Immunological therapeutics in acute aortic syndrome.

Acute aortic syndrome is a group of interlinked conditions with common presenting symptoms, including aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. Pharmacological management of acute aortic syndrome is a growing area, with key themes to address the underlying inflammatory pathways believed to be the cause. Research into interleukins, matrix metalloproteinases, and granulocyte macrophage colony-stimulating factor are just some of the many immunological properties being investigated and translated into medical therapies. Stem cell experiments may indicate further advances in the pathologies of acute aortic syndrome. The study of pharmacogenomics to improve treatment across different genomes is also a novel area outlined in this paper.

Recurrent, Severe Aphthous Stomatitis and Mucosal Ulcers as Primary Manifestations of a Novel STAT1 Gain-of-Function Mutation.

Chronic mucocutaneous candidiasis (CMC) characterized by persistent and recurrent Candida infection of the skin, nails, and the mucosa membranes has been proposed as the major infectious phenotype in patients with gain-of-function mutation of signal transducer and activator of transcription 1 (STAT1) 1. However, viral infections caused mostly by herpesviruses, and a broad range of autoimmune disorders may also be part of the clinical phenotype. We report here on a 31 years old female patient suffering from severe mucosal aphthous mucositis and ulcers and recurrent herpes simplex for decades. We found a previously unknown heterozygous sequence variant in STAT1 (c.1219C>G; L407V) affecting the DNA-binding domain of the protein in the patient and her 4 years old daughter. We found this mutation gain-of-function (GOF) by using immunoblot and luciferase assays. We detected low proportion of IL-17A-producing CD4+ T cell lymphocytes by using intracellular staining and flow cytometry. Candida-induced secretion of IL-17A and IL-22 by mononuclear cells from the patient was markedly decreased compared to controls. These data suggest that the novel mutant allele may result in impaired differentiation of CD4+ T cells to CD4+/IL-17+ cells. The clinical phenotype of the disease in this patient was unique as it was dominated primarily by severe aphthous stomatitis and ulcerative esophagitis and only partly by typical CMC resulting in diagnostic delay. We suggest that patients with severe recurrent aphthous stomatitis and esophagitis should be evaluated for STAT1 GOF mutation. Based on the broad clinical spectrum of the disease, we also suggest that CMC and CMC disease may not be an appropriate term to define clinically STAT1 GOF mutation.

Epstein-Barr Virus-Positive Mucocutaneous Ulcer in a Pediatric Patient-Case Report.

The Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a rare entity in the spectrum of lymphoproliferative diseases associated with the EBV. It occurs typically in patients with immunosuppression associated with immunosenescence, as well as due to iatrogenic causes, posttransplant patients and primary immunodeficiency disorders. It is often a benign and self-limited disease that recedes by stopping or reducing the immunosuppressive agents in most of the cases. Histologically, it is characterized by a population of EBV-positive atypical lymphoid cells. Here, we present a rare case of a 5-month-old pediatric patient, born preterm at 24 weeks of gestational age, presenting a lump on the right shoulder, later evolving to EBV-positive mucocutaneous ulcer.

Immunomodulator-associated Epstein-Barr virus-positive mucocutaneous ulcer in a patient with refractory Crohn's disease.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer is a B-cell lymphoproliferative disorder occurring in elderly or iatrogenic immunocompromised patients. We report a 27-year-old male patient with Crohn's disease (CD) who developed immunomodulator-associated lymphoproliferative disorder. The patient was diagnosed with CD at the age of 17 and was treated with maintenance therapy including high-dose infliximab and azathioprine. When he was admitted to our hospital with a diagnosis of intestinal obstruction, his abdominal computed tomography findings showed not only colonic wall thickening and narrowing of the descending colon but also multiple liver tumor lesions. His ileus symptom improved with conservative therapy, and a pathological evaluation of the tissue biopsy specimens from the descending colon and liver lesions indicated a morphological diagnosis of EBV-positive diffuse large B-cell lymphoma. This was a case of iatrogenic immunodeficiency-associated lymphoproliferative disorder due to an immunomodulator. The treatment was initiated with chemotherapy, but he died of disease progression 10 months after the diagnosis of lymphoma. Although cases of lymphoproliferative disorder due to treatment modalities used for CD are rare in Japan, an increase in the risk of lymphoproliferative diseases should be considered in patients with CD treated with immunomodulatory agents.

Neonatal Cytomegalovirus Palatal Ulceration and Bocavirus Pneumonitis Associated With a Defect of Lymphocyte Cytotoxicity Caused by Mutations in UNC13D.

