Complement: Its nuances in health and disease: The focus of my lab is to study the role of complement in the kidney and brain. There is a resurgence of interest in the complement field due to a growing list of novel and non-canonical complement functions, increase in functional locations and rapidly expanding list of complement therapeutics. Complement activation is a crucial event for maintaining health. However, if it is overwhelmed or restricted, it can be destructive, causing disease pathology. Recently, it has been recognized and appreciated that complement is synthesized at different locale and the intrinsic complement modulates microenvironmental homeostasis. The goal of the kidney arm of the work is to understand glomerular inflammation using the immune complex mediated glomerulonephritis mouse model. Complement signaling directs macrophages (MØs) to sites of inflammation, the numbers of which correlate negatively with organ function. We are studying the mechanisms at play in the regulation of trafficking and polarization of MØs by complement. The kidney is the size of a human fist (0.5% body weight). Yet 20-25 % of cardiac output traverses the kidney with filtration of toxic wastes occurring at the glomeruli, rendering it vulnerable to injury, resulting in loss of renal function. Endothelial layer is an integral part of the kidney filtration unit. Our recent studies revealed for the first time that intrinsic endothelial complement is of significance in maintaining kidney endothelial layer integrity. The molecular pathways involved is the focus of ongoing studies. Our studies showed that inhibition of complement protected the blood-brain barrier (BBB) integrity, reduced the severity of disease and improved brain function in systemic lupus erythematosus (lupus) model. The goal of the brain arm of the work is to understand CNS inflammation using the lupus mouse model, specifically the role of complement in it. The BBB consists of endothelial cells, astrocytic end feet and pericytes, and protects the brain from systemic circulation. Complement activation generates small molecules such as C5a, that bind to its G-coupled receptor and alters the structural integrity of the BBB. We are currently studying the complement dependent pathways involved in brain endothelial cells. These studies will open avenues for identification of novel therapeutics for diseases that have no effective therapies and will contribute to shaping the expanding complement therapeutic toolbox.
Education and Training:
PhD, Biochemistry, University of Hyderabad (1990)
MS, Science with Zoology, Osmania University (1982)
Employment:
Associate Editor, Frontiers in Immunology (2022-present)
2021 Lab grant, American Association of Immunology (2021)
Individual Development Award (2021)
Excellence in Immunology (2019)
Faculty Award of Excellence for promoting inclusion and cultural diversity (2019)
Fulbright Scholar (2019)
Manuscript published received editorial invite since it got 2537 downloads in a year (2018)
SUNY award ‘Conversations in the Disciplines’ (2017)
Article chosen for cover page by Immunology journal (2015)
Article chosen for cover page by Immunology journal (2014)
Journal of Immunology paper given write up in Lupus Research Update (2006)
Invited speaker at the MPGN Type II Focus Group: Towards a Cure, UK (2006)
Paper in Inaugural Issue of Fast Track Manuscripts, JASN (2004)
Abstract chosen by the American Society of Nephrology (2004)
Certificate for Original Research, Neuroscience Program Committee, Chicago Medical School (1992)
ICMR travel award (1990)
American Society of Neurochemistry Travel Award (1989)
Chosen as “highlights from literature”: Hyperammonemia causes many changes found after portacaval shunting, Biochem. J., 272:311-317, by Cerebrovascular and Brain Metabolism Reviews (1989)
SS Parmer Foundation Award (1986)
Senior Research Fellowship, CSIR, India (1984)
Junior Research Fellowship, CSIR, India (1982)
National Merit Scholarship (1975)
Research Expertise:
Experimental renal inflammation
Monocytes in circulation and Macrophages in tissues
Mouse models of sterile inflammation and autoimmunity
Neuropsychiatric lupus
Nuances of complement and endothelial cells
Pathobiology of the complement system
Research Centers:
Clinical and Translational Research Center (CTRC)
Grants and Sponsored Research:
July 2018–July 2021 NIH R01 National Institute of Health Role: Principal Investigator $717,750
January 2018–December 2018 American Hearing Research Foundation American Hearing Research Foundation Role: Principal Investigator $20,000
January 2018–April 2018 course infusion award University at Buffalo Role: Principal Investigator $785
October 2002–December 2011 Kidneed Foundation Kidneed Foundation Role: Principal Investigator $250,000
January 1999–January 2001 Arthritis Foundation Arthritis Foundation Role: Principal Investigator $90,000
March 1992–March 1994 Omega oxidation and Reyes syndrome. NIH Role: Principal Investigator $50,000
Alexander Jacob, Michael Phelps, Shane Fraher, Marcos Lopez, Anthony Chang, Richard J. Quigg, and Jessy J. Alexander. (2022) Macrophage depletion reduces disease pathology in factor H dependent immune complex-mediated glomerulonephritis. Journal of Immunology Research (Jan)
Jacob A, Nina Peralta L, Pegues D, Okamura K, Chang A, McSkimming D, Alexander J. (2021) Exercise alleviates symptoms of CNS lupus. Brain Research (Jul)(1765): 147478. doi:0.1016/j.brainres
Alexander JJ, Jacob A, Quigg RJ. (2015) Effects of Conventional Immunosuppressive Therapy on Functional and Pathological Features of CNS Lupus in NZB/W Mice. F1000Research (Jun), 4: 163-173.
