Autoimmune Pathology Research Articles

CMTM4 is a subunit of the IL-17 receptor and mediates autoimmune pathology

Interleukin-17A (IL-17A) is a key mediator of protective immunity to yeast and bacterial infections but also drives the pathogenesis of several autoimmune diseases, such as psoriasis or psoriatic arthritis. Here we show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor (IL-17R). CMTM4 constitutively associated with IL-17R subunit C to mediate its stability, glycosylation and plasma membrane localization. Both mouse and human cell lines deficient in CMTM4 were largely unresponsive to IL-17A, due to their inability to assemble the IL-17R signaling complex. Accordingly, CMTM4-deficient mice had a severe defect in the recruitment of immune cells following IL-17A administration and were largely resistant to experimental psoriasis, but not to experimental autoimmune encephalomyelitis. Collectively, our data identified CMTM4 as an essential component of IL-17R and a potential therapeutic target for treating IL-17-mediated autoimmune diseases.

Trichinella spiralis excretory-secretory antigens selectively inhibit the release of extracellular traps from neutrophils without affecting their additional antimicrobial functions

Neutrophil extracellular traps (NETs) are fiber structures composed of chromatin and granular proteins that capture and eliminate microorganisms. The NETs formation is induced in response to pathogens and physiological stimuli; however, some pathogens have developed strategies to evade NETs activity. Trichinella spiralis excretory-secretory (ES) antigens are proteins that allow the establishment of the parasite in the host, facilitating penetration, migration, nutrition, and survival. In this paper we described that ES antigens inhibit NETs release, since neutrophils incubated with these antigens maintains a delobulated nucleus, without the release fibers structures indicative of NETs. We also found that other antimicrobial functions of neutrophils, such as phagocytic activity, degranulation, and ROS production, remain unchanged after incubation with ES antigens. This is relevant since it could constitute a novel strategy for the treatment of autoimmune pathologies in which the formation of NETs performs an important role.

Ecotoxicological studies of surface and groundwater in the adjacent territories of the Shuakhevi HPP (Adjara AR)

In the pathogenesis of autoimmune diseases, including immune thrombocytopenia (ITP), maintenance of inflammation and the loss of immune tolerance is essential. Transforming growth factor-beta (TGF-β) is a regulatory cytokine with pleiotropic function. TGF-β inhibits differentiation of T helper (Th1, Th2) cells and promotes the development of peripheral Tregs. The aim of our study was to explore the plasma levels of TGF-β and to perform its correlative analyses with peripheral blood biomarkers of systemic inflammation (NLR, PLR, PMR, SII, dNLR) in patients with ITP who did not respond to the first line treatment and had splenectomy as a second line therapy. The concentrations of TGF-β in plasma was quantified using ELISA kits by eBioscience. Statistical analyses was performed using Graph Pad Prism - Mann Whitney U test; for the correlation analyses we used spearman rank correlation by SPSS program. Our study revealed that the level of TGF-β in patients with refractory ITP is significantly diminished compared to the healthy subjects or patients undergoing splenectomy for other reasons than autoimmune or malignant hematological pathologies. There was no correlation observed between the plasma concentrations of TGF-β and the peripheral blood biomarkers of systemic inflammation.

Ecotoxicological studies of surface and groundwater in the adjacent territories of the Shuakhevi HPP (Adjara AR)

