The Potential Negative Effects of Interleukin 1 B in Multiple Sclerosis Patients with MEFV Mutation

  • Abstract
  • FullTEXT
  • Additional info
  • Attachments
  • Related items
  • Video

Multiple sclerosis patients, who are carriers of MEditerranean FeVer (MEFV) gene mutation, have faster progression than the non-carriers. However, its underlying mechanism is not well understood. This article proposes the potential role of interleukin-1? (IL-1?) that may be responsible for this rapid progression. Mutations in MEFV, the gene encoding for protein pyrin, cause familial Mediterranean fever, lead to gain of pyrin function, resulting in inappropriate IL-1? release. Interleukin-1? is a major mediator of systemic inflammation and fever, and also it contributes to permeability of the blood-brain barrier in active lesions of multiple sclerosis. Moreover, IL-1? promotes apoptosis of neurons and oligodendrocytes that produce the myelin sheath, which insulates axons. Thus, inflammatory damage, the blood-brain barrier disfunction, effects of fever on the central nervous system (or Uhthoff?s phenomenon), and apoptosis of neurons and oligodendrocytes, which play an important role in the pathogenesis and clinical course of multiple sclerosis, can be induced by increased activation and release of IL-1? in the presence of MEFV gene mutations. Therefore, screening for MEFV mutations in patients with multiple sclerosis and treatment planning with IL-1? targeting drugs for the carriers, may be a logical idea that will be a source of inspiration for scientific studies.

ntroduction

MEditerranean FeVer (MEFV) gene locates on chromosome 16 and encodes a protein called pyrin [1,2]. Mutations of the MEFV gene result in increased synthesis of pyrin [3] and cause familial Mediterranean fever (FMF) that is the prototype of autoinflammatory syndromes [4]. Pyrin is a significant intracellular regulator of apoptosis, inflammation, and cytokine processing. It appears to be a major regulator of inflammation and innate immunity in patients with FMF [3], and a mutated pyrin probably results in uncontrolled inflammation [5]. Experimental studies [6,7] have demonstrated that MEFV gene mutations can lead to gain of pyrin function, resulting in inappropriate interleukin-1β (IL-1β) release [6], and pyrin mutations induce IL-1β activation and severe autoinflammation in mice [7]. Also, it has been found that mononuclear cells from FMF patients release higher levels of IL-1β [8]. IL-1β is a major cytokine of systemic inflammation and fever [9,10]. It increases the expression of other cytokines, such as tumor necrosis factor (TNF)-α and IL-6, and the chemokines as well as adhesion molecules [10]. Moreover, IL-1 plays an important role in the regulation of T-cells’ activation, and it is considered an essential cytokine for T helper (Th) cell differentiation [11].

Multiple sclerosis (MS) is a chronic and progressive inflammatory disorder of the central nervous system (CNS) that is generally considered to be autoimmune and characterized by widespread lesions, plaques and demyelination in the brain and spinal cord [12]. Multiple sclerosis lesions show a great heterogeneity in terms of structural and immunopathologic characteristics. This varies depending on the phase of the demyelinating activity. Whereas active lesions show dense macrophage infiltration, chronic inactive lesions are poor in cells. In chronic lesions, number of mature oligodendrocytes and axon density have prominently decreased, and remyelination is not complete [13,14].

Increased evidences indicate a strong genetic contribution to MS susceptibility, although others support the view that it is also influenced by environmental factors, such as virus infections, geographical distribution, smoking, hypovitaminosis D and exposure to sunlight [15,16]. Recent genetic studies confirmed that immunologically relevant genes within the major histocompatibility complex are especially implicate Th cell differentiation in the pathogenesis of MS [17].

Although the actual cause of MS is not known exactly, inflammation of the CNS is the primary reason of damage in this disease [18]. The specific factors that start this inflammation are still unknown. Approximately 87% of patients present with relapsing remitting MS (RRMS), characterized by acute attacks (relapses) followed by partial or full recovery (remission) [18]. Relapses result from acute focal inflammation of the CNS. The acute focal lesion is characterized by an inflammmatory central region and indistinct margin [14]. Increased proinflammatory cytokin IL-1β levels have been detected in MS lesions, and elevated IL-1β cerebrospinal fluid and serum lev¬els have also been reported in patients with RRMS in comparison to healthy controls [11].

