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Autoimmunity and PBM

By Jan Tunér

Autoimmunity is the system of immune responses of an organism against its own healthy cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Prominent examples include celiac disease, diabetes mellitus type 1, systemic lupus erythematosus (SLE), Sjögren’s syndrome, rheumatoid arthritis (RA), ankylosing spondylitis, multiple sclerosis and autoimmune hypo thyroiditis, to mention a few. Autoimmune diseases are very often treated with steroids. Can they also be treated with PBM? The literature for each separate condition is limited, so the scientific documentation is not too convincing. On the other hand, these conditions affect millions and the traditional therapies do not lead to a cure but rather to limitations of the symptoms.

Already in 1993, Takaduma (Possible application of the laser in immunobiology. Keio J Med. 1993 Dec;42(4):180-2) pointed at the potential of PBM for such conditions. Takaduma writes:

The human immune system acts a defence mechanism against exogenous or indigenous potentially harmful bodies, such as bacteria and viruses. The major histocompatibility complex (MHC class I and class II antigens) form key elements of legitimate body components, and the organization of MHC molecules allows T-lymphocytes to distinguish between legitimate and foreign bodies. On detection of a foreign component, T-cells activate the necessary pathways for destruction of the foreign body. Occasionally however the system breaks down and the result is a disease of an autoimmune nature. Both visible light and infrared low reactive-level laser therapy (LLLT) has been shown to act on immune system cells in a number of ways, activating the irradiated cells to a higher level of activity. Infrared LLLT has been shown to increase both the phagocytic and chemotactic activity of human leukocytes in vitro, for example. This is an example of photobiological activation. Photobiological cell-specific destruction is also possible using doses of low incident laser energy on cells which have been photosensitized for the specific wavelength of the laser, such as in photodynamic therapy (PDT) for superficial cancers. LLLT has also been shown to act directly and selectively on the autoimmune system, restoring immunocompetence to immunocompetence cells. Although much more research needs to be done, there are enough experimental and clinical data to show that the laser, and LLLT in particular, has a possibly exciting role both in immunobiological therapy for diseases of the immune system, and to activate and boost the normal reaction of the immune system components against harmful foreign bodies.

PBM is known to have a non-specific stimulation of cells in a reduced state and there are no known serious side effects. Therefore, it seems reasonable to look further into the potential of PBM as an adjunct therapy for such conditions. In this article, we will have a brief look at the available scientific documentation for three autoimmune conditions.

 

Autoimmune thyroiditis, scientific reports.

  1. Höfling DB, Chavantes MC, Juliano AG, Cerri GG, Knobel M, Yoshimura EM, Chammas MC. Assessment of the effects of low-level laser therapy on the thyroid vascularization of patients with autoimmune hypothyroidism by color Doppler ultrasound. ISRN Endocrinol. 2012;2012:126720.

Chronic autoimmune thyroiditis (CAT) frequently alters thyroid vascularization, likely as a result of the autoimmune process. To evaluate the effects of low-level laser therapy (LLLT) on the thyroid vascularization of patients with hypothyroidism induced by CAT using color Doppler ultrasound parameters. In this randomized clinical trial, 43 patients who underwent levothyroxine replacement for CAT-induced hypothyroidism were randomly assigned to receive either 10 sessions of LLLT (L group, n = 23) or 10 sessions of a placebo treatment (P group, n = 20). Color Doppler ultrasounds were performed before and 30 days after interventions. To verify the vascularity of the thyroid parenchyma, power Doppler was performed. The systolic peak velocity (SPV) and resistance index (RI) in the superior (STA) and inferior thyroid arteries (ITAs) were measured by pulsed Doppler. Results. The frequency of normal vascularization of the thyroid lobes observed in the post intervention power Doppler examination was significantly higher in the L than in the P group (P = 0.023). The pulsed Doppler examination revealed an increase in the SPV of the ITA in the L group compared with the P group. No significant differences in the SPV of the STA and in the RI were found between the groups. These results suggest that LLLT can ameliorate thyroid parenchyma vascularization and increase the SPV of the ITA of patients with hypothyroidism caused by CAT.

  1. Höfling DB, Chavantes MC, Juliano AG, Cerri GG, Knobel M, Yoshimura EM, Chammas MC. Low-level laser in the treatment of patients with hypothyroidism induced by chronic autoimmune thyroiditis: a randomized, placebo-controlled clinical trial. Lasers Med Sci. 2013 May;28(3):743-53.

Chronic autoimmune thyroiditis (CAT) is the most common cause of acquired hypothyroidism, which requires lifelong levothyroxine replacement therapy. Currently, no effective therapy is available for CAT. Thus, the objective of this study was to evaluate the efficacy of low-level laser therapy (LLLT) in patients with CAT-induced hypothyroidism by testing thyroid function, thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb), and ultrasonographic echogenicity. A randomized, placebo-controlled trial with a 9-month follow-up was conducted from 2006 to 2009. Forty-three patients with a history of levothyroxine therapy for CAT-induced hypothyroidism were randomly assigned to receive either 10 sessions of LLLT (830 nm, output power of 50 mW, and fluence of 707 J/cm²; L group, n=23) or 10 sessions of a placebo treatment (P group, n=20). The levothyroxine was suspended 30 days after the LLLT or placebo procedures. Thyroid function was estimated by the levothyroxine dose required to achieve normal concentrations of T3, T4, free-T4 (fT4), and thyrotropin after 9 months of postlevothyroxine withdrawal. Autoimmunity was assessed by measuring the TPOAb and TgAb levels. A quantitative computerized echogenicity analysis was performed pre- and 30 days postintervention. The results showed a significant difference in the mean levothyroxine dose required to treat the hypothyroidism between the L group (38.59 ± 20.22 μg/day) and the P group (106.88 ± 22.90 μg/day, P<0.001). Lower TPOAb (P=0.043) and greater echogenicity (P<0.001) were also noted in the L group. No TgAb difference was observed. These findings suggest that LLLT was effective at improving thyroid function, promoting reduced TPOAb-mediated autoimmunity and increasing thyroid echogenicity in patients with CAT hypothyroidism.

 

  1. Höfling DB, Chavantes MC, Acencio MM, Cerri GG, Marui S, Yoshimura EM, Chammas MC. Effects of low-level laser therapy on the serum TGF-β1 concentrations in individuals with autoimmune thyroiditis. Photomed Laser Surg. 2014 Aug;32(8):444-9.

The objective of this study was to evaluate the serum concentration of transforming growth factor-β1 (TGF-β1) after low-level laser therapy (LLLT) in patients with hypothyroidism resulting from chronic autoimmune thyroiditis (CAT). Certain data indicate that LLLT is effective in patients with hypothyroidism caused by CAT; however, the mechanisms of action of LLLT in thyroid tissue are unknown. Cytokines could play a role in the response to LLLT.

A randomized, placebo-controlled trial included 43 patients with a history of levothyroxine therapy for CAT-induced hypothyroidism. The patients were randomly assigned to receive either 10 sessions of LLLT (830 nm, 50 mW output power, and 707 J/cm² fluence; L group, n=23) or 10 sessions of a placebo treatment (P group, n=20) twice a week. Levothyroxine was maintained at the same dose during the entire study period. TGF-β1 was measured both pre-intervention and 30 days post-intervention in both groups. The differences were calculated between the TGF-β1 values observed 30 days post-intervention and the pre-intervention TGF-β1 values for each group (intragroup).

Comparing the differences in TGF-β1 levels between the L group (874.9±541.7 pg/mL) and the P group (-128.4±832.8 pg/mL) revealed that there was a statistically significant increase in TGF-β1 levels 30 days post-intervention in group L compared with the placebo group (p=0.0379). This finding suggested that the significant increase in serum TGF-β1 levels in patients with CAT-induced hypothyroidism was associated with the thyroid LLLT procedure. Future studies of the effect of LLLT on TGF-β1 gene expression in thyroid tissue are necessary to confirm these findings.

 

Multiple sclerosis

 

Multiple sclerosis is the most common autoimmune disorder affecting the central nervous system. In 2013, about 2.3 million people were affected globally with rates varying widely in different regions and among different populations. That year about 20,000 people died from MS, up from 12,000 in 1990. The disease usually begins between the ages of 20 and 50 and is twice as common in women as in men.

 

  1. Kubsik A, Klimkiewicz P, Woldańska-Okońska M. [Application of laser therapy in the physiotherapy of patients with multiple sclerosis]. Wiad Lek. 2012;65(1):55-61.[Article in Polish]

Multiple sclerosis is a chronic disease of the nervous system, which main manifestations are disseminated demyelinated the changes in the central nervous system. The pathogenesis of this disease is still not known, the curative treatment is not possible. In connection with the alleged autoimmune genesis of MS patients are administered immunomodulatory drugs. Patients with multiple sclerosis suffer from a number of symptoms associated with this disease. The aim of this article is to present the main clinical symptoms characteristic of MS and to present biological effects of low-energy lasers used in the treatment of multiple sclerosis.

 

  1. Kubsik A, Klimkiewicz R, Janczewska K, Klimkiewicz P, Jankowska A, Woldańska-Okońska M. Application of laser radiation and magnetostimulation in therapy of patients with multiple sclerosis. ; 2016 Feb 18;38(2):183-90.

The material studied consisted of 120 patients of both sexes (82 women and 38 men) aged 21-81 years. The study involved patients with a diagnosis of multiple sclerosis. The aim of the study was to evaluate the effect of laser radiation and other therapies on the functional status of patients with multiple sclerosis.

Patients were randomly divided into four treatment groups. The evaluation was performed three times - before the start of rehabilitation, immediately after rehabilitation (21 days of treatment) and subsequent control - 30 days after the patients leave the clinic. The following tests were performed for all patients to assess functional status: Expanded Disability Status Scale (EDSS) of Kurtzke and Barthel Index. Results of all testing procedures show that the treatment methods are improving the functional status of patients with multiple sclerosis, with the significant advantage of the synergistic action of laser and magneto stimulation. The combination of laser and magneto stimulation significantly confirmed beneficial effect on quality of life. The results of these studies present new scientific value and are improved compared to program of rehabilitation of patients with multiple sclerosis by laser radiation which was previously used.

This study showed that synergic action of laser radiation and magneto stimulation has a beneficial effect on improving functional status, and thus improves the quality of life of patients with multiple sclerosis. The effects of all methods of rehabilitation are persisted after cessation of treatment applications, with a particular advantage of the synergistic action of laser radiation and magneto stimulation, which indicates the possibility to elicitation in these methods the phenomenon of the biological hysteresis

 

  1. Kubsik A, Klimkiewicz R, Klimkiewicz P, Janczewska K, Jankowska A, Kociuga N, Woldańska-Okońska M. [The overall assessment of the quality of the physical health of patients with multiple sclerosis after the application of physical therapy. Part 1]. Wiad Lek. 2016;69(1 Pt 2):69-76.

The study involved 120 patients with multiple sclerosis at the age of 21 - 81 years. Patients were divided into four groups, and the test was performed three times. In the first group was used laser therapy, group II laser and magnetostimulation, in the third group kinesiotherapy in the fourth group magnetostimulation. In all patients MSQOL (Quality of Life Questionnaire-54) was carried out, this survey analyzed overall assessment of physical health. In all test groups was observed tends to decrease as a result of a point in Quality of Life Questionnaire MSQOL-54 and continuation in this relationship even after cessation of use of these therapies. The correlation between the two groups showed a statistically significant result at the level of p <0.001 in the group I and II in relation to group III and IV.

Synergic action of laser radiation and magnetic stimulation, causing a plurality of changes at the cellular and tissue level, has a beneficial effect on improving functional status, and thereby improves the quality of life of patients with multiple sclerosis. Thanks to physical therapy, it is possible to achieve long-term effects of therapy, which proves the biological hysteresis phenomenon. Such results cannot be achieved with using monotherapy only - by kinesiotherapy.

 

  1. Gonçalves ED, Souza PS, Lieberknecht V, Fidelis GS, Barbosa RI, Silveira PC, de Pinho RA, Dutra RC. Low-level laser therapy ameliorates disease progression in a mouse model of multiple sclerosis. Autoimmunity. 2016;49(2):132-42.

Multiple sclerosis (MS) is an autoimmune demyelinating inflammatory disease characterized by recurrent episodes of T cell-mediated immune attack on central nervous system (CNS) myelin, leading to axon damage and progressive disability. The existing therapies for MS are only partially effective and are associated with undesirable side effects. Low-level laser therapy (LLLT) has been clinically used to treat inflammation, and to induce tissue healing and repair processes. However, there are no reports about the effects and mechanisms of LLLT in experimental autoimmune encephalomyelitis (EAE), an established model of MS. Here, we report the effects and underlying mechanisms of action of LLLT (660 nm and 904 nm) irradiated on the spinal cord during EAE development. EAE was induced in female C57BL/6 mice by immunization with MOG35-55 peptide emulsified in complete Freund’s adjuvant. Our results showed that LLLT consistently reduced the clinical score of EAE and delayed the disease onset, and also prevented weight loss induced by immunization. Furthermore, these beneficial effects of LLLT seem to be associated with the down-regulation of NO levels in the CNS, although the treatment with LLLT failed to inhibit lipid peroxidation and restore antioxidant defence during EAE. Finally, histological analysis showed that LLLT blocked neuro-inflammation through a reduction of inflammatory cells in the CNS, especially lymphocytes, as well as preventing demyelination in the spinal cord after EAE induction. Together, our results suggest the use of LLLT as a therapeutic application during autoimmune neuroinflammatory responses, such as MS.

 

  1. Cezary Peszyñski-Drews, Andrzej Klimek, Marek Sopiñskia, Dominik Obrzejta. Laser biostimulation of the patients suffering from multiple sclerosis in respect of biological influence of laser light. Laser Technology VII: Applications of Lasers, Wieslaw L. Wolinski, Zdzislaw Jankiewicz, Ryszard Romaniuk, Editors, Proceedings of SPIE Vol. 5229 (2003): 101-103.

22 patients with a diagnosis of a primarily or secondarily progressing form of multiple sclerosis were selected for laser therapy. These were patients suffering from this disease for many years, with a significant degree of disability. Each patient’s disability was assessed on EDSS Kurtzki scale, and the minimum result necessary for entering the therapy was 5.5 points. Each patient’s diagnosis was verified with magnetic resonance test (NMR), which identified foci of demyelination. The analysed group consisted of 19 females and 3 males, 35 – 60 years of age, the average age was 47.13 years, and duration of the disease varied from 2 to 25 years, the average duration was 13.77 years. The patients were irradiated with the use of helium — neon laser (632.8 nm) of 10 mW at the outlet of the light guide. Multipoint contact irradiation was applied. Each series of irradiation consisted of 21 daily (except Sundays) sessions, lasting 10 minutes each time. 12 patients out of this group were subjected to one series of irradiation, the rest of the group — two or three series, whereas in the case of the latter, the interval between each series of irradiation lasted two months. After completion of each series, patients were subjected to neurological tests under supervision of the same doctor, who selected them for the therapy.

After the completion of laser therapy the results obtained fell into three categories: I-st — patients did not report any subjective tactile sensation improvement. Neurological tests did not identify any changes, either. Il-nd — patients reported subjective improvement, such as better appetite, numbness reduction, urination imperative reduction, while neurological tests did not identify any changes. III-rd — patient reported subjective improvement, confirmed by neurological tests which also identified reduction of disability by at least I point on EDSS Kurtzki scale ( which proves that the improvement could not have been reported as a result of a mere subjected sensation). Thus, 7 (31.8%) patients were classed for the I-st group, 7 (31.8%) for the II-nd group, and 8 (36.4%) for the III-rd group.

Apart from their neurological condition, patients assessing the results of laser therapy they had undergone, stressed such changes as: muscular strength improvement, motor drive improvement, vitality, mental comfort improvement, lower ataxiae, better walking skill, muscular tone reduction, less frequent urinating during the day as well as during the night, balance improvement.

 

Familial amyotrophic lateral sclerosis (FALS).

There is evidence that the immune system, particularly immunologic cells in the nervous system known as microglia, can be both beneficial and harmful in ALS. Microglia may be protective up to a certain point and then become damaging. Modifying the actions of the immune system is an active area of ALS research.

