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Interactions between the peripheral nervous system and resident macrophages (MMs) modulate intestinal homeostatic functions. Activation of β2-adrenergic receptors on MMs has been shown to reduce bacterial challenges. These MMs are also crucial for the development of bowel inflammation in postoperative ileus (POI), an iatrogenic, noninfectious inflammation-based motility disorder. However, the role of the sympathetic nervous system (SNS) in the immune modulation of these MMs during POI or other noninfectious diseases is largely unknown. By employing 6-OHDA-induced denervation, we investigated the changes in the muscularis externa by RNA-seq, quantitative PCR, and flow cytometry. Further, we performed transcriptional phenotyping of sorted CX3CR1 + MMs and ex vivo LPS/M-CSF stimulation on these MMs. By combining denervation with a mouse POI model, we explored distinct changes on CX3CR1 + MMs as well as in the muscularis externa and their functional outcome during POI. Our results identify SNS as an important mediator in noninfectious postoperative inflammation. Upon denervation, MMs anti-inflammatory genes were reduced, and the muscularis externa profile is shaped toward a proinflammatory status. Further, denervation reduced MMs anti-inflammatory genes also in the early phase of POI. Finally, reduced leukocyte infiltration into the muscularis led to a quicker recovery of bowel motility in the late phase of POI.

Gastrointestinal inflammatory neuropathy, namely, eosinophilic myenteric ganglioneuronitis (EMG) and lymphocytic ganglioneuronitis (LG), is a form of chronic intestinal pseudo-obstruction and results from the infiltration of the myenteric plexus by eosinophils and lymphocytes, respectively. The literature related to the clinicopathological features of adult inflammatory neuropathy is scarce. We aim to elucidate the clinical and histological details of 7 cases of inflammatory neuropathy (EMG, n = 4, and LG, n = 3) and compare the features of EMG and LG retrospectively. There was no difference between these two entities in terms of clinical, hematological, or biochemical parameters. Histologically, almost all cases (n = 6/7) showed accompanying elements of ganglion cell vacuolization, mesenchymopathy, and partial/complete desmosis in addition to the disease-defining pathology. Besides, all cases of EMG showed infiltration of the inner circular muscle of muscularis propria by eosinophils. Two cases of LG showed additional muscular pathology pertaining to the muscularis propria. Inflammatory infiltration of the myenteric plexus is pathognomonic for the diagnosis of gastrointestinal inflammatory neuropathy although additional features in the form of ganglion cell vacuolization, reduction in the number of ganglia, desmosis, mesenchymopathy, and inflammation of the muscularis propria (eosinophils in EMG) can be seen. The pathologists need proper awareness along with judicious use of special and immunostains for clinching the diagnosis.

Background: Postoperative ileus is common and is a major clinical problem. It has been widely studied in patients and in experimental models in laboratory animals. A wide variety of treatments have been tested to prevent or modify the course of this disorder., Purpose: This review draws together information on animal studies of ileus with studies on human patients. It summarizes some of the conceptual advances made in understanding the mechanisms that underlie paralytic ileus. The treatments that have been tested in human subjects (both pharmacological and non-pharmacological) and their efficacy are summarized and graded consistent with current clinical guidelines. The review is not intended to provide a comprehensive overview of ileus, but rather a general understanding of the major clinical problems associated with it, how animal models have been useful to elucidate key mechanisms and, finally, some perspectives from both scientists and clinicians as to how we may move forward with this debilitating yet common condition., (© 2020 John Wiley & Sons Ltd.)

Background: The identification of autoantibodies directed against neuronal antigens has led to the recognition of a wide spectrum of neurological autoimmune disorders (NAD). With timely recognition and treatment, many patients with NAD see rapid improvement. Symptoms associated with NAD can be diverse and are determined by the regions of the nervous system affected. In addition to neurological symptoms, a number of these disorders present with prominent gastrointestinal (GI) manifestations such as nausea, diarrhea, weight loss, and gastroparesis prompting an initial evaluation by gastroenterologists., Purpose: This review provides a general overview of autoantibodies within the nervous system, focusing on three scenarios in which nervous system autoimmunity may initially present with gut symptoms. A general approach to evaluation and treatment, including antibody testing, will be reviewed., (© 2019 John Wiley & Sons Ltd.)

Background: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO)., Methods: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups., Results: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia., Conclusions: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.

Inflammation plays a role in abdominal surgery (AS)-induced intestinal ileus that is alleviated by electrical vagal stimulation. Intracisternal injection of RX-77368, the stable thyrotropin-releasing hormone agonist, activates dorsal motor nucleus neurons and gastric vagal efferent discharges. We investigated the gastric inflammation induced by AS and the modulation by intracisternal RX-77368 in rats. RX-77368 (50 ng/rat) or saline was injected followed, 1 h later, by laparotomy and small intestinal/cecal manipulation. The sham group had anesthesia alone. After 6 h, gastric emptying (GE) and the inflammation in gastric corpus were determined. AS inhibited GE by 72% vs. control and doubled the number of M1-like macrophage immunoreactive for major histocompatibility complex class II (MHCII; M1 marker) but not for cluster of differentiation 206 (CD206; M2 marker) (MHCII + /CD206 - ) while there was no change in M2-like macrophages (MHCII - /CD206 + ). AS increased mRNA levels of interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) by 1.7- and 1.5-fold, respectively, in the gastric submucosa plus muscle layers and the infiltration of neutrophils labeled by myeloperoxidase by 9.5-fold in the muscularis externa. RX-77368 inhibited AS-related gastric changes while not altering these parameters in the sham group. There was a significant negative correlation between GE and IL-1β ( r = -0.46), TNF-α ( r = -0.44), M1 macrophage ( r = -0.82), and neutrophils ( r = -0.91). The M2-like macrophages and IL-10 expression were unchanged by AS with intracisternal saline or RX-77368. These data indicate that AS activates gastric M1 macrophages and increases proinflammatory cytokines expression, which are prevented by central vagal activation and may contribute to the correlated dampening of postoperative gastric ileus. NEW & NOTEWORTHY MHCII + /CD206 - (M1) and MHCII - /CD206 + (M2) constitute two distinct populations of macrophages that are in close apposition to the cholinergic neurons in the rat gastric myenteric plexus (MP). Abdominal surgery (6 h) activates M1 macrophage leading to inflammation in the gastric MP correlated with the delayed gastric emptying, which was abolished by central vagal stimulation via intracisternal injection of RX-77368. Vagal stimulation linked with the cephalic phase may have potential beneficial effects to curtail postoperative gastric ileus.

A 37-year-old woman who had previously been diagnosed with idiopathic chronic intestinal pseudo-obstruction (CIPO) at another hospital was admitted to our institution with severe abdominal pain. She had a history of several abdominal surgeries to treat ileus at the previous hospital, and contrast-enhanced computed tomography on admission revealed subileus without any apparent causes of obstruction. Total parenteral nutrition, a gastrointestinal prokinetic agent, and opiates reduced persistent pain;however, breakthrough pain continued. A neurologist at our hospital suggested autoimmune autonomic ganglionopathy (AAG) as a potential cause of CIPO. The patient was diagnosed with suspected AAG on the basis of seropositive results for anti-ganglionic acetylcholine receptor antibody. Intravenous immunoglobulin administration and plasma exchange were performed in combination with immunosuppressive drugs;however, her symptoms barely improved. Although percutaneous endoscopic gastrostomy and enterostomy were subsequently performed to reduce internal intestinal pressure, her pain relief was insufficient.

Postoperative ileus (POI) is defined as a transient episode of impaired gastrointestinal motility after abdominal surgery, which prevents effective transit of intestinal contents or tolerance of oral intake. This frequent postoperative complication is accompanied by a considerable increase in morbidity and hospitalisation costs. The aetiology of POI is multifactorial. Besides a suppression of peristalsis by inhibitory neuronal signalling and administration of opioids, particularly in the prolonged form, immunological processes play an important role. After surgical trauma, resident macrophages of the muscularis externa (ME) are activated leading to the liberation of proinflammatory mediators and a spreading of the inflammation along the entire gastrointestinal tract. To date, no prophylaxis or evidence-based single approach exists to treat POI. Since none of the current treatment approaches (i.e., prokinetic drug treatment) has provided a benefit in randomised trials, immunoregulatory interventions appear to be more promising in POI prevention or treatment. The present contribution gives an overview of immunological mechanisms leading to POI focusing on current and future therapeutic and prophylactic approaches., (Georg Thieme Verlag KG Stuttgart · New York.)

A 26-year-old patient was diagnosed as having chronic intestinal pseudo-obstruction with manometric and histopathologic features suggestive of an intestinal myopathy. Histology was characterized by smooth muscle degeneration without inflammatory or immune cells. The severe gut dysfunction required full parenteral nutritional support. After a few months, the patient developed symptomatic tachy-brady arrhythmia episodes with syncopes. A thorough diagnostic work-up led to a diagnosis of sick sinus syndrome, which was managed by pacemaker implantation and administration of β-blockers. This led to a partial improvement in tachy-brady arrhythmia episodes. Nonetheless, the patient continued to experience sustained supraventricular tachyarrhythmia runs, poorly responsive to increasing β-blocker doses. To investigate the origin of the cardiologic impairment, the patient was tested for anticonductive tissue autoantibodies, which were positive, thus supporting a possible autoimmune origin of the dysrhythmia. Other autoantibodies were negative. On the basis of these findings, the patient was treated with high-dose steroids, which were then tapered. The patient responded to the steroid treatment and did not experience further episodes of syncope and tachyarrhythmias. The severe gut dysfunction remained unchanged. This case highlights an association between severe gut dysfunction and cardiac conductive tissue abnormalities, with autoantibodies to conductive tissue possibly causing the dysrhythmia. The severe gut and heart (likely autoimmune-mediated) dysfunction presented in this case provides a basis to further assess a link between intestinal and cardiac abnormal rhythmicity.

Background: Systemic sclerosis (SSc) is a rare systemic connective tissue disease characterized by abnormal fibroblast proliferation and micro-vascular inflammatory changes., Aim: To assess serum B-cell activating factor (BAFF) levels in patients with systemic sclerosis and to correlate this with disease features and disease severity., Methods: This is a case-control study in which patients with the established diagnosis of SSc were recruited. The diagnosis of SSc was established according to the American Rheumatology Association 1980 criteria for the classification of scleroderma. Patients' assessment included evaluation of skin involvement using the Modified Rodnan score and disease severity using the Medsger score. Twenty-five healthy matching controls were included. The sandwich enzyme-linked immunosorbent assay technique was used for direct assessment of serum BAFF in patients and controls., Results: The study included 60 patients (54 female and 6 male), with a mean age of 38.18 ± 12.06 years, with mean disease duration of 7.85 ± 4.075 years. Serum BAFF in patients ranged 98.2-5015 pg/mL with mean BAFF 1100 ± 835.4 pg/mL. In controls serum BAFF levels ranged 188.5-2314 pg/mL with mean BAFF 546.1 ± 471.1 pg/mL, showing a statistically significant elevation of serum BAFF levels in SSc patients (P = 0.0001) with insignificant correlation to skin disease or total Medsgar Score of the study population (P > 0.05). Serum BAFF levels showed significant correlation with episodes of pseudo-obstruction and methotrexate (MTX) use in the patients studied (P < 0.05)., Conclusion: Serum BAFF levels were significantly elevated in patients with SSc irrespective of disease subtype, disease duration or age of patients. This elevation in serum BAFF significantly related to gastrointestinal track involvement and MTX therapy.

Objective: Many patients, especially women, suffer from severe gastrointestinal pain and dysmotility for several years without being diagnosed. Depletion of gonadotropin-releasing hormone (GnRH) in the enteric nervous system (ENS) has been described in some patients. The aim of this study was to examine the expression of GnRH in ENS and antibodies against GnRH in serum, in a dysmotility patient cohort of southern Sweden., Materials and Methods: All consecutive patients (n = 35) referred for laparoscopic full-thickness biopsy because of symptoms or signs of severe dysmotility between 1998 and 2009, or patients with a severe dysmotility disorder having had a bowel resection within the time frame, were considered for inclusion. In 22 cases, representative biopsy material containing ganglia was available, and these patients were included. Medical records were scrutinized. The expression of GnRH was determined by immunohistochemistry in bowel biopsies from these patients and in patients with carcinoma or diverticulosis without ENS histopathology. Antibodies against GnRH in serum were determined by ELISA in patients and controls., Results: 14 patients were diagnosed with enteric dysmotility (ED) and 8 with chronic intestinal pseudo-obstruction due to varying etiology. Immunostained biopsies showed expression of GnRH in the ENS. A reduced expression of GnRH-containing neurons was found in 5 patients, as well as antibodies against GnRH in serum. 3 of these patients had a history of in vitro fertilization (IVF) using GnRH analogs., Conclusions: A subgroup of patients with severe dysmotility had a reduced expression of GnRH-containing neurons in the ENS and expressed antibodies against GnRH in serum.

Objectives: Although postoperative ileus (POI) is considered multifactorial, intestinal inflammation resulting from manipulation-induced mast cell activation is recognized as an important pathophysiological mechanism. Therefore, mast cell stabilization may represent a new therapeutic approach to shortening POI. The aim of this paper was to study the effect of ketotifen, a mast cell stabilizer, on postoperative gastrointestinal transit in patients who underwent abdominal surgery., Methods: In this pilot study, 60 patients undergoing major abdominal surgery for gynecological malignancy with standardized anesthesia were randomized to treatment with ketotifen (4 or 12 mg) or placebo. Patients were treated for 6 days, starting 3 days before surgery. Gastric emptying of liquids, selected as a primary outcome parameter, was measured 24 h after surgery using scintigraphy. Secondary end points were (scintigraphically assessed) colonic transit, represented as geometrical center of activity (segment 1(cecum) to 7(stool)) and clinical parameters., Results: Gastric retention 1 h after liquid intake was significantly reduced by 12 mg (median 3% (1-7), P=0.01), but not by 4 mg ketotifen (18% (3-45), P=0.6) compared with placebo (16% (5-75)). Twenty-four hour colonic transit in placebo was 0.8 (0.0-1.1) vs. 1.2 (0.2-1.4) colon segments in the 12 mg ketotifen group (P=0.07). Abdominal cramps were significantly relieved in patients treated with 12 mg ketotifen, whereas other clinical parameters were not affected., Conclusions: Ketotifen significantly improves gastric emptying after abdominal surgery and warrants further exploration of mast cell stabilizers as putative therapy for POI.

The acetylcholine receptor ganglionic (G-AchR) antibody is a very specific serologic test for autoimmune autonomic ganglionopathy. The spectrum of autoimmune (or presumed to be autoimmune) autonomic disorders, however, is quite broad and positivity to this antibody has been reported in a variety of other conditions, albeit infrequent and with low titer. This review describes the autonomic neuropathies most frequently encountered in clinical practice in which an autoimmune etiology is suspected. They include a chronic form (pure autonomic failure) and limited autonomic neuropathies with predominant involvement of one neurotransmitter type (i.e., cholinergic vs. adrenergic) or one system (such as the gastrointestinal system) or a distal small fiber dysfunction. In each of these conditions, occasional positivity to the G-AchR antibody has been found, but the pathogenetic significance of such finding is still uncertain. Other antigens and antibodies yet to be identified are more likely to be responsible in these disorders.

Background & Aims: Activation of autoimmune pathways has been implicated as a contributing mechanism to the pathophysiology in some patients with chronic intestinal pseudoobstruction (CIP). In this study we tested the hypothesis that sera from a subpopulation of patients with CIP contain autoantibodies that activate autophagy via a Fas-dependent pathway in cultured human neuroblastoma SH-Sy5Y cells., Methods: Twenty-five patients with established neurogenic CIP (20 women, 5 men; age range, 21-57 y) were investigated and circulating antineuronal antibodies to enteric neurons were found in 6 (24%) patients. The ability of antineuronal antibodies to induce autophagy was assessed using immunohistochemical, Western immunoblot, and molecular techniques. The presence of autophagosomes was monitored using a specific immunohistochemical marker, anti-microtubule-associated light chain immunoreactivity, and colocalization with mitochondrial- and Fas-activated death domain immunofluorescence using appropriate antibodies in cells exposed to sera from matched healthy controls and patients with neurogenic CIP., Results: Exposure of SH-Sy5Y cells to sera from patients with CIP containing antineuronal antibodies revealed increased binding of autoimmune immunoglobulin (IgG class) to the surface of SH-Sy5Y cells and increased formation of autophagosomes showing colocalization with mitochondria and Fas-activated death domain compared with control sera. Pretreatment of sera with either protein L agarose beads or a soluble Fas receptor (extracellular domain) chimera prevented the stimulation of autophagy., Conclusions: We provide novel evidence that antineuronal antibodies may contribute to neuronal dysfunction observed in a subset of patients with neurogenic CIP via autoantibody-mediated activation of autophagy involving the Fas receptor complex.

Chronic intestinal pseudo-obstruction (CIPO), a recently recognized manifestation of systemic lupus erythematosus (SLE) with only 23 cases reported in the English literature, may appear as a complication or as the initial presentation of SLE and usually occurs during the setting of an active lupus. The pathogenic mechanism in SLE is unknown. We describe four additional cases with clinical, radiological, and manometric features of CIPO. As SLE-related CIPO usually responds to treatment with high doses of corticosteroids and/or immunosuppressive and prokinetic agents, a high level of awareness of this complication is needed to avoid unnecessary surgical intervention.

Aims: To report three children displaying gastric metaplasia antral pyloric type of the small bowel mucosa., Methods: Analysis of clinical, histopathological and immunohistochemical data., Results: The first patient was a 14-year-old girl with history of chronic intestinal pseudo-obstruction and chronic jejunitis; the second patient was a 6-year-old girl with a long-lasting jejunostomy; and the third patient was a 5-year-old girl with ileal-rectal anastomosis. The foci of gastric metaplasia were obvious with H&E-stained sections. The cells at the gastric metaplasia mucosa proved to be MUC-1 and sialyl-Tn positive by immunohistochemistry and they were in a pattern that was different from that of the adjacent mucosa; the cells were autofluorescent in H&E-stained sections., Conclusions: Gastric metaplasia of the small bowel mucosa in these cases seems to have resulted from chronic inflammation and persistent regenerative activity. This has rarely been reported outside Crohn disease, and if ever in children.

A 32-year-old woman was diagnosed with leucopenia in 2002, being antinuclear antibody, anti-DNA antibody, and antiphospholipid antibody positive, and she was administered low-dose aspirin. In July 2006, she was admitted to our hospital because of pyrexia and abdominal pain. Examination revealed paralytic ileus, absence of the pupillary light reflex, dyshidrosis and anuresis. In addition, with high-level interleukin-6 in cerebrospinal fluid, the sensory nerve conduction velocity was derivation impotence. She was subsequently diagnosed with systemic lupus erythematosus (SLE) with central nervous system involvement, peripheral neuropathy as well as acute pan-dysautonomia. After pulse corticosteroid therapy, paralytic ileus was improved, however, the urination disorder persisted, and syncope due to orthostatic hypotension became marked. Plasma exchange and a second course of pulse corticosteroid therapy were performed, and were ineffective, whereas intravenous cyclophosphamide was effective. This patient is a rare case of central nervous system, peripheral neuropathy as well as acute pan-dysautonomia with SLE.

Background & Aims: A 30-year-old woman, treated with buserelin, an analogue of gonadotropin-releasing hormone (GnRH) (also called luteinizing hormone-releasing hormone, LH-RH), developed chronic intestinal pseudo-obstruction (CIPO). The sudden onset of this disease in a previously healthy woman perplexed us. CIPO refers to a gastrointestinal disorder that can have a variety of causes, such as drugs, among others. Thus, we wanted to examine whether in this patient the development of CIPO is related to the treatment with buserelin., Methods: The patient was examined using esophagogastroduodenoscopy, esophageal, and antroduodenojejunal manometry, gastric emptying tests, and histologic analyses and immunohistochemistry on full-thickness biopsies including staining with anti-GnRH antibody. Plasma samples were examined by the standard serologic analyses and specifically for the occurrence of anti-GnRH antibodies by enzyme-linked immunosorbent assay methods., Results: CIPO was diagnosed based on symptoms (abdominal pain, vomiting, and constipation), and the results of the clinical examinations, such as signs of esophageal aperistalsis, delayed gastric emptying, and small intestinal bursts. Histologic examination revealed a decreased number of myenteric neurons as well as increased neuronal degeneration and an abnormal immune profile. There was a loss of GnRH-containing neurons. The patient had high plasma titers of anti-GnRH antibodies, which occurred on the occasions of the treatment with buserelin., Conclusions: Our findings suggest that the patient has developed CIPO due to buserelin-induced formation of anti-GnRH antibodies destroying GnRH-producing neurons of the myenteric plexus.

Autoimmune enteric leiomyositis is an extraordinary rare cause of acquired chronic intestinal pseudo-obstruction in children. We report a 5-year-old girl who developed chronic intestinal pseudo-obstruction 3 years after an autoimmune hepatitis. Mucosal biopsies of the upper gastrointestinal tract and colon showed minimal inflammatory changes. On full-thickness biopsies of the small intestine, a dense lymphocytic infiltrate of the muscularis propria was seen, mainly consisting of cytotoxic T lymphocytes. Smooth muscle fibers were degenerated and diminished, but the myenteric plexus was intact. The coexistence of an autoimmune hepatitis in our case indicates an expansion of autoreactive T cells to homologous self-antigens. It is of practical importance for histopathological diagnosis that inflammation in autoimmune enteric leiomyositis affects the muscularis propria of the small intestine, whereas mucosa and submucosa do not show severe inflammatory changes. Therefore, correct diagnosis may be missed in peroral and peranal mucosal biopsies, but full-thickness biopsies are required.

Objective: To investigate local inflammatory events within the colonic muscularis as a causative factor of postoperative ileus., Summary Background Data: Surgically induced intestinal muscularis inflammation has been hypothesized as a mechanism for postoperative ileus. The colon is a crucial component for recovery of gastrointestinal motor function after surgery but remains unaddressed. The authors hypothesize that colonic manipulation initiates inflammatory events that directly mediate postoperative smooth muscle dysfunction., Methods: Rats underwent colonic manipulation. In vivo transit and colonic motility was estimated using geometric center analysis and intraluminal pressure monitoring. Leukocyte extravasation was investigated in muscularis whole mounts. Mediator mRNA expression was determined by real-time reverse transcriptase-polymerase chain reaction. In vitro circular muscle contractility was assessed in a standard organ bath. The relevance of iNOS and COX-2 inhibition was determined using DFU or L-NIL perfusion., Results: Colonic manipulation resulted in a massive leukocyte recruitment and an increase in inflammatory mRNA expression. This inflammatory response was associated with an impairment of in vivo motor function and an inhibition of in vitro smooth muscle contractility (56%). L-NIL but not DFU significantly ameliorated smooth muscle dysfunction., Conclusions: The results provide evidence for a surgically initiated local inflammatory cascade within the colonic muscularis that mediates smooth muscle dysfunction, which contributes to postoperative ileus.

We describe a previously healthy boy who developed intestinal pseudo-obstruction following an episode of gastroenteritis at age 2 years. At presentation, the patient had mildly raised erythrocyte sedimentation rate and C-reactive protein level, and elevated antineutrophil cytoplasmic antibodies, antinuclear anti-DNA, and anti-smooth muscle antibodies. His electrogastrography was myopathic with no dominant frequency. First full-thickness intestinal biopsies showed a T lymphocytic myositis, particularly in the circular muscle. Steroid therapy resulted in clinical remission; cessation of steroids, in relapse. Further full-thickness biopsies showed an initial reduction in alpha-smooth muscle actin immunostaining in circular muscle myocytes and later atrophy and disappearance of many myocytes. Vascular and the remaining enteric smooth muscle cells showed HLA-DR and intercellular adhesion molecule 1 expression. These observations demonstrate the ability of enteric myocytes to take part in an inflammatory response and to change their phenotype, allowing them to act as antigen-presenting cells and to activate T cells. This and possible cytokine production by the myocytes play a role in their own destruction. This process responded to immunosuppressive therapy.

Recovery from hemorrhagic shock (HS) is frequently accompanied by bowel stasis. The aim of this study was to examine whether or not HS initiates an inflammatory response that includes production of cytokines, specifically G-CSF and interleukin-6 (IL-6), and recruitment of leukocytes within the intestinal muscularis which contribute to impaired muscle contractility. Sprague-Dawley rats were subjected to HS (MAP 40 mm Hg for 156 min) followed by resuscitation, and then they were killed at 4 hr. Shock animals demonstrated accumulation of PMNs in the jejunal muscularis and decreased spontaneous and bethanechol-stimulated muscle contractility. Semiquantitative RT-PCR demonstrated elevated levels of IL-6 and G-CSF mRNA in shock animals in full-thickness jejunum and in mucosa and muscularis layers compared to sham controls. Immunostaining demonstrated increased IL-6 protein production within the muscularis externa and submucosa. In situ hybridization studies localized G-CSF mRNA production to the submucosa. Gel shift assays revealed increased NF-kappaB and Stat3 activity in full-thickness jejunum and jejunal layers of shock animals. Activation of Stat3 also was demonstrated in normal muscularis tissue exposed to IL-6 and G-CSF in vitro. IL-6 and G-CSF are produced in the muscularis and mucosa layers of the gut in HS where they may contribute to PMN recruitment and smooth muscle dysfunction.

Intestinal pseudo-obstruction occurs rarely in patients with myasthenia gravis (MG) and thymoma. The etiology of the intestinal pseudo-obstruction remains to be elucidated, although an autoimmune mechanism is postulated. We present the first report of neuronal nicotinic acetylcholine receptor (AChR)-specific antibody in a patient with seropositive MG, malignant thymoma, and intestinal pseudo-obstruction. This finding provides evidence that intestinal pseudo-obstruction associated with thymoma and possibly other neoplasms may be related to antibodies against the neuronal nicotinic receptors at autonomic ganglia., (Copyright 1999 John Wiley & Sons, Inc.)

A 67-year-old woman was admitted for intestinal pseudoobstruction associated with peripheral sensitive neuropathy. Jejunal biopsies performed during laparotomy, showed axonal degeneration and lympho-plasmocytic infiltration in myenteric plexus. High titer of seric anti-Hu antibodies suggested a paraneoplastic syndrome. Thoracic CT scan showed mediastinal lymph nodes. Their histological examination confirmed the diagnosis of metastatic small-cell lung carcinoma. Her condition gradually deteriorated despite supportive parenteral nutrition, chemotherapy, steroids and intravenous immunoglobulins. She died 12 months after the onset of symptoms.

Aim: Chronic intestinal pseudo-obstruction has been associated with urinary disorders, myopathy, and ophthalmoplegia in adults and cholelithiasis in children. We observed a high percentage of total-parenteral-nutrition-dependent patients with pseudo-obstruction and recurrent infections requiring gammaglobulin infusions., Methods: All records for 23 children with chronic intestinal pseudo-obstruction (10 females and 13 males, mean age 9.8 y +/- 4.9 y, range 4-24 y) referred for a nutritional evaluation from 1992 to 1995 were reviewed. Chronic intestinal pseudo-obstruction was diagnosed by clinical, radiographic findings and antroduodenal manometry. Intestinal full-thickness biopsies were performed in seven children., Results: Hypogammaglobulinemia was diagnosed in 18 patients (78%): 16 patients had various immunoglobulin deficiencies and 2 had selective antibody deficiency. Intravenous gammaglobulin was administered in 14 patients. Other medical conditions affecting the children are summarized as follows: autonomic dysfunction in 10 patients (43%), recurrent hypoglycemia in 9 (39%), asthma in 9 (39%), cholecystitis in 7 (30%), low serum carnitine level in 6 (26%), urinary dysfunction in 6 (26%), pancreatitis in 5 (22%), behavioral problems in 5 (22%), myopathy in 2 (9%), idiopathic thrombocytopenia in 2 (8%), velopharyngeal insufficiency in 1 (4%), oculocutaneous albinism in 1 (4%), Pierre-Robin syndrome in 1 (4%), and protein C deficiency in 1 (4%). Munchausen syndrome was suspected in two patients., Conclusions: Chronic intestinal pseudo-obstruction appears to be associated with immune deficiencies. It is unclear if the immune deficiencies, intestinal pseudo-obstruction, and the other medical conditions have a common underlying etiology. Repeated infections may be due to impaired immune function in children with chronic intestinal pseudo-obstruction. We recommend screening for immune deficiencies in children with chronic intestinal pseudo-obstruction.

The authors describe the clinical and biological data of seven patients with anti-Hu antibodies. Six of them displayed a small cell lung carcinoma (SCLC), but no cancer was detected in the 7th patient in spite of an extensive workup. The clinical heterogeneity of the anti-Hu syndrome is emphasized. The major symptoms were linked to a severe sensory neuropathy in three cases, to cerebellitis in two cases, to dysautonomia in one case, and to gastro-intestinal pseudo-obstruction in one case. One patient also displayed EMG abnormalities characteristic of the Lambert-Eaton myasthenic syndrome. Two patients developed opsoclonus or ocular flutter associated with severe confusion in the late stage of their disease. In four patients, the neurological signs and symptoms preceded the discovery of the SCLC, and in two cases the initial detection of anti-Hu antibodies prompted the successful search for this tumor. Immunopathological events injuring the peripheral and central nervous system are briefly discussed.

Autoantibodies against proliferating cell nuclear antigen (PCNA) have been detected almost exclusively in sera from patients with systemic lupus erythematosus (SLE). Because of the extremely low prevalence of anti-PCNA, however, it has been difficult to establish its disease specificity and clinical associations. We present 2 cases in which patients with anti-PCNA developed severe gastrointestinal dysfunction that led to chronic intestinal pseudoobstruction. Neither patient had manifestations suggestive of SLE. Although sclerodermatous skin changes were minimal or absent in these patients, physical and radiographic findings indicated that systemic sclerosis was a likely cause of the gastrointestinal dysfunction. The similarity of the clