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Clark L. Anderson

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Clark Lawrence Anderson, internist and immunologist, is Professor Emeritus in the Division of Immunology and Rheumatology, Department of Internal Medicine, The Ohio State University (OSU), Columbus, Ohio, United States.

Anderson studied medicine and biochemistry at the University of Chicago (MD 1964) after a grounding in the liberal arts at Brown University and the University of Arizona [1]. Subsequent to postgraduate training in internal medicine at the University of Colorado and postdoctoral research with Richard Farr, Percy Minden [2], and Howard Grey [3] at the National Jewish Hospital in Denver, CO, he joined the faculty in 1977 at the University of Rochester. In 1986 he moved to The OSU as Professor in the Departments of Internal Medicine, Molecular and Cellular Biochemistry, and Molecular Genetics. Anderson is married to Carole Ann Anderson who enjoyed a distinguished career as an administrator in higher education [4]

His academic career, focused on how IgG antibodies mediate their cell biological effects, has been funded continuously for more than 40 years by R01 grants from the National Institutes of Health [5]. His research contributions to biomedicine and immunology fall into four major groups:

1. The Fcγ Receptor (FcγR) family of molecules [6][7]. Anderson's early work on identifying and characterizing the high affinity FcγRI and low affinity FcγRII for IgG on human monocytes and other cells was aided by his development of monoclonal antibodies (mab) to both of these receptors, mab 32.2 (US Patent US4954617A awarded in 1990) to the former in collaboration with Michael Fanger and Paul Guyre, and mab IV.3 to the latter in collaboration with R. John Looney [8] [9][10] To facilitate the clinical application of these antibodies, Anderson enabled the establishment by Fanger and Guyre of Medarex, Inc., a biotech company since acquired by Bristol-Myers Squibb for 2.4 billion $US [11] . Further studies by Anderson showed FcRI to be associated with the FcRγ chain, and that both receptors upon clustering mediated intracellular kinase cascades that triggered various biological effects. This early work catalyzed an avalanche of studies that have allowed the elaboration of the FcγR family of proteins, now known to consist of several genes (8 in human, 5 in mouse), over 20 transcripts, and at least 9 expressed protein receptors; further, it has become clear that clustering of these receptors results in a variety of biological effects such as superoxide and cytokine output, cell-mediated killing, endocytosis, all resulting in removal of the antigen and perversely in disease-causing auto-immune effects [12]

2. IgG turnover mediated by the neonatal Fc receptor (FcRn) Anderson, reading the published work of others describing IgG deficiency in the beta2m KO mouse [13] [14] [15], realized that this strain was likely IgG deficient not because of low IgG production but because of rapid IgG degradation due to an FcRn deficiency. He formally affirmed this explanation by measuring the serum IgG decay rate in this KO strain [16]. Brambell’s prediction of the 1960s was thus confirmed, that a single Fc receptor served both to transport IgG across the placenta and to divert IgG from degradation [17]. This high affinity characteristic of IgG for FcRn is exploited by the drug industry to prolong the lifespan of protein drugs [18].

3. Albumin homeostasis mediated by FcRn. Anderson observed in vitro in detergent solution that albumin co-purified with a soluble variant of FcRn in roughly equimolar proportions, and realized that FcRn likely prolongs the half-life of albumin as it does IgG, thus explaining the lengthy lifespan of albumin in humans and lab animals. He formally affirmed this conclusion analyzing albumin decay in b2m and FcRn KO mouse strains [19], and then showed that the two ligands bound to FcRn at different sites, independently, that the stoichiometric ratio of interaction was 2:1:1::IgG:FcRn:albumin, that comparison of the published sequences of FcRn in many species suggested that albumin bound to FcRn near the A peptide pocket, that the site on albumin responsible for interaction was the II domain [20]. Co-crystal studies by others have confirmed these conclusions [21]. Kinetic studies indicate that the evolution of FcRn was a great boon to metabolic economy: Were it not for the presence of FcRn the mouse would require a liver twice as large and an immune system five times larger to maintain albumin and IgG concentrations [22] The albumin-FcRn interaction described by Anderson has also been exploited by the pharmaceutical industry to prolong the lifespan of protein drugs [18].

4. The removal of small particles from blood by liver sinusoidal endothelium (LSEC)Cite error: There are <ref> tags on this page without content in them (see the help page).. Anderson quite by chance observed that an astonishingly high fraction of the body’s FcγRIIb was expressed in the sinusoidal endothelium of the liver. This receptor earlier had been studied only as an inhibitory molecule of the immune system. Rigorously exploring this observation, his laboratory found that fully 70% of the total body content of FcγRIIb is expressed in the sinusoidal endothelium; that FcγRIIb is unassociated with the FcRγ chain and thus likely does not convey inhibitory signals; that it mediates the uptake and ultimate degradation of small pinocytosable immune complexes [23] [24]. His lab demonstrated in mice that HIV particles, in the absence of antibody opsonization, are taken up from blood and degraded by the liver sinusoidal endothelium at a rate of 100 million per minute [25]. These cells (LSEC) take up other viruses and other particles [26] in their capacity as the body’s garbage dump, clearing small particles from the blood stream. 




(2-4), realized that this strain was likely IgG deficient not because of low IgG production but because of rapid IgG degradation due to an FcRn deficiency.  He formally affirmed this explanation by measuring the serum IgG decay rate in this KO strain (5).  Brambell’s prediction of the 1960s was thus confirmed, that a single Fc receptor served both to transport IgG across the placenta and to divert IgG from degradation (6).  This high affinity characteristic of IgG for FcRn is exploited by the drug industry to prolong the lifespan of protein drugs (7).





Clark Lawrence Anderson, a physician and immunologist, is Professor Emeritus in the Division of Immunology and Rheumatology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, United States. His academic career has focused on the biological effects of Immunoglobulin G (IgG) antibodies that are mediated through the family of Fcγ receptors (a class of Fc receptors that are members of the immunoglobulin superfamily and bind IgG), as well as the functions of sinusoidal endothelial cells of the liver.

Anderson's research has been funded by the National Institutes of Health for more than 40 years [27] for fundamental research into medicine and biology. His contributions to biomedical research and immunology fall into four major groups:

Anderson's work on identifying and characterizing the high affinity (CD64) and low affinity (CD32) Fc receptors for IgG on human monocytes and other cells has been influential [38] [39] [40]. Anderson, along with Dartmouth University faculty Paul Guyre, PhD [41], and Michael Fanger, PhD [42] developed and patented monoclonal antibodies 32.2 and IV.3, which bind human CD64 and CD32 respectively (US Patent US4954617A awarded in 1990) . Guyre and Fanger founded Medarex, which produced and marketed these two monoclonal antibodies. Medarex has since been acquired by Bristol-Myers Squibb for 2.4 billion US$ [43]. These two antibodies, mabs 32.2 and IV.3, have since been used as reference activating or blocking reagents in multiple subsequent studies on FcγR, e.g., work on soluble FcγRII [44] by Hogarth[45]and colleagues, a study on TNF secretion by human monocytes by van de Winkel and colleagues [46], and a study on anaphylaxis and thrombocytopenia in mice by Amirkhosravi and colleagues[47].

Anderson received his MD from the University of Chicago in 1964 and studied chemistry and biology, as an undergraduate, at the University of Arizona and Brown University respectively [48]. After postdoctoral work with Richard Farr and Percy Minden[49], and Howard Grey[50] at the National Jewish Hospital in Denver, CO he was tenured at the University of Rochester in 1982. In 1986 he moved to The Ohio State University (OSU) in Columbus, OH as Professor in the Departments of Internal Medicine, Molecular and Cellular Biochemistry, and Molecular Genetics.

Among the students, postdoctoral fellows, visiting scientists, and collaborators of the Anderson laboratory are Jan GJ Van de Winkel[51], President and Chief Executive Officer of Genmab, John Looney [52], Susheela Tridandapani[53],Tim Leyden[54],Malcolm Lowry[55], and Jonghan Kim[56].


