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Front. Neurol., 16 March 2023
Sec. Multiple Sclerosis and Neuroimmunology
This article is part of the Research Topic Multiple Sclerosis and Neuroimmunology – Case Report Collection, Volume II View all 35 articles

Commentary: Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies

\nJoseph R. Berger
Joseph R. Berger1*Hans-Peter Hartung,,
Hans-Peter Hartung2,3,4*
  • 1Department of Neurology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, United States
  • 2Department of Neurology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
  • 3Brain and Mind Center, University of Sydney, Sydney, NSW, Australia
  • 4Department of Neurology, Palacky University, Olomouc, Czechia

A Commentary on
Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies

by Hatchwell, E., Smith III, E. B., Jalilzadeh, S., Bruno, C. D., Taoufik, Y., Hendel-Chavez, H., Liblau, R., Brassat, D., Martin-Blondel, G., Wiendl, H., Schwab, N., Cortese, I., Monaco, M. C., Imberti, L., Capra, R., Oksenberg, J. R., Gasnault, J., Stankoff, B., Richmond, T. A., Rancour, D. M., Koralnik, I. J., Hanson, B. A., Major, E. O., Chow, C. R., and Eis, P. S. (2022). Front. Neurol. 13:1016377. doi: 10.3389/fneur.2022.1016377


Progressive multifocal leukoencephalopathy (PML) is a dreaded serious complication of immunotherapies. The drug with which it has been most frequently associated is natalizumab, a monoclonal antibody directed to alpha integrin that prevents the entry of lymphocytes to the central nervous system. It is approved for the treatment of relapsing multiple sclerosis (1, 2). As of 31 July 2022, 895 cases (892 in MS and 3 in patients with Crohn's disease) with a global overall incidence of 3.1 per 100,000, with 215 recorded deaths and 690 survivors with varying degrees of disability have been recorded (Biogen data on file). Previously, a number of risk factors were identified for the development of PML in patients on natalizumab: prior exposure to immunosuppressants, the duration of natalizumab treatment, and the presence of antibodies to the causative agent JC virus (human polyomavirus 2, HuPyV-2) (1, 2). There has been an intensive search to determine molecular factors governing susceptibility to this drug-related catastrophic CNS infection. Genetic variations have long been suspected to play an important role.

Genetic risk factors

In a refinement of an earlier study in which 19 genes were identified as increasing the risk of progressive multifocal leukoencephalopathy (PML) (3), Hatchwell et al. performed a case–control analysis that matched patients with PML to JCV antibody-positive patients with multiple sclerosis on natalizumab for 2 or more years who did not develop PML. This study demonstrated that four gene variants from those with natalizumab-associated PML are robustly linked to the risk of drug-associated PML (4). In total, two of these four genes only appeared in cases of drug-associated PML and were never observed in the drug-exposed controls. None of the drug-exposed PML cases was presented with more than one of the four genetic variants. The presence of any one of the four variants was observed in 10.9% of the drug-exposed PML cases vs. only 1.4% of the drug-exposed controls. When drug-associated patients with PML were compared to drug-exposed matched controls, the risk of PML with any one of these variants was exceptionally high (p-value 3.50 E-06, OR = 8.7 (3.7–20.6) (4).

All four genes (LY9, STXBP2, C8B, and FCN2) are involved in immune mechanisms, including viral defense mechanisms. LY9 encodes an immunomodulatory receptor on the surface of T-lymphocytes (5). STXBP2 encodes proteins that are involved in intracellular trafficking and the release of cytotoxic granules by natural killer cells and is associated with familial hemophagocytic lymphohistiocytosis (6). The other two genes (C8B and FCN2) are involved in complement activation. C8B codes for the late-acting complement proteins (C5-C9) that form the membrane attack complex (7), whereas, FCN2 is involved in the lectin pathway of complement (8).

Genetic risk factors related to host anti-pathogen defense mechanisms

These findings are not surprising. The immune system controls the response to infectious disease, conferring either vulnerability or resistance to a specific pathogen. Host adaptations to infectious pathogens have been among the strongest selective forces on the human genome (9). The expression of illness and its severity are simply the consequence of the combination of the offending organism and the host's response. The latter is determined by immunogenetics. Examples of this interaction are abundant. For instance, the Black Death of the middle ages that resulted from the bacterium Yersinia pestis led to an increase in salutary genetic variants in the human population that alters the cytokine response to Y. pestis and increase intracellular control of the pathogen in macrophages (10), thereby providing resistance to infection. CCR5-Δ32 deletion that confers resistance to HIV-1 infection has been attributed to this plague (11). In contrast, there are examples in which disease susceptibility is increased, such as deficiency of the membrane attack complex and properdin increasing the invasive nature of Neisseria infection; IL-12/23 and interferon-gamma deficiencies increasing the likelihood of disseminated tuberculosis; and signaling lymphocytic activation molecule (SLAM)-associated protein deficiency increasing the risk of X-linked lymphoproliferative disease with Epstein–Barr virus (12). More recently, the genetic variants of cytokine genes have been associated with COVID-19 disease susceptibility and cytokine storm (13). With respect to the genes identified in this study, the polymorphisms of FCN2 increase the risk of recurrent and severe streptococcal infections and rheumatic heart disease (14). Therefore, it should not be surprising that certain immune gene variants involved in the response to the JC virus (human polyomavirus 2) enhance the risk of PML.

Four PML epochs and risk factors

When considering the underlying risk factors for PML, four epochs of PML are identified. The first epoch was encompassed from the time of its framing as an illness in 1958 by Astrom et al. (15) to the beginning of the AIDS era in 1981. During this timeframe, the disease was associated chiefly, albeit not exclusively, with hematological malignancies, particularly B cell disorders (16). The second epoch began with the AIDS pandemic. PML was observed to be remarkably common with HIV infection ultimately occurring in 4–10% of patients with AIDS (17). HIV/AIDS became and remains the single greatest predisposing factor for PML. The third epoch of PML occurred with the introduction of highly active antiretroviral therapies in 1996 when the incidence of the disease in HIV/AIDS declined precipitously and almost invariably fatal disease is survived by about 50% of those with AIDS-associated PML (17). The next and most recent epoch of PML was initiated in 2005 with the observation of PML occurring with natalizumab (1, 1820). While immunosuppressive agents had previously been linked to PML, their use in most individuals was for diseases that also increased the likelihood of PML. However, natalizumab was unique as it was not broadly immunosuppressive. Its α4β1 component prevented lymphocyte interaction with VCAM inhibiting lymphocyte entry into the brain and its α4β7 component interfered with lymphocyte binding to the gut endothelial cells through MAdCAM. Therefore, it is effective against MS and inflammatory bowel diseases. The former mode of action is believed to be responsible for the increased risk of PML with its use. Agents that inhibit α4β7 exclusively, such as vedolizumab, have a vanishingly small risk of PML, if any at all.

Risk mitigation

Although HIV/AIDS remains the most common predisposing cause of PML, a substantial and increasing number of patients are exposed to drugs that increase the risk of PML. As the authors highlight, a large number of drugs have been associated with PML risk, and eight drugs currently carry FDA black box warnings. These drugs have varied indications. While risk stratification methods have been developed for natalizumab-associated PML, this is not available for other agents that predispose to PML and would be very difficult to devise for a variety of reasons, including the relatively small numbers of patients who develop PML with some of these drugs and the difficulty excluding the contribution of the underlying disorder or concomitant therapies to the development of PML. Furthermore, despite the broader adoption of the risk mitigation strategy employed with natalizumab, PML remains a substantial concern given the mortality, persistent disability, and the lack of established treatments.


Testing for these genes will not eliminate the risk of PML but can be very helpful in identifying a subpopulation (~10%) at particularly high risk for its occurrence when being treated with drugs that predispose to the disorder. The availability of a simple, relatively inexpensive test that can identify the genes that put one at risk for PML would be enormously helpful in the management of patients. The widespread use of such testing could potentially allow the physician to use alternative therapies that do not carry the same risk of PML, such as using alternative therapies for MS rather than using natalizumab in the JCV-positive individual. In those instances where alternative therapies do not exist, it would alert the treating physician to the importance of careful and frequent evaluation of PML. Tests for these genes would also be helpful for informing the patient and the family about relative risks.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


1. Cortese I, Reich DS, Nath A. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol. (2021) 17:37–51. doi: 10.1038/s41582-020-00427-y

PubMed Abstract | CrossRef Full Text | Google Scholar

2. Major EO, Yousry TA, Clifford DB. Pathogenesis of progressive multifocal leukoencephalopathy and risks associated with treatments for multiple sclerosis: a decade of lessons learned. Lancet Neurol. (2018) 17:467–80. doi: 10.1016/S1474-4422(18)30040-1

PubMed Abstract | CrossRef Full Text | Google Scholar

3. Eis PS, Bruno CD, Richmond TA, Koralnik IJ, Hanson BA, Major EO, et al. Germline genetic risk variants for progressive multifocal leukoencephalopathy. Front Neurol. (2020) 11:186. doi: 10.3389/fneur.2020.00186

PubMed Abstract | CrossRef Full Text | Google Scholar

4. Hatchwell E, Smith EB III, Jalilzadeh S, Bruno CD, Taoufik Y, Hendel-Chavez H, et al. Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies. Front Neurol. (2022) 13:1016377. doi: 10.3389/fneur.2022.1016377

