Single-cell RNA sequencing identifies distinct transcriptomic signatures between PMA/ionomycin- and αCD3/αCD28-activated primary human T cells

Immunologists have activated T cells in vitro using various stimulation methods, including phorbol myristate acetate (PMA)/ionomycin and αCD3/αCD28 agonistic antibodies. PMA stimulates protein kinase C, activating nuclear factor-κB, and ionomycin increases intracellular calcium levels, resulting in activation of nuclear factor of activated T cell. In contrast, αCD3/αCD28 agonistic antibodies activate T cells through ZAP-70, which phosphorylates linker for activation of T cell and SH2-domain-containing leukocyte protein of 76 kD. However, despite the use of these two different in vitro T cell activation methods for decades, the differential effects of chemical-based and antibody-based activation of primary human T cells have not yet been comprehensively described. Using single-cell RNA sequencing (scRNA-seq) technologies to analyze gene expression unbiasedly at the single-cell level, we compared the transcriptomic profiles of the non-physiological and physiological activation methods on human peripheral blood mononuclear cell–derived T cells from four independent donors. Remarkable transcriptomic differences in the expression of cytokines and their respective receptors were identified. We also identified activated CD4 T cell subsets (CD55+) enriched specifically by PMA/ionomycin activation. We believe this activated human T cell transcriptome atlas derived from two different activation methods will enhance our understanding, highlight the optimal use of these two in vitro T cell activation assays, and be applied as a reference standard when analyzing activated specific disease-originated T cells through scRNA-seq.

Analysis of the Dermatologic Side Effects and the Factors Affecting the Efficacy of Immune Checkpoint Inhibitor in Melanoma: A Single-Center, Retrospective Study / 대한피부과학회지

Background@#Programmed death 1 inhibitors enhance pre-existing immune responses by directly blocking anti-programmed cell death receptor-1. They have been widely used these days, but little is known about the dermatologic side effects and the factors affecting the response to therapy. @*Objective@#To determine the association between dermatologic side effects and oncologic response to programmed death 1 inhibitors and to investigate the factors affecting the response to programmed death 1 inhibitors. @*Methods@#We retrospectively reviewed the records of patients with melanoma who were referred to the dermatology department for their newly arising skin lesions after treatment with pembrolizumab and nivolumab from January 1, 2015, to April 30, 2019. The oncologic outcomes of the patients were determined by medical records from the hemato-oncology department. Sex, stage, dermatologic side effects, and age at the time of initial diagnosis were analyzed as the factors affecting oncologic outcomes. Progression-free survival was analyzed between the patients with and those without dermatologic side effects. @*Results@#Of the 177 patients screened for the study, 14 were referred to the dermatology department for cutaneous side effects. There was no difference between the dermatologic side effect group and the non-dermatologic side effect group in terms of oncologic outcome and progression-free survival. Sex and stage significantly increased the risk of disease progression with pembrolizumab treatment. @*Conclusion@#Although it has been reported that there could be a strong association between dermatologic side effects and oncologic outcomes, we were not able to reach the same conclusion among melanoma patients.

Clinical Benefit of Early Laser Treatment of Scars in Children: A Single-Center Retrospective Study / 대한피부과학회지

Background@#Scars in children are highly concerning to most parents who usually seek prompt treatment for these lesions. However, compared with adults, children show a greater tendency to develop hypertrophic scars and a higher likelihood of scar widening with increasing age. @*Objective@#We investigated the role of laser treatment for scars in pediatric patients in view of the fact that this approach is challenging in this age group. @*Methods@#This retrospective study included patients aged ＜17 years who visited the Samsung Medical Center between 2013 and 2018 for scar treatment. Of the 28 children who visited the center during this time, 14 presented within 4 to 5 weeks from scar onset and received laser therapy and 14 presented after 4 to 5 weeks and received topical treatment. The Stony Brook Scar Evaluation Scale (SBSES) was used to assess scar formation. @*Results@#The mean initial SBSES scores were lower in the laser than in the topical group (1.93±0.92 vs. 2.71±0.83, p=0.0363). No intergroup difference was observed in SBSES scores upon treatment completion (4.50±0.94 vs. 4.21±1.19, p=0.4673). Multivariable analysis after adjustment for age, sex, and initial SBSES scores showed that the type (laser vs. topical) of treatment was not significantly associated with an SBSES score=5 or duration of treatment. @*Conclusion@#Laser intervention may be useful for scar therapy in children who present early and can receive prompt treatment before scar maturation; however, further studies are warranted to validate our results.