In the pathogenesis of autoimmune diseases, including immune thrombocytopenia (ITP), maintenance of inflammation and the loss of immune tolerance is essential. Transforming growth factor-beta (TGF-β) is a regulatory cytokine with pleiotropic function. TGF-β inhibits differentiation of T helper (Th1, Th2) cells and promotes the development of peripheral Tregs. The aim of our study was to explore the plasma levels of TGF-β and to perform its correlative analyses with peripheral blood biomarkers of systemic inflammation (NLR, PLR, PMR, SII, dNLR) in patients with ITP who did not respond to the first line treatment and had splenectomy as a second line therapy. The concentrations of TGF-β in plasma was quantified using ELISA kits by eBioscience. Statistical analyses was performed using Graph Pad Prism - Mann Whitney U test; for the correlation analyses we used spearman rank correlation by SPSS program. Our study revealed that the level of TGF-β in patients with refractory ITP is significantly diminished compared to the healthy subjects or patients undergoing splenectomy for other reasons than autoimmune or malignant hematological pathologies. There was no correlation observed between the plasma concentrations of TGF-β and the peripheral blood biomarkers of systemic inflammation.

S2748 Necrobiotic Lung Nodules in Patient With Ulcerative Colitis

Introduction: Ulcerative colitis and Crohn’s disease are two forms of inflammatory bowel disease (IBD). 25-40% of IBD patients have extra-intestinal manifestations (EIM). Pulmonary manifestations are one of the rarest forms of EIM, particularly necrobiotic nodules. It is a challenge to diagnose as it presents with symptoms similar to autoimmune, vasculitis, or infectious pathologies. We present a rare case of a patient who was found to have necrobiotic lung nodules during an acute ulcerative colitis flare. Case Description/Methods: 44-year-old male with newly diagnosed ulcerative pancolitis, presented with diarrhea and hematochezia for 8 weeks and 4 weeks of leg ulcers. He denied any other symptoms. 4 months ago, he was started on high dose steroids and switched to vedolizumab, however began to relapse after steroids were tapered. On admission, vitals significant for tachycardia at 118 bpm. Physical exam was significant for lower extremity ulcers consistent with pyoderma gangrenosum. Labs significant for leukocytosis (16,500/µL), Hg of 6.8, and elevated CRP at 160.26. Findings were suggestive of IBD flare and he also underwent chest x-ray which showed multifocal nodular airspace opacities, which appeared to have developed cavitations. CT chest revealed bilateral pulmonary nodules. He underwent infectious, autoimmune and vasculitis work up including HIV, tuberculosis, bacterial, viral, endocarditis, ANA, ANCA as well as fungal serologies which were all negative. He had CT guided biopsies, which were suggestive of necrobiotic lung nodules. Repeat CT chest showed interval improvement in solid and cavitary nodules. Given extensive negative infectious work up and improvement with steroids and infliximab, his presentation was consistent with necrobiotic lung nodules secondary to uncontrolled inflammatory bowel disease. (Figure) Discussion: We describe a rare case of necrobiotic lung nodules as an extra-intestinal manifestation of uncontrolled ulcerative colitis. Histologically, these nodules are sterile aggregates of neutrophils, that can cavitate and have a high degree of resemblance to pyoderma gangrenosum in cases of IBD. Few cases of necrobiotic lung nodules with IBD have been reported and most of them had respiratory symptoms but our case did not present with respiratory manifestations. In conclusion, necrobiotic lung nodules should be considered as a differential diagnosis of lung nodules in patients with IBD while excluding any infectious etiologies as mandatory before starting treatment with steroids and biologics.Figure 1.: CT guided biopsy suggestive of necrobiotic lung nodule.

Podocyte expression of human phospholipase A2 receptor 1 causes immune-mediated membranous nephropathy in mice

Antibody-mediated autoimmune pathologies like membranous nephropathy are difficult to model, particularly in the absence of local target antigen expression in model organisms such as mice and rats; as is the case for phospholipase A2 receptor 1 (PLA2R1), the major autoantigen in membranous nephropathy. Here, we generated a transgenic mouse line expressing the full-length human PLA2R1 in podocytes, which has no kidney impairment after birth. Beginning from the age of three weeks, these mice spontaneously developed anti-human PLA2R1 antibodies, a nephrotic syndrome with progressive albuminuria and hyperlipidemia, and the typical morphological signs of membranous nephropathy with granular glomerular deposition of murine IgG in immunofluorescence and subepithelial electron-dense deposits by electron microscopy. Importantly, human PLA2R1-expressing Rag2-/- mice, which lack mature and functioning B and T lymphocytes, developed neither anti-PLA2R1 antibodies nor proteinuria. Thus, our work demonstrates that podocyte expression of human PLA2R1 can induce membranous nephropathy with an underlying antibody-mediated pathogenesis in mice. Importantly, this antibody-mediated model enables proof-of-concept evaluations of antigen-specific treatment strategies, e.g., targeting autoantibodies or autoantibody-producing cells, and may further help understand the autoimmune pathogenesis of membranous nephropathy.

