Monocyte-Independent and -Dependent Regulation of Regulatory T-Cell Development in Mycoplasma Infection.

BACKGROUND: Although Mycoplasma pneumoniae (MP) infection has been implicated in the pathogenesis of allergic diseases, the mechanism of this trigger remains unknown. We explored the mechanism for how MP infection could tilt the balance between regulatory T cells (Tregs) and Th17 cells. METHODS: We analyzed the frequency, phenotype, and function of Tregs in patients at the different stages of MP and various virus infections over a period of more than 1 year. We examined the effect of monocytes to elucidate signals that can regulate the balance between Treg and Th17 cells. RESULTS: The functional activity of Tregs was profoundly impaired during the acute stage of MP as well as viral infections. Upon resolution, however, the Treg function remained impaired even 1 year after MP infection. In the resolution stage, the impaired Treg function was associated with an increase in interleukin (IL) 17A+ Tregs and Th17 cells. Development of Th17 cells was dependent on the "aberrant" proinflammatory monocytes (pMOs), characterized by potent ability to produce IL-6 in a Toll-like receptor 2-dependent manner. CONCLUSIONS: Depending on the prevalence of the pMOs, Tregs and Th17 cells could mutually regulate the number and function of the other. The pMOs/IL-6 could be crucial therapeutic targets against MP-induced allergic diseases.

Intracellular accumulation of PD-1 molecules in circulating T lymphocytes in advanced malignant melanoma: an implication for immune evasion mechanism.

BACKGROUND: The blockade of cell surface PD-1 ((sur)PD-1) by monoclonal antibodies, represented by nivolumab, provides the strategy to treat advanced malignant melanoma (AMM). The intracellular presence of PD-1 molecules have been reported in some T cell subsets, however, their kinetic association with those expressed on the cell surface, let alone their significance in antitumor immunity has been ill-investigated. METHODS: Intracellular PD-1 expression status in T cell subsets in AMM cases during nivolumab administration was chronologically characterized. The kinetics of PD-1 molecules within AMM-derived T cells was assessed in vitro in conjunction with their functional properties. RESULTS: Increase in (sur)PD-1 and intracellular PD-1 ((int)PD-1+) expression was characteristic for AMM T cells. After short-term culture, virtually (sur)PD-1- nivolumab-treated AMM T cells restore (sur)PD-1 expression, which could not be explained by the detachment of nivolumab from PD-1 epitopes alone. The blockade of trans-Golgi network resulted in the decrease in the extent of (sur)PD-1 recovery, suggesting the translocation of accumulated (int)PD-1 to the cell surface. Antigen-specific PD-1+ T cells significantly increased in (int)PD-1+ cells after treatment. In addition, a surge in (int)PD-1+CD4+ T cells was observed prior to the emergence of skin rash as an immune-related adverse event (irAE). CONCLUSIONS: Accumulated (int)PD-1 in T cells may contribute to enhanced immune evasion in AMM. Evaluation of intracellular PD-1 expression would be useful for better management of nivolumab-treated AMM patients in view of predicting treatment response and the incidence of irAE. Our findings further support the necessity of periodical administration of nivolumab for treating AMM.

Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms severity score: A useful tool for assessing disease severity and predicting fatal cytomegalovirus disease.

BACKGROUND: The prognosis of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is highly unpredictable. Severe complications, either related or unrelated to cytomegalovirus (CMV) reactivation, are a highly probable cause of death. OBJECTIVES: The aim was to establish a scoring system for DiHS/DRESS that can be used to monitor severity, predict prognosis, and stratify the risk of developing CMV disease and complications. METHODS: A retrospective analysis of 55 patients with DiHS/DRESS was performed. A composite score was created using clinical data. DiHS/DRESS patients were also stratified into 3 groups based on the scores to predict the risk of CMV reactivation and complications. RESULTS: This scoring system made it possible to predict CMV disease and complications. Scores ≥4 were associated with the later development of CMV disease and complications, while no patients with scores <4 developed complications. LIMITATIONS: This was a single-institution study with a relatively small patient cohort that lacked a validation cohort. CONCLUSIONS: Our scoring system may be useful for predicting CMV-related complications, and early intervention with anti-CMV agents should be considered in patients with scores ≥4 or with evidence of CMV reactivation.

Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): An update in 2019.

