediate

this recognition.

" What we have exploited is a new technology for remodeling glycans and making

them visible at a molecular level, " says Prestegard, a professor at the

UGA Complex Carbohydrate Research Center and corresponding author of the

research. " Using powerful isotope-labeling and NMR tools has let us look deeply

into the way molecular interactions with IgG occur. "

( " Glycan " is a general term that refers to a chain of sugar molecules. Glycans

can in turn be linked to other molecules, such as the IgG protein in this study,

making a glycoprotein.)

The co-author of the paper is Adam Barb, a postdoctoral fellow at the CCRC. In

addition to his position at CCRC, Prestegard is a professor in the departments

of biochemistry and molecular biology, and chemistry at UGA.

The new structural knowledge about how IgG binds to the body through receptors

could offer a point for therapeutic intervention, though the current research is

only a first step in that direction. More immediately important, it opens the

entire subject of glycoprotein function to the possibility of new studies, says

Prestegard.

IgG is involved in an extremely complex process when health is compromised by

certain threats. It triggers the process by interacting with characteristic

molecules at the invaders' cell surface and signaling through what is called the

" fragment crystallizable " (Fc) region or domain of IgG. The immune system is

activated, and a localized inflammation occurs. At this point, a sensitive

cellular balancing act is kicked off. If the biochemical reaction becomes

unbalanced, the result can be a serious disease, such as rheumatoid arthritis.

" There is good reason to believe the glycans attached to the Fc fragment play a

role in maintaining this balance in sensitivity, " says Prestegard, " and that the

molecular structure of glycans and the way they sample various structures could

help in the design of new glycoforms with a modified immune response. The NMR

studies we present in this study take a step toward that understanding. "

Current structural knowledge of the Fc region and its glycans is substantial,

but up to this point that knowledge has done little to resolve questions

regarding how the glycan mediates the interaction between the Fc and the body.

The new approach combining glycan remodeling and solution NMR spectroscopy to

look at dynamics as well as structure may surmount many previous problems

involved in glycan studies.

According to the authors, the findings presented in the new research have,

" significant implications for possible improvements in intravenous IgG therapy

for patients suffering from severe cases of rheumatoid arthritis " Prestegard

says that work from the laboratory of Ravetch at Rockefeller Univ. on

the importance of specific glycans to the anti-inflammatory activity of the IgG

antibody has been particularly important in motivating the UGA studies of glycan

accessibility.

" In addition to the findings in this study, we now believe these techniques will

be applicable to a wide range of glycoprotein studies, " says Prestegard, " though

further methodological improvements will be required for more complex systems.

What we do believe now is that these methods will be central to studying the

association of the Fc fragment with cell-surface receptors and characterizing

the role glycans play in these interactions. "

While the new findings could apply to treatment of many diseases, the

possibility of their adding to our understanding of rheumatoid arthritis alone

would be significant, says Prestegard. According to the National Institute of

Arthritis and Musculoskeletal and Skin Diseases, more than a million people in

the United States suffer from this disease.

Source: UGA

[Guest guest]

pretty interesting, humm, Many molds produce glycoprotein

Glyco-engineering of human IgG1-Fc through combined yeast expression and in

vitro chemoenzymatic glycosylation

DISCUSSION

Protein glycosylation, the attachment of a carbohydrate moiety to specific amino

acid residues in a protein, plays important roles in many biological recognition

processes such as protein folding and quality control, cell adhesion,

host-pathogen interaction, development, and immune responses (51-56). Compelling

evidence has implicated that the precise structure of the attached glycans is

critical for the diverse functions of glycoproteins in biological recognition

processes. This is clearly true for the Fc glycosylation of IgG antibodies as

related to their immune activation functions (5, 57). Human antibodies of the

IgG class are glycoproteins that carry a conserved N-glycan at the Asn-297 of

the Fc domain. Recent structure-activity relationship studies have revealed that

structural variants of the attached N-glycan can differentially impact the

effector functions of monoclonal antibodies, and confer upon them diverse

therapeutic properties. For example, the lack of the core fucose residue and/or

the presence of a bisecting GlcNAc moiety in the biantennary complex type

N-glycan dramatically enhances the beneficial ADCC activity of some therapeutic

mAbs (12-18). Moreover, a small fraction of the sialylated IgG glycoform in the

intravenous immunoglobulin (IVIG) preparation was shown to be responsible for

the anti-inflammatory activity of the IVIG, whereas the desialylated and

degalactosylated glycoforms of IgG were found to be pro-inflammatory (22, 23).

These findings underscore the importance of a precise glycosylation for the

efficacy of therapeutic mAbs and/or IgG1-Fc fragments.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628294/

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