Early life and education

  • M.D., University of Chicago, 1964
  • Biochemistry Graduate Program, University of Chicago, 1965
  • Medicine Internship: University of Colorado, 1965-1966
  • Vietnam War Doctor Draft, 1966-1969
  • Medicine Residency: University of Colorado, 1969-1971
  • Clinical Immunology Fellowship: National Jewish Center and U. Colorado, 1973-1974.
  • Immunochemistry Fellowship: National Jewish Center, 1971-1977

Honors

  • Leukemia Society of America Special Fellow 1975-77
  • Research Career Development Award, NIAID 1979-84
  • Medical Biochemistry Study Section, DRG, NIH 1987-91
  • University Distinguished Scholar Award, OSU 1994

References

  1. ^ Clark Anderson Internal Medicine OSU
  2. ^ Farr R. and Minden P. (1968) Biology of the mycobacterioses. Ann N Y Acad Sci. 1968 Sep 5;154(1):107-14. PMID: 4909582
  3. ^ National Academy of Sciences member page for Howard M. Grey
  4. ^ https://hsl.osu.edu/mhc/local-nursing-legends/carole-anderson.
  5. ^ Ohio State University, College of Medicine News article on $1.7M Grant awarded to Anderson in 2014
  6. ^ Anderson CL, Looney RJ. 1986. Human leukocyte IgG Fc receptors. Immunol Today. 1986 Sep;7(9):264-6. doi: 10.1016/0167-5699(86)90007-1. PMID: 25290629
  7. ^ Anderson CL. 1989. Human IgG Fc receptors. Clin. Immunol. Immunopathol. 1989 Nov;53(2 Pt 2):S63-71. Review. PMID: 2529071
  8. ^ http://celdaramedical.com/site-administrator/2016-04-19-14-06-54/110-paul-guyre
  9. ^ http://celdaramedical.com/site-administrator/2016-04-19-14-06-54/109-michael-w-fanger
  10. ^ https://www.urmc.rochester.edu/medicine/airresearch/translational-research/looney-lab.aspx
  11. ^ Allison M. Bristol-Myers Squibb swallows last of antibody pioneers. Nat Biotechnol. 2009 Sep;27(9):781-3. doi: 10.1038/nbt0909-781. PMID 19741612
  12. ^ Nimmerjahn, F., and J. V. Ravetch. 2008. Fc receptors as regulators of immune responses. Nature Reviews Immunology 8: 34-47
  13. ^ Spriggs, M. K., B. H. Koller, T. Sato, P. J. Morrissey, W. C. Fanslow, O. Smithies, R. F. Voice, M. B. Widmer, and C. R. Maliszewski. 1992. Beta 2-microglobulin-, CD8+ T-cell-deficient mice survive inoculation with high doses of vaccinia virus and exhibit altered IgG responses. Proc. Natl. Acad. Sci. U. S. A. 89: 6070-6074.
  14. ^ Israel, E. J., V. K. Patel, S. F. Taylor, A. Marshak-Rothstein, and N. E. Simister. 1995. Requirement for a b2-microglobulin-associated Fc receptor for acquisition of maternal IgG by fetal and neonatal mice. J. Immunol. 154: 6246-6251.
  15. ^ Christianson, G. J., R. L. Blankenburg, T. M. Duffy, D. Panka, A. Marshak-Rothstein, J. B. Roths, and D. C. Roopenian. 1996. beta2-Microglobulin dependence of the lupus-like autoimmune syndrome of MRL-lpr mice. J. Immunol. 156: 4932-4939.
  16. ^ Junghans, R. P., and C. L. Anderson. 1996. The protection receptor for IgG catabolism is the 2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. U. S. A. 93: 5512-5516.
  17. ^ Brambell, F. W. R. 1970. The Transmission of Passive Immunity from Mother to Young. North Holland Publishing Company, Amsterdam.
  18. ^ a b Template:Sockolosky, J. T., and R. C. Szoka. 2017. The neonatal Fc receptor, FcRn, as a target for drug delivery and therapy. Adv drug Deliv Rev 91: 109-124.