The aim of this review was to provide an updated overview of drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS). Several new insights have been made, particularly with regards to the diagnosis, pathogenesis and care of some important complications and sequelae. The indication of herpesvirus reactivations in diagnosis in the assessment of disease severity is now better specified. Nevertheless, because fatal complications and autoimmune sequelae have been under-recognized, there is a clear need to identify effective parameters for assessing disease severity and predicting prognosis of the disease in the early phase. In this regard, we have established a scoring system that can be used to monitor severity, predict prognosis and stratify the risk of developing severe complications including fatal cytomegalovirus (CMV) disease. Regulatory T cells are likely to be central to the mechanism and would represent potential targets for therapeutic approaches that can ameliorate inflammatory responses occurring at the acute phase while preventing the subsequent development of harmful outcomes, such as CMV disease and autoimmune diseases.

Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine-tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS. OBJECTIVE: To investigate whether the shift from Treg to Th17 could specifically occur during the course of DiHS/DRESS and to elucidate which subsets of monocytes could be involved in the shift. METHODS: We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of DiHS/DRESS and SJS/TEN, and long after their clinical resolutions. We next examined whether pMOs and cMOs could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by in vitro cocultures. RESULTS: Selective depletion of pMOs occurring at the acute stage of DiHS/DRESS was associated with the relative increase in the frequencies of cMOs producing IL-10 and it did drive Treg expansions. After clinical resolution, pMOs producing IL-6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. CONCLUSIONS AND CLINICAL RELEVANCE: The gradual shift from Treg to Th17 cell development observed during the clinical course of DiHS/DRESS is mediated by the predominance of cMOs at the acute stage and alternatively recruited pMOs at the resolution stage, respectively.

A novel method to assess the potential role of sweating abnormalities in the pathogenesis of atopic dermatitis.

Although atopic dry skin is believed to be caused by defects in skin genes important for maintaining skin barrier function, the role of sweat in atopic dermatitis (AD) has been apparently underestimated. Given the great capacity of sweat to maintain and increase skin hydration, defective sweating responses may be a logical place to look for changes that predispose individuals to the disease. We investigated how disease process and sweating defects progress from early asymptomatic stages to the onset of clinically apparent disease by employing the impression mould technique, which allows an accurate quantification of individual sweat gland/duct activity in relation to skin surface topography. Insensible and sensible sweating responses under baseline conditions and after thermal stimulus, respectively, were measured in various stages of AD patients and healthy controls. In controls, under baseline conditions, sweat ducts/glands at the dermal folds secreted basal levels of sweat (insensible sweating), thereby maintaining skin hydration. Not only such insensible sweating but also sensible sweating markedly decreased even in the earliest asymptomatic stage and the decrease was followed by compensatory hyperhidrosis at the ridge: leakage of sweat into the dermis could represent the initial event resulting in the decreased sweating and inflammation. The defects eventually progressed involving all of the ducts/glands to develop systemic dry skin. AD skin is characterized by varying degrees of functional impairment of sweat ducts/glands depending on the stage, and this defect would be among the reasons for the inability of AD patients to maintain skin hydration.

Sweat is a most efficient natural moisturizer providing protective immunity at points of allergen entry.

Although there is a growing acceptance that sweat could play a detrimental role in various allergic skin diseases, the possibility that sweat is also involved in maintenance of skin hydration and skin-specific immune responses has not been acknowledged. We initially describe physiological role of sweat in both maintaining skin hydration and thermoregulation. The purpose of this article is to provide the reader with objective evidence that sweating is intimately linked to vital stratum corneum barrier function and usefulness of application of moisturizers in clinical care of allergic skin diseases. This review also covers how sweating disturbance would leave the skin vulnerable to the development of various allergic skin diseases, such as atopic dermatitis. New therapeutic approaches would specifically target such sweating disturbance in these allergic skin diseases.

Pathological role of regulatory T cells in the initiation and maintenance of eczema herpeticum lesions.