Analysis of the Dermatologic Side Effects and the Factors Affecting the Efficacy of Immune Checkpoint Inhibitor in Melanoma: A Single-Center, Retrospective Study / 대한피부과학회지

Background@#Programmed death 1 inhibitors enhance pre-existing immune responses by directly blocking anti-programmed cell death receptor-1. They have been widely used these days, but little is known about the dermatologic side effects and the factors affecting the response to therapy. @*Objective@#To determine the association between dermatologic side effects and oncologic response to programmed death 1 inhibitors and to investigate the factors affecting the response to programmed death 1 inhibitors. @*Methods@#We retrospectively reviewed the records of patients with melanoma who were referred to the dermatology department for their newly arising skin lesions after treatment with pembrolizumab and nivolumab from January 1, 2015, to April 30, 2019. The oncologic outcomes of the patients were determined by medical records from the hemato-oncology department. Sex, stage, dermatologic side effects, and age at the time of initial diagnosis were analyzed as the factors affecting oncologic outcomes. Progression-free survival was analyzed between the patients with and those without dermatologic side effects. @*Results@#Of the 177 patients screened for the study, 14 were referred to the dermatology department for cutaneous side effects. There was no difference between the dermatologic side effect group and the non-dermatologic side effect group in terms of oncologic outcome and progression-free survival. Sex and stage significantly increased the risk of disease progression with pembrolizumab treatment. @*Conclusion@#Although it has been reported that there could be a strong association between dermatologic side effects and oncologic outcomes, we were not able to reach the same conclusion among melanoma patients.

Clinical Benefit of Early Laser Treatment of Scars in Children: A Single-Center Retrospective Study / 대한피부과학회지

Background@#Scars in children are highly concerning to most parents who usually seek prompt treatment for these lesions. However, compared with adults, children show a greater tendency to develop hypertrophic scars and a higher likelihood of scar widening with increasing age. @*Objective@#We investigated the role of laser treatment for scars in pediatric patients in view of the fact that this approach is challenging in this age group. @*Methods@#This retrospective study included patients aged ＜17 years who visited the Samsung Medical Center between 2013 and 2018 for scar treatment. Of the 28 children who visited the center during this time, 14 presented within 4 to 5 weeks from scar onset and received laser therapy and 14 presented after 4 to 5 weeks and received topical treatment. The Stony Brook Scar Evaluation Scale (SBSES) was used to assess scar formation. @*Results@#The mean initial SBSES scores were lower in the laser than in the topical group (1.93±0.92 vs. 2.71±0.83, p=0.0363). No intergroup difference was observed in SBSES scores upon treatment completion (4.50±0.94 vs. 4.21±1.19, p=0.4673). Multivariable analysis after adjustment for age, sex, and initial SBSES scores showed that the type (laser vs. topical) of treatment was not significantly associated with an SBSES score=5 or duration of treatment. @*Conclusion@#Laser intervention may be useful for scar therapy in children who present early and can receive prompt treatment before scar maturation; however, further studies are warranted to validate our results.