Single gene defects that impair lymphocyte cytotoxicity can predispose to severe viral infection that normally remains subclinical. The classic severe presentation is hemophagocytic lymphohistiocytosis. Here, we report the case of a neonate who presented with cytomegalovirus palatal ulceration and bocavirus pneumonitis secondary to impaired cytotoxicity caused by biallelic mutations in the UNC13D gene.

Primary classic Hodgkin lymphoma of the ileum and Epstein-Barr virus mucocutaneous ulcer of the colon: two entities compared.

Primary classic Hodgkin lymphoma of the gastrointestinal tract represents a rare occurrence. A full patient's work-up is essential in order to exclude a secondary intestinal involvement. Histologically Epstein-Barr virus mucocutaneous ulcer closely resembles Hodgkin lymphoma. The differential diagnosis between these two entities is relevant, since both the therapeutic approach and the clinical behavior are different. Herein, we describe a case of primary classic Hodgkin lymphoma arising in the ileum and a case of Epstein-Barr virus mucocutaneous ulcer of the colon, focusing on the main clinicopathological differences.

[The clinical characteristics of immunocompetent adults with chronic active Epstein-Barr virus associated enteritis].

Objective: To investigate the clinical and pathological characteristics of chronic active Epstein-Barr virus associated enteritis (CAEAE) . Methods: The clinical data of 6 CAEAE patients in Peking Union Medical College Hospital were retrospectively analyzed from January 2010 to November 2017, including clinical manifestations, endoscopic, pathological features, medications and clinical outcome. Results: The male∶female ratio was 4∶2 and the average age was 34 years old. All patients did not have personal and family history of immunodeficiency. The common symptoms consisted of fever (6/6), abdominal pain (6/6), hematochezia (6/6) and diarrhea (5/6). The most frequently affected sites were colorectum (5/6), followed by small intestine (3/6). Further serologic tests revealed a high load of serum Epstein-Barr virus(EBV) DNA. The main manifestations under endoscopy were multifocal or diffuse irregular ulcers. There was inflammation in the ulcer bases and surrounding areas, where EBV-encoded small RNA (EBER) was positive by in situ hybridization (6/6). The common complications were massive hemorrhage (3/6) and intestinal perforation (2/6). None of treatment agents including glucocorticoid, ganciclovir, foscarnet sodium and cytotoxic drugs was effective. All patients died within 0.5 to 13 months after diagnosis. Conclusions: CAEAE in immunocompetent individuals is a rare disorder with poor prognosis. It is difficult to differentiate CAEAE from inflammatory bowel disease due to similar clinical and endoscopic manifestations.

A case of refractory intestinal Behçet's disease treated with tocilizumab, a humanised anti-interleukin-6 receptor antibody.

We describe a young female patient who had refractory intestinal Behçet's disease that responded to tocilizumab, a humanised anti-interleukin-6 receptor antibody. The patient had suffered from long disease activity courses and was treated with multiple medications, and the disease became refractory when immunosuppressants (e.g., thalidomide, sulfasalazine and azathioprine) were limited for poor remission, methylprednisolone pulse therapy, cyclophosphamide, and biological agents (e.g., adalimumab or infliximab) were restricted due to side effects after administration. Therefore, tocilizumab was considered as a therapeutic option and the symptoms resolved during 9 months of administration. Tocilizumab may be a good choice for intestinal Behçet's disease refractory to conventional treatment.

Colonic ulcerations may predict steroid-refractory course in patients with ipilimumab-mediated enterocolitis.

AIM: To investigate management of patients who develop ipilimumab-mediated enterocolitis, including association of endoscopic findings with steroid-refractory symptoms and utility of infliximab as second-line therapy. METHODS: We retrospectively reviewed all patients at our center with metastatic melanoma who were treated with ipilimumab between March 2011 and May 2014. All patients received a standard regimen of intravenous ipilimumab 3 mg/kg every 3 wk for four doses or until therapy was stopped due to toxicity or disease progression. Basic demographic and clinical data were collected on all patients. For patients who developed grade 2 or worse diarrhea (increase of 4 bowel movements per day), additional data were collected regarding details of gastrointestinal symptoms, endoscopic findings and treatment course. Descriptive statistics were used. RESULTS: A total of 114 patients were treated with ipilimumab during the study period and all were included. Sixteen patients (14%) developed ≥ grade 2 diarrhea. All patients were treated with high-dose corticosteroids (1-2 mg/kg prednisone daily or equivalent). Nine of 16 patients (56%) had ongoing diarrhea despite high-dose steroids. Steroid-refractory patients received one dose of intravenous infliximab at 5 mg/kg, and all but one had brisk resolution of diarrhea. Fourteen of the patients underwent either colonoscopy or sigmoidoscopy with variable endoscopic findings, ranging from mild erythema to colonic ulcers. Among 8 patients with ulcers demonstrated by sigmoidoscopy or colonoscopy, 7 patients (88%) developed steroid-refractory symptoms requiring infliximab. With a median follow-up of 264 d, no major adverse events associated with prednisone or infliximab were reported. CONCLUSION: In patients with ipilimumab-mediated enterocolitis, the presence of colonic ulcers on endoscopy was associated with a steroid-refractory course.

