Bio

Professional Education


  • Doctor of Philosophy, University of Medicine and Dentistry of New Jersey (2009)

Stanford Advisors


Publications

Journal Articles


  • Amyloid Fibrils Composed of Hexameric Peptides Attenuate Neuroinflammation SCIENCE TRANSLATIONAL MEDICINE Kurnellas, M. P., Adams, C. M., Sobel, R. A., Steinman, L., Rothbard, J. B. 2013; 5 (179)

    Abstract

    The amyloid-forming proteins tau, ?B crystallin, and amyloid P protein are all found in lesions of multiple sclerosis (MS). Our previous work established that amyloidogenic peptides from the small heat shock protein ?B crystallin (HspB5) and from amyloid ? fibrils, characteristic of Alzheimer's disease, were therapeutic in experimental autoimmune encephalomyelitis (EAE), reflecting aspects of the pathology of MS. To understand the molecular basis for the therapeutic effect, we showed a set of amyloidogenic peptides composed of six amino acids, including those from tau, amyloid ? A4, major prion protein (PrP), HspB5, amylin, serum amyloid P, and insulin B chain, to be anti-inflammatory and capable of reducing serological levels of interleukin-6 and attenuating paralysis in EAE. The chaperone function of the fibrils correlates with the therapeutic outcome. Fibrils composed of tau 623-628 precipitated 49 plasma proteins, including apolipoprotein B-100, clusterin, transthyretin, and complement C3, supporting the hypothesis that the fibrils are active biological agents. Amyloid fibrils thus may provide benefit in MS and other neuroinflammatory disorders.

    View details for DOI 10.1126/scitranslmed.3005681

    View details for Web of Science ID 000317037000005

    View details for PubMedID 23552370

  • Piet Mondrian's trees and the evolution in understanding multiple sclerosis, Charcot Prize Lecture 2011 MULTIPLE SCLEROSIS JOURNAL Steinman, L., Axtell, R. C., Barbieri, D., Bhat, R., Brownell, S. E., de Jong, B. A., Dunn, S. E., Grant, J. L., Han, M. H., Ho, P. P., Kuipers, H. F., Kurnellas, M. P., Ousman, S. S., Rothbard, J. B. 2013; 19 (1): 5-14

    Abstract

    Four questions were posed about multiple sclerosis (MS) at the 2011 Charcot Lecture, Oct. 22, 2011. 1. The Male/Female Disparity: Why are women developing MS so much more frequently than men? 2. Neuronal and Glial Protection: Are there guardian molecules that protect the nervous system in MS? 3. Predictive Medicine: With all the approved drugs, how can we rationally decide which one to use? 4. The Precise Scalpel vs. the Big Hammer for Therapy: Is antigen-specific therapy for demyelinating disease possible? To emphasize how our views on the pathogenesis and treatment of MS are evolving, and given the location of the talk in Amsterdam, Piet Mondrian's progressive interpretations of trees serve as a heuristic.

    View details for DOI 10.1177/1352458512470730

    View details for Web of Science ID 000313272100003

    View details for PubMedID 23303879

  • Chaperone Activity of Small Heat Shock Proteins Underlies Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis JOURNAL OF BIOLOGICAL CHEMISTRY Kurnellas, M. P., Brownell, S. E., Su, L., Malkovskiy, A. V., Rajadas, J., Dolganov, G., Chopra, S., Schoolnik, G. K., Sobel, R. A., Webster, J., Ousman, S. S., Becker, R. A., Steinman, L., Rothbard, J. B. 2012; 287 (43): 36423-36434

    Abstract

    To determine whether the therapeutic activity of ?B crystallin, small heat shock protein B5 (HspB5), was shared with other human sHsps, a set of seven human family members, a mutant of HspB5 G120 known to exhibit reduced chaperone activity, and a mycobacterial sHsp were expressed and purified from bacteria. Each of the recombinant proteins was shown to be a functional chaperone, capable of inhibiting aggregation of denatured insulin with varying efficiency. When injected into mice at the peak of disease, they were all effective in reducing the paralysis in experimental autoimmune encephalomyelitis. Additional structure activity correlations between chaperone activity and therapeutic function were established when linear regions within HspB5 were examined. A single region, corresponding to residues 73-92 of HspB5, forms amyloid fibrils, exhibited chaperone activity, and was an effective therapeutic for encephalomyelitis. The linkage of the three activities was further established by demonstrating individual substitutions of critical hydrophobic amino acids in the peptide resulted in the loss of all of the functions.