Clinical Features of the Patients with Merkel Cell Carcinoma in Korea / 대한피부과학회지

Background@#Merkel cell carcinoma is an uncommon primary cutaneous neuroendocrine cancer. It is a highly aggressive cancer with high rates of local recurrence and nodal metastasis. While there are some case reports on Korean patients with Merkel cell carcinoma, there has been no comparison study between Western patients and Korean patients regarding its clinical features. @*Objective@#This study aimed to identify the clinical features of Merkel cell carcinoma in Korean patients and compare them with those seen in Western studies. @*Methods@#We retrospectively reviewed the medical records of patients who were diagnosed with Merkel cell carcinoma between January 1995 and May 2019. Clinical features were compared with those seen in Western studies. @*Results@#Thirty-one patients were enrolled in the analysis. The mean age of onset was 67.6 years, and there were more female patients (1:1.58). The head and neck was the most common primary site (38.7%, 12/31). Patients treated by surgical methods alone were the most common (58.1%, 18/31). Twelve patients (38.7%) had recurrence, and seven patients (22.6%) died of Merkel cell carcinoma. Patients younger than 70 years were more frequent in Korea than in Western countries (Fishers exact test, p＜0.05). In addition, patients with distant metastasis were less frequent in Korea than in Western countries (Fishers exact test, p＜0.05). @*Conclusion@#Compared with Western studies, there were no differences between demographic and clinical features, except that older patients and patients with distant metastasis were less frequent in Korea.

An analysis of age-related loss of skeletal muscle mass and its significance on osteoarthritis in a Korean population

BACKGROUND/AIMS: This study was conducted in order to analyze the effects of sarcopenia on age-related osteoarthritis (OA) of the knee in a Korean population. METHODS: All the Korean subjects who visited the Yeungnam University Medical Center Health Promotion Center between 2008 and 2012 in order to undergo a routine medical examination were enrolled. A total of 5,723 young, healthy people (2,959 males, 2,764 females) enrolled as normal subjects and 23,473 subjects (13,006 males and 10,467 females) were included for evaluation of the effects of sarcopenia on OA. There were 266 subjects who followed-up bioelectrical impedance analysis at a 4-year interval. Of 327 subjects enrolled in this study, knees with anteroposterior X-rays were assessed according to the Kellgren-Lawrence (K/L) grade. RESULTS: Skeletal muscle mass index (SMI) and basal metabolic rate (BMR) showed a steady decrease with the advance of age (p < 0.01), but SMI showed strong positive correlation with BMR (r = 0.72, β = 30.96, p < 0.01). During the 4-year interval, BMR showed a significant decrease with aging (p < 0.01), consistently with the decrease of SMI. Knees with normal SMI were prone to be designated as K/L grade 0 or 1; however, subjects with sarcopenia showed a trend toward the higher K/L grade, classified as knee radiological osteoarthritis (ROA) (p < 0.01). CONCLUSIONS: The results of this study may indicate that sarcopenia as age-related loss of skeletal muscle mass is interactively correlated with the presence and severity of age-related OA.

An overlap syndrome of Churg-Strauss syndrome and rheumatoid arthritis / 영남의대학술지

Churg-Strauss syndrome (CSS) is a necrotizing vasculitis with extra-, peri-vascular eosinophilic infiltration. Chronic symmetric polyarthritis with the presence of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody are the mainstay of rheumatoid arthritis (RA) diagnosis. Mononeuritis multiplex is a peripheral neuropathy involving more than 2 separate nerve areas. A 62-year-old male patient was referred for left foot drop and polyarthritis of both hands and feet for 4 months. During evaluation, mononeuritis multiplex was detected on nerve conduction study and electromyography tests: vasculitis with neutrophil, eosinophil, and lymphocyte infiltration on peroneal nerve biopsy. A positive response to methacholin and bronchodilator was observed on the pulmonary function test. Radiologic tests showed peri-articular soft tissue swelling and osteopenia on both hand and foot. Marked peripheral eosinophilia, high RF, and positive perinuclear anti-neutrophil cytoplasmic antibody were detected on blood tests. Here, we report on a patient with overlap syndrome of CSS and RA with review of the relevant literature, from which a few references to overlap syndrome of CSS and RA were available.

Polyglandular Autoimmune Syndrome Type 2 Complicated by Multiple Organ Failure, Empty Sella Syndrome and Aplastic Anemia

Polyglandular autoimmune syndrome (PAS) is a group of syndromes comprised of glandular and extra-glandular disorders characterized by autoimmunity. A 57-year-old woman presented with acute progressive dyspnea and generalized weakness for several months. The patient was assessed to have acute congestive heart failure with cardiomyopathy, chronic renal failure with hyporeninemic hypoaldosteronism, and pancytopenia in addition to primary hypothyroidism and adrenal insufficiency. With the diagnosis of PAS type 2 complicated by multiple organ failure (MOF), medium-dose prednisolone (30 mg/d) was introduced primarily to control the activity of autoimmunity, which triggered MOF over the adrenal insufficiency. Levothyroxine (25 microg/d) was followed for replacement of the thyroid hormone deficiency. However, the symptoms and signs fluctuated, depending on the dosage of prednisolone, and progressively worsened by empty sella syndrome and aplastic anemia. Here, we report on a case of PAS type 2 with MOF and atypical complications, and suggest that recognition, assessment, and control of PAS as a systemic autoimmune disease may be essential.