To date there is no cure for MS, but treatment with IL-1 targeting drugs such as IFNβ and glatiramer acetate display beneficial effect by reducing the disease severity. Interleukin-1β activity is inhibited by the secreted form of IL-1 receptor antagonist whose production is increased in patients’ blood and induced in human monocytes by IFNβ and glatiramer acetate [19].

Discussion

Recent studies have found that MS patients, who are carriers of MEFV gene mutation, have faster progression than the non-carriers [20,21]. However, its mechanism has not been enlightened in full yet. This article proposes the potential role of IL-1β that may be responsible for this rapid progression.

MEFV gene mutations lead to gain of pyrin function, resulting in inappropriate IL-1β release [6], and pyrin mutations induce IL-1β activation and severe autoinflammation in mice [7]. Also, mononuclear cells from FMF patients release higher levels of IL-1β [8]. Moreover, a recent study by Yildirim et al. [22] confirmed the presence of increased IL-1β levels in FMF patients during attack-free period.

It has been shown that innate production of IL-1β is a risk factor for susceptibility and progression of relapse-onset MS [23]. Interleukin-1β is a major mediator of systemic inflammation [9,10], and inflammation of the CNS is the primary cause of damage in MS [18]. Interleukin-1β increases the expression of other proinflammatory cytokines, such as TNF-α and IL-6 [10]. Therefore, expressed MEFV mutations in MS patients can increase the inflammatory damage by proinflammatory cytokin IL-1β.

Moreover, IL-1β promotes apoptosis of neurons and oligodendrocytes, thereby contributing to the inflammation-mediated damage of the CNS parenchyma [11,24]. Researchers who investigated the active lesions of MS have described four different immunopathologic types [25,26]. These are demyelination associated with macrophages, demyelination related to antibody/complement, oligodendrogliopathy concurrent with apoptosis, and primary oligodendrocyte degeneration. Accordingly, while the 1st and 2nd types target the myelin, and the 3rd and 4th types target the oligodendrocytes. The oligodendrocytes of the CNS and the Schwann cells of the peripheral nervous system (PNS) are best known for making the myelin that sheaths and insulates neuronal axons [27]. The induction of apoptosis of neurons and oligodendrocytes due to increased IL-1β levels may delay and prevent the re-myelination of demyelinated axons. Thus, inflammation and demyelination, when combined by the effects of IL-1β, might increase the axonal damage and affect the prognosis of MS, because axonal degeneration causes irreversible neurological damage in MS [28].

In the existence of MEFV mutations, another factor causing rapid progression in MS may be BBB disfunction by IL-1β, because IL-1β contributes to permeability of the BBB in active MS lesions [11,29]. Owing to the function of BBB that is an endothelial barrier, CNS parencyma is immunologically protected. However, endothelial dysfunction, vascular damage and vasculitis, which occur in the existence of MEFV gene mutation [30,31], may cause the BBB deterioration that is an early and prominent event in the development of MS lesions [29]. Some studies [30] showing elevation of circulating markers of endothelial dysfunction and vascular damage such as thrombomodulin, adrenomedullin, nitrite, and acute-phase reactants during symptom-free intervals of FMF support this view. Furthermore, IL-1β is detected in active MS lesion in the microglia, astrocytes and in brain endothelial cells, where it contributes to BBB permeability via induction of the vascular endothelial growth factor-A, upregulation of adhesion molecules, and reactivation of the hypoxia-angiogenesis program [11,29]. All of these can lead to penetration of inflammatory cells or toxic substances from the vascular system to the CNS parenchyma, and cause rapid progression in MS.