    View details for DOI 10.1074/jbc.M112.371229

    View details for Web of Science ID 000310364000062

    View details for PubMedID 22955287

  • Therapeutic Effects of Systemic Administration of Chaperone alpha B-Crystallin Associated with Binding Proinflammatory Plasma Proteins JOURNAL OF BIOLOGICAL CHEMISTRY Rothbard, J. B., Kurnellas, M. P., Brownell, S., Adams, C. M., Su, L., Axtell, R. C., Chen, R., Fathman, C. G., Robinson, W. H., Steinman, L. 2012; 287 (13): 9708-9721

    Abstract

    The therapeutic benefit of the small heat shock protein ?B-crystallin (HspB5) in animal models of multiple sclerosis and ischemia is proposed to arise from its increased capacity to bind proinflammatory proteins at the elevated temperatures within inflammatory foci. By mass spectral analysis, a common set of ?70 ligands was precipitated by HspB5 from plasma from patients with multiple sclerosis, rheumatoid arthritis, and amyloidosis and mice with experimental allergic encephalomyelitis. These proteins were distinguished from other precipitated molecules because they were enriched in the precipitate as compared with their plasma concentrations, and they exhibited temperature-dependent binding. More than half of these ligands were acute phase proteins or members of the complement or coagulation cascades. Consistent with this proposal, plasma levels of HspB5 were increased in patients with multiple sclerosis as compared with normal individuals. The combination of the thermal sensitivity of the HspB5 combined with the high local concentration of these ligands at the site of inflammation is proposed to explain the paradox of how a protein believed to exhibit nonspecific binding can bind with some relative apparent selectivity to proinflammatory proteins and thereby modulate inflammation.

    View details for DOI 10.1074/jbc.M111.337691

    View details for Web of Science ID 000302167200005

    View details for PubMedID 22308023

  • Chaperone Activity of alpha B-Crystallin Is Responsible for Its Incorrect Assignment as an Autoantigen in Multiple Sclerosis JOURNAL OF IMMUNOLOGY Rothbard, J. B., Zhao, X., Sharpe, O., Strohman, M. J., Kurnellas, M., Mellins, E. D., Robinson, W. H., Steinman, L. 2011; 186 (7): 4263-4268

    Abstract

    For 15 y, ? B-crystallin (heat shock protein [Hsp] B5) has been labeled an autoantigen in multiple sclerosis (MS) based on humoral and cellular responses found in humans and animal models. However, there have been several scientific inconsistencies with this assignment, ranging from studies demonstrating small differences in anticrystallin responses between patients and healthy individuals to the inability of crystallin-specific T cells to induce symptoms of experimental allergic encephalomyelitis in animal models. Experiments in this article demonstrate that the putative anti-HspB5 Abs from 23 MS patients cross-react with 7 other members of the human small Hsp family and were equally present in normal plasma. Biolayer interferometry demonstrates that the binding was temperature dependent, and that the calculated K(a) increased as the concentration of the sHsp decreased. These two patterns are characteristic of multiple binding sites with varying affinities, the composition of which changes with temperature, supporting the hypothesis that HspB5 bound the Ab and not the reverse. HspB5 also precipitated Ig heavy and L chains from sera from patients with MS. These results establish that small Hsps bind Igs with high affinity and refute much of the serological data used to assign ? B-crystallin as an autoantigen.

    View details for DOI 10.4049/jimmunol.1003934

    View details for Web of Science ID 000288751200051

    View details for PubMedID 21357544

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