PubMed Abstract | CrossRef Full Text | Google Scholar

5. Hamosh A. T-lymphocyte Surface Antigen LY-9; Ly9. Washington, DC: National Center for Biotechnology Information (2022). Available online at:

Google Scholar

6. National Institute of Biotechnology Information. STXBP2 Syntaxin Binding Protein 2 [Homo sapiens (human)]. Washington, DC: National Library of Medicine (2022). Available online at:

Google Scholar

7. Hamosh A. Complement Component 8, Beta Subunit, C8B. Washington, DC: National Center for Biotechnology Information; 2022 [Available from:

Google Scholar

8. Garred P, Honore C, Ma YJ, Munthe-Fog L, Hummelshøj T. MBL2, FCN1, FCN2 and FCN3-The genes behind the initiation of the lectin pathway of complement. Mol Immunol. (2009) 46:2737–44. doi: 10.1016/j.molimm.2009.05.005

PubMed Abstract | CrossRef Full Text | Google Scholar

9. Karlsson EK, Kwiatkowski DP, Sabeti PC. Natural selection and infectious disease in human populations. Nat Rev Genet. (2014) 15:379–93. doi: 10.1038/nrg3734

PubMed Abstract | CrossRef Full Text | Google Scholar

10. Klunk J, Vilgalys TP, Demeure CE, Cheng X, Shiratori M, Madej J, et al. Evolution of immune genes is associated with the Black Death. Nature. (2022) 611:312–9. doi: 10.1038/s41586-022-05349-x

PubMed Abstract | CrossRef Full Text | Google Scholar

11. Galvani AP, Slatkin M. Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta 32 HIV-resistance allele. Proc Natl Acad Sci USA. (2003) 100:15276–9. doi: 10.1073/pnas.2435085100

PubMed Abstract | CrossRef Full Text | Google Scholar

12. Casanova JL, Abel L. Human genetics of infectious diseases: a unified theory. EMBO J. (2007) 26:915–22. doi: 10.1038/sj.emboj.7601558

PubMed Abstract | CrossRef Full Text | Google Scholar

13. Fricke-Galindo I, Falfan-Valencia R. Genetics insight for COVID-19 susceptibility and severity: a review. Front Immunol. (2021) 12:622176. doi: 10.3389/fimmu.2021.622176

PubMed Abstract | CrossRef Full Text | Google Scholar

14. Messias-Reason IJ, Schafranski MD, Kremsner PG, Kun JF. Ficolin 2 (FCN2) functional polymorphisms and the risk of rheumatic fever and rheumatic heart disease. Clin Exp Immunol. (2009) 157:395–9. doi: 10.1111/j.1365-2249.2009.03975.x

PubMed Abstract | CrossRef Full Text | Google Scholar

15. Astrom KE, Mancall EL, Richardson EP. Jr. Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin's disease. Brain. (1958) 81:93–111. doi: 10.1093/brain/81.1.93

PubMed Abstract | CrossRef Full Text | Google Scholar

16. Brooks BR, Walker DL. Progressive multifocal leukoencephalopathy. Neurol Clin. (1984) 2:299–313. doi: 10.1016/S0733-8619(18)31105-8

CrossRef Full Text | Google Scholar

17. Berger JR. Progressive multifocal leukoencephalopathy. Handb Clin Neurol. (2014) 123:357–76. doi: 10.1016/B978-0-444-53488-0.00017-1

PubMed Abstract | CrossRef Full Text | Google Scholar

18. Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal leukoencephalopathy complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. (2005) 353:369–74. doi: 10.1056/NEJMoa051782

PubMed Abstract | CrossRef Full Text | Google Scholar

19. Langer-Gould A, Atlas SW, Green AJ, Bollen AW, Pelletier D. Progressive multifocal leukoencephalopathy in a patient treated with natalizumab. N Engl J Med. (2005) 353:375–81. doi: 10.1056/NEJMoa051847

PubMed Abstract | CrossRef Full Text | Google Scholar

20. Van Assche G, Van Ranst M, Sciot R, Dubois B, Vermeire S, Noman M, et al. Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease. N Engl J Med. (2005) 353:362–8. doi: 10.1056/NEJMoa051586

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: progressive multifocal leucoencephalopathy (PML), multiple sclerosis, natalizumab, risk factors, immunogenetics

Citation: Berger JR and Hartung H-P (2023) Commentary: Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies. Front. Neurol. 14:1146027. doi: 10.3389/fneur.2023.1146027

Received: 16 January 2023; Accepted: 09 February 2023;
Published: 16 March 2023.

Edited by:

Joep Killestein, VU Medical Center, Netherlands

Reviewed by:

Elena Grebenciucova, Northwestern University, United States

Copyright © 2023 Berger and Hartung. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Joseph R. Berger,; Hans-Peter Hartung,

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.