Effects of Methotrexate on Carotid Intima-media Thickness in Patients with Rheumatoid Arthritis

The purpose of this study was to evaluate the effects of rheumatoid arthritis (RA) and antirheumatic drugs on atherosclerosis by comparing carotid intima-media thickness (CIMT) as an indicator for cardiovascular diseases (CVD). This study included 44 female RA patients who met the 2010 ACR/EULAR criteria and age-matched 22 healthy females. CIMT was measured on both carotid arteries using a B-mode ultrasound scan. The mean value of both sides was taken as the CIMT of the subject. The CIMT was evaluated according to the use of drugs, disease activity and CVD risk factors in RA patients as a case-control study. Higher CIMT was observed in RA patients as compared with healthy subjects (0.705 +/- 0.198 mm, 0.611 +/- 0.093 mm, respectively, P < 0.05). With adjustment for the CVD risk factors, disease activity and the use of anti-rheumatic drugs, methotrexate (MTX) only showed a favorable effect on CIMT in RA. A significantly lower CIMT was observed in RA with MTX as compared with RA without MTX (0.644 +/- 0.136 mm, 0.767 +/- 0.233 mm, respectively, P < 0.05). The effects were correlated with MTX dosage (beta = -0.029, P < 0.01). The use of MTX should be considered in high priority not only to control arthritis but also to reduce the RA-related CVD risk to mortality.

Age-related NADPH Oxidase (arNOX) Activity Correlated with Cartilage Degradation and Bony Changes in Age-related Osteoarthritis

The purpose of this study was to investigate the age-related NADPH oxidase (arNOX) activity in patients with age-related knee osteoarthritis (OA). Serum and cartilage arNOX activities were determined using an oxidized ferricytochrome C reduction assay. Full-thickness knee joint cartilages obtained through total knee replacement surgery were graded according to the Outerbridge (OB) classification. Radiographic severity of OA was determined on Knee X-rays according to the Kellgren-Lawrence (K/L) grading system. Cartilage beta-galactosidase, HIF-1alpha, and GLUT-1 expression levels were evaluated as markers for tissue senescence, hypoxia, and glycolysis. Higher arNOX activities occurred with higher levels of cartilage beta-galactosidase, HIF-1alpha, and GLUT-1 (P = 0.002). arNOX activity in cartilages with surface defects (OB grade II, III) was higher than in those without the defects (OB grade 0, I) (P = 0.012). Cartilage arNOX activity showed a positive correlation with serum arNOX activity (r = -0.577, P = 0.023). Serum arNOX activity was significantly higher in the OA subgroup with bilateral ROA than in the OA with no or unilateral ROA (2.449 +/- 0.81, 2.022 +/- 0.251 nM/mL, respectively, P = 0.019). The results of this study demonstrate that OA itself is not a cause to increase arNOX activities, however, arNOX hyperactivity is related to a high degree of cartilage degradation, and a high grade and extent of ROA in age-related OA.

Cutaneous Mycobacterium massiliense Infection of the Sole of the Feet

Mycobacterium massiliense which is recognized as a separate species from M. abscessus is little known regarding its clinical patterns and the response to treatment. We present a case of a localized cutaneous infection due to M. massiliense of the sole associated with acupuncture. M. massiliense was identified via polymerase chain reaction-hybridization analysis. We treated the patient with single-drug therapy consisting of clarithromycin for 4 months and the patient showed a significant response to this treatment.

