ABSTRACT
Chikungunya virus (CHIKV) is a single-stranded RNA virus belonging to the family Togaviridae and genus Alphavirus that causes an acute febrile illness, chikungunya fever, which is transmitted to humans by Aedes species mosquitoes. During acute illness, patients have high fever, polyarthralgias or polyarthritis, maculopapular rash, headache, and myalgia that lasts for days to weeks. Following resolution of acute infection, a significant proportion of patients develop chronic chikungunya arthritis that can resemble rheumatoid arthritis. In this review, we first consider the historical background of infectious causes of inflammatory arthritis, and then the pathogenic and clinical manifestations of chronic chikungunya arthritis as a rheumatoid arthritis mimic. We believe that chronic chikungunya arthritis may be a postinfectious inflammatory process, and that an understanding of the parallels and differences between chronic chikungunya arthritis and rheumatoid arthritis may offer insights into better diagnosis and treatment of both diseases.
Subject(s)
Arthritis, Rheumatoid/etiology , Chikungunya Fever/complications , Arthritis, Rheumatoid/therapy , HumansABSTRACT
Introduction. Macrophage migration inhibitory factor (MIF) is a pleiotropic inflammatory cytokine with upstream regulatory roles in innate and adaptive immunity and is implicated in the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Several classes of MIF inhibitors such as small molecule inhibitors and peptide inhibitors are in clinical development. Areas covered. The role of MIF in the pathogenesis of RA and SLE is examined; the authors review the structure, physiology and signaling characteristics of MIF and the related cytokine D-DT/MIF-2. The preclinical and clinical trial data for MIF inhibitors are also reviewed; information was retrieved from PubMed and ClinicalTrials.gov using the keywords MIF, D-DT/MIF-2, CD74, CD44, CXCR2, CXCR4, Jab-1, rheumatoid arthritis, systemic lupus erythematosus, MIF inhibitor, small molecule, anti-MIF, anti-CD74, and peptide inhibitor. Expert opinion. Studies in mice and in humans demonstrate the therapeutic potential of MIF inhibition for RA and SLE. MIF- directed approaches could be particularly efficacious in patients with high expression MIF genetic polymorphisms. In patients with RA and SLE and high expression MIF alleles, targeted MIF inhibition could be a precision medicine approach to treatment. Anti-MIF pharmacotherapies could also be steroid-sparing in patients with chronic glucocorticoid dependence or refractory autoimmune disease.
Subject(s)
Arthritis, Rheumatoid/drug therapy , Intramolecular Oxidoreductases/antagonists & inhibitors , Lupus Erythematosus, Systemic/drug therapy , Macrophage Migration-Inhibitory Factors/antagonists & inhibitors , Animals , Arthritis, Rheumatoid/physiopathology , Humans , Intramolecular Oxidoreductases/genetics , Intramolecular Oxidoreductases/metabolism , Lupus Erythematosus, Systemic/physiopathology , Macrophage Migration-Inhibitory Factors/genetics , Macrophage Migration-Inhibitory Factors/metabolism , Mice , Polymorphism, Genetic , Precision Medicine/methodsABSTRACT
Here, we investigated the relationship of the age-associated expansion of IL-7 receptor alpha low (IL-7Rαlow ) effector memory (EM) CD8+ T cells with the global transcriptomic profile of peripheral blood cells in humans. We found 231 aging signature genes of IL-7Rαlow EM CD8+ T cells that corresponded to 15% of the age-associated genes (231/1,497) reported by a meta-analysis study on human peripheral whole blood from approximately 15,000 individuals, having high correlation with chronological age. These aging signature genes were the target genes of several transcription factors including MYC, SATB1, and BATF, which also belonged to the 231 genes, supporting the upstream regulatory role of these transcription factors in altering the gene expression profile of peripheral blood cells with aging. We validated the differential expression of these transcription factors between IL-7Rαlow and high EM CD8+ T cells as well as in peripheral blood mononuclear cells (PBMCs) of young and older adults. Finally, we found a significant association with influenza vaccine responses in older adults, suggesting the possible biological significance of the aging signature genes of IL-7Rαlow EM CD8+ T cells. The results of our study support the relationship of the expansion of IL-7Rαlow EM CD8+ T cells with the age-associated changes in the gene expression profile of peripheral blood cells and its possible biological implications.
Subject(s)
Aging/immunology , CD8-Positive T-Lymphocytes/immunology , Immunologic Memory/immunology , Influenza Vaccines/immunology , Receptors, Interleukin-7/genetics , Transcriptome , Adult , Aged , Cohort Studies , Female , Gene Expression Profiling/methods , Gene Regulatory Networks/genetics , Healthy Volunteers , Humans , Male , Middle Aged , Transcription Factors/genetics , Young AdultABSTRACT
In 50% of patients, chikungunya fever (CHIKF) is followed by arthritic pain that is often chronic, painful, and disabling. To better define the spectrum of pain and disability in chronic CHIK arthritis (CCA), we evaluated 35 consecutive CCA patients seen in a Brazilian rheumatology clinic, using a pain Visual Analog Scale and the Health Assessment Questionnaire Disability Index. In our patients, pain and disability levels were of the same magnitude as are seen in other serious rheumatic diseases. The mean score for 19 patients with moderate disability was 1.42± 0.20 (median 1.37). The median HAQ-DI score for the entire group was 1.25. These findings underscore the morbidity imposed by CCA and the urgent need for improvements in management.
Subject(s)
Arthralgia/diagnosis , Arthritis/diagnosis , Chikungunya Fever/physiopathology , Disability Evaluation , Adult , Aged , Aged, 80 and over , Arthralgia/etiology , Arthritis/etiology , Brazil , Cross-Sectional Studies , Female , Humans , Male , Middle Aged , Severity of Illness Index , Young AdultABSTRACT
The Taxus phenylalanine aminomutase (PAM) enzyme converts several (S)-alpha-arylalanines to their corresponding (R)-beta-arylalanines. After incubating various racemic substrates with 100 microg of PAM for 20 h at 31 degrees C, each (S)-alpha-arylalanine was enantioselectively isomerized to its corresponding (R)-beta-product. With racemic starting materials, the ratio of (R)-beta-arylalanine product to the (S)-alpha-substrate ranged between 0.4 and 1.8, and the remaining nonproductive (R)-alpha-arylalanine became enriched. To utilize the (R)-alpha-isomer, the catalysis of a promiscuous alanine racemase from Pseudomonas putida (KT2440) was coupled with that of PAM to increase the production of enantiopure (R)-beta-arylalanines from racemic alpha-arylalanine substrates. The inclusion of a biocatalytic racemization along with the PAM-catalyzed reaction moderately increased the overall reaction yield of enantiopure beta-arylalanines between 4% and 19% (depending on the arylalanine), which corresponded to as much as a 63% increase compared to the turnover with the aminomutase reaction alone. The use of these biocatalysts, in tandem, could potentially find application in the production of chiral beta-arylalanine building blocks, particularly, as refinements to the process are made that increase reaction flux, such as by selectively removing the desired (R)-beta-arylalanine product from the reaction mixture.
