key: cord-0814955-e0nwgcfk authors: Witman Tsur, Shani; Adrian Zaher, Eli; Tsur, Meydan; Kania, Karolina; Kalinowska-Łyszczarz, Alicja title: Current Immunological and Clinical Perspective on Vaccinations in Multiple Sclerosis Patients: Are They Safe after All? date: 2021-04-08 journal: Int J Mol Sci DOI: 10.3390/ijms22083859 sha: a5e1a9fb99080e08b4c500ef210cac3e39e08f4d doc_id: 814955 cord_uid: e0nwgcfk Vaccines work by stimulating the immune system, and their immunogenicity is key in achieving protection against specific pathogens. Questions have been raised whether in Multiple Sclerosis (MS) patients they could induce disease exacerbation and whether vaccines could possibly act as a trigger in the onset of MS in susceptible populations. So far, no correlation has been found between the vaccinations against influenza, hepatitis B, tetanus, human papillomavirus, measles, mumps, rubella, varicella zoster, tuberculosis, yellow fever, or typhoid fever and the risk of MS. Further research is needed for the potential protective implications of the tetanus and Bacillus Calmette–Guerin vaccines in MS patients. Nowadays with the emerging coronavirus disease 2019 (COVID-19) and recent vaccinations approval and arrival, the risk-benefit in MS patients with regards to safety and efficacy of COVID-19 vaccination in those treated with immunosuppressive therapies is of paramount importance. In this manuscript, we demonstrate how different vaccine types could be related to the immunopathogenesis of MS and discuss the risks and benefits of different vaccinations in MS patients. World Health Organization (WHO) estimates that between the years 2010 and 2015 more than 10 million deaths were prevented owing to vaccinations carried out around the world, making vaccines one of the most important triumph stories of modern age medicine [1] . On the other hand, vaccines have been a source of public controversy with regards to their safety. While generally considered safe in people with healthy immune systems, a special consideration needs to be taken when it comes to patients with altered immune status, namely with autoimmune diseases or under immunosuppression. Since vaccinations work on activating the immune system, it has been hypothesized that a stimulus of the immune system (e.g., a vaccine) may trigger an autoimmune disease or its exacerbation [2] . Multiple sclerosis (MS) is the most common cause of nontraumatic disability in young adults worldwide [3] . There are currently over 2 million people living with MS around the world, with nearly 1 million in the US alone [3, 4] . MS is a condition of the central nervous system (CNS) with proven autoimmune pathology. While the disease is incurable and, thus far, the scientific community has not been able to induce tolerance towards myelin self-antigens, MS is controlled by immunomodulating or immunosuppressive therapies. Both autoimmunity and immune therapies are potentially problematic with regards to vaccinating MS patients. Hence, many patients with MS and their physicians face an ongoing dilemma on whether or not to vaccinate. This should be especially important nowadays, when we are facing a global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which causes coronavirus disease 2019 (COVID- 19) , with vaccinations against SARS-CoV-2 approaching. Several aspects regarding MS must be taken into consideration when discussing immunizations. The aim of this review is to demonstrate how different vaccine types could be related to the immunopathogenesis of MS and to discuss the risks and benefits of different vaccinations in MS patients. MS is a chronic disease primarily driven by immune-mediated mechanisms. It is currently believed that autoreactive CNS-directed B and T cells are activated in the periphery, gaining access to the CNS and thus becoming effector cells. The mechanism of this activation is diverse and includes molecular mimicry or recognition of a CNS antigen released into the periphery from damaged CNS cells. It needs to be underscored that the primary antigen that triggers this response is yet unknown and possibly diverse in different patients [5] . Following damage to CNS tissue, resident immune cells within the CNS, particularly microglial cells, are activated. By upregulating their major histocompatibility complex (MHC) class I and II and cell surface co-stimulatory molecules, as well as secreting cytokines and chemokines, other immune cells such as CD4+ and CD8+ T cells, B cells, monocytes, macrophages and dendritic-like cells can easily find their way into CNS lesions [6] . At the same time, CNS antigens never seen by the immune system from the lesion are getting exposed and processed to be introduced to incoming T cells. CD8+ T cells recognize