A Case of Pseudolymphomatous IgG4-Related Disease Involving the Maxilla / 영남의대학술지

Immunoglobulin G4 (IgG4)-related disease is an inflammatory condition characterized by IgG4 positive plasma cell infiltration. It can affect any organ in the body and mainly involves the pancreas, liver, biliary tracts, orbits, salivary glands and lymph nodes. It can manifest as an inflammatory pseudotumor. Pseudolymphoma as an inflammatory pseudotumor is a group of benign tumors that exhibit histological and clinical features suggestive of malignant lymphoma. Studies on IgG4-related disease are rarely reported, and no case of the disease that involved the maxillary bone and adjacent soft tissue, except for the skin, has been reported. Therefore, we report herein a case of pseudolymphomatous IgG4-related disease that involved the maxilla, with a literature review.

Application of Regulatory T Cells in Transplantation Field / 대한이식학회지

The development of immunosuppressant treatments has enabled remarkable progress in the tissue and organ transplantation field by helping to prevent acute graft rejection. However, complications related to transplantation, such as infection by bacteria and viruses, and the occurrence of cancers resulting from prolonged immune suppression are major obstacles to overcome. Therefore, transplantation immunology research efforts should focus on the induction of donor-specific immune tolerance which preserves patient immune competence which promotes infection and cancer surveillance. Additionally, lifelong administration of immunosuppressants should be forgone in preference to short term therapies. In the 1990s, Dr. Shimon Sakaguchi identified the CD4+CD25+ regulatory T cells which develop in the thymus, and demonstrated that these cells play crucial roles in the maintenance of immune self tolerance. Studies which followed proved that these regulatory T cells are important to the control of autoimmune disease and prevention of graft rejection. Regulatory T cells have also been found to induce immune tolerance in rodent models. In this review, we discuss several considerations for the use of regulatory T cell therapy in the clinical transplantation field.

IL-31 Serum Protein and Tissue mRNA Levels in Patients with Atopic Dermatitis

BACKGROUND: Severe pruritus is the primary symptom in atopic dermatitis (AD). Recently, the novel cytokine IL-31 has been implicated in the itching associated with AD. OBJECTIVE: We performed this study to determine whether IL-31 serum levels are elevated in AD patients and to better characterize the relationship between serum IL-31 level and other established laboratory parameters. METHODS: We recruited 55 AD patients, 34 with allergic type AD and 21 with non-allergic type AD, and 38 healthy, non-atopic controls. We checked the laboratory values, severity score, and serum IL-31 levels in all patients and controls, and IL-31 mRNA levels in lesion skin were measured in 13 subjects with AD and in four controls. RESULTS: AD patients displayed significantly higher levels of serum IL-31 that were associated with serum IgE, disease severity, and subjective itch intensity. In AD patients, IL-31 mRNA levels from the lesional skin samples also correlated with serum IL-31 level. CONCLUSION: IL-31 is likely one of the many mediators inducing inflammation and pruritus in AD. Although our limited sample size prevents us from making any definitive conclusions, our data demonstrate a strong correlation between IL-31 mRNA level and serum IL-31 protein level, which has never been reported before. Moreover, we found correlations between serum IL-31 level and serum IgE, eosinophil cationic protein, disease severity, and subject itch intensity in certain degrees in AD patients.

Increased Left Side Prevalence of Head and Neck Skin Cancers / 대한피부과학회지

BACKGROUND: Several studies have shown an increase in skin cancers on the left side of the face. But such studies have not been conducted in Korean patients. OBJECTIVE: In this study, we analyzed the prevalence of left or right sided skin cancers in head and neck areas. METHODS: We retrospectively included 384 head and neck skin cancers (Basal cell carcinoma, Squamous cell carcinoma, Bowen disease, Malignant melanoma) diagnosed at our center from January 1995 to February 2011. Location, age, and sex were recorded and analyzed. RESULTS: All types of skin cancers occurred more on the left (54.17%) than on the right (45.83%) (p=0.051), with no stronger trend in men. CONCLUSION: There are more skin cancers on the left than the right side in Korean patients. But further study is needed because of the small patient population studied.

