Clark L. Anderson

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Clark Lawrence Anderson is an internist and immunologist. He is professor emeritus in the Division of Immunology and Rheumatology, Department of Internal Medicine, Ohio State University (OSU), Columbus, Ohio, United States.

Contents

Education and personal life

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] Upon being drafted as a physician into the Army during the Vietnam War, he served three years in Germany and then continued postgraduate education in internal medicine at the University of Colorado. Subsequent to postdoctoral research in immunochemistry with Richard Farr, [2] Percy Minden, [3] and Howard Grey [4] at the National Jewish Hospital in Denver, CO, he joined the faculty at the University of Rochester in 1977; and in 1986 he moved to OSU as professor in the Departments of Internal Medicine, Molecular and Cellular Biochemistry, and Molecular Genetics. Anderson is married to Carole Ann Anderson, administrator in higher education, former dean of the OSU College of Nursing, the College of Dentistry, and the Graduate School; former president of the American Association of Colleges of Nursing and fellow of the American Academy of Nursing. [5] The couple has three daughters.

Research areas

Anderson's academic career, funded continuously for more than 40 years by R01 grants from the National Institutes of Health, has focused on how Immunoglobulin G (IgG) antibodies mediate their cell biological effects through the family of Fcγ receptors (a class of Fc receptors that are members of the immunoglobulin superfamily). [6] His research contributions to biomedicine and immunology fall into four major groups:

  1. The Fcγ Receptor (FcγR) family of molecules. [7] [8] 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, [9] and mab IV.3 to the latter in collaboration with R. John Looney. [10] [11] [12] 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. [13] 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. [14]
  2. IgG turnover mediated by the neonatal Fc receptor (FcRn) [15] [16] [17] [18] Anderson, reading the published work of others describing IgG deficiency in the beta2-microglobulin knock out mouse, [19] [20] [21] 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. [22] 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. [23] This high affinity characteristic of IgG for FcRn is exploited by the drug industry to prolong the lifespan of protein drugs. [24]
  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, [25] and then showed that the two ligands bound to FcRn at different sites, independently, that the stoichiometric ratio of the IgG:FcRn:albumin interaction was 2:1:1, 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 III domain. [26] Co-crystal studies by others have confirmed these conclusions. [27] 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 [28] The albumin-FcRn interaction described by Anderson has also been exploited by the pharmaceutical industry to prolong the lifespan of protein drugs. [24]
  4. The removal of small particles from blood by liver sinusoidal endothelium (LSEC) [29] Anderson serendipitously 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. [30] [31] 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. [32] These cells (LSEC) take up other viruses and other particles [33] in their capacity as the body's garbage dump, clearing small particles from the blood stream.

The distinctive features of Anderson's career have been the linearity of his scientific pursuit; the aggressive borrowing of technical solutions; a pursuit of basic and not translational questions; the publication of only model-changing work; collaborations only with helpers; a focus on hypothesis-denying experiments; an avoidance of review- and chapter-writing; no commercial backing but 40 years of continuous NIH R01 support.[ citation needed ]

Honors

Related Research Articles

<span class="mw-page-title-main">Antibody</span> Protein(s) forming a major part of an organisms immune system

An antibody (Ab) is the secreted form of a B cell receptor; the term immunoglobulin (Ig) can refer to either the membrane-bound form or the secreted form of the B cell receptor, but they are, broadly speaking, the same protein, and so the terms are often treated as synonymous. Antibodies are large, Y-shaped proteins belonging to the immunoglobulin superfamily which are used by the immune system to identify and neutralize antigens such as bacteria and viruses, including those that cause disease. Antibodies can recognize virtually any size antigen with diverse chemical compositions from molecules. Each antibody recognizes one or more specific antigens. Antigen literally means "antibody generator", as it is the presence of an antigen that drives the formation of an antigen-specific antibody. Each tip of the "Y" of an antibody contains a paratope that specifically binds to one particular epitope on an antigen, allowing the two molecules to bind together with precision. Using this mechanism, antibodies can effectively "tag" a microbe or an infected cell for attack by other parts of the immune system, or can neutralize it directly.

<span class="mw-page-title-main">Phagocytosis</span> Cell membrane engulfing a large particle

Phagocytosis is the process by which a cell uses its plasma membrane to engulf a large particle, giving rise to an internal compartment called the phagosome. It is one type of endocytosis. A cell that performs phagocytosis is called a phagocyte.

<span class="mw-page-title-main">CD32</span> Surface receptor glycoprotein

CD32, also known as FcγRII or FCGR2, is a surface receptor glycoprotein belonging to the Ig gene superfamily. CD32 can be found on the surface of a variety of immune cells. CD32 has a low-affinity for the Fc region of IgG antibodies in monomeric form, but high affinity for IgG immune complexes. CD32 has two major functions: cellular response regulation, and the uptake of immune complexes. Cellular responses regulated by CD32 include phagocytosis, cytokine stimulation, and endocytic transport. Dysregulated CD32 is associated with different forms of autoimmunity, including systemic lupus erythematosus. In humans, there are three major CD32 subtypes: CD32A, CD32B, and CD32C. While CD32A and CD32C are involved in activating cellular responses, CD32B is inhibitory.