 

Moges H, Vasconcelos O M, Campbell W W, Borke R C, McCoy J A, Kaczmarczyk L, Feng J, Anders J J. Light therapy and supplementary Riboflavin in the SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis (FALS). Lasers Surg Med. 2009; 41 (1): 52-59.

Familial amyotrophic lateral sclerosis (FALS) is a neurodegenerative disease characterized by progressive loss of motor neurons and death. Mitochondrial dysfunction and oxidative stress play an important role in motor neuron loss in ALS. Light therapy (LT) has biomodulatory effects on mitochondria. Riboflavin improves energy efficiency in mitochondria and reduces oxidative injury. The purpose of this study was to examine the synergistic effect of LT and riboflavin on the survival of motor neurons in a mouse model of FALS.

G93A SOD1 transgenic mice were divided into four groups: Control, Riboflavin, Light, and Riboflavin+Light (combination). Mice were treated from 51 days of age until death. A single set of LT parameters was used: 810 nm diode laser, 140 mW output power, 1.4 cm² spot area, 120 seconds treatment duration, and 12 J/cm² energy density. Behavioural tests and weight monitoring were done weekly. At end stage of the disease, mice were euthanized, survival data was collected and immunohistochemistry and motor neuron counts were performed.

There was no difference in survival between groups. Motor function was not significantly improved with the exception of the rotarod test which showed significant improvement in the Light group in the early stage of the disease. Immunohistochemical expression of the astrocyte marker, glial fibrillary acidic protein, was significantly reduced in the cervical and lumbar enlargements of the spinal cord as a result of LT. There was no difference in the number of motor neurons in the anterior horn of the lumbar enlargement between groups.

The lack of significant improvement in survival and motor performance indicates study interventions were ineffective in altering disease progression in the G93A SOD1 mice. Our findings have potential implications for the conceptual use of light to treat other neurodegenerative diseases that have been linked to mitochondrial dysfunction.

 

More about the mechanisms

 

Song S, Zhou F, Chen WR, Xing D. Low-level laser therapy regulates microglial function through Src-mediated signaling pathways: implications for neurodegenerative diseases. J Neuroinflammation. 2012 Sep 18;9:219.

 

Activated microglial cells are an important pathological component in brains of patients with neurodegenerative diseases. The purpose of this study was to investigate the effect of He-Ne (632.8 nm, 64.6 mW/cm²) low-level laser therapy (LLLT), a non-damaging physical therapy, on activated microglia, and the subsequent signaling events of LLLT-induced neuroprotective effects and phagocytic responses.

To model microglial activation, we treated the microglial BV2 cells with lipopolysaccharide (LPS). For the LLLT-induced neuroprotective study, neuronal cells with activated microglial cells in a Transwell cell-culture system were used. For the phagocytosis study, fluorescence-labeled microspheres were added into the treated microglial cells to confirm the role of LLLT.

Our results showed that LLLT (20 J/cm²) could attenuate toll-like receptor (TLR)-mediated proinflammatory responses in microglia, characterized by down-regulation of proinflammatory cytokine expression and nitric oxide (NO) production. LLLT-triggered TLR signaling inhibition was achieved by activating tyrosine kinases Src and Syk, which led to MyD88 tyrosine phosphorylation, thus impairing MyD88-dependent proinflammatory signaling cascade. In addition, we found that Src activation could enhance Rac1 activity and F-actin accumulation that typify microglial phagocytic activity. We also found that Src/PI3K/Akt inhibitors prevented LLLT-stimulated Akt (Ser473 and Thr308) phosphorylation and blocked Rac1 activity and actin-based microglial phagocytosis, indicating the activation of Src/PI3K/Akt/Rac1 signaling pathway.

The present study underlines the importance of Src in suppressing inflammation and enhancing microglial phagocytic function in activated microglia during LLLT stimulation. We have identified a new and important neuroprotective signaling pathway that consists of regulation of microglial phagocytosis and inflammation under LLLT treatment. Our research may provide a feasible therapeutic approach to control the progression of neurodegenerative diseases.

 

Links:

http://www.warsawvoice.pl/WVpage/pages/article.php/22147/article

http://spie.org/newsroom/5900-light-therapy-to-treat-autoimmune-disease

http://www.physiotherapyjournal.com/article/S0031-9406(15)01351-6/abstract

 

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