Multiple sclerosis, or MS, is an autoimmune disease that affects the ability of the nervous system to carry signals to and from the brain. Inflammation causes damage to myelin, the protective covering that surrounds nerve cells, slowing and sometimes blocking nerve impulses. The disease carries with it a variety of symptoms, including problems with vision, tremors, paralysis, painful spasms, imbalance and cognitive changes.
While MS shares some similarities with lupus, Sjögren’s Syndrome and other autoimmune diseases, it actually is the “black sheep” of autoimmune diseases. Drugs that are used to treat rheumatoid arthritis and lupus actually make MS worse and vice versa.
In my lab, we use animal models and patient samples from OMRF’s MS Center of Excellence to understand why MS behaves differently from other autoimmune diseases and why some MS patients do not respond well to standard therapy. By studying human disease specimens and animal models, we have great potential to identify new therapeutic targets and develop prognostic tests that will bring clinical care of multiple sclerosis into the forefront of personalized medicine.
Multiple sclerosis (MS) is a highly heterogeneous disease with significant variability in the clinical course to the pathological patterns observed in brain lesions. Clinically, the heterogeneity in MS is illuminated by the variability in response to interferon-β (IFN-β) therapy. Even though there are clear responders and non-responders to IFN-β, there are limited tools to predict and monitor responsiveness to this therapy. My laboratory has utilized both clinical samples from MS patients and animal models of MS to identify the biological pathways that impact response to IFN-β therapy. These studies have uncovered key biological mechanisms that are specific to IFN-β therapy and furthermore, they have shed light on general immunological processes of MS and neuro-inflammation.
- Immunological heterogeneity impacts treatment response to IFN-β in patients with MS.
I recently led a collaboration which assessed serum cytokines for their utility to predict and monitor response to IFN-β therapy in a large cohort of MS patients (Hegen et al; Neurol Neuroimmunol Neuroinflamm 2016). We found that specific cytokine profiles could separate MS into six distinct subgroups that have differential clinical response to therapy. Two subsets, which had similar but distinct TH17 signatures, were associated poor response to IFN-β therapy. Two other immunologically distinct subsets were associated with good response to therapy. These data suggest that the MS population has immunologically distinct subgroups that can stratify treatment response to IFN-β. Moreover these data provide strong evidence that serum cytokines can be informative biomarkers for monitoring disease in MS patients.
- The T Helper (TH) 17 pathway dictates non-response to IFN-β therapy in mice with EAE.
Neuro-autoimmune disorders can be initiated by two different T-cell subtypes, TH1 and TH17 cells. Using the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, I discovered that the response to IFN-β is dictated by whether the disease is TH1 or TH17 driven (Axtell et al Nat Med 2010). IFN-β treatment reduced disease in mice with TH1-driven EAE, and conversely, IFN-β treatment exacerbated disease in mice with TH17-driven EAE. These animal data are congruent with our studies of serum samples from MS patients (described above) and further supports that the EAE model has clinical relevance for MS.
- Regulatory B-cells play a key role in the efficacy of IFN-β in both patients with MS and mice with EAE.
We published that MS patients successfully treated with IFN-β had significant increases in BAFF (a cytokine that supports B-cell development and function) and a skewing in the B-cell population away from inflammatory B-cells and toward anti-inflammatory B-cells. Similarly, in mice with TH1-EAE, effective IFN-β treatment increased serum BAFF levels and numbers of regulatory B-cells. Furthermore, mice deficient in B-cells do not benefit from IFN-β treatment (Schubert et al, J.Immunol 2015). These data show that IFN-β therapy requires immune regulation via B-cells to effectively reduce TH1-mediated neuro-inflammation in both EAE and MS.
These results may also explain the failure of the large clinical trial of Atacicept for relapsing remitting MS. Atacicept (a BAFF blocker) increased relapse rates in MS and we speculate that this treatment suppressed the same B-cell regulatory activity required for IFN-β efficacy.
Impact of Our Research
Our research has shown that specific immune pathways driving neuro-inflammation have clinically significant consequences. We demonstrated that disease phenotypes with elevated TH17/neutrophil signatures, unlike Th1 driven disease, do not respond well to conventional MS therapies. Clinically, these include highly inflamed relapsing remitting MS, neuromyelitis optica (NMO), and progressive MS (data from Dr. Segal at the University of Michigan). Currently, there is a lack of effective treatment options for progressive MS and NMO. Therefore, further characterization of these diseases will provide insights into novel treatment strategies for these underserved patients.
Our observations from human and mouse studies suggest the following biological paradigm. Neuro-autoimmune patients who do not respond to conventional therapies have a strong auto-reactive TH17 response that initiates the recruitment of neutrophils and other inflammatory myeloid cells into the CNS where they support the proliferation of inflammatory B-cells. In contrast, patients who are effectively managed with conventional therapies have a TH1-predominant disease where B-cells have a regulatory response. My studies have addressed 3 key issues in the field of MS/neuro-inflammation.