Eadon MT, Hack BK, Alexander JJ, Xu C, Dolan ME, Cunningham PN. (2013) Cell Cycle Arrest in a Model of Colistin Nephrotoxicity. Physiol Genomics (Jul), Epub.
Alexander JJ. (2007) Systemic lupus erythematosus and the brain: What mice are telling us. Neurochem Int. (Jan), 50: 5.
Alexander JJ. (2007) Rodent Factor H Functions as a Counterpart of Human CR1 in Renal Immune Complex Processing. J Am Soc Nephrol (Jan), 18: 1157-1166.
Alexander JJ. (2007) New Approaches to the Treatment of Dense Deposit Disease. J Am Soc Nephrol. (Jan), 18: 2447-2456.
Alexander JJ. (2005) MRL/lpr Mice have Alterations in Brain Metabolism as Shown with [(1)H-(13)C] NMR Spectroscopy. Neurochem Intl (Jan), 47: 143-151.
Alexander JJ. (2003) Rat Glomerular Epithelial Cells Produce and Bear Factor H on their Surface that is Up-regulated Under Complement Attack. Kidney Int (Jan), 64: 914.
Alexander JJ. (2003) Administration of the Soluble Complement Inhibitor, Crry-Ig, Reduces Inflammation and Aquaporin 4 Expression in Lupus Cerebritis. Biochim Biophys Acta. (Jan), 1639: 169-176.
Alexander JJ. (2002) Prominent Renal Expression of a Murine Leukemia Retrovirus in Experimental Systemic Lupus Erythematosus. J Am Soc Nephrol. (Jan), 13: 2869.
Alexander JJ. (2002) Injury in Renal Ischemia-reperfusion is Independent from Immunoglobulins and T Lymphocytes. Am J Physiol Renal Physiol (Jan), 282: F352-F357.
Alexander JJ. (2002) Genetic Inhibition of the Complement Cascade Accelerates Alzheimer’s Pathology in Transgenic Mice. PNAS (Jan), 99: 10837-10842.
Alexander JJ. (2002) A Complement-dependent Model of Thrombotic Thrombocytopenic Purpura Induced by Antibodies Reactive with Endothelial Cells. Clinical Immunology (Jan), 103: 43-53.
Alexander JJ. (2001) Factor H is Present on Rodent Platelets and Functions as the Immune Adherence Receptor. JBC (Jan), 276: 32129-32135.
Alexander JJ. (2000) Production and Functional Analysis of Rat CD59 and Chimeric CD59-Crry as Active Soluble Proteins in Pichia Pastoris. Immunology (Jan)99-46.
Alexander JJ. (2000) Complement is Activated in Kidney by Endotoxin but does not Cause the Ensuing Acute Renal Failure. Kidney Int. (Jan), 58: 1580.
Alexander JJ. (1999) Renal, Central Nervous System and Pancreatic Overexpression of Recombinant Soluble Crry in Transgenic Mice. A Novel Means of Protection from Complement-mediated Injury. Immunopharmacology (Jan), 42: 245-254.
Alexander JJ. (1998) Inhibition of Complement Regulation is Key to the Pathogenesis of Active Heymann Nephritis. J Exp. Med. (Jan), 188: 1353.
Alexander JJ. (1998) Immune Complex Glomerulonephritis in C4- and C3-Deficient Mice. Kidney Int. (Jan), 53: 32.
Alexander JJ. (1997) Characterization of C3 Receptors on Cultured Rat Glomerular Endothelial Cells. Kidney International (Jan), 51: 1124.