MYC-mediated silencing of miR-181a-5p promotes pathogenic Th17 responses by modulating AKT3-FOXO3 signaling

SummaryPathogenic Th17 cells drive autoimmune pathology, but the molecular mechanisms underlying Th17 pathogenicity remain poorly understood. Here, we have shown that miR-181a-5p was significantly decreased in pathogenic Th17 cells, and it negatively regulated pathogenic Th17 cell responses in vitro and in vivo. Th17 cells overexpressing miR-181a-5p exhibited impaired ability to induce pathogenesis in an adoptive transfer model of experimental autoimmune uveitis (EAU). Mechanistically, miR-181a-5p directly targeted AKT3, diminishing AKT3-mediated phosphorylation of FOXO3, and thereby activating FOXO3, a transcriptional repressor of pathogenic Th17 cell program. Supporting this, decreasing miR-181a-5p and up-regulated AKT3 expression were found in uveitis patients. Furthermore, intravitreal administration of miR-181a-5p mimics in mice effectively attenuated clinical and pathological signs of established EAU. Collectively, our results reveal a previously unappreciated T cell-intrinsic role of miR-181a-5p in restraining autoimmunity and may provide a potential therapeutic target for uveitis treatment.

Systemic lupus erythematosus variants modulate the function of an enhancer upstream of TNFAIP3.

TNFAIP3/A20 is a prominent autoimmune disease risk locus that is correlated with hypomorphic TNFAIP3 expression and exhibits complex chromatin architecture with over 30 predicted enhancers. This study aimed to functionally characterize an enhancer ∼55 kb upstream of the TNFAIP3 promoter marked by the systemic lupus erythematosus (SLE) risk haplotype index SNP, rs10499197. Allele effects of rs10499197, rs58905141, and rs9494868 were tested by EMSA and/or luciferase reporter assays in immune cell types. Co-immunoprecipitation, ChIP-qPCR, and 3C-qPCR were performed on patient-derived EBV B cells homozygous for the non-risk or SLE risk TNFAIP3 haplotype to assess haplotype-specific effects on transcription factor binding and chromatin regulation at the TNFAIP3 locus. This study found that the TNFAIP3 locus has a complex chromatin regulatory network that spans ∼1M bp from the promoter region of IL20RA to the 3′ untranslated region of TNFAIP3. Functional dissection of the enhancer demonstrated co-dependency of the RelA/p65 and CEBPB binding motifs that, together, increase IL20RA and IFNGR1 expression and decreased TNFAIP3 expression in the context of the TNFAIP3 SLE risk haplotype through dynamic long-range interactions up- and downstream. Examination of SNPs in linkage disequilibrium (D’ = 1.0) with rs10499197 identified rs9494868 as a functional SNP with risk allele-specific increase in nuclear factor binding and enhancer activation in vitro. In summary, this study demonstrates that SNPs carried on the ∼109 kb SLE risk haplotype facilitate hypermorphic IL20RA and IFNGR1 expression, while suppressing TNFAIP3 expression, adding to the mechanistic potency of this critically important locus in autoimmune disease pathology.

Arid5a Mediates an IL-17-Dependent Pathway That Drives Autoimmunity but Not Antifungal Host Defense.

