Inflammatory bowel disease: the classic gastrointestinal autoimmune disease
Kaistha, Abha; Levine, Jeremiah
Inflammatory bowel disease (IBD) is an idiopathic disease thought to be caused by a dysregulated immune response to host intestinal microflora. The role of genetic factors is indicated by familial clustering of cases and higher incidence in monozygotic twins. An interaction between genetic and environmental factors is thought to play a role in the pathogenesis of these disorders. Changes in diet, antibiotic use and intestinal colonization have likely contributed to increased prevalence of inflammatory bowel disease in the past century. Environmental factors or infections are thought to alter the barrier function of the epithelium, leading to loss of immune tolerance to intestinal antigens. This loss of tolerance activates dendritic cells, triggering their transport to mesenteric lymph nodes, where they promote differentiation of naive T cells to TH-1, TH-2, TH-17 cells or T regulatory cells. Production of proinflammatory cytokines and chemokines then follows. Circulating effector and regulatory cells enter the intestine through a highly selective mechanism that involves interaction with the vascular endothelium, diapedesis through the vessel wall and migration to the lamina propria. There are several genes implicated in IBD. Mutations in certain genes can cause defective down regulation of the innate immune response, ineffective clearance of intracellular bacteria and proliferation of both luminal and mucosal-adherent commensal bacteria. IBD is a chronic relapsing inflammatory condition that is immune mediated. Results from research in animal models, human genetics, basic science and clinical trials provide evidence that it is heterogeneous, characterized by various genetic abnormalities, leading to a dysregulated and overly aggressive T cell response to commensal enteric bacteria. Different genetic abnormalities can be characterized as causing defects in mucosal barrier function, immunoregulation or bacterial clearance. Advances in our understanding of the interplay between components of innate and adaptive immune response will be central to future progress.
Autoimmune hepatitis: a classic autoimmune liver disease
Moy, Libia; Levine, Jeremiah
AIH is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia, and production of autoantibodies. Based on the nature of the serum autoantibodies, two types of AIH are recognized: type 1 (AIH-1), positive for ANA and/or anti-smooth muscle antibody, and type 2 (AIH-2), defined by the positivity for anti-liver kidney microsomal type 1 antibody or for anti-liver cytosol type 1 antibody. AIH demonstrates a female preponderance with the female-to-male ratio of 4:1 in AIH-1 and 10:1 in AIH-2. Several genes confer susceptibility to AIH and influence clinical manifestation, response to treatment, and overall prognosis. Most are located within the human leukocyte antigen (HLA) region, which is involved in the presentation of antigenic peptides to T cells and thus in the initiation of adaptive immune responses. The strongest associations are found within the HLA-DRB1 locus. In patients with increased genetic susceptibility to AIH, immune responses to liver autoantigens could be triggered by molecular mimicry. Because of molecular mimicry, different environmental agents, drugs, and viruses might produce AIH. In AIH, T cells are numerically and functionally impaired, permitting the perpetuation of effector immune responses with ensuing persistent liver destruction. AIH is rare but highly treatable inflammatory condition of the liver. Subclinical and asymptomatic disease is common. AIH therefore needs to be considered in the differential diagnosis of all patients with elevated liver enzymes. Clinical response to immunosuppressive therapy is characteristic and supports the diagnosis.