short peptides in the context of MHC class I, while CD4+ T cells recognize these peptides in the context of MHC class II molecules [7] . Major pathophysiological mechanisms of MS involve autoreactive Th-17 cells and T helper Th-1 CD4+ T cells which secrete interleukin IL-17 and IL-22 and interferon gamma (IFN-ү), respectively [8] . Th-17 cells increase the secretion of proinflammatory molecules, activate microglia, recruit other inflammatory cells and aid in augmenting permeability of the blood brain barrier (BBB) via disrupting tight junctions on BBB endothelial cells mainly through the action of IL-17 and IL-22. Th-1 cells increase the expression of MHC molecules of cells in the CNS, thereby participating in direct killing of oligodendrocytes and activating microglia [8, 9] . Each cell has its own role in the pathogenesis of MS. While CD4+ T cells recruit macrophages, the later release proinflammatory cytokines and toxic molecules; CD8+ T cells can directly attack MHC class I-expressing cells such as oligodendrocytes and neurons, and finally, B cells are stimulated and produce the pathogenic autoantibodies that aid myelin destruction [7] . The intrathecal production of humoral immune response, namely oligoclonal bands, represents an inseparable part of the disease [10] . However, the exact target specificity of these autoantibodies remains unknown and seems patient-specific [11] . Various autoreactive immunoglobulins found in MS patients' cerebral spinal fluid (CSF) and serum have been acknowledged to target CNS antigens and further support the involvement of humoral immunity in the pathogenesis of MS [12] . Of note are the intrathecal antibodies against Measles, Rubella and Varicella Zoster viruses [13] (see the discussion section). Another factor holding diagnostic and prognostic values include the light subunit of neurofilaments (NFL), which correlate with axonal injury and displays higher prevalence in progressive MS [12] . The ultimate effects of this inflammatory cascade, myelin sheath damage and BBB breakdown, lead to further axonal damage, loss and dysfunction as well as demyelination of CNS, which contribute to the clinical presentation of MS patients [6] . MS epidemiology is broad spectrum, comprising of genetic, environmental and infectious causes. Clinical studies support that genetic factors are directly linked to an increased Int. J. Mol. Sci. 2021, 22 , 3859 3 of 26 risk of developing MS although there is no evidence that MS is directly inherited. A study done in Canada demonstrated an increased familial risk of disease as high as 300-fold for monozygotic twins and up to 40-fold for biological 1st-degree relatives of patients with MS [14] . Another study which was done in Canada as well, focused on conjugal MS couples (both parents have MS) and assessed the recurrence risk in progeny of such pairs. The study estimated that the offspring of such relationships have a considerably increased risk of developing MS compared to both the lifetime risk for MS in the general population in Canada, which is approximately 0.2%, and the crude risk for MS in children of matings with only 1 affected parent which is estimated to be 0.7% [15] . In addition, the human leukocyte antigens (HLA), HLA-DR1501 and HLA-DQ0601 alleles, which encode for restriction elements of T lymphocytes, are associated with up to 4-fold increased risk of developing MS in Caucasian populations [16] . Besides a genetic association, studies have suggested that certain environmental factors such as low vitamin D levels and smoking may make specific individuals more susceptible to the disease [17] . Infectious mononucleosis caused by Epstein Barr virus (EBV) is also believed to play a major role in increasing the risk of developing MS [18] . MS also occurs more frequently in women and certain ethnic groups, including African-Americans, Asians and Hispanics/Latinos, but is most recurrently in Caucasians of northern European ancestry [19] . There are several distinct disease courses: relapsing remitting MS (RRMS), primary progressive MS (PPMS), secondary progressive MS (SPMS), clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS) [20] . RRMS is found in about 85% of MS patients, making it the most common subtype. It is identified by alternating periods of clearly defined neurological impairment such as bouts of weakness and fatigue, anomalous sensation, and balance and vision damage (defined as relapses) and periods of partial or complete recovery in which symptoms can either disappear or become permanent; during these, a patient is considered relatively clinically stable (defined as remissions). Of note, there is no apparent progression of the disease during remission periods [20] . PPMS is characterized by