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Eosinophilic esophagitis (EoE) is a chronic, local immune-mediated esophageal disease with eosinophil-dominated inflammation. The incidence of the disease is rapidly increasing in both children and adults. The pathogenesis of the disease is still not well understood. We present a review of the literature devoted to the EoE immunopathology, in particular the markers of inflammation and epithelial integrity, and their usefulness in disease monitoring and therapy.We performed a systematic search of the MEDLINE/PubMed databases for studies to examine the use of immunohistochemistry as a diagnostic tool for EoE.The gold standard of EoE diagnosis requires multiple endoscopies with biopsies for histological assessment. The minimum number of eosinophils evaluated in hematoxylin-eosin staining to diagnose EoE is 15 per high-power field in at least one esophageal mucosa biopsy. However, in some cases, the count of eosinophils is not specific and insufficient as the only indicator. Recent works confirm the usefulness of assessment of some biomarkers in establishing the diagnosis and monitoring the treatment effects.Immunohistochemistry seems to be a promising option not only in clinical recognition, but also in the selection and monitoring of treatment effects. However, these methods have not yet recommended for routine clinical use.

Background: Inflammatory bowel disease (IBD) in children is frequently associated with liver pathology manifested as transient elevation of liver enzymes or specified liver diseases. The aim of the study was to evaluate the prevalence and the type of liver pathology in children with IBD within 2 years’ follow-up after the IBD diagnosis. Methods: We retrospectively reviewed records of children with IBD. Liver pathology was defined as elevated activity of liver enzymes (alanine transaminase (ALT) and/or gamma-glutamyl transpeptidase (GGT)) and bilirubin concentration in serum and/or as pathological changes of the organ on imaging tests (abdominal ultrasound and/or magnetic resonance cholangiopancreatography) or on liver histology performed when indicated. Results: Liver pathology was detected in 21 from 119 children (18%), including 7 (17%) with Crohn’s disease (CD) and 14 (18%) with ulcerative colitis (UC). Specified diagnosis for liver abnormality was found in 14 of 21 children (67%), including primary sclerosing cholangitis (PSC, 19%), non-alcoholic fatty liver disease (NAFLD, 19%), autoimmune sclerosing cholangitis (ASC, 5%), autoimmune hepatitis (AIH, 5%), cholelithiasis (5%), drug-induced liver disease (9%) and viral infection (herpes simplex virus, 5%). Most patients manifested mild IBD or were in clinical remission at the time of liver pathology diagnosis. 14% of patients with liver disease (including only cases with PSC) were diagnosed before IBD, 33% at the same time, and 52% in the later period. Patients with the specified diagnosis of liver pathology were younger, had higher ALT activity and more often demonstrated liver abnormalities on imaging tests. UC patients with idiopathic elevation of liver enzymes had higher pediatric ulcerative colitis activity index scores compared to children with specified liver disease. Conclusions: Liver pathology was observed in a significant percentage of children with IBD in our study. The majority of cases of hepatobiliary abnormalities were detected after diagnosis of IBD; therefore, children with IBD should undergo routine monitoring of liver enzymes.

Neutropenia, congenital or acquired, is related to impaired granulocyte production in the bone marrow or increased destruction by antibodies. Autoimmune neutropenia of infancy (AIN) is associated with the occurrence of antineutrophil antibodies. AIN is the most common cause of neutropenia in infants and young children. However, its incidence is low. Detection of anti-neutrophil antibodies is an important step in confirming the diagnosis of AIN, although their detection is difficult due to low titer and poor avidity. In differential diagnosis, another cause of neutropenia should be considered, such as a drug-induced mechanism, viral infection, autoimmune and metabolic disease, hematological conditions or immune deficiency syndromes. Despite the benign course of AIN, serious infectious complications can occur. Spontaneous remission of neutropenia was observed in 95% of patients during 24 months of follow-up. We present a case of a 10-month-old boy with deafness, heart defect and Morgagni-Larrey hernia diagnosed in our department because of formation of a skin abscess due to autoimmune neutropenia.