IL-17 contributes to the pathogenesis of certain autoimmune diseases, but conversely is essential for host defense against fungi. Ab-based biologic drugs that neutralize IL-17 are effective in autoimmunity but can be accompanied by adverse side effects. Candida albicans is a commensal fungus that is the primary causative agent of oropharyngeal and disseminated candidiasis. Defects in IL-17 signaling cause susceptibility to candidiasis in mice and humans. A key facet of IL-17 receptor signaling involves RNA-binding proteins, which orchestrate the fate of target mRNA transcripts. In tissue culture models we showed that the RNA-binding protein AT-rich interaction domain 5A (Arid5a) promotes the stability and/or translation of multiple IL-17-dependent mRNAs. Moreover, during oropharyngeal candidiasis, Arid5a is elevated within the oral mucosa in an IL-17-dependent manner. However, the contribution of Arid5a to IL-17-driven events in vivo is poorly defined. In this study, we used CRISPR-Cas9 to generate mice lacking Arid5a. Arid5a -/- mice were fully resistant to experimental autoimmune encephalomyelitis, an autoimmune setting in which IL-17 signaling drives pathology. Surprisingly, Arid5a -/- mice were resistant to oropharyngeal candidiasis and systemic candidiasis, similar to immunocompetent wild-type mice and contrasting with mice defective in IL-17 signaling. Therefore, Arid5a-dependent signals mediate pathology in autoimmunity and yet are not required for immunity to candidiasis, indicating that selective targeting of IL-17 signaling pathway components may be a viable strategy for development of therapeutics that spare IL-17-driven host defense.

Gut Dysbiosis and Fecal Microbiota Transplantation in Autoimmune Diseases.

Gut microbiota dysbiosis has recently been reported in a number of clinical states, including neurological, psychiatric, cardiovascular, metabolic and autoimmune disorders. Yet, it is not completely understood how colonizing microorganisms are implicated in their pathophysiology and molecular pathways. There are a number of suggested mechanisms of how gut microbiota dysbiosis triggers or sustains extraintestinal diseases; however, none of these have been widely accepted as part of the disease pathogenesis. Recent studies have proposed that gut microbiota and its metabolites could play a pivotal role in the modulation of immune system responses and the development of autoimmunity in diseases such as rheumatoid arthritis, multiple sclerosis or type 1 diabetes. Fecal microbiota transplantation (FMT) is a valuable tool for uncovering the role of gut microbiota in the pathological processes. This review aims to summarize the current knowledge about gut microbiota dysbiosis and the potential of FMT in studying the pathogeneses and therapies of autoimmune diseases. Herein, we discuss the extraintestinal autoimmune pathologies with at least one published or ongoing FMT study in human or animal models.

Systemic lupus erythematosus: history and modernity

Systemic lupus erythematosus (SLE) is a systemic autoimmune rheumatic disease of unknown etiology, characterized by hyperproduction of non-organ-specific autoantibodies to various components of the cell nucleus and the development of immune-inflammatory damage to internal organs. Currently, SLE is considered as a prototype of a systemic human autoimmune pathology, the central mechanism of immunopathogenesis of which is a violation of immunological tolerance to self-antigens, due to a complex interaction of genetic, epigenetic, environmental factors. The publication discusses the history of the study of SLE, the contribution of Russian scientists (V.A. Nasonova and others) to the study of th is problem, current trends in clinical and scientific research related to the improvement of diagnostic criteria and pharmacotherapy of this disease.

