Involvement of B cells in the development of systemic sclerosis

Systemic sclerosis (SSc) is a rare intractable systemic disease that causes fibrosis and vasculopathy against a background of autoimmune abnormalities. Although the etiology is not yet fully understood, the type of autoantibodies detected in SSc is closely associated with disease severity and prognosis, supporting that those autoimmune abnormalities play an important role in the pathogenesis of SSc. Although the direct pathogenicity of autoantibodies found in SSc is unknown, many previous studies have shown that B cells are involved in the development of SSc through a variety of functions. Furthermore, a number of clinical studies have been conducted in which B-cell depletion therapy has been tried for SSc, and many of these studies have found B-cell depletion therapy to be effective for SSc. However, the involvement of B cells in pathogenesis is complex, as they not only promote inflammation but also play an inhibitory role. This article outlines the role of B cells in the development of SSc, including the latest research

Comprehensive autoantibody profiling in systemic autoimmunity by a highly-sensitive multiplex protein array

Comprehensive autoantibody evaluation is essential for the management of autoimmune disorders. However, conventional methods suffer from poor sensitivity, low throughput, or limited availability. Here, using a proteome-wide human cDNA library, we developed a novel multiplex protein assay (autoantibody array assay; A-Cube) covering 65 antigens of 43 autoantibodies that are associated with systemic sclerosis (SSc) and polymyositis/dermatomyositis (PM/DM). The performance of A-Cube was validated against immunoprecipitation and established enzyme-linked immunosorbent assay. Further, through an evaluation of serum samples from 357 SSc and 172 PM/DM patients, A-Cube meticulously illustrated a diverse autoantibody landscape in these diseases. The wide coverage and high sensitivity of A-Cube also allowed the overlap and correlation analysis between multiple autoantibodies. Lastly, reviewing the cases with distinct autoantibody profiles by A-Cube underscored the importance of thorough autoantibody detection. Together, these data highlighted the utility of A-Cube as well as the clinical relevance of autoantibody profiles in SSc and PM/DM

The differential role of L-selectin and ICAM-1 in Th1-type and Th2-type contact hypersensitivity.

Sensitization and challenge using DNFB induce contact hypersensitivity (CHS) with predominant type 1 helper (Th1) cell infiltration, whereas those using FITC generate CHS with Th2 cell infiltration. CHS results from inflammatory cell infiltration, a process that is highly regulated by the expression of multiple adhesion molecules. We attempted to determine the role of L-selectin and ICAM-1 in Th1- and Th2-type CHS induced by DNFB or FITC in mice lacking either L-selectin, ICAM-1, or both. Th1-type CHS induced by DNFB was inhibited by L-selectin and/or ICAM-1 deficiency, which was associated with reduced IFN-gamma expression. Similarly, Th2-type CHS induced by FITC was inhibited by L-selectin deficiency. However, Th2-type CHS was increased by ICAM-1 deficiency and accompanied by increased Th2 cytokine expression. Infiltration of in vitro-generated Th1 cells into the FITC-challenged skin decreased in ICAM-1-deficient mice, whereas in vitro-generated Th2 cell infiltration increased, suggesting that ICAM-1 mediates Th1 cell migration and that in the absence of ICAM-1, Th1 cell recruitment decreased, whereas relative Th2 cell migration increased. These results suggest that ICAM-1 mediates Th1 cell recruitment irrespective of DNFB or FITC and that L-selectin recruits Th1 cells in Th1-type CHS, whereas it recruits Th2 cells in Th2-type CHS

Increased Serum Levels of Tumor Necrosis Factor-like Ligand 1A in Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic skin disease with pruritus, affecting 5–20% of the population in developed countries. Though its cause varies from genetic polymorphisms to the environmental factors, the T-helper (Th) 2 inflammation is one of the main characteristic pathoses. TNF superfamily ligand A (TL1A) is a recently discovered cytokine, which is released by various immune cells and reported to have an ability to stimulate Th1, Th2, and Th17 responses. Its association was investigated in chronic inflammatory disease, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, its role on AD is unclear. To elucidate the association of TL1A in AD, we measured the serum TL1A levels in AD patients and healthy controls and performed the immunohistochemistry of TL1A. The result showed that the serum TL1A levels were higher in AD patients than healthy controls, and they positively correlated with the serum immunoglobulin E levels, serum Lactate dehydrogenase, and the number of eosinophils in peripheral blood. The immunohistochemistry of TL1A also showed TL1A expression in epithelium of AD samples. Because previous studies indicate TL1A has a certain role as an inflammation enhancer in Th2 and/or Th17 polarized disease, TL1A in AD may also has a role as an inflammation generator

Increased Serum Levels of Tumor Necrosis Factor-like Ligand 1A in Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic skin disease with pruritus, affecting 5–20% of the population in developed countries. Though its cause varies from genetic polymorphisms to the environmental factors, the T-helper (Th) 2 inflammation is one of the main characteristic pathoses. TNF superfamily ligand A (TL1A) is a recently discovered cytokine, which is released by various immune cells and reported to have an ability to stimulate Th1, Th2, and Th17 responses. Its association was investigated in chronic inflammatory disease, such as rheumatoid arthritis, inflammatory bowel disease, and psoriasis. However, its role on AD is unclear. To elucidate the association of TL1A in AD, we measured the serum TL1A levels in AD patients and healthy controls and performed the immunohistochemistry of TL1A. The result showed that the serum TL1A levels were higher in AD patients than healthy controls, and they positively correlated with the serum immunoglobulin E levels, serum Lactate dehydrogenase, and the number of eosinophils in peripheral blood. The immunohistochemistry of TL1A also showed TL1A expression in epithelium of AD samples. Because previous studies indicate TL1A has a certain role as an inflammation enhancer in Th2 and/or Th17 polarized disease, TL1A in AD may also has a role as an inflammation generator