It remains unknown why the occurrence of eczema herpeticum (EH) caused by an extensive disseminated cutaneous infection with HSV-1 or HSV-2 is associated with the exacerbation of atopic dermatitis lesions after withdrawal of treatment. Although regulatory T cells (Tregs) limit the magnitude of HSV-specific T cell responses in mice, their role in the induction and resolution of EH has not been defined. We initially investigated the frequencies, phenotype, and function of Tregs in the peripheral blood of atopic dermatitis with EH (ADEH) patients at onset and after clinical resolution, atopic dermatitis patients without EH, and healthy controls. Tregs with the skin-homing phenotype and the activated/induced phenotype were expanded at onset and contracted upon resolution. Treg-suppressive capacity was retained in ADEH patients and, the expanded Tregs suppressed IFN-γ production from HSV-1-specific CD8(+) and CD4(+) T cells. The increased frequency of CD14(dim)CD16(+) proinflammatory monocytes (pMOs) was also observed in the blood and EH skin lesions. Thus, pMOs detected in ADEH patients at onset were characterized by an increased ability to produce IL-10 and a decreased ability to produce proinflammatory cytokines, unlike their normal counterparts. Our coculture study using Tregs and pMOs showed that the pMOs can promote the expansion of inducible Tregs. Tregs were detected frequently in the vicinity of HSV-expressing and varicella zoster virus-expressing CD16(+) monocytes in the EH lesions. Expansions of functional Tregs, together with pMOs, initially required for ameliorating excessive inflammation occurring after withdrawal of topical corticosteroids could, in turn, contribute to the initiation and progression of HSV reactivation, resulting in the onset of EH.

Differences in clinical features and outcomes between group A and group G Streptococcus -induced cellulitis.

BACKGROUND: Streptococci are the main causative agents of cellulitis, and group G Streptococcus (GGS) shares many important virulent factors with group A Streptococcus (GAS). The difference in the clinical features of GAS- and GGS-induced cellulitis, however, has not been thoroughly characterized. OBJECTIVE: Our aim was to recognize the differences in the clinical manifestations and outcomes of lower limb cellulitis caused by GAS and GGS. METHODS: We retrospectively analyzed a total of 29 patients diagnosed with GAS- or GGS-induced lower limb cellulitis during the period from January 2008 to September 2013. RESULTS: While the clinical manifestations of GAS-induced cellulitis were likely to be uniform, those of GGS-induced cellulitis were variable, depending on the predisposing factors. GGS-induced cellulitis occurred more frequently in older person who had chronic underlying illness. CONCLUSION: We identified clinical predisposing factors that can predict the clinical course and outcomes of GGS-induced cellulitis.

Improvement of the Ocular Prognosis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: A National Survey in Japan.

PURPOSE: To investigate the incidence and prognostic factors of ocular sequelae in Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) cases arising between 2016 and 2018 in Japan, and compare the findings with those presented in the previous 2005-2007 survey. DESIGN: Retrospective, national trend survey. METHODS: Dermatologic case report forms (CRFs) (d-CRFs) were sent to 257 institutions that treated at least 1 SJS/TEN case, and 508 CRFs were collected from 160 institutions. Ophthalmologic CRFs (o-CRFs) regarding patient demographic data, onset date, ocular findings (first appearance, day of worst severity, and final follow-up), topical treatment (betamethasone), outcome (survival or death), and ocular sequelae (visual disturbance, eye dryness) were sent to the ophthalmologists in those 160 institutions. The results of this survey were then compared with that of the previous 2005-2007 survey. RESULTS: A total of 240 cases (SJS/TEN: 132/108) were included. The incidence of ocular sequelae incidence was 14.0%, a significant decrease from the 39.2% in the previous survey (SJS/TEN: 87/48). In 197 (82.1%) of the cases, systemic treatment was initiated within 3 days after admission, an increase compared to the previous survey (ie, treatment initiated in 82 [60.7%] of 135 cases). Of the 85 cases with an Acute Ocular Severity Score of 2 and 3, 62 (72.9%) received corticosteroid pulse therapy and 73 (85.9%) received 0.1% betamethasone therapy; an increase compared to the 60.0% and 70.8%, respectively, in the previous survey. Ocular-sequelae-associated risk factors included Acute Ocular Severity Score (P < .001) and specific year in the survey (P < .001). CONCLUSIONS: The ophthalmologic prognosis of SJS/TEN has dramatically improved via early diagnosis, rapid assessment of acute ocular severity, and early treatment.

Genome-wide association study identifies HLA-A*3101 allele as a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in Japanese population.