Forced Fox-P3 expression can improve the safety and antigen-specific function of engineered regulatory T cells

Regulatory T cells (Treg) are potent inhibitors of autoreactive T cells. The intracellular transcription factor FoxP3 controls the expression levels of a diverse set of genes and plays a critical role in programming functional Tregs. Although, antigen-specific Tregs are more potent than polyclonal Tregs in treating ongoing autoimmunity, phenotype plasticity associated with loss of FoxP3 expression in Tregs can lead to the conversion into antigen-specific effector T cells which might exacerbate autoimmune pathology. In this study, we designed a retroviral vector driving the expression of FoxP3 and a human HLA-DR-restricted TCR from the same promoter. Transduction of purified human Tregs revealed that all TCR-positive cells had elevated levels of FoxP3 expression, increased CD25 and CTLA4 expression and potent suppressive function. Elevated FoxP3 expression did not impair the in vitro expansion of engineered Tregs. Adoptive transfer into HLA-DR transgenic mice revealed that FoxP3+TCR engineered Tregs showed long-term persistence with stable FoxP3 and TCR expression. In contrast, adoptive transfer of Tregs engineered with TCR only resulted in the accumulation of TCR-positive, FoxP3-negative T cells which displayed antigen-specific effector function when stimulated with the TCR-recognised peptides. Our data indicate that forced expression of FoxP3 can prevent accumulation of antigen-specific effector T cells without impairing the engraftment and persistence of engineered Tregs.

Autoantibodies against Complement Classical Pathway Components C1q, C1r, C1s and C1-Inh in Patients with Lupus Nephritis.

Autoantibodies against the complement component C1q (anti-C1q) are among the main biomarkers in lupus nephritis (LN) known to contribute to renal injury. C1q, the recognition subcomponent of the complement classical pathway, forms a heterotetrameric complex with C1r and C1s, and can also associate a central complement regulator and C1 Inhibitor (C1-Inh). However, the frequency and the pathogenic relevance of anti-C1r, anti-C1s and anti-C1-Inh autoantibodies remain poorly studied in LN. In this paper, we screened for anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh autoantibodies and evaluated their association with disease activity and severity in 74 LN patients followed up for 5 years with a total of 266 plasma samples collected. The presence of anti-C1q, anti-C1r, anti-C1s and anti-C1-Inh was assessed by ELISA. IgG was purified by Protein G from antigen-positive plasma and their binding to purified C1q, C1r and C1s was examined by surface plasmon resonance (SPR). The abilities of anti-C1q, anti-C1r and anti-C1s binding IgG on C1 complex formation were analyzed by ELISA. The screening of LN patients’ plasma revealed 14.9% anti-C1q positivity; only 4.2%, 6.9% and 0% were found to be positive for anti-C1r, anti-C1s and anti-C1-Inh, respectively. Significant correlations were found between anti-C1q and anti-dsDNA, and anti-nuclear antibodies, C3 and C4, respectively. High levels of anti-C1q antibodies were significantly associated with renal histologic lesions and correlated with histological activity index. Patients with the most severe disease (A class according to BILAG Renal score) had higher levels of anti-C1q antibodies. Anti-C1r and anti-C1s antibodies did not correlate with the clinical characteristics of the LN patients, did not interfere with the C1 complex formation, and were not measurable via SPR. In conclusion, the presence of anti-C1q, but not anti-C1s or anti-C1r, autoantibodies contribute to the autoimmune pathology and the severity of LN.

Detection of Anti-Vimentin Antibodies in Patients with Sarcoidosis.

There is a need to further characterize the antibody response to vimentin in relation to its possible involvement in pathogenicity of sarcoidosis and other lung disorders. Objectives: We investigated serum samples from patients with sarcoidosis, healthy controls and controls with other non-infectious lung diseases., to evaluate levels and frequency of these antibodies. Materials and methods: A retrospective-prospective comparative study was performed in the years 2015–2019. Sera from 93 patients with sarcoidosis, 55 patients with non-infectious lung diseases and 40 healthy subjects was examined for presence of autoantibodies to mutated citrullinated vimentin (anti-MCV). Patients with elevated anti-MCV levels were tested for antibodies to a cyclic citrullinated peptide (anti-CCP) and citrullinated vimentin (anti-Sa). In all cases ELISA assays was used. The results were considered statistically significant at p-value less than 0.05. Results of the study: The high concentrations of anti-MCV antibodies were more frequent in patients with sarcoidosis (40.9% of the cases, 38/93), compared to the control groups (23.6% and 25.0% of cases, respectively). In sarcoidosis, clinical symptoms similar to the autoimmune pathology were described. A moderate positive correlation between the anti-MCV and anti-Sa antibodies (r = 0.66) was found in 13 patients with sarcoidosis. There was no significant difference between the levels of the anti-MCV and the anti-CCP in patients with non-infectious lung diseases and the healthy control group. Conclusion: Antibodies to citrullinated cyclic peptides are not significant in the pathogenesis of sarcoidosis and other investigated pulmonary diseases (COPD, granulomatosis with polyangiitis, alveolitis) and based on their low concentration, it can be assumed that citrullination and modification of vimentin is not a key factor in the development of an autoimmune response in patients with sarcoidosis.