Background: the molecular mechanism of gastric cancer development related to Helicobacter pylori (H. pylori) infection has not been fully understood, and further studies are still needed. Information regarding nanomechanical aspects of pathophysiological events that occur during H. pylori infection can be crucial in the development of new prevention, treatment, and diagnostic measures against clinical consequences associated with H. pylori infection, including gastric ulcer, duodenal ulcer, and gastric cancer. Methods: in this study, we assessed mechanical properties of children’s healthy and H. pylori positive stomach tissues and the mechanical response of human gastric cells exposed to heat-treated H. pylori cells using atomic force microscopy (AFM NanoWizard 4 BioScience JPK Instruments Bruker). Elastic modulus (i.e., the Young’s modulus) was derived from the Hertz–Sneddon model applied to force-indentation curves. Human tissue samples were evaluated using rapid urease tests to identify H. pylori positive samples, and the presence of H. pylori cells in those samples was confirmed using immunohistopathological staining. Results and conclusion: collected data suggest that nanomechanical properties of infected tissue might be considered as markers indicated H. pylori presence since infected tissues are softer than uninfected ones. At the cellular level, this mechanical response is at least partially mediated by cell cytoskeleton remodeling indicating that gastric cells are able to tune their mechanical properties when subjected to the presence of H. pylori products. Persistent fluctuations of tissue mechanical properties in response to H. pylori infection might, in the long-term, promote induction of cancer development.

Background and Objectives: Inflammatory bowel disease (IBD) is a chronic condition and mainly affects the intestines, however, the involvement of the other organs of the gastrointestinal tract (upper part, pancreas, and liver) have been observed. The coexistence of IBD with pancreatic pathology is rare, however, it has been diagnosed more frequently during recent years in the pediatric population. This article reviews the current literature on the most common pancreatic diseases associated with IBD in the pediatric population and their relationship with IBD activity and treatment. Materials and Methods: We performed a systematic review of data from published studies on pancreatic disorders, also reported as extraintestinal manifestations (EIMs), among children with IBD. We searched PubMed and Web of Science to identify eligible studies published prior to 25 April 2020. Results: Forty-four papers were chosen for analysis after a detailed inspection, which aimed to keep only the research studies (case control studies and cohort studies) or case reports on children and only those which were written in English. The manifestations of IBD-associated pancreatic disorders range from asymptomatic increase in pancreatic enzymes activity to severe disease such as acute pancreatitis. Acute pancreatitis (AP) induced by drugs, mainly thiopurine, seems to be the most- often-reported pancreatic disease associated with IBD in children. AP associated with other than drug etiologies, and chronic pancreatitis (CP), are rarely observed in the course of pediatric IBD. The pancreatic involvement can be strictly related to the activity of IBD and can also precede the diagnosis of IBD in some pediatric patients. The course of AP is mild in most cases and may occasionally lead to the development of CP, mainly in cases with a genetic predisposition. Conclusions: The involvement of the pancreas in the course of IBD may be considered as an EIM or a separate co-morbid disease, but it can also be a side effect of IBD therapy, therefore a differential diagnosis should always be performed. As the number of IBD incidences with concomitant pancreatic diseases is constantly increasing in the pediatric population, it is important to include pancreatic enzymes level measurement in the workup of IBD.

Background: An increase in the incidence of eosinophilic esophagitis worldwide is being observed in children. The aim of the study was to analyze the incidence, clinical manifestations, biochemical markers and endoscopic features of children with eosinophilic esophagitis in comparison to patients with non-eosinophilic esophagitis. Methods: This single-center retrospective study included newly diagnosed children with eosinophilic (EoE) and non-eosinophilic (non-EoE) esophagitis based on endoscopic and histopathological results between January 2013 and December 2018. Result: Among 433 of enrolled children with esophagitis, 36 (8.31%) were diagnosed with EoE (median age of 10 years). Male predominance and an increased percentage of allergy cases in the EoE group were noticed. Dysphagia was the only symptom that significantly differentiated both groups (p = 0.006). Endoscopic findings with relevant relationships with EoE included linear fissuring, decreased vascular pattern, trachealization and whitish exudates. No significant difference in the prevalence of other reported diseases between groups was observed. Conclusion: The results of EoE analysis in children from North-Eastern Poland did not differ from reports from other countries. The reported symptoms were not specific for EoE, and only dysphagia and some endoscopic lesions were helpful to differentiate children with EoE from non-EoE.