An anticonvulsant, carbamazepine (CBZ), is known to show incidences of cutaneous adverse drug reactions (cADRs) including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). To identify a gene(s) susceptible to CBZ-induced cADRs, we conducted a genome-wide association study (GWAS) in 53 subjects with the CBZ-induced cADRs, including SJS, TEN and DIHS, and 882 subjects of a general population in Japan. Among the single nucleotide polymorphisms (SNPs) analyzed in the GWAS, 12 SNPs showed significant association with CBZ-induced cADRs, and rs1633021 showed the smallest P-value for association with CBZ-induced cADRs (P = 1.18 × 10⁻¹³). These SNPs were located within a 430 kb linkage disequilibrium block on chromosome 6p21.33, including the HLA-A locus. Thus, we genotyped the individual HLA-A alleles in 61 cases and 376 patients who showed no cADRs by administration of CBZ (CBZ-tolerant controls) and found that HLA-A*3101 was present in 60.7% (37/61) of the patients with CBZ-induced cADRs, but in only 12.5% (47/376) of the CBZ-tolerant controls (odds ratio = 10.8, 95% confidence interval 5.9-19.6, P = 3.64 × 10⁻¹5), implying that this allele has the 60.7% sensitivity and 87.5% specificity when we apply HLA-A*3101 as a risk predictor for CBZ-induced cADRs. Although DIHS is clinically distinguished from SJS and TEN, our data presented here have indicated that they share a common genetic factor as well as a common pathophysiological mechanism. Our findings should provide useful information for making a decision of individualized medication of anticonvulsants.

Evidence for reactivation of human herpesvirus 6 in generalized lymphadenopathy in a patient with drug-induced hypersensitivity syndrome.

The present case provides direct evidence of human herpesvirus 6 reactivation in resected lymph node tissue in a patient with drug-induced hypersensitivity syndrome. This case clearly demonstrates that appropriate pathological evaluation of lymphadenopathy for drug-induced hypersensitivity syndrome, which mimics malignant lymphoma in clinical, radiological, and pathological findings, is required.

A syringotropic variant of cutaneous sarcoidosis: presentation of 3 cases exhibiting defective sweating responses.

BACKGROUND: Although nodular collections of epithelioid histiocytes and multinuclear cells can be present at all levels of the dermis in cutaneous sarcoidosis, sarcoidal granulomas characterized by marked syringotropism of epithelioid histiocytes have not been previously reported to our knowledge. OBJECTIVE: We sought to determine whether syringotropic sarcoidosis bears characteristic clinical and histologic features and exhibits defective sweating responses. METHODS: We investigated the clinical, histologic, and immunohistochemical features of syringotropic sarcoidosis, and sweating responses to thermal stress in 3 patients. RESULTS: Multiple erythematous patches/plaques predominantly affected the extensor aspect of the lower legs and thighs. Immunohistochemical analyses of the sweat glands surrounded by syringotropic granulomas exhibited profoundly decreased expression of dermcidin and aquaporin 5, both of which are constitutively expressed in sweat glands of control subjects, suggesting functional defects. Indeed, sweating responses to thermal stress were markedly decreased in the involved area, as compared with those in the uninvolved area and in healthy control subjects. LIMITATIONS: There were a limited number of cases in our study. CONCLUSION: A syringotropic variant of cutaneous sarcoidosis might be a distinct entity clinically and histologically or represent an abortive variant.

Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic hypersensitivity reaction caused by specific drugs, in which herpesvirus reactivations and organ dysfunction occur during the course of the disease. Although recent reports have documented the development of autoimmune disease after complete resolution of DIHS/DRESS, relatively little is known about long-term outcomes after complete resolution of the disease. OBJECTIVE: The aim of this study was to retrospectively analyze complications and sequelae in the early and late phases of DIHS/DRESS according to treatment. METHODS: In all, 34 patients were classified into 2 groups: 14 patients with oral corticosteroid treatment; and 20 with noncorticosteroid treatment. The disease time course was divided into 2 periods: the first 6 months after onset of the drug reaction (early phase); and the period thereafter (late phase). Investigations to detect the presence of viral/bacterial infectious diseases, organ dysfunction, and autoantibodies were performed in both early and late phases. RESULTS: Herpesvirus infections and pneumonia were detected in 6 and 2 patients, respectively, in the corticosteroid treatment group in the early phase. In the noncorticosteroid treatment group, 2 patients developed autoimmune diseases, namely lupus erythematosus and autoimmune thyroiditis. Autoantibodies were detected in 44.4% of patients examined in the late phase of the disease. LIMITATIONS: This study only evaluated a small number of autoantibodies. CONCLUSION: The need for anti-inflammatory effects from systemic corticosteroids should be balanced with the risk of infectious diseases and the benefits of preventing the appearance of later autoimmune conditions in patients with DIHS/DRESS.