<span class="mw-page-title-main">Immunoglobulin G</span> Antibody isotype

Immunoglobulin G (IgG) is a type of antibody. Representing approximately 75% of serum antibodies in humans, IgG is the most common type of antibody found in blood circulation. IgG molecules are created and released by plasma B cells. Each IgG antibody has two paratopes.

<span class="mw-page-title-main">Immunoglobulin M</span> One of several isotypes of antibody

Immunoglobulin M (IgM) is the largest of several isotypes of antibodies that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also be called an acute phase antibody. In humans and other mammals that have been studied, plasmablasts in the spleen are the main source of specific IgM production.

Alloimmunity is an immune response to nonself antigens from members of the same species, which are called alloantigens or isoantigens. Two major types of alloantigens are blood group antigens and histocompatibility antigens. In alloimmunity, the body creates antibodies against the alloantigens, attacking transfused blood, allotransplanted tissue, and even the fetus in some cases. Alloimmune (isoimmune) response results in graft rejection, which is manifested as deterioration or complete loss of graft function. In contrast, autoimmunity is an immune response to the self's own antigens. Alloimmunization (isoimmunization) is the process of becoming alloimmune, that is, developing the relevant antibodies for the first time.

<span class="mw-page-title-main">Fc receptor</span> Surface protein important to the immune system

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<span class="mw-page-title-main">Immune complex</span> Molecule formed binding antigens to antibodies

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<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

An immunoreceptor tyrosine-based inhibitory motif (ITIM), is a conserved sequence of amino acids that is found intracellularly in the cytoplasmic domains of many inhibitory receptors of the non-catalytic tyrosine-phosphorylated receptor family found on immune cells. These immune cells include T cells, B cells, NK cells, dendritic cells, macrophages and mast cells. ITIMs have similar structures of S/I/V/LxYxxI/V/L, where x is any amino acid, Y is a tyrosine residue that can be phosphorylated, S is the amino acid serine, I is the amino acid isoleucine, and V is the amino acid valine. ITIMs recruit SH2 domain-containing phosphatases, which inhibit cellular activation. ITIM-containing receptors often serve to target immunoreceptor tyrosine-based activation motif (ITAM)-containing receptors, resulting in an innate inhibition mechanism within cells. ITIM bearing receptors have important role in regulation of immune system allowing negative regulation at different levels of the immune response.

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References

  1. ↑ Clark Anderson Internal Medicine OSU
  2. ↑ Farr RS (1958) A Quantitative Immunochemical Measure of the Primary Interaction Between I*BSA and Antibody. The Journal of Infectious Diseases, Volume 103, Issue 3, 1 November 1958, Pages 239–262, https://doi.org/10.1093/infdis/103.3.239
  3. ↑ Farr R. and Minden P. (1968) Biology of the mycobacterioses. Ann N Y Acad Sci. 1968 Sep 5;154(1):107-14. PMID   4909582
  4. ↑ National Academy of Sciences member page for Howard M. Grey
  5. ↑ "Carole A. Anderson | Health Sciences Library". hsl.osu.edu. Archived from the original on 2013-06-25.
  6. ↑ Ohio State University, College of Medicine News article on $1.7M Grant awarded to Anderson in 2014
  7. ↑ 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
  8. ↑ Anderson CL. 1989. Human IgG Fc receptors. Clin. Immunol. Immunopathol. 1989 Nov;53(2 Pt 2):S63-71. Review. PMID   2529071
  9. ↑ Anderson CL, Guyre PM, Whitin JC, Ryan DH, Looney RJ, Fanger MW. (1986) Monoclonal antibodies to Fc receptors for IgG on human mononuclear phagocytes. Antibody characterization and induction of superoxide production in a monocyte cell line. J Biol Chem. Sep 25;261(27):12856-64
  10. ↑ "The Celdara Team".
  11. ↑ "The Celdara Team".
  12. ↑ "Looney Lab - Rochester, NY - University of Rochester Medical Center".
  13. ↑ 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
  14. ↑ Nimmerjahn, F., and J. V. Ravetch. 2008. Fc receptors as regulators of immune responses. Nature Reviews Immunology 8: 34-47
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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
  18. ↑ 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
  19. ↑ 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.
  20. ↑ 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.
  21. ↑ 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.
  22. ↑ Junghans, R. P., and C. L. Anderson. 1996. The protection receptor for IgG catabolism is the b2-microglobulin-containing neonatal intestinal transport receptor. Proc. Natl. Acad. Sci. U. S. A. 93: 5512-5516.
  23. ↑ Brambell, F. W. R. 1970. The Transmission of Passive Immunity from Mother to Young. North Holland Publishing Company, Amsterdam.
  24. 1 2 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.
  25. ↑ 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.
  26. ↑ Chaudhury, C. 2005. Identification and biochemical characterization of a novel receptor: ligand interaction between FcRn and albumin. The Ohio State University. 1-95.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ Anderson, C. L. 2015. The liver sinusoidal endothelium reappears after being eclipsed by the Kupffer cell: a 20th century biological delusion corrected. J. Leukoc. Biol. 98: 875-876.
  30. ↑ 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
  31. ↑ 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.
  32. ↑ 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.
  33. ↑ 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.
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