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Structural Characterization of Pro-inflammatory and Anti-inflammatory Immunoglobulin G Fc Proteins

Citation

Ahmed, Alysia Ashley (2015) Structural Characterization of Pro-inflammatory and Anti-inflammatory Immunoglobulin G Fc Proteins. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9GT5K33. http://resolver.caltech.edu/CaltechTHESIS:05292015-064617250

Abstract

Immunoglobulin G (IgG) is central in mediating host defense due to its ability to target and eliminate invading pathogens. The fragment antigen binding (Fab) regions are responsible for antigen recognition; however the effector responses are encoded on the Fc region of IgG. IgG Fc displays considerable glycan heterogeneity, accounting for its complex effector functions of inflammation, modulation and immune suppression. Intravenous immunoglobulin G (IVIG) is pooled serum IgG from multiple donors and is used to treat individuals with autoimmune and inflammatory disorders such as rheumatoid arthritis and Kawasaki’s disease, respectively. It contains all the subtypes of IgG (IgG1-4) and over 120 glycovariants due to variation of an Asparagine 297-linked glycan on the Fc. The species identified as the activating component of IVIG is sialylated IgG Fc. Comparisons of wild type Fc and sialylated Fc X-ray crystal structures suggests that sialylation causes an increase in conformational flexibility, which may be important for its anti-inflammatory properties.

Although glycan modifications can promote the anti-inflammatory properties of the Fc, there are amino acid substitutions that cause Fcs to initiate an enhanced immune response. Mutations in the Fc can cause up to a 100-fold increase in binding affinity to activating Fc gamma receptors located on immune cells, and have been shown to enhance antibody dependent cell-mediated cytotoxicity. This is important in developing therapeutic antibodies against cancer and infectious diseases. Structural studies of mutant Fcs in complex with activating receptors gave insight into new protein-protein interactions that lead to an enhanced binding affinity.

Together these studies show how dynamic and diverse the Fc region is and how both protein and carbohydrate modifications can alter structure, leading to IgG Fc’s switch from a pro-inflammatory to an anti-inflammatory protein.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:sialylated IgG Fc, inflammation, IVIG, ADCC, N-linked glycan, X-ray crystallography
Degree Grantor:California Institute of Technology
Division:Biology and Biological Engineering
Major Option:Molecular Biology and Biochemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Bjorkman, Pamela J.
Thesis Committee:
  • Deshaies, Raymond Joseph (chair)
  • Rees, Douglas C.
  • Rothenberg, Ellen V.
  • Campbell, Judith L.
  • Bjorkman, Pamela J.
Defense Date:21 May 2015
Record Number:CaltechTHESIS:05292015-064617250
Persistent URL:http://resolver.caltech.edu/CaltechTHESIS:05292015-064617250
DOI:10.7907/Z9GT5K33
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1016/j.jmb.2014.07.006DOIArticle adapted for Chapter 2
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:8914
Collection:CaltechTHESIS
Deposited By: Alysia Ahmed
Deposited On:29 May 2015 21:51
Last Modified:14 Jun 2016 19:37

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