An altered ceramide composition in patients with inflammatory bowel disease (IBD) has been reported recently. The aim of this study was to evaluate the concentrations of sphingolipids in the serum of treatment-naive children with newly diagnosed IBD and to determine the diagnostic value of the tested lipids in pediatric IBD. The concentrations of sphingolipids in serum samples were evaluated using a quantitative method, an ultra-high-performance liquid chromatography-tandem mass spectrometry in children with Crohn&rsquo, s disease (CD) (n=34), ulcerative colitis (UC) (n = 39), and controls (Ctr) (n = 24). Among the study groups, the most significant differences in concentrations were noted for C16:0-LacCer, especially in children with CD compared to Ctr or even to UC. Additionally, the relevant increase in C20:0-Cer and C18:1-Cer concentrations were detected in both IBD groups compared to Ctr. The enhanced C24:0-Cer level was observed only in UC, while C18:0-Cer only in the CD group. The highest area under the curve (AUC), specificity, and sensitivity were determined for C16:0-LacCer in CD diagnosis. Our results suggest that the serum LacC16-Cer may be a potential biomarker that distinguishes children with IBD from healthy controls and differentiates IBD subtypes. In addition, C20:0-Cer and C18:0-Cer levels also seem to be closely connected with IBD.

Background Metabolic profiling might be used to identify disease biomarkers. The aim of our study was to determine the usefulness of untargeted metabolomics analysis to detect differences in serum metabolites between newly diagnosed and untreated pediatric patients with Crohn's disease (CD) or ulcerative colitis (UC) in comparison with a control group (Ctr). Moreover, we investigated the potential of profiling metabolomics and inflammatory markers to improve the noninvasive diagnosis of CD and UC in children. Methods Metabolic fingerprinting of serum samples was estimated with liquid chromatography coupled with mass spectrometry in children with CD (n = 9; median age, 14 years), UC (n = 10; median age, 13.5 years), and controls (n = 10; median age, 12.5 years). Results The majority of chemically annotated metabolites belonged to phospholipids and were downregulated in CD and UC compared with the Ctr. Only 1 metabolite, lactosylceramide 18:1/16:0 (LacCer 18:1/16:0), significantly discriminated CD from UC patients. Interestingly, combining LacCer 18:1/16:0 with other inflammatory markers resulted in a significant increase in the area under the curve with the highest specificity and sensitivity. Conclusions Using serum untargeted metabolomics, we have shown that LacCer 18:1/16:0 is a very unique metabolite for CD patients.

It is known that certain patients with very early onset IBD (diagnosis before 6 years of age) have a higher possibility of immune deficiency with monogenetic aetiology. The growing prevalence of these types of disorders forces the gastroenterologist to gain some knowledge about the symptoms and further diagnostic management, which includes consultation with the clinical immunologist. The resemblance of the clinical manifestation of early-onset Crohn's disease with ulcerative colitis and high incidence rate of unclassified IBD suggests caution in IBD diagnosis in younger patients.