Circulating interleukin-38 concentrations in healthy adults.

Interleukin (IL)-38 is the latest discovered member of the interleukin-1 family, which has anti-inflammatory properties similar to IL-36Ra. Several studies compared circulating IL-38 concentrations in healthy and diseased populations to characterize its role in both auto-immune and inflammatory pathologies, with both higher and lower concentrations being associated with certain diseases. However, in order to use IL-38 as a biomarker, a reference range in healthy adults is needed. To establish a reference IL-38 circulating concentration, accessible data from 25 eligible studies with IL-38 concentrations in healthy adults was collected. To validate the values found in literature, we measured IL-38 concentrations by enzyme-linked immunosorbent assay (ELISA) in several cohorts from our own institute. Additionally, the effect of blood collection techniques, freeze thawing cycles, and hemolysis on IL-38 measurements was assessed. To evaluate the importance of the genetic background of individuals as confounding factor of IL-38 synthesis, we used publicly available eQTL databases with matched data on allele frequencies in individuals of different ethnicities. Mean IL-38 concentrations in the various studies were weighted by their corresponding sample size, resulting in a weighted mean, and weighted upper and lower limits were calculated by mean ± 2 SD. Differences of over 10.000-fold were found in the weighted means between studies, which could not be attributed to the blood collection method or assessment of IL-38 in plasma or serum. Although IL-38 concentrations were markedly higher in Chinese then in European population studies, we could not show an association with the genetic background. From our analysis, a reference range for circulating IL-38 in healthy adults could thus not yet be established.

Immunoregulation via Cell Density and Quorum Sensing-like Mechanisms: An Underexplored Emerging Field with Potential Translational Implications.

Quorum sensing (QS) was historically described as a mechanism by which bacteria detect and optimize their population density via gene regulation based on dynamic environmental cues. Recently, it was proposed that QS or similar mechanisms may have broader applications across different species and cell types. Indeed, emerging evidence shows that the mammalian immune system can also elicit coordinated responses on a population level to regulate cell density and function, thus suggesting that QS-like mechanisms may also be a beneficial trait of the immune system. In this review, we explore and discuss potential QS-like mechanisms deployed by the immune system to coordinate cellular-level responses, such as T cell responses mediated via the common gamma chain (γc) receptor cytokines and the aryl hydrocarbon receptors (AhRs). We present evidence regarding a novel role of QS as a multifunctional mechanism coordinating CD4+ and CD8+ T cell behavior during steady state and in response to infection, inflammatory diseases, and cancer. Successful clinical therapies such as adoptive cell transfer for cancer treatment may be re-evaluated to harness the effects of the QS mechanism(s) and enhance treatment responsiveness. Moreover, we discuss how signaling threshold perturbations through QS-like mediators may result in disturbances of the complex crosstalk between immune cell populations, undesired T cell responses, and induction of autoimmune pathology. Finally, we discuss the potential therapeutic role of modulating immune-system-related QS as a promising avenue to treat human diseases.

Heterotropic roles of divalent cations in the establishment of allostery and affinity maturation of integrin αXβ2.