Epstein-Barr virus-positive mucocutaneous ulcer in Crohn's disease. A condition to consider in immunosuppressed IBD patients.

Epstein-Barr virus-positive mucocutaneous ulcer (EBVMCU) is a little known entity that can affect the oropharyngeal mucosa, the gastrointestinal tract and the skin. The main risk factor for the development of this lesion is immunosuppression. Because its features are similar to other Epstein-Barr virus-associated lymphoproliferative disorders, a differential diagnosis can sometimes prove challenging. Here, we report the case of a man diagnosed with Crohn's disease and treated with azathioprine and infliximab who developed ulceration at the rectum that was refractory to conventional medical treatment. Although the histological characteristics were suggestive of an EBVMCU, lymphoproliferative disease could not be ruled out. The patient did not improve after discontinuation of the treatment, a proctectomy was performed and the diagnosis of this disease was confirmed. Although very few cases of EBVMCU affecting the colon have been reported, its diagnosis should be always considered in refractory cases of inflammatory bowel disease with patients undergoing immunosuppressive treatment.

Epstein-Barr virus-positive mucocutaneous ulcer arising in a post-hematopoietic cell transplant patient followed by polymorphic posttransplant lymphoproliferative disorder and cytomegalovirus colitis.

Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is a newly described entity occurring in elderly or iatrogenically immunocompromised patients. We describe a case of EBVMCU arising in a post-hematopoietic cell transplant patient and followed by EBV-positive polymorphic posttransplant lymphoproliferative disorder (EBV+ polymorphic PTLD). The patient, a 52-year-old woman, received chemotherapy and autologous peripheral blood stem cell transplantation for relapsed diffuse large B-cell lymphoma (DLBCL). She achieved complete remission and was followed up in an outpatient clinic after discharge. One year later, EBVMCU appeared in the tongue and exhibited spontaneous regression. Six months after the regression of the EBVMCU, she had EBV+ polymorphic PTLD, analogous to EBV+ polymorphic DLBCL. The therapy for PTLD was not effective, and the patient finally died of disease progression. This was the first case of EBVMCU characterized by both an association with autologous peripheral blood stem cell transplantation and subsequent emergence of malignant lymphoma in a patient with relapsed DLBCL.

Chronic signs of memory B cell activation in patients with Behçet's disease are partially restored by anti-tumour necrosis factor treatment.

OBJECTIVES: Behçet's disease (BD), an auto-inflammatory vasculitis with oro-genital ulcerations, skin lesions and uveitis, is regarded as T cell mediated. A successful trial with rituximab suggests an additive role for B cells in the pathogenesis. Therefore, we studied B cell abnormalities in BD patients and the effect of TNF-blocking therapy. METHODS: B cells in blood (n = 36) and tissue (n = 6) of BD patients were analysed with flow cytometry and/or immunohistochemistry and compared with healthy controls (n = 22). BD current activity form (BDCAF) in relation to B cell somatic hypermutations (SHMs) and immunoglobulin class-switching were studied. RESULTS: Thirty-six patients (17 males) were included, mean age 44 years, average disease duration 10 years and mean BDCAF 2.7. Blood B cell numbers were significantly lower in patients than in controls (P = 0.0061), mostly due to decreased CD27+ memory B cells expressing IgM (P = 0.0001), IgG (P = 0.0002) and IgA (P = 0.0038) B cell subsets. CD27+ IgA+ B cells showed the highest magnitude of decrease in active disease, measured with BDCAF (P = 0.02). CD27+ IgM+ IgD+ B cells were impaired in replication history (P = 0.0133) and selection of SHM, whereas IgA+ B cells carried elevated SHM levels (P = 0.04) and lower IgA2 subclass usage (P = 0.0004) than controls. Immunohistochemistry revealed B cells in tissue of active mucosal ulcers. In adalimumab-treated patients, blood B cells were similar to controls. CONCLUSION: We show significant deviations in the memory B cell compartment, related to disease activity and therapeutic efficacy. Pronounced molecular impairments were seen in the fast-responding IgM+-memory and the mucosal IgA+-memory B cells. Because of the demonstrated abundance of B cells in affected tissue, we hypothesize relocation of memory B cells to the site of inflammation could account for the deviations found in blood of BD patients. These peripheral B cells are easily accessible as a marker to monitor therapeutic efficacy.