ongoing, worsening progression of neurological dysfunction from symptom onset, with accumulation of incapacities and lack of relapses and remission found in RRMS [20] . SPMS is traditionally detected retrospectively, following a primary relapsing and remitting course after which untreated patients ultimately advance into SPMS. Disease burden steadily increases as clinical disability becomes more apparent and relapses become less frequent and eventually disappear [20] . CIS is defined as the first episode of neurological demyelinating CNS pathology symptoms which last more than 24 h. It does not meet the criteria for MS diagnosis due to lack of dissemination in time and space [21] . These may include optic neuritis (ON), transverse myelitis, brainstem syndromes and cerebral hemispheres pathologies. CIS may or may not progress into clinically definitive MS in the future time. The presence and amount of brain magnetic resonance imaging (MRI) abnormalities are highly suggestive of risk of progression to definite MS conversion [21, 22] . Although the last is not considered a separate MS phenotype, RIS identifies patients with CNS anomalies on MRI reminiscent of MS demyelination lesions not explained by another diagnosis, in the absence of neurological symptoms on physical examination [20] . There are few clinical studies that support a strong likelihood of patients diagnosed with RIS to further develop radiological and clinical progression or even meeting the criteria for MS years after being diagnosed with RIS [23] [24] [25] [26] . The hallmark pathology of MS is plaques. They affect chiefly white matter of the brain, spinal cord and optic nerve but may involve cerebral cortex as well. The plaques are essentially a combination of inflammation, demyelination and axonal injury or loss [27] . Although they are found in all subtypes of MS, plaques exhibit fundamental differences. These profound heterogenicities manifest as variable degrees of different cell damage levels and inflammatory response and can be histologically distinguished as active, chronic or remyelinated lesions [28] . Active lesions are common in RRMS. They are identified as distinctive focal plaques of demyelination, inconstant degree of axonal loss that is relatively preservative, perivascular and parenchymal inflammatory infiltrates and reactive gliosis [28] . Remyelinated lesions are commonly seen at the boundaries of these active plaques. They encompass thin myelinated axons and numerous oligodendrocyte precursor cells [28] . Chronic lesions, which are seen in the progressive courses, display more extensive demyelination and axonal injury and limited low-grade active inflammation with diffuse gray and white matter atrophy [27, 28] . The two fundamental halves of the immune system are the innate and adaptive immunities. These cooperate with one another repeatedly throughout life, each taking care of different tasks to provide an efficacious and continuous immune response [29] . Innate immunity provides an immediate response through recognizing danger signals found on pathogens. Situated at "hot" susceptible anatomic sites, the physical barriers and internal defenses, such as acidic environments, temperature changes, mucus and cilia components, complement pathways and various cell types including mononuclear phagocytes, granulocytic cells, natural killer cells and dendritic cells and associated products like lysozymes, interferons and collectins, being equipped with various tools allowing them to quickly fight nonspecific infections. The innate immune system can either work independently and potentially eradicate pathogens without assistance from the adaptive system, or it can combine forces with and stimulate the adaptive system to become involved [29] . Adaptive immunity which is slower in response acts through recognizing specific proteins ultimately inducing tools for targeting specific pathogens. It is composed of B cells and T cells that exert their effects through humoral-immunity by means of antibodies, and cell-mediated immunity by means of CD4+ helper cells and CD8+ cytotoxic cells, respectively. It utilizes an ongoing mechanism that encourages a memory response that lasts years. This acquired immunity is achieved by either passive or active means and can be done by natural or artificial sources [29] . Vaccine-induced protection is achieved either by antibodies, T cell-dependent factors or by a combination of the two, which ultimately induces a cascade of mechanisms and mediators such as cytokines and neutralizing or antitoxic antibodies. There are 5 main types of vaccines: live-attenuated, inactivated, toxoid, subunit ecombinant\ polysaccharide World Health Association. 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