The goal of my research has been to understand how the immune system communicates with the brain. This is important in elucidating diseases, such as brain cancers, multiple sclerosis, movement disorders (Tourettes syndrome) and possibly autism. It was once thought that the brain's immune protection was passive. It is now clear that the immune response to antigen in the brain is actively regulated. The brain's "choice" for immune protection appears to be the antibody response, since it poses less risk of damage to the brain's cellular architecture than that of cellular immune responses.

Institutions

Bu

Research Description

My main research interest has been to understand how the immune system communicates with the brain. Understanding this relationship is important in elucidating diseases, such as brain cancers, multiple sclerosis, movement disorders (Tourettes syndrome, TS; Sydenham's chorea, SC) and possibly autism. The brain is unique with respect to its relationship to the immune system. The brain does not have conventional lymphatic vessels and lymph nodes, which are critical in delivering antigens, foreign proteins and cells, to the immune system and subsequently stimulating an antigen-specific immune response. Also, the brain is isolated from components in blood (cells and proteins of the immune system do not freely leave the blood and enter the brain) by the tight junctions of the endothelial cells that form the cerebral capillaries often referred to as the "blood-brain barrier" (BBB). The brain has been classified as an "immunologically privileged" organ due to these anatomical characteristics plus early studies which showed that the survival of foreign tissues transplanted into certain regions of the brain were prolonged. Originally, it was thought that the brain's only immune protection was to barricade itself behind the BBB. We now know that the immune response to antigen in the brain is actively regulated; antigen introduced into the normal brain can stimulate an immune response in lymph nodes outside the central nervous system, and once immune cells are activated, the brain microenvironment can support the development of an antibody response.

My graduate work demonstrated in rats that small amounts of protein antigens, microinfused into the brain, can reach lymph nodes located in the head and neck. Antigens are able to leave the brain by flowing with brain fluids, cerebrospinal fluid (CSF) and interstitial fluid, along cerebral blood vessels and nerves and across a porous region of the skull (cribriform plate). Antigens leaving the brain are picked up by the lymphatic vessels in the nasal region and are delivered to the cervical lymph nodes. Antigen delivered to the cervical lymph nodes results in a strong immune stimulus: high levels of antibodies, specifically made to bind to the antigen and neutralize it, are secreted into blood for months. A few antigen-activated B lymphocytes (cellular source of antibodies) breech the BBB and locally secrete antibodies in brain tissue. My collaborators and I have shown that following antigen introduction into brain, antibody-secreting B cells can be found in the brain, and elevated levels of specific antibodies can be measured in CSF. We have also shown that inflammatory immune reactions to antigens in the brain, delayed-type hypersensitivity response and cytotoxic T cell response, are suppressed. For the latter it is clear that CSF components, specifically transforming growth factor-β, suppress cytotoxic responses. The brain's "choice" for immune protection may be the antibody response, posing less risk of damage to the brain's cellular architecture. Not all antibodies in the brain are beneficial or protective. Some antibodies cross-react with fundamental components in the brain, mistakenly binding and disrupting neural function. For example, when antibodies from children with TS are infused into rat brains, antibodies bind to neurons and rat behavior is altered. This effect persists for days. Similar effects are seen with the blood from SC patients, and antibodies made against rheumatogenic streptococcus and Semiliki-Forest virus.

Awards

1977-1978 Undergraduate Academic Scholarship at Boston University
1978 Graduated cum laude from Boston University
1986 Elected to Sigma Xi, full member
1987 Awarded travel grant to present abstract at IBRO Second World Congress of Neuroscience, Budapest, Hungary. Provided by the Soc. for Neuroscience, MacArthur Foundation, NSF, and Dept. Air Force and Navy
1991 Selected Participant for Woods Hole Marine Biological Laboratory Course, "Pathogenesis of Neuroimmunological Diseases"
2003 Lecturer at Woods Hole Marine Biological Laboratory Course, Woods Hole, MA, "Pathogenesis of Neuroimmunological Diseases"

Affiliations

1999 to present, Medical Research Committee, Progeria Research Foundation (PRF), Inc. Mission is to find a cure for children with Hutchinson-Guilford Progeria syndrome (HGPS; often called "accelerated aging syndrome"). Advise on funding of grants submitted to PRF. Participant in NIH-sponsored Progeria Workshop (2001), Genetics Consortium (2002). Progeria gene identified and published in Nature-genetics.

2005 to present, Co-Organizer, HGPS International Workshop (11/2005, Boston, MA). Assist in speaker selection and grant writing to fund workshop.

Funded Research

GRANTS

1. Principle Investigator, "Mechanism of Suppression Induced by CSF-Infused MBP", Rhode Island Foundation and the Rhode Island Community Foundation Grant (1990-1991), total budget $4,800.


2. Co-Principle Investigator, "AIDS and the Th-2 Dominant Immunity of the Normal CNS", NIH R01 NS 33070-05 (1994-1999), total budget $1,001,146.


3. Co-Principle Investigator, "Effects of the Suppressive CNS Micro-Environment on Tumor Growth in the Brain", Brain Tumor Society (1996-1998), total budget $40,000.