Effects of MBL-associated serine protease-2 (MASP-2) on liquefaction and ulceration in rabbit skin model of tuberculosis.

Tuberculosis is a chronic infectious disease, which caused by Mycobacterium tuberculosis. It typically affects the functions of the lung and causes high morbidity and mortality rates worldwide. The lectin pathway, one of the complement cascade systems, provides the primary line of defense against invading pathogens. However, what is the specific effection between tuberculosis and complement is unknown. Mannose-binding lectin (MBL), a recognition subunit, binds to arrays of carbohydrates on the surfaces of pathogens, which results in the activation of MBL-associated serine protease-2 to trigger a downstream reaction cascade of complement system. The effects of human MBL-associated serine protease-2 (hMASP-2) were assessed in a rabbit-skin model by intradermal injection of 5 × 106 viable BCG bacilli. The rAd-hMASP-2 accelerated the formation of liquefaction and healing of the granuloma lesions, reduced the bacteria loads of the skin nodules. The serum levels of IL-2 and IFN-γ were significantly increasing during the granuloma and liquefaction phases in the rAd-hMASP-2 group. This study suggests that hMASP-2 can induce a protective efficacy in BCG-infected rabbit skin models, which affects both the progress of lesions and the survival of the mycobacteria within them.

Rare cause of odynophagia: Giant esophageal ulcer.

Gastrointestinal complications are a frequent cause of morbidity after transplantation and may affect up to 40% of kidney transplant recipients. Here we report a rare case of idiopathic giant esophageal ulcer in a kidney transplant recipient. A 37-year-old female presented with a one-week history of odynophagia and weight loss. Upon admission, the patient presented cold sores, and a quantitative cytomegalovirus polymerase chain reaction was positive (10(5) copies/mL). An upper endoscopy demonstrated the presence of a giant ulcer. Serological test and tissue biopsies were unable to demonstrate an infectious origin of the ulcer. Immunosuppression was reduced and everolimus was introduced. An empirical i.v. therapy with acyclovir was started, resulting in a dramatic improvement in symptoms and complete healing of the ulcer. Only two cases of idiopathic giant esophageal ulcer in kidney transplant recipients have been reported in the literature; in both cases, steroid therapy was successful without recurrence of symptoms or endoscopic findings. However, this report suggests that correction of immune imbalance is mandatory to treat such a rare complication.

Mechanisms of NLRP3 inflammasome activation and its role in NSAID-induced enteropathy.

Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cytokines, including tumor necrosis factor-α and interleukins (ILs), in the small intestine via a Toll-like receptor 4 (TLR4)-dependent pathway, leading to intestinal ulceration. Activation of the inflammasome promotes pro-caspase-1 cleavage, leading to pro-IL-1ß maturation. We examined the role of NLRP3 inflammasome in NSAID-induced enteropathy. Small intestinal damage developed 3 h after indomethacin administration, accompanied by increases in IL-1ß and NLRP3 mRNA expression and mature caspase-1 and IL-1ß levels. In vivo blocking of IL-1ß using neutralizing antibodies attenuated indomethacin-induced damage, whereas exogenous IL-1ß aggravated it. NLRP3(-/-) and caspase-1(-/-) mice exhibited resistance to the damage with reduction of mature IL-1ß production. This resistance was abolished by exogenous IL-1ß. TLR4 deficiency prevented intestinal damage and inhibited upregulation of NLRP3 and IL-1ß mRNAs and maturation of pro-caspase-1 and pro-IL-1ß, whereas TLR4 activation by its agonists exerted opposite effects. Apyrase, an adenosine triphosphate (ATP) scavenger, or Brilliant Blue G, a purinergic P2X7 receptor antagonist, inhibited the damage as well as caspase-1 activation and IL-1ß processing, despite there being sufficient amounts of pro-IL-1ß and NLRP3. These results suggest that NLRP3 inflammasome-derived IL-1ß plays a crucial role in NSAID-induced enteropathy and that both TLR4- and P2X7-dependent pathways are required for NLRP3 inflammasome activation.