  19. ^ Chaudhury, C., S. Mehnaz, J. M. Robinson, W. L. Hayton, D. K. Pearl, D. C. Roopenian, and C. L. Anderson. 2003. The major histocompatibility complex-related Fc receptor for IgG (FcRn) binds albumin and prolongs its lifespan. J. Exp. Med. 197: 315-322.
  20. ^ Chaudhury, C. 2005. Identification and biochemical characterization of a novel receptor: ligand interaction between FcRn and albumin. The Ohio State University. 1-95.
  21. ^ Schmidt, M. M., S. A. Townson, A. J. Andreucci, B. M. King, E. B. Schirmer, A. J. Murillo, C. Dombrowski, A. W. Tisdale, P. A. Lowden, A. L. Masci, J. T. Kovalchin, D. V. Erbe, K. D. Wittrup, E. S. Furfine, and T. M. Barnes. 2013. Crystal Structure of an HSA/FcRn Complex Reveals Recycling by Competitive Mimicry of HSA Ligands at a pH-Dependent Hydrophobic Interface. Structure.
  22. ^ Kim, J., C. L. Bronson, W. L. Hayton, M. D. Radmacher, D. C. Roopenian, J. M. Robinson, and C. L. Anderson. 2006. Albumin turnover: FcRn-mediated recycling saves as much albumin from degradation as the liver produces. Am J Physiol Gastrointest Liver Physiol 290: G352-G360.
  23. ^ Ganesan, L. P., S. Mohanty, J. Kim, K. R. Clark, J. M. Robinson, and C. L. Anderson. 2011. Rapid and Efficient Clearance of Blood-borne Virus by Liver Sinusoidal Endothelium 1. PLoS. Pathog. 7: e1002281
  24. ^ Ganesan, L. P., J. Kim, Y. Wu, S. Mohanty, G. S. Phillips, D. J. Birmingham, J. M. Robinson, and C. L. Anderson. 2012. FcgammaRIIb on Liver Sinusoidal Endothelium Clears Small Immune Complexes. J. Immunol. 189: 4981-4988.
  25. ^ Mates, J. M., Z. Yao, A. M. Cheplowitz, O. Suer, G. S. Phillips, J. J. Kwiek, M. V. Rajaram, J. Kim, J. M. Robinson, L. P. Ganesan, and C. L. Anderson. 2017. Mouse Liver Sinusoidal Endothelium Eliminates HIV-Like Particles from Blood at a Rate of 100 Million per Minute by a Second-Order Kinetic Process. Front Immunol. 8: 35.
  26. ^ Yao, Z., J. M. Mates, A. M. Cheplowitz, L. P. Hammer, A. Maiseyeu, G. S. Phillips, M. D. Wewers, M. V. Rajaram, J. M. Robinson, C. L. Anderson, and L. P. Ganesan. 2016. Blood-Borne Lipopolysaccharide Is Rapidly Eliminated by Liver Sinusoidal Endothelial Cells via High-Density Lipoprotein. J. Immunol. 197: 2390-2399.
  27. ^ Ohio State University, College of Medicine News article on $1.7M Grant awarded to Anderson in 2014
  28. ^ Anderson CL, Looney RJ. 1986. Human leukocyte IgG Fc receptors. Immunol Today. 1986 Sep;7(9):264-6. doi: 10.1016/0167-5699(86)90007-1. PMID: 25290629
  29. ^ Anderson CL. 1989. Human IgG Fc receptors. Clin. Immunol. Immunopathol. 1989 Nov;53(2 Pt 2):S63-71. Review. PMID: 2529071
  30. ^ Junghans RP, and Anderson CL. 1996. The protection receptor for IgG catabolism is the b2- microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. 93:5512-5516.
  31. ^ Brambell FW (1969) The transmission of immune globulins from the mother to the foetal and newborn young.Proc Nutr Soc. 1969 Mar;28(1):35-41.
  32. ^ Ward ES, Ober RJ (2015) Commentary: “There’s been a flaw in our thinking”. Front. Immunol., 16 July 2015 | https://doi.org/10.3389/fimmu.2015.00351
  33. ^ Anderson CL (2014) Commentary: “There’s been a flaw in our thinking”. Front Immunol. 2014 Oct 31;5:540. doi: 10.3389/fimmu.2014.00540. eCollection 2014