On the other hand, high body temperature can also increase the MS symptoms. This condition is known as Uhthoff’s phenomenon [32]. It is explained by a conduction block because of the ionic channels properties change under high temperature [33]. However, the effect of heat changes on MS can be multi-factorial. Blockage of ion channels, changes in circulation, heat shock proteins, effects of serum calcium, and unidentified humoral substances can play a part in this effect [34]. Uhthoff’s phenomenon and the characteristic deterioration of MS symptoms by increased body temperature due to physical exercise may also be observed with triggering factors such as fever, hot meals, hot bath or shower, weather, menstruation, but also smoking and psychological stres [33]. Similarly, MEFV gene mutations can also raise the body temperature by increased release of IL-1β that is a potent pyrogenic cytokine, because healthy heterozygotes for MEFV mutations have higher than normal blood levels of acute phase reactants [20], and many FMF patients have continued subclinical inflammation during attack-free periods [35]. Now that the symptoms that accompany the fever are also caused by increased inflammation, MEFV mutations may exacerbate MS symptoms via production of IL-1β that is a major mediator of inflammation and fever. Probably the temperature will be higher in the CNS that is a closed area compared with the PNS and thus increased heat will enhance already existing CNS damage in MS [36].

Conclusion

In MS, inflammatory damage, apoptosis of neurons and oligodendrocytes, BBB disfunction, and Uhthoff’s phenomenon, which play an important role in the pathogenesis and clinical course of the disease, can be induced by increased activation and release of IL-1β in the presence of MEFV gene mutations. Probably the potential devastating effects of IL-1β can accelerate the course of the disease. Therefore, screening for MEFV mutations in MS patients and treatment planning with IL-1β targeting drugs for the carriers seems a reasonable idea that will be a source of inspiration for scientific studies.

Competing interests

The authors declare that they have no competing interests.

References

1. Onen F. Familial Mediterranean fever. Rheumatol Int 2006;26(6):489-96.

2. Chae JJ, Wood G, Richard K, Jaffe H, Colburn NT, Masters SL, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood 2008;112(5):1794–803.

3. Solak Y, Atalay H, Polat I, Bıyık Z, Gaipov A, Kucuk A, et al. A Case of Familial Mediterranean Fever After Renal Transplantation: From Phenotype II to I. Turk J Rheumatol 2012;27(2):140-3.

4. Savic S, Dickie LJ, Battellino M, Mc Dermott MF. Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol 2012;24(1):103-12.

5. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP, Feigenbaum L, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 2011;34(5):755-68.

6. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 2009;27:621–68.

7. Dinarello CA. Blocking IL-1 in systemic inflammation. J Exp Med 2005;201(9):1355-9.

8. Dinarello CA. Interleukin-1β. Crit Care Med 2005;33(12 Suppl):S460–2.

9. Sha Y, Markovic-Plese S. A role of IL-1R1 signaling in the differentiation of Th17 cells and the development of autoimmune diseases. Self Nonself 2011;2(1):35-42.

10. Ozdemir L, Asiret GD. A Holistic Look at Patients With Multiple Sclerosis: Focusing on Social Life, Household and Employment Issues. Turk J Phys Med Rehab 2011;57:19-24.

11. Pittock SJ, Lucchinetti CF. The pathology of MS: new insights and potential clinical applications. Neurologist 2007;13(2):45-56.

12. Raine CS. Novel Molecular Mechanisms in MS. Adv Stud Med 2004;4(4):316-21.

13. Hoffjan S, Akkad DA. The genetics of multiple sclerosis: an update 2010. Mol Cell Probes 2010;24(5):237-43.

14. Pierrot-Deseilligny C, Souberbielle JC. Is hypovitaminosis D one of the environmental risk factors for multiple sclerosis?. Brain 2010;133(7):1869-88.

15. Sawcer S, Hellenthal G, Pirinen M, Spencer CC, Patsopoulos NA, Moutsianas L, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 2011;476(7359):214-9.

16. Loma I, Heyman R. Multiple sclerosis: pathogenesis and treatment. Curr Neuropharmacol 2011;9(3):409-16.

17. Carpintero R, Burger D. IFNβ and glatiramer acetate trigger different signaling pathways to regulate the IL-1 system in multiple sclerosis. Commun Integr Biol 2011;4(1):112-4.

18. Unal A, Dursun A, Emre U, Tascilar NF, Ankarali H. Evaluation of common mutations in the Mediterranean fever gene in Multiple Sclerosis patients: is it a susceptibility gene? J Neurol Sci 2010;294(1-2):38-42.

19. Shinar Y, Livneh A, Villa Y, Pinhasov A, Zeitoun I, Kogan A, et al. Common mutations in the familial Mediterranean fever gene associate with rapid progression to disability in non-Ashkenazi Jewish multiple sclerosis patients. Genes Immun 2003;4(3):197-203.

20. Yildirim K, Uzkeser H, Keles M, Karatay S, Kiziltunc A, Kaya MD, et al. Relationship between serum interleukin-1beta levels and acute phase response proteins in patients with familial Mediterranean fever. Biochem Med (Zagreb) 2012;22(1):109-13.

21. de Jong BA, Huizinga TW, Bollen EL, Uitdehaag BM, Bosma GP, van Buchem MA, et al. Production of IL-1beta and IL-1Ra as risk factors for susceptibility and progression of relapse-onset multiple sclerosis. J Neuroimmunol 2002;126(1-2):172-9.

22. Dujmovic I, Mangano K, Pekmezovic T, Quattrocchi C, Mesaros S, Stojsavljevic N, et al. The analysis of IL-1 beta and its naturally occurring inhibitors in multiple sclerosis: The elevation of IL-1 reseptor antagonist and IL-1 receptor type II after steroid therapy. J Neuroimmunol 2009;207(1-2):101-6.

23. Lucchinetti C, Brück W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47(6):707-17.

24. Lassmann H, Brück W, Lucchinetti C. Heterogeneity of multiple sclerosis pathogenesis: implications for diagnosis and therapy. Trends Mol Med 2001;7(3):115-21.

25. Nave KA. Myelination and the trophic support of long axons. Nat Rev Neurosci 2010;11(4):275-83.

26. Trapp BD, Stys PK. Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009;8(3):280-91.

27. Argaw AT, Zhang Y, Snyder BJ, Zhao ML, Kopp N, Lee SC, et al. IL-1beta regulates blood-brain barrier permeability via reactivation of the hypoxia-angiogenesis program. J Immunol 2006;177(8):5574-84.

28. Yüksel S, Ayvazyan L, Gasparyan AY. Familial mediterranean Fever as an emerging clinical model of atherogenesis associated with low grade inflammation. Open Cardiovasc Med J 2010;4:51-6.

29. Aksu K, Keser G. Coexistence of vasculitides with Familial Mediterranean Fever. Rheumatol Int 2011;31(10):1263-74.

30. Humm AM, Beer S, Kool J, Magistris MR, Kesselring J, Rösler KM. Quantification of Uhthoff’s phenomenon in multiple sclerosis: a magnetic stimulation study. Clin Neurophysiol 2004;115(11):2493-501.

31. Stutzer P, Kesselring J. Wilhelm Uhthoff: a phenomenon 1853 to 1927. Int MS J 2008;15(3):90-3.

32. Guthrie TC, Nelson DA. Influence of temperature changes on multiple sclerosis: critical review of mechanisms and research potential. J Neurol Sci 1995;129(1):1-8.

33. Ben-Zvi I, Livneh A. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol 2011;7(2):105-12.

34. Alpayci M, Bozan N, Erdem S, Gunes M, Erden M. The possible underlying pathophysiological mechanisms for development of multiple sclerosis in familial Mediterranean fever. Med Hypotheses 2012;78(6):717-20.

Additional Info

  • Recieved: 17.12.2012
  • Accepted: 02.01.2013
  • Published Online: 02.01.2013
  • Printed: 01.05.2014
  • DOI: 10.4328/JCAM.1476
  • Author: Mahmut Alpayci, Yasemin Ozkan
  • Identifier: J Clin Anal Med. 2014;5(3):253-255
  • Index Page: 253-255
  • How to Cite: Mahmut Alpayci, Yasemin Ozkan. The Potential Negative Effects of Interleukin 1 B in Multiple Sclerosis Patients with MEFV Mutation. J Clin Anal Med. 2014;5(3):253-255
  • Running Title: Interleukin-1β in Multiple Sclerosis
Download attachments:
More in this category: New Adipokines and Cytokines »

Last Issued ACAM

Covers ACAM

Article & Author Search ACAM

Please publish modules in offcanvas position.