Alexander JJ. (1997) Characterization of C3-binding Proteins on Mouse Neutrophils and Platelets. J Immunol. (Jan), 159: 2438.
Alexander JJ. (1997) Production of the Rat Complement Regulator, Crry, as an Active Soluble Protein in Pichia Pastoris. Arch. Biochem. Biophys (Jan), 341: 3.
Alexander JJ. (1995) Molecular Characterization of Rat Crry: Widespread Distribution of Two Alternative Forms of Crry mRNA. Immunogenetics (Jan), 42: 362.
Alexander JJ. (1993) Alterations in Mitochondrial Branched-chain Amino Acid Metabolism in Brain in Acute Hyperammonemic States. Neuroscience Letters (Jan), 149: 221-224.
Chang A., P. Kadambi and J. J. Alexander. (2006) Encyclopedic Reference of Molecular Mechanisms of Disease. In: Membranoproliferative Glomerulonephritis. Springer Verlag
Alexander JJ and Hawkins R. (1994) In Hepatic Encephalopathy, Hyperammonemia and Ammonia toxicity. In: Neomycin Reduces the Metabolic Ability of the Small Intestine to Produce Ammonia from Glutamine. Plenum Press
Alexander JJ. (1989) .Hepatic Encephalopathy. In: Acute Action of Ammonia on Leucine Metabolism in Isolated Astrocytes, Neurons and Oligocells of Rat Brain. Humana Press
Alexander JJ. (1989) In: Cellular and Subcellular Branched-chain Keto Acid Decarboxylase in Rat Brain and its Response to Hyperammonemia.
Alexander JJ and Murthy RK. (1987) Biochemical Pathology of Astrocytes. In: Cerebral Cellular Branched-chain Amino Acid Transaminases in Hyperammonemia. Alan R.Liss.
Alexander JJ and Murthy RK. (1987) In Biochemical Pathology of Astrocytes. In: Acute Effects of Ammonia on the Metabolism of Isolated and Cultured Astrocytes. Alan R. Liss
Professional Memberships:
International Society of Neurochemistry (2014–present)
American Association of Immunologists (2010–present)
American Society of Clinical Investigation (2009–present)
Complement Society (2005–present)
Presentations:
"Effective undergraduate research mentoring panel" CSTEP (2022)
"Intracellular complement and kidney disease." International complement society symposium: Complement: The road less traveled at the American Association of Immunology (2022)
"Complement and its non-canonical functions" Christian Medical College, Vellore, India (2022)
"Role of Factor H in macrophages" Toronto Complement Conference (2021)
"“Complement factor H: A story unfolding”." Seminar, Kidney diseases branch, NIH (2021)
"Complement Factor H regulates kidney function by modulating macrophages" American Association of Immunology-Virtual conference. (2021)
"Effective Undergraduate Research Panel" CSTEP program (2021)
"“Complement and the kidney.”" Department of Immunology & Microbiology, University of Pittsburg, PA. (2020)
"Complement and the kidney" Seminar, Wayne State University (2020)
"“Complement and blood-brain barrier integrity.”" International Society of Neurochemistry/American Society of Neurochemistry (2019)
"“Complement in health and disease”" Fulbright lecture series, GITAM University (2019)
"“Understanding the role of complement in CNS lupus towards personalized medicine and drug development”" 5th Meeting on Precision Medicine (2019)
"A journey with complement & kidney" Women in Science, CTRC, UB (2019)
"“Complement in health and disease”" University at Buffalo Dental School (2019)
"1. Complement in the brain during health and disease 2. Complement and blood-brain barrier in lupus 3. Complement in kidney during health and disease 4. Double negative T cells and lupus" Lecture series, Rheumatology, Christian Medical College, Vellore, India (2019)
"C5a/C5aR1 signaling alters blood-brain barrier integrity and brain function in systemic lupus erythematosus" European complement-based Drug development summit (2018)
"“Cultural competence in healthcare”" UB’s First: Living Our Commitment: UB’s Inaugural Summit on Inclusive Excellence” (2018)
"Lupus and Complement" Section of Nephrology, University at Buffalo (2018)
"“Complement as a modulator of Neurodegeneration in lupus.”" Dept. of Cell & Molecular Biology, SUNY Downstate Medical Center, (2017)
"Macrophages and complement-the culprits in glomerulonephritis" "Fueling conversations in Complement", Buffalo, NY (2017)
"Specific Targeting of Complement Pathways for Clinical Benefit" American Association of Immunology; American Association of Immunology; Complement (2016)
"Complement and the blood-brain barrier" Interdisciplinary Conversations in Blood-Brain Barrier Re-modelling (2016)
"Unexpected Roles for Immune Signaling in the Healthy and Diseased Brain" American Society of Neurochemistry (2013)
"Role of Factor H in kidney disease" Section of Nephrology, University of Chicago (2012)
"Complement in Hepatic Encephalopathy" I.S.H.E.N. 14th symposium on Hepatic Encephalopathy & Nitrogen metabolism. (2010)
"Distinct and separable role of FH in chimaeric mice" Dense Deposit Disease; Kidneeds/Wellcome Group (2008)
"The Complement Cascade: Yin-Yang in Neuroinflammation: Neuro-protection and degeneration" American Society of Neurochemistry (2008)
"Complement factor H on podocytes serve as immune adherence receptor similar to CR1 in humans" DDD Focus Group, Welcome Trust, UK (2007)
"Distinct and separable roles of the complement system in factor H- deficient bone marrow chimeric mice with immune complex disease" MPGN Focus Group, Welcome Trust, UK (2005)
"Complement: Good and Bad" American Society of Neurochemistry (2004)
"Complement in the brain: New and exciting insights in an old arena of Immunology" American Society of Neurochemistry (2003)
Faculty senate Bylaws committee; Member (2018–2023)
BDCN-E (04): Neurobiology of Brain Degenerative Disorders, Autoimmune Disea;; Ad Hoc Reviewer (2018–present)
Presenter: Workshop for CLIMB PhD scholars regarding the importance of Cultural Competency as part of the Professional Development Catalyst (PDC) workshop series (2018)
American Association of University Women;; Grant Reviewer (2018–2019)
Search committee for Center for Diversity Innovation Director; Member (2018)
NIH; Special Emphasis Panel ZRG1 VH-N 80 A, Vascular and Hematology;; Ad Hoc Reviewer (2018–present)
Wellcome Research Foundation, UK;; Ad Hoc Reviewer (2018–present)
University of Sharjah, UAE;; Ad Hoc Reviewer (2018–present)
German Research Foundation;; Ad Hoc Reviewer (2018–present)
NIH; Anonymization Study by CSR;; Grant Reviewer (2018–present)
Steering Committee to Study Promotion and Professional Development of Faculty in Qualified Ranks; Member (2018–present)
Ad hoc panel for promotions in Research track; Univ. at Buffalo; Chair (2017–2019)
UB Faculty Senate Secetary (2017–2022)
Presenter: Workshop for students regarding the importance of Cultural Competency iSEED students (2017–2018)
Subcommittee Inclusion & Engagement of International Students Task Force : “Recruitment and Communications Strategy”; Member (2017–2018)
Research Symposium Judge for CSTEP Summer Research Program (2017–present)
Faculty senate executive committee; Member (2016–2023)
CSTEP program Mentor; CSTEP program Mentor (2016–2023)
Medicine Research Day; Judge (2016–2018)
Grant reviewer: CTSI; Grant reviewer: CTSI (2016–2017)
Israel Science Foundation;; Ad Hoc Reviewer (2016–present)
CLIMB UP Mentor; CLIMB UP Mentor (2015–2023)
MRC England;; Ad Hoc Reviewer (2015–2024)
Ad hoc panel for promotions in Research track; Univ. at Buffalo; Member (2014–2023)
CLIMB-PRO Mentoring of undergraduates during summer; Mentor (2014)
NIH; Innate Immunity III;; Ad Hoc Reviewer (2014–2016)
Pennsylvania Department of Health and the Oak Ridge Associated Universities;; Ad Hoc Reviewer (2013–present)
American Association of University Women, American Fellowships, Grant selec;; Chair (2010–2012)
Frontiers in Immunology, J. Neuroinflammation, J. Neurochemistry, Molecular Immunology, Brain Research, etc,; Adhoc Manuscript Reviewer (2010–present)
Institutional Animal Care and Use Committee, University of Chicago; Member (2009–2013)
American Association of University Women, International Fellowships, Grant;; Chair (2004–2006)
American Association of University Women, Nat. Science Subpanel of the In;; Chair (2003–present)