  34. ^ Chaudhury C,Mehnaz S, Robinson JM, Hayton WL, Pearl DK, Roopenian DC, and Anderson CL. 2003. The MHC-related Fc receptor for IgG binds albumin and prolongs its lifespan. J. Exp. Med. 197:315- 322
  35. ^ Sand et al. (2014) Unraveling the Interaction between FcRn and Albumin: Opportunities for Design of Albumin-Based Therapeutics Front Immunol. 2014; 5: 682
  36. ^ Anderson CL. 2015. The liver sinusoidal endothelium reappears after being eclipsed by the Kupffer cell: a 20th century biological delusion corrected. J Leukoc Biol. 98(6):875-6. PMID: 26628636
  37. ^ Anderson CL, Ganesan LP, Robinson JM. 2015. The biology of the classical Fcγ receptors in non-hematopoietic cells. Immunol Rev. 2015. 268(1):236-40. PMID: 26497524
  38. ^ Anderson, CL (1982). Isolation of the receptor for IgG from a human monocyte cell line (U937) and from human peripheral blood monocytes. J. Exp. Med. 156:1794‑1806. (120)
  39. ^ The high-affinity Fc gamma RI on PMN: regulation of expression and signal transduction Hoffmeyer F, Witte K, Schmidt RE (1997). Immunology. 1997 Dec;92(4):544-52
  40. ^ Signal transduction via Fc gamma R and Mac-1 alpha-chain in monocytes and polymorphonuclear leucocytes Gadd SJ, Eher R, Majdic O, Knapp W (1994) Immunology. 1994 Apr;81(4):611-7
  41. ^ http://celdaramedical.com/site-administrator/2016-04-19-14-06-54/110-paul-guyre
  42. ^ http://celdaramedical.com/site-administrator/2016-04-19-14-06-54/109-michael-w-fanger
  43. ^ Allison M. Bristol-Myers Squibb swallows last of antibody pioneers. Nat Biotechnol. 2009 Sep;27(9):781-3. doi: 10.1038/nbt0909-781. PMID 19741612
  44. ^ Wines BD1, Gavin A, Powell MS, Steinitz M, Buchanan RR, Mark Hogarth P (2003) and Soluble FcγRIIa inhibits rheumatoid factor binding to immune complexes. Immunology. 2003 Jun;109(2):246-54
  45. ^ https://www.burnet.edu.au/staff_members/182_mark_hogarth
  46. ^ Debets JM, van de Winkel JGJ, Ceuppens JL, Dieteren IE, Buurman WA (1990) Cross-linking of both Fc gamma RI and Fc gamma RII induces secretion of tumor necrosis factor by human monocytes, requiring high affinity Fc-Fc gamma R interactions. Functional activation of Fc gamma RII by treatment with proteases or neuraminidase. J Immunol February 15, 1990, 144 (4) 1304-1310;
  47. ^ Meyer T, Robles-Carrillo L, Davila M, Brodie M, Desai H, Rivera-Amaya M, Francis JL, Amirkhosravi A. (2015) CD32a antibodies induce thrombocytopenia and type II hypersensitivity reactions in FCGR2A mice. Blood 2015 126:2230-2238; doi: https://doi.org/10.1182/blood-2015-04-638684
  48. ^ Clark Anderson Internal Medicine OSU
  49. ^ Farr R. and Minden P. (1968) Biology of the mycobacterioses. Ann N Y Acad Sci. 1968 Sep 5;154(1):107-14. PMID: 4909582
  50. ^ National Academy of Sciences member page for Howard M. Grey
  51. ^ http://www.genmab.com/about-us/senior-leadership/jan-g-j-van-de-winkel
  52. ^ https://www.urmc.rochester.edu/medicine/airresearch/translational-research/looney-lab.aspx
  53. ^ https://internalmedicine.osu.edu/hematology/directory/facultycont/susheelatridandapani/
  54. ^ https://www.uwrf.edu/FacultyStaff/2030168.cfm
  55. ^ http://microbiology.science.oregonstate.edu/content/malcolm-lowry
  56. ^ https://bouve.northeastern.edu/directory/jonghan-kim/
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