Regulation of IgA production by naturally occurring TNF/iNOS-producing dendritic cells.

Immunoglobulin-A has an irreplaceable role in the mucosal defence against infectious microbes. In human and mouse, IgA-producing plasma cells comprise approximately 20% of total plasma cells of peripheral lymphoid tissues, whereas more than 80% of plasma cells produce IgA in mucosa-associated lymphoid tissues (MALT). One of the most biologically important and long-standing questions in immunology is why this 'biased' IgA synthesis takes place in the MALT but not other lymphoid organs. Here we show that IgA class-switch recombination (CSR) is impaired in inducible-nitric-oxide-synthase-deficient (iNOS-/-; gene also called Nos2) mice. iNOS regulates the T-cell-dependent IgA CSR through expression of transforming growth factor-beta receptor, and the T-cell-independent IgA CSR through production of a proliferation-inducing ligand (APRIL, also called Tnfsf13) and a B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF, also called Tnfsf13b). Notably, iNOS is preferentially expressed in MALT dendritic cells in response to the recognition of commensal bacteria by toll-like receptor. Furthermore, adoptive transfer of iNOS+ dendritic cells rescues IgA production in iNOS-/- mice. Further analysis revealed that the MALT dendritic cells are a TNF-alpha/iNOS-producing dendritic-cell subset, originally identified in mice infected with Listeria monocytogenes. The presence of a naturally occurring TNF-alpha/iNOS-producing dendritic-cell subset may explain the predominance of IgA production in the MALT, critical for gut homeostasis.

Drug-Induced Hypersensitivity Syndrome/Drug Reaction With Eosinophilia and Systemic Symptoms: Predictive Score and Outcomes.

BACKGROUND: We previously developed a drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) severity (DDS) score that may predict DIHS/DRESS-associated complications (DACs), including myocarditis, gastrointestinal bleeding, and autoimmune diseases. OBJECTIVE: To externally confirm the predictive accuracy of the DDS score, clarify its ability to identify patients at high risk of DACs and fatal outcome, and determine which treatments might reduce or increase the risk. METHODS: We conducted a nationwide multicenter retrospective study in which we followed 48 patients with DIHS/DRESS at 5 university hospitals in Japan for 1 year after onset. Patients were divided into mild, moderate, and severe DIHS/DRESS groups depending on their early DDS score. RESULTS: Eight cases had DACs in the severe group (n = 17); no DACs were observed in the mild group (n = 12). Receiver-operating characteristic curve analysis showed that a cutoff DDS score of ≥4.0 and ≤2.0 could differentiate patients who would and would not develop DACs, respectively. In the moderate-to-severe disease groups, DACs occurred only in patients who received corticosteroids and not in those who received supportive care. None of the patients who received early treatment for cytomegalovirus developed DACs. Autoimmune DACs were significantly more common in patients who received pulse corticosteroid therapy. Four deaths occurred within the 1-year follow-up; all were in patients with infectious DACs who received systemic corticosteroids. CONCLUSION: Our scoring system allows early identification of patients at increased risk for DACs. Risk factors for DACs include systemic or pulse corticosteroid therapy.

Risk of Progression to Autoimmune Disease in Severe Drug Eruption: Risk Factors and the Factor-Guided Stratification.

The identification of risk factors is key not only to uncover the pathogenesis of autoimmune disease but also to predict progression to autoimmune disease. Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms is likely the best prototypic example for analyzing the sequential events. We conducted a retrospective study of 55 patients with drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms followed up for the possibility of later development of autoimmune disease ∼18 years after resolution. Nine patients progressed to autoimmune sequelae regardless of treatment. The generation of autoantibodies was preceded by 8 years in eight of the nine patients. The combination of increases in lymphocyte counts, severe liver damage, a rebound increase in globulin, persistent reactivations of Epstein‒Barr virus and human herpesvirus-6, and low IL-2 and IL-4 at the acute/subacute phases were significant risk factors for the future development of autoimmune disease. On the basis of these factors, we established a scoring system that can identify high-risk patients. When stratified these patients into three risk categories (low/intermediate/high), occurrence of autoimmune disease was exclusively detected in the high group. Our data represent a scoring system to identify patients at high risk of developing autoimmune disease, although a larger study is required to validate the scoring system.