4. Co-Principle Investigator, "Role of Anti-Neuronal Antibodies in Tourette Syndrome, Disorder of the Central Nervous System: Development of an Animal Model for the Antibody-Mediated Neurological Phenomenon", Rhode Island Foundation and the Rhode Island Community Foundation Grant (1997-1998), total budget $5,000.


5. Consultant, "Neuroanatomical Correlates of Tourette Syndrome IgG Induced Dyskinesias in Rats", Tourette Society (1997-1998), total budget $40,000.


6. Co-Principle Investigator, "CNS Antibody Synthesis against Rat Neuronal Epitopes", NIH R01 NS38721-01, submitted 7/1999, request for 3 years of support, total budget $1,233,780 (grant was not funded).


7. Principle Investigator, "Induction of Subthalamic Dysfunction by Tourette Antibodies and Anti-rheumatogenic M -Protein Antibodies: Development of a Rodent Model of Neuronal Dysfunction", Tourette Society (5/2000-9/2001), total budget $40,000.


8. Co-Investigator, "Immunocytochemical Localization of Dyskinesia-Inducing Tourette IgG in the Striatum", Tourette Society (9/2001-9/2002), total budget $70,000.

View My Full Publication List in pdf format

Selected Publications

• 11. Harling-Berg, C.J., Nguyen, L.H., Dale, J.B., Stopa, E., Knopf, P.M., and Hallett, J.J. Microinfusion of rat antisera specific for rheumatogenic strptococcal M protein into naive rat brain elicits abnormal motor behavior and IgG binding in ventral striatum. Society for Neuroscience Abstract presented as poster at Neuroscience meeting Orlando, FL Nov. 2002.(2002)
• 10. Harling-Berg, C. J., J.J. Hallett, J.T. Park, and P.M. Knopf. Chapter entitled: Hierarchy of immune responses to antigen in the normal brain. In: Current Topics in Microbiology and Immunology: Protective and Pathological and Immune Responses in the CNS. Editors: B. Dietzschold and Juergen Richt. Springer-Verlag, Berlin. pp. 1-22, 2002. Also assisted in peer review of chapters.(2002)
• 8. Hallett, J.J., C. J. Harling-Berg, P. M. Knopf, E. G. Stopa, and L. S. Kiessling. Stereotypies and episodic utterances in rats after intrastriatal microinfusion of sera from children with Tourette Syndrome. J. Neuroimmunol. 111:195-202, 2000.(2000)
• 7. C. J. Harling-Berg, J.T. Park and P.M.Knopf. Invited Review: Role of the cervical lymphatics in the Th2-type hierarchy of CNS immune regulation. J. Neuroimmunol. 101:111-127, 1999.(1999)
• 6. Gordon, L.B., S.C. Nolan, B. Ksander, P.M. Knopf and C.J. Harling-Berg. Normal cerebrospinal fluid suppresses the in vitro development of cytotoxic T cells: Role of the brain microenvironment in CNS immune regulation . J. Neuroimmunol. 88:77-84, 1998.(1998)
• 5. Knopf, P.M., Harling-Berg, C.J., Cserr, H.F., Basu, D., Sirulnick, E.J., Nolan, S.C., Park, J.T., Keir, G., Thompson, E.J., and Hickey, W.F. Intrathecal antibody synthesis in rats with a functionally intact blood-brain barrier: Tissue entry and local retention of antigen-specific. B cells J. Immunol. 161:692-701, 1998.(1998)
• 4. Gordon, L.B., S.C. Nolan, P.M. Knopf, C.J. Harling-Berg. Growth of P511 mastocytoma cells in Balb/c mouse brain elicits afferent arm of cytotoxic immunity in the periphery without tumor elimination. A new tumor model for regional CNS immunity. J. Immunol. 159:2399-2408, 1997.(1997)
• 3. Cserr, H.F., M. DePasquale, C.J. Harling-Berg, J.T. Park, P.M. Knopf. Afferent and efferent arms of the humoral immune response to CSF-administered albumin in a rat model with normal blood-brain-barrier permeability. J. Neuroimmunol. 44:195-202, 1992.(1992)
• 2. Harling-Berg, C.J., P.M. Knopf, H.F. Cserr. Myelin basic protein infused into cerebrospinal fluid suppresses experimental autoimmune encephalomyelitis in the Lewis rat. J. Neuroimmunol. 35:45-91, 1991.(1991)
• 9. Cserr, H.F., C. J. Harling-Berg, T. Ichimura, P. Knopf, and S. Yamada. Chapter entitled: Drainage of cerebral extracellular fluids into cervical lymph: an afferent limb in brain/immune system interactions. In: Pathophysiology of the Blood-Brain Barrier: Long Term Consequences of Barrier Dysfunction for the Brain. Editors: B.B. Johansson C. Owman. Elsevier, Fernstrom Symposium Series, Amsterdam, Vol. 14, pp. 413-420, 1990.(1990)
• 1. Harling-Berg, C.J., P. Knopf, H. Cserr- Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into CSF. J. Neuroimmunol. 25:185-193, 1989.(1989)