Eosinophilic esophagitis: an autoimmune esophageal disorder
Malhotra, Neha; Levine, Jeremiah
Eosinophilic esophagitis (EoE) represents a chronic, immune/antigen-mediated esophageal inflammatory disease associated with esophageal dysfunction resulting from severe inflammation. The incidence and prevalence of EoE have been increasing in the past decade; however, the reason for this increase is unclear. There is a chronic inflammatory infiltrate that is present in EoE which promotes inflammation, symptoms, and dysfunction. In addition to eosinophils, interleukin (IL)-5 expressing T cells, B cells, eotaxin-3, IL-13, and IgE-bearing mast cells are present in EoE and are thought to contribute to the disease process. Eosinophils are pro-inflammatory and modulate multiple aspects of the immune response. Eosinophils produce a wide range of inflammatory cytokines, chemokines, granulocyte-monocyte colony-stimulating factors, and tumor necrosis factors. Once activated, eosinophils release granule components, which are toxic to a variety of tissues. Transforming growth factor beta1 is a pro-fibrotic molecule produced by epithelial and inflammatory cells, is overexpressed in EoE, and plays a role in esophageal remodeling. Fibrous remodeling in EoE could be associated with symptoms of dysphagia and may explain and predict future esophageal strictures and dysmotility. EoE is a complex disease involving multiple activation pathways, a large number of cells, and various inflammatory molecules. It, along with other atopic disease, is becoming increasingly prevalent and has an important genetic load and may represent as an immunological tolerance disorder of the GI tract.
The impact of immune dysregulation on the development of autoimmune gastrointestinal and liver disease
The intestinal epithelium plays an active immunologic role in preventing the uptake of foreign antigens. Additionally, the intestinal mucosa is an active site for immune suppression through the development of oral tolerance. Dysfunction of any aspect of the intestinal barrier, such as impairment of intestinal tight junctions, immunologic dysregulation or decreased oral tolerance will lead to overstimulation of the immune system upon exposure to foreign antigens and subsequent unregulated chronic intestinal inflammation. This persistent inflammatory activity may potentially predispose the patient to the development of intestinal autoimmune disease. An active immune response possibly directed against intestinal flora has been postulated to be the underlying etiology for inflammatory bowel disease. Failure of oral tolerance is thought predispose a patient to celiac disease and possibly eosinophilic esophagitis. Additionally, an active immunologic response to absorbed antigen may be the underlying etiology for the development of autoimmune liver disease.
Cholesteryl ester storage disease is associated with progressive liver disease and childhood onset cirrhosis in a series of six liver biopsies spanning 22 years [Meeting Abstract]
Bernstein, Donna L.; Edelman, Morris; Alexis, Claudine; Bialer, Martin G.; Levine, Jeremiah; Fox, Joyce E.; Desnick, Robert J.
Severe obesity and diabetes insipidus in a patient with PCSK1 deficiency
Frank, Graeme R; Fox, Joyce; Candela, Ninfa; Jovanovic, Zorica; Bochukova, Elena; Levine, Jeremiah; Papenhausen, Peter R; O'Rahilly, Stephen; Farooqi, I Sadaf
Non-synonymous mutations affecting both alleles of PCSK1 (proprotein convertase 1/3) are associated with obesity and impaired prohormone processing. We report a proband who was compound heterozygous for a maternally inherited frameshift mutation and a paternally inherited 474kb deletion that encompasses PCSK1, representing a novel genetic mechanism underlying this phenotype. Although pro-vasopressin is not a known physiological substrate of PCSK1, the development of central diabetes insipidus in this proband suggests that PCSK1 deficiency can be associated with impaired osmoregulation.
Simultaneous development of ulcerative colitis in the colon and sigmoid neovagina [Case Report]
Webster, Toni; Appelbaum, Heather; Weinstein, Toba A; Rosen, Nelson; Mitchell, Ian; Levine, Jeremiah J
Vaginoplasty using sigmoid colon is a common technique for creation of a neovagina. However, special consideration must be given to potential long term consequences of using a colonic conduit for vaginal replacement. We report on the youngest described case in which a patient developed ulcerative colitis refractory to medical therapy with simultaneous involvement of a sigmoid neovagina requiring total proctocolectomy and neovaginectomy. A 17 year old XY female with a history of gonadal dysgenesis and sigmoid graft vaginoplasty presented with a history of bloody, mucoid vaginal discharge, abdominal pain, bloody diarrhea and weight loss. Colonic and neovaginal biopsies demonstrated active colitis with diffuse ulcerations, consistent with ulcerative colitis. Despite aggressive immunosuppressive treatment she had persistent neovaginal and colonic bleeding requiring multiple transfusions, subtotal colectomy and ultimately completion proctectomy and neovaginectomy. It is imperative to recognize that colectomy alone may be an inadequate surgical intervention in patients with ulcerative colitis and a colonic neovaginal graft and that a concomitant neovaginectomy may be integral in providing appropriate treatment.