Background Cigarette smoke (CS) exerts protective effect against ulcerative colitis. The mechanism of this phenomenon remains unknown. One of the possible explanation by which CS exerts its anti-inflammatory action is modulation of immune system. Therefore, the aim of the study was to evaluate the effect of CS on the course of inflammation and subpopulations of lymphocytes in the blood and colon in mice with dextran sulfate sodium (DSS)-induced colitis. Methods C57BL6/cmdb mice were exposed to CS for 4 weeks. Colitis was induced with 3.5% DSS given for 10 days. Severity of colitis was determined by disease activity index (DAI), body weight changes, and macro- and microscopic characteristics of inflammation. Peripheral subpopulations of lymphocytes were assessed by flow cytometry (blood) or immunohistochemistry (colonic tissue). Results Mice treated with 3.5% DSS developed severe colitis with significantly decreased body weight, increased DAI, and macroscopic and histological features of colonic inflammation. These findings were diminished after concomitant exposure to CS. Mice exposed to DSS alone demonstrated significantly decreased percentage of total CD4+ cells (73.1 vs. 52%, p = 0.0007), accompanied by increase of CD8+ cells (18.4 vs. 39.5%, p = 0.0001). Concomitant CS exposure reversed inappropriate CD4+/CD8+ ratio both in the blood and colon and significantly increased B cell presence in the colon. Conclusions Our study has demonstrated that CS exposure decreases severity of DSS-induced colitis. This phenomenon was accompanied by changes in CD4/CD8 ratio and B cell level in the peripheral blood and colon. These mechanisms may be responsible for protective effect of smoking in ulcerative colitis. Electronic supplementary material The online version of this article (doi:10.1007/s00384-017-2882-9) contains supplementary material, which is available to authorized users.

Since Kupffer cells/macrophages (KCs/MPs) may be involved in the pathogenesis of autoimmune hepatitis (AIH), this pioneer study was undertaken to evaluate KCs/MPs in pediatric AIH in transmission-electron microscope. Methods Ultrastructural analyses were performed using liver biopsies from 14 children with clinicopathologically diagnosed AIH. Results In all AIH children, ultrastructural findings revealed changes in the cells lining sinusoidal vessels, especially KCs/MPs and endothelial cells. KCs/MPs showed increased phagocytic activity and damaged mitochondria, frequently with accompanying intense fibrosis. In 10/14 AIH patients, the cytoplasm of sinusoidal KCs/MPs contained characteristic glassy droplet inclusions. They were round, sharply circumscribed, and contained homogeneous material and distinct translucent fields. Their ultrastructure was identical with the Russel bodies of plasma cells, which were also found in liver biopsies in the same patients. Conclusion Ultrastructural identification of characteristic cytoplasmic droplets with glassy appearance in KCs/MPs, never before described in AIH, provides a useful novel morphological feature in the diagnosis of this disease.

AIM The aim of this study was to determine the relation of non-invasive markers representing gut mucosal damage (metalloproteinase-9 (MMP-9)) and remodelling (tissue inhibitor of metalloproteinase-1 (TIMP-1)) with Crohn's disease (CD) phenotype, disease activity scores (clinical and endoscopic) and radiological evaluation of the ileum in newly diagnosed children. METHODS Serum and faecal MMP-9 and TIMP-1 concentrations were determined with the sandwich enzyme-linked immunoassay technique. The performance of each marker with reference to the Paris classification, disease activity scores and magnetic resonance enterography results was assessed using non-parametric tests. RESULTS A total of 32 children with CD demonstrated higher levels of serum and faecal MMP-9 and TIMP-1 compared with a control group including children without gastrointestinal inflammatory disease (all P

Inflammatory bowel disease (IBD) diagnosis and therapy is challenging for every pediatrician, especially when complicated with extraintestinal manifestations. The article reviews current literature on the hepatobiliary manifestations associated with inflammatory bowel disease in the pediatric population.

BACKGROUND Changing the resources of vitamin D and antioxidant nutrients may affect the course of allergic diseases. The aim of the study was to investigate the association between CoQ10, vitamin D, retinol, and α-tocopherol serum levels and severity of atopic dermatitis (AD) in children. METHODS Twenty-nine children with AD aged from 1 to 15 years were enrolled into the study. The severity of AD was categorized into mild or moderate (≤50 points in SCORAD - Scoring Atopic Dermatitis index) and severe (>50 SCORAD points). The control group was comprised of 22 children with negative history of allergy aged from 2 to 15. The serum measurements included vitamin D, retinol, α-tocopherol, CoQ10, C-reactive protein (CRP), complete blood count (CBC), and total immunoglobulin E (IgE). RESULTS Low vitamin D concentration (

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and a risk factor for cardiovascular disease (CVD). Research conducted in adults has proven that GGT can also be an independent risk factor for CVD. The aim of this study was to ascertain if GGT can be regarded as a simple biomarker of cardiovascular risk in obese children with NAFLD. One hundred obese children, aged 7-17 years, with suspected liver pathology were admitted to our Department. Viral hepatitis and autoimmune, toxic and selected metabolic liver diseases were excluded. Anthropometry, laboratory tests, 1HMR spectroscopy and evaluation of the common carotid artery intima-media thickness (IMT) were performed in all subjects. NAFLD was confirmed in 38 obese patients. There was a significantly higher activity of GGT and ALT, the concentration of total and LDL cholesterol, waist circumference, left coronary artery IMT, mean IMT value and total lipids in 1HMRS in children with NAFLD in comparison to non-hepatopathic obese children. Logistic regression analysis indicated that GGT, total cholesterol, LDL-cholesterol, left IMT and waist circumference significantly affected the development of NAFLD in obese children. In ROC analysis only GGT, waist circumference and left IMT allowed to differentiate children with NAFLD from those without steatosis with GGT having the highest result (AUC=0.94). GGT activity in patients revealed weak or at the upper limit of statistical significance correlation with traditional cardiovascular risk factors: glucose level, waist circumference, BMI, total cholesterol, LDL-cholesterol and insulin level. This allows to suggest, that GGT might be a potential reliable, simple and non-invasive biochemical marker for estimation of cardiovascular risk in obese children with NAFLD. However, further studies on larger population are necessary to confirm that observation.

Purpose Increased fecal calprotectin is a sensitive marker of various types of intestinal inflammation. We investigated correlations between high fecal calprotectin concentration and serum inflammatory markers in children with different intestinal diseases with diarrhea with/without blood and/or abdominal pain, to test whether the combination of these markers can differentiate potential patients with inflammatory bowel disease. Materials/methods The study included 128 children with high fecal calprotectin concentration (>150ug/g) and symptoms suggesting bowel disorders, hospitalized in the years 2013– 2015. Twenty-six (20%) patients were diagnosed with Crohn’s disease, 55 (43%) with ulcerative colitis, 32 (25%) with intestinal infection and 15 (12%) with food protein induced proctocolitis. Results Significantly increased inflammatory markers were detected in children with inflammatory bowel disease, with a correlation between calprotectin and erythrocyte sedimentation rate – ESR (R = 0.53), mean corpuscular volume – MCV (R=-0.64), red blood cell distribution width (R = 0.56), albumin (R = −0.52), hemoglobin (R = −0.53) only in Crohn’s disease patients. To discriminate Crohn’s disease patients from patients with intestinal infection and patients with food protein induced proctocolitis, AUC analysis was performed. It revealed that considering ESR, CRP and albumin as additional markers to fecal calprotectin significantly improved diagnostic performance (AUC 0.917, p = 0.038). Conclusions In children with abdominal pain and/or diarrhea, increased ESR, CRP and decreased albumin combined with a high fecal calprotectin level yields additional diagnostic value in screening potential patients with Crohn’s disease. As far as differentiation of ulcerative colitis is concerned, low additional diagnostic value was found when high fecal calprotectin was combined with albumin.

Purpose. Recently, it has been emphasized that hepatic progenitor/oval cells (HPCs) are significantly involved in liver fibrogenesis. We evaluated the multipotential population of HPCs by transmission electron microscope (TEM), including relations with adherent hepatic nonparenchymal cells (NPCs) in rats with biliary fibrosis induced by bile duct ligation (BDL). Methods. The study used 6-week-old Wistar Crl: WI(Han) rats after BDL for 1, 6, and 8 weeks. Results. Current ultrastructural analysis showed considerable proliferation of HPCs in experimental intensive biliary fibrosis. HPCs formed proliferating bile ductules and were scattered in periportal connective tissue. We distinguished 4 main types of HPCs: 0, I, II (bile duct-like cells; most common), and III (hepatocyte-like cells). We observed, very seldom presented in literature, cellular interactions between HPCs and adjacent NPCs, especially commonly found transitional hepatic stellate cells (T-HSCs) and Kupffer cells/macrophages. We showed the phenomenon of penetration of the basement membrane of proliferating bile ductules by cytoplasmic processes sent by T-HSCs and the formation of direct cell-cell contact with ductular epithelial cells related to HPCs. Conclusions. HPC proliferation induced by BDL evidently promotes portal fibrogenesis. Better understanding of the complex cellular interactions between HPCs and adjacent NPCs, especially T-HSCs, may help develop antifibrotic therapies in the future.

Background Long-term studies on the evolution of elevated total IgE (tIgE) concentration are in demand. Objective To investigate the prevalence of allergic diseases and influential factors in children with high tIgE levels during a 5-year period. Methods Children with high tIgE levels (>100 IU/mL) were study subjects. After the 5-year follow-up, an interview with the parents, clinical examination, and evaluation of tIgE and specific IgE (sIgE) to selected food and inhalant allergens were performed. Results The mean tIgE decreased significantly after 5 years in girls and boys regardless of the place of residence. Monosymptomatic patients accounted for most cases throughout the study, with the highest tIgE level at the beginning. After follow-up, the percentage of polysymptomatic patients increased. Their mean tIgE level was significantly higher than in the other groups. After follow-up, 11.7% of participants remained asymptomatic, and another 11.7% reported relief from symptoms. Allergy symptoms persisted in most children with normal tIgE levels. The 2-allergen sensitization was the most common through the study. Only patients sensitized to 4 allergens had unchanged levels of mean tIgE after follow-up and those with the highest mean tIgE level had a newly diagnosed sensitization to at least 1 allergen. A significant decrease of sIgE level was observed for food allergens. The values of sIgE to inhalant allergens even increased after the 5-year follow-up, despite decreased tIgE levels. Conclusion In children with allergy and an elevated concentration of tIgE, the increasing or stable value of tIgE could be a useful parameter for the prediction of the development of polysymptomatic allergy.

Uncontrolled proliferation of the cells and their resistance to programmed cell death are main features of malignant cells. The effectiveness in the treatment of cancers is based on the restoration of the sensitivity of transformed cells to apoptotic signals. Although significant progress has been made in this field during last decades, the resistance to chemotherapy becomes a problem in many cases. The association between cancer and modifiable health behaviors is well supported. At least one-half of all cancers are suggested to have a dietary component. Therefore many of the dietary agents and natural health products have attracted the attention of scientists. One of them is probiotics, the nonpathogenic microorganisms living in the intestinal tract which benefit the host. In human clinical trials, probiotics has been used successfully in the treatment of acute diarrhea. Other clinical indications for probiotics, mainly in inflammatory bowel disease, are still evaluated with promising preliminary data.

The long-term expression of human herpesvirus 8 (HHV-8) K1 produces hyperplasia of lymph nodes, splenomegaly, and lymphomas in mice. The mechanism of how K1 causes hyperplasia and lymphomas is not known. K1 is known to activate Akt and nuclear factor kappa B (NF-kB) through immunoreceptor tyrosine-based activation motif (ITAM) and may also bind to Fas receptor through its immunoglobulin (Ig) chain-like domain and interfere with apoptosis. We thus hypothesized that development of hyperplasia and lymphomas in K1-expressing mice is driven by altered Fas signaling. Examination of mice expressing K1 via a ubiquitous promoter showed that 90% K1 transgenic mice (n=10) had developed lymphoid hyperplasia (at least 3 lymph nodes >3 mm) and 60% developed lymphomas after 18 months, while all (26) control nontransgenic mice remained free of lymph node hyperplasia, splenomegaly, and lymphoma. Some K1 mice developed liver or mesenteric tumors (4 of 10 mice). The spleens of 78% of K1 mice were enlarged at 18 months and were on average 3.5 times heavier than spleens of non-K1 transgenic control mice. Hematoxylin and eosin staining of spleen sections showed lymphocyte expansion in the periarteriolar lymphocyte sheath with disruption of normal spleen architecture. Anti-kappa and anti-lambda light chain antibodies revealed the presence of monoclonal foci in 3 out of 3 K1 mice (average 6 foci per single section of spleen), but no foci were present in 4 control non-transgenic mice. Moreover, K1 protein was expressed in approximately 10% of splenic cells after staining with anti-K1 antibody 2H5. In vitro overexpression of an Ig domain-containing protein CD79b or treatment cells with K1 peptides revealed competition with K1-Fas binding in a dose-dependent manner and rate enhancement of Fas-mediated apoptosis. We have also shown that K1 suppressed Fas-mediated apoptosis, even in cells that did not express K1. Transfection of K1 into one pool of mouse cells protected against Fas-mediated apoptosis of a second pool of human Fas-transfected mouse cells indicating protection in trans. This analysis indicates a key role of K1 in suppression of Fas-mediated apoptosis which operates in a cis and trans protective role against apoptosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1254.

Abstract 2965 Poster Board II-941 The long-term expression of human herpesvirus 8 (HHV-8) K1 produces hyperplasia of lymph nodes, splenomegaly, and lymphomas in mice. The mechanism of how K1 causes hyperplasia and lymphomas. The immunoreceptor tyrosine-based activation motif (ITAM) of K1 was shown previously to activate of Akt and nuclear factor kappa B (NF-kB). However, we have recently shown that K1 suppresses Fas-mediated apoptosis through its extracellular immunoglobulin-like domain and that K1-transfected mice survive a lethal dose of agonistic anti-Fas antibody (Jo2). We thus hypothesized that development of hyperplasia and lymphomas in K1-expressing mice is driven by altered Fas signaling. Examination of mice expressing K1 via a ubiquitous promoter showed that K1 transgenic mice (n=10) had 90% developed lymphoid hyperplasia (at least 3 lymph nodes >3 mm) and 60% developed lymphomas after 18 months, while all (26) control nontransgenic mice remained free of lymph node hyperplasia, splenomegaly, and lymphoma. Some K1 mice developed liver or mesenteric tumors (4 of 10 mice). The spleens of 78% of K1 mice were enlarged at 18 months and were on average 3.5 times heavier than spleens of non-K1 transgenic control mice. Hematoxylin and eosin staining of spleen sections showed lymphocyte expansion in the periarteriolar lymphocyte sheath with disruption of normal spleen architecture. Anti-kappa and anti-lambda light chain antibodies revealed the presence of monoclonal foci in 3 out of 3 K1 mice (average 6 foci per single section of spleen), but no foci were present in 4 control non-transgenic mice. Moreover, K1 protein was expressed in approximately 10% of splenic cells after staining with anti-K1 antibody 2H5. To test the hypothesis that expression of K1 protein confers resistant to Fas-mediated apoptosis, splenic cells of 6-month-old K1 mice (n=3) and matched controls (n=3) were isolated and incubated with 50 ng/mL of agonistic anti-Fas antibody Jo2. At 12 hours of treatment, only 4±1% of splenocytes from K1 mice versus 17±2% of control splenocytes showed morphology of apoptosis (P We mapped the region that K1 uses to bind to Fas to an immunoglobulin (Ig) chain-like domain by expressing deletion mutants of K1. Overexpression of an Ig domain-containing protein CD79b competed with K1-Fas binding in a dose-dependent manner. Two 20-amino acid peptides (N251, N253) representing the Ig domain of K1 competed with K1-Fas binding in immunoprecipitation/immunoblotting analysis. The N251 and N253 peptides (100 mM) enhanced anti-Fas antibody (CH-11, 50 ng/mL)-induced apoptosis of BJAB lymphoma cells that expressed K1 but not that of vector-transfected BJAB cells. K1 splenocytes incubated with N251 and N253 showed enhanced rates of Fas-mediated apoptosis over control peptide-treated K1, and peptides did not enhance the apoptosis rates of control non-K1 expressing splenocytes. This analysis indicates a key role of K1 in lymphoid hyperplasia and lymphoma and that K1 direct binding to Fas occurs in vivo, which is effectively targeted by competing peptides to restore apoptosis. Disclosures: No relevant conflicts of interest to declare.