A Case of Type I Cryoglobulinemia Associated with Smoldering Myeloma and Acutely Reactivated Chronic Hepatitis B

A 58-year-old male patient with chronic hepatitis B infection and hypertension was referred for the evaluation of a skin rash. The skin biopsy showed multiple hyaline thrombi in small blood vessels, red blood cell extravasation, and epidermal atrophy. The CBC, chemistry, UA, and radiological studies were unremarkable except for elevated AST/ALT on liver function tests. The hepatitis B virus markers were compatible with the diagnosis of acute replicative phase chronic hepatitis B; HBeAg 86,646 cpm (count per minute), anti-HBeAb (-), HBV PCR (Quantitative) >1.10x108 IU/mL, and >640,200,000 copies/mL. Rouleaux formation was seen on the peripheral blood smears. Serum PEP/IEP demonstrated an M-spike (27.53%) in the gamma region and abnormal bowed arcs in IgG, kappa light chain with Cryoglobulin (+), ANCA (+), FANA (-), and rheumatoid factor (-) on the serological test. The percent of plasma cells on the bone marrow biopsy was approximately 15%. Type I cryoglobulinemia is a rare disease that can be associated with hematologic disorders, but smoldering myeloma or/and hepatitis B has not been reported in association with Type I cryoglobulinemia. Here, we report a case of Type I cryoglobulinemia that showed multiple skin ulcers due to vascular occlusion related to the monoclonal cryoglobulin with smoldering myeloma and acutely reactivated chronic hepatitis B.

Acute Generalized Exanthematous Pustulosis Caused by Diltiazem

Acute generalized exanthematous pustulosis is clinically characterized by fever, pruritus and an acute pustular eruption. It can be described as having an abrupt onset and then spontaneous resolution occurs shortly after the start of symptoms, and there is usually only a single episode. Most cases have been triggered by the ingestion of drugs. Diltiazem hydrochloride is a calcium channel blocker that is commonly used for treating hypertension and angina. This drug was found to be the responsible agent in our current patient. There have been 9 such case reports in the English medical literature, yet this is the first such report in the Korean medical literature. We present the case of a 51-year-old male who experienced an acute generalized exanthematous pustulosis due to diltiazem hydrochloride and we review the relevant literature.

A Clinical Study of Childhood and Adolescent Psoriasis / 대한피부과학회지

BACKGROUND: Few clinical studies are available on childhood and adolescent psoriasis in Korea. OBJECTIVE: The purpose of this study was to analyze clinical features of childhood and adolescent psoriasis in a referral center in Korea. METHODS: We performed retrospective medical record-based analyses for 255 psoriasis patients younger than 16 years of age at the time of diagnosis at our center from March 2001 to July 2010. Age, sex, onset age, familial history, site of involvement, type of psoriasis, nail involvement, initial PASI score, and treatment modality were analyzed. RESULTS: There was no sexual predominance; mean age of onset was 8.85 years; 17.25% of patients had a familial history. Upper extremities, lower extremities, trunk, scalp and face were the most commonly involved sites in sequence. Guttate psoriasis (58.90%) was the most common type of psoriasis. Nail involvement was observed in 11.11% of patients. The mean initial PASI score at the time of diagnosis was 7.9. The most common treatment was topical steroids and topical vitamin D in combination. CONCLUSION: Childhood and adolescent psoriasis is not an uncommon disease. A larger scale epidemiological study is needed.

A Case of Minimal Change Disease Treated Successfully with Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus

The World Health Organization classifies lupus nephritis as class I to V or VI. However, a few cases of minimal change glomerulopathy have been reported in association with systemic lupus erythematosus (SLE). Mycophenolate mofetil has been shown to be effective for treatment of minimal change disease and lupus nephritis. A 24-year-old woman diagnosed with SLE five years prior to presentation complained of a mild generalized edema. The urinalysis showed microscopic hematuria and proteinuria. The assessed amount of total proteinuria was 1,618 mg/24 hours. A renal biopsy demonstrated diffuse fusion of the foot processes of podocytes on electron microscopy. Mycophenolate mofetil was started in addition to the maintenance medications of prednisolone 10 mg/day and hydroxychloroquine 400 mg/day. After six months of treatment, the microscopic hematuria and proteinuria resolved, and the total urine protein decreased to 100 mg/24 hours.