Combination of CFTR gene mutation and autoimmune pancreatitis presenting as necrotizing pancreatitis [Letter]
Patel, Henna; Levine, Jeremiah; Weinstein, Toba
Impedance and extraesophageal manifestations of reflux in pediatrics
Greifer, Melanie; Ng, Kenneth; Levine, Jeremiah
OBJECTIVES/HYPOTHESIS: Extraesophageal manifestations of gastroesophageal reflux (GER) include such signs and symptoms as cough, asthma, respiratory symptoms, hoarseness, and laryngoscopic findings. We reviewed the role of MII-pH monitoring in the evaluation of these findings in children to determine whether there is an association with pathological acid or nonacid reflux. STUDY DESIGN: Retrospective chart review. METHODS: We retrospectively reviewed charts from patients who underwent MII-pH. Inclusion criteria were ages 0 to 21 years with extraesophageal signs or symptom. Data were analyzed using dedicated software and manually reviewed. Reflux composite score was calculated based on DeMeester criteria. Impedance scores were calculated based on adult criteria. Symptom indexes were calculated. RESULTS: A total of 119 MII-pH studies were performed. Of those, 63 studies met inclusion criteria. There were 39 males and 24 females with mean age 7.32 +/- 4.1 years. The most common indication was cough. Six children had pathological GER based on DeMeester score. Using impedance criteria, only 10 of 63 patients had an abnormal evaluation (mean reflux episodes 107). Seven patients (15.2%) were found to have an association between symptom and reflux event. CONCLUSIONS: No association was demonstrated between the extraesophageal signs and symptoms and pathological GER based on DeMeester score or the number of reflux events based on impedance testing.
Conservative long-term treatment of children with eosinophilic esophagitis
Levine, Jeremiah; Lai, Joanne; Edelman, Morris; Schuval, Susan J
BACKGROUND: Current treatments of eosinophilic esophagitis (EoE), including restrictive diets or glucocorticoids, provide only transient improvement. Proton pump inhibitor (PPI) use in EoE does not lead to histologic improvement; however, the long-term use of PPI on symptoms and prevention of complications has not been evaluated. OBJECTIVE: To evaluate the use of PPI as maintenance therapy in children with EoE. METHODS: Eosinophilic esophagitis was diagnosed based on initial endoscopic biopsies and persistent eosinophilic inflammation despite PPI therapy. Inclusion criteria included diagnosis of EoE and PPI use as primary maintenance treatment. Patients were excluded if they were treated with dietary or glucocorticoid therapy. Histologic evidence of inflammation as well as degree of subepithelial fibrosis at presentation was compared with most recent biopsies while receiving PPI therapy. RESULTS: Thirty-eight patients (30 males and 8 females; average age 6.7 +/- 5.4 years) fulfilled inclusion criteria. Duration of follow-up was 3.0 +/- 2.4 years. At presentation, vomiting was significantly more frequent in the younger patients, whereas dysphagia occurred more frequently in the older patients. At follow-up, 26 patients were asymptomatic, and the remaining 12 patients' symptoms were significantly improved. No complications of stricture or food impaction were seen. Significant eosinophilic inflammation persisted in 28 patients. No difference in degree of subepithelial fibrosis at diagnosis compared with most recent biopsies. The z-scores of the treated EoE patients significantly improved. CONCLUSION: Patients with EoE treated with PPIs show an improvement in symptoms and z-scores despite persistent eosinophilic inflammation. PPI treatment may be useful maintenance therapy in children with EoE.