- The biological heterogeneity in the MS population impacts the prognosis of this disease. Our studies have identified a series of serum based biomarkers that could have prognostic utility in MS.
- The balance of inflammatory and regulatory B-cells have are key in modulating disease activity in MS. Considering that therapies specifically targeting B-cells are emerging for MS, our studies on B-cells populations are highly relevant and could impact how patients are monitored while on B-cell depleting therapies.
- Our studies have described an underappreciated role of BAFF in TH1- and TH17- induced inflammation which has provided a plausible explanation for the failure of Atacicept in MS.
B.S., Idaho State University, Pocatello, ID, 1999
M.S., Idaho State University, Pocatello, ID, 2001
Ph.D., University of Alabama at Birmingham, 2007
Postdoc, Stanford University, 2007-2013
Honors and Awards
2003 UAB Microbiology Retreat: Outstanding Oral Presentation Award
2004 UAB Medicine Trainee Research Symposium: 1st place graduate student poster
2005 UAB Graduate Research Day symposium: 1st place oral presentation
2007 UAB Department of Microbiology: Outstanding Student Award
2007 UAB Joint Health Sciences: Outstanding Student Award
2010 Stanford Cancer and Immunology Postdoc Symposium: 1st Place Oral Presentation
2010 The Whitaker Prize for MS Research. The Consortium of Multiple Sclerosis Centers
2010 Stanford Program of Immunology: Post Doctoral Mentor of the Year
2011 European Committee for Treatment and Research in Multiple Sclerosis
2011 3rd place, young scientist poster presentation
American Association of Immunologists
International Society for Interferon and Cytokine Research
Joined OMRF scientific staff in 2013
Larabee CM, Desai S, Agasing A, Georgescu C, Wren JD, Axtell RC, Plafker SM. Loss of Nrf2 exacerbates the visual deficits and optic neuritis elicited by experimental autoimmune encephalomyelitis. Mol Vis. 2016 Dec 30;22:1503-1513. [Abstract]
Larabee CM, Hu Y, Desai S, Georgescu C, Wren JD, Axtell RC, Plafker SM. Myelin-specific Th17 cells induce severe relapsing optic neuritis with irreversible loss of retinal ganglion cells in C57BL/6 mice. Mol Vis. 2016 Apr 11;22:332-41. [Abstract]
Schaffert SA, Loh C, Wang S, Arnold CP, Axtell RC, Newell EW, Nolan G, Ansel KM, Davis MM, Steinman L, Chen CZ. mir-181a-1/b-1 Modulates tolerance through opposing activities in selection and peripheral T cell function. J Immunol 2015. [Abstract] EPub
Schubert RD, Hu Y, Kumar G, Szeto S, Abraham P, Winderl J, Guthridge JM, Pardo G, Dunn J, Steinman L, Axtell RC. IFN-beta Treatment Requires B Cells for Efficacy in Neuroautoimmunity. J Immunol 2015. [Abstract] EPub
Cekanaviciute E, Dietrich HK, Axtell RC, Williams AM, Egusquiza R, Wai KM, Koshy AA, Buckwalter MS. Astrocytic TGF-beta signaling limits inflammation and reduces neuronal damage during central nervous system Toxoplasma infection. J Immunol 193:139-149, 2014. [Abstract]
Marabelle A, Kohrt H, Sagiv-Barfi I, Ajami B, Axtell RC, Zhou G, Rajapaksa R, Green MR, Torchia J, Brody J, Luong R, Rosenblum MD, Steinman L, Levitsky HI, Tse V, Levy R. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J Clin Invest 123:4980, 2013. [Abstract]
Axtell RC, de Jong BA, Boniface K, van der Voort LF, Bhat R, De Sarno P, Naves R, Han M, Zhong F, Castellanos JG, Mair R, Christakos A, Kolkowitz I, Katz L, Killestein J, Polman CH, de Waal Malefyt R, Steinman L, Raman C. T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med 2010; 16:406-412. [Abstract]
Lee LF, Axtell R, Tu GH, Logronio K, Dilley J, Yu J, Rickert M, Han B, Evering W, Walker MG, Shi J, de Jong BA, Killestein J, Polman CH, Steinman L, Lin JC. IL-7 promotes T(H)1 development and serum IL-7 predicts clinical response to interferon-beta in multiple sclerosis. Sci Transl Med 2011; 3:93ra68. [Abstract]
Herges K, de Jong BA, Kolkowitz I, Dunn C, Mandelbaum G, Ko RM, Maini A, Han MH, Killestein J, Polman C, Goodyear AL, Dunn J, Steinman L, Axtell RC. Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein. Mult Scler 2012; 18:398-408. [Abstract]
Arthritis and Immunology Research Program, MS 53
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