The Role of Mammalian STK38 in DNA Damage Response and Targeting for Radio-Sensitization

Protein kinases, found in the nucleus and cytoplasm, play essential roles in a multitude of cellular processes, including cell division, proliferation, apoptosis, and signal transduction. STK38 is a member of the protein kinase A (PKA)/PKG/PKC family implicated in regulating cell division and morphogenesis in yeast and C. elegans. However, its function remained largely unknown in mammals. In recent years, advances in research on STK38 and the identification of its substrates has led to a better understanding of its function and role in mammals. This review discusses the structure, expression, and regulation of activity as a kinase, its role in the DNA damage response, cross-talk with other signaling pathways, and its application for radio-sensitization

Involvement of Molecular Mechanisms between T/B Cells and IL-23: From Palmoplantar Pustulosis to Autoimmune Diseases

Palmoplantar pustulosis (PPP) is a disease that causes recurrent blisters and aseptic pustules on the palms and soles. It has been suggested that both innate and acquired immunity are involved. In particular, based on the tonsils and basic experiments, it has been assumed that T and B cells are involved in its pathogenesis. In addition, the results of clinical trials have suggested that IL-23 is closely related to the pathogenesis. This review describes PPP and the genetic background, the factors involved in the onset and exacerbation of disease and its relation to the molecular mechanism. In addition, we describe the usefulness of biological therapy and its implications in relation to the importance in pathology, the pathogenesis of PPP, the importance of the role of the IL-23–Th17 axis and IL-36 in PPP. Furthermore, we describe an animal experimental model of PPP, the efficacy and mechanism of action of guselkumab, an anti-IL-23 antibody, the latest research, and finally the possibility for it to be effective for other autoimmune diseases

Pharmacotherapy of Itch—Antihistamines and Histamine Receptors as G Protein-Coupled Receptors

Itching can decrease quality of life and exacerbate skin symptoms due to scratching. Itching not only contributes to disease progression but also triggers complications such as skin infections and eye symptoms. Therefore, controlling itching is very important in therapeutic management. In addition to the well-known histamine, IL-31, IL-4 and IL-13 have recently been reported as factors that induce itching. Itching may also be caused by factors other than these histamines. However, we do not know the extent to which these factors are involved in each disease. In addition, the degree of involvement is likely to vary among individuals. To date, antihistamines have been widely used to treat itching and are often effective, suggesting that histamine is more or less involved in itchy diseases. This review discusses the ligand-receptor perspective and describes the dynamics of G protein-coupled receptors, their role as biased agonists, their role as inverse agonists, proactive antihistamine therapy, and drug selection with consideration of impaired performance and anti-PAF effects

Increased Red Blood Cell Distribution Width in the First Year after Diagnosis Predicts Worsening of Systemic Sclerosis-Associated Interstitial Lung Disease at 5 Years: A Pilot Study

The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) varies among individuals. Red blood cell distribution width (RDW) has been reported to be a predictor of idiopathic pulmonary fibrosis. However, there are no studies on the relationship between RDW and SSc-ILD. We conducted a retrospective study of 28 patients who were diagnosed with SSc-ILD on their first visit to our hospital and were followed-up for 5 years. The correlation between the changes in RDW, KL-6, and SP-D (ΔRDW, ΔKL-6, ΔSP-D) and the changes in percent-predicted forced lung volume and % carbon monoxide diffusion (Δ%FVC, Δ%DLco) was investigated. ΔRDW at 1 year after diagnosis was significantly inversely correlated with Δ%FVC at 5 years after diagnosis (r = −0.51, p < 0.001) and Δ%DLco at 5 years after diagnosis (r = −0.47, p < 0.001), whereas ΔKL-6 and ΔSP-D at 1 year were not correlated with Δ%FVC or Δ%DLco at 5 years. In the group of SSc-ILD patients with RDW increase in the first year after diagnosis, %FVC and %DLco were significantly lower than baseline at 3-, 4-, and 5-year assessments. In the group of patients without RDW increase in the first year, %FVC and %DLco did not decrease during the follow-up period. In conclusion, the changes in RDW in the first year after diagnosis may be useful surrogate markers to predict the long-term course of SSc-ILD

Serum TARC Levels in Patients with Systemic Sclerosis: Clinical Association with Interstitial Lung Disease

Systemic sclerosis (SSc) is a multisystem fibrotic disorder with autoimmune background. Accumulating evidence has highlighted the importance of T helper (Th) 2 cells in the pathogenesis of SSc and its complications. Because thymus and activation-regulated chemokine (TARC) is a potent chemoattractant for Th2 cells, we measured serum TARC levels in SSc patients and analyzed their correlation with interstitial lung disease (ILD), a major complication of SSc. Serum TARC levels were significantly elevated in patients with SSc, especially in those with the diffuse subtype, compared with healthy controls. In particular, dcSSc patients with SSc-associated ILD (SSc-ILD) showed higher TARC levels than those without SSc-ILD. However, there was no significant correlation between serum TARC levels and pulmonary function in SSc patients. Serum TARC levels did not correlate with serum levels of interleukin-13, an important Th2 cytokine, either. Furthermore, in the longitudinal study, serum TARC levels did not predict the onset or progression of SSc-ILD in patients with SSc. These results were in contrast with those of KL-6 and surfactant protein D, which correlated well with the onset, severity, and progression of SSc-ILD. Overall, these results suggest that serum TARC levels are not suitable for monitoring the disease activity of SSc-ILD