SUMMARYAllosteric activation and silencing of leukocyte β2-integrins transpire through cation-dependent structural changes, which mediate integrin biosynthesis and recycling, and are essential to designing leukocyte-specific drugs. Stepwise addition of Mg2+ reveals two mutually coupled events for the αXβ2 ligand-binding domain—the αX I-domain—corresponding to allostery establishment and affinity maturation. Electrostatic alterations in the Mg2+-binding site establish long-range couplings, leading to both pH− and Mg2+-occupancy-dependent biphasic stability change in the αX I-domain fold. The ligand-binding sensorgrams show composite affinity events for the αX I-domain accounting for the multiplicity of the αX I-domain conformational states existing in the solution. On cell surfaces, increasing Mg2+ concentration enhanced adhesiveness of αXβ2. This work highlights how intrinsically flexible pH− and cation-sensitive architecture endows a unique dynamic continuum to the αI-domain structure on the intact integrin, thereby revealing the importance of allostery establishment and affinity maturation in both extracellular and intracellular integrin events.

Regulation of CD4+ and CD8+ T Cell Biology by Short-Chain Fatty Acids and Its Relevance for Autoimmune Pathology.

The gut microbiota encodes a broad range of enzymes capable of synthetizing various metabolites, some of which are still uncharacterized. One well-known class of microbiota-derived metabolites are the short-chain fatty acids (SCFAs) such as acetate, propionate, butyrate and valerate. SCFAs have long been considered a mere waste product of bacterial metabolism. Novel results have challenged this long-held dogma, revealing a central role for microbe-derived SCFAs in gut microbiota-host interaction. SCFAs are bacterial signaling molecules that act directly on host T lymphocytes by reprogramming their metabolic activity and epigenetic status. They have an essential biological role in promoting differentiation of (intestinal) regulatory T cells and in production of the anti-inflammatory cytokine interleukin-10 (IL-10). These small molecules can also reach the circulation and modulate immune cell function in remote tissues. In experimental models of autoimmune and inflammatory diseases, such as inflammatory bowel disease, multiple sclerosis or diabetes, a strong therapeutic potential of SCFAs through the modulation of effector T cell function was observed. In this review, we discuss current research activities toward understanding a relevance of microbial SCFA for treating autoimmune and inflammatory pathologies from in vitro to human studies.

Elimination of iodine deficiency is a concern for the health of the nation. An excursion into the history, scientific aspects and the current state of the legal regulation of the problem in Russia

The article presents current data on the prevalence of thyroid diseases associated with iodine deficiency in Russia, focuses on the features of the comorbidity of iodine deficiency and autoimmune thyroid pathologies, methods for assessing the iodine supply of the population. Information about the study and prevention of iodine deficiency diseases (IDD) in the USSR and the Russian Federation is given. The history of legislative initiatives aimed at eliminating dietary iodine deficiency and preventing IDD is illustrated in detail. The ways of solving the problem of iodine deficiency at the present stage, both at the federal and regional levels, are proposed.

CAN LOCAL MILLIMETRIC WAVES EXPOSURE BE HELPFUL FOR INFLAMMATORY RHEUMATISM CARE? A 4 CASES REPORT ON RHEUMATOID ARTHRITIS AND ANKYLOSING SPONDYLITIS

Rheumatoid arthritis (RA) and ankylosing spondylitis (SPA) are painful autoimmune, acute or chronic pathologies the joints, muscles and other tissues. Global care implies both medical more or less aggressive therapies, and physical treatments ght against pain and stiffness, vicious positions, and also improve autonomy in daily life. Anti-inammatory properties of millimetric waves (MMW) have been identied since the end of 20th century, and recently tested using miniaturized MMW transmitter bracelet. We report here 4 cases (2SPA and 2RA) who experienced pain relief, functional and autonomy improvement, while limiting their intake of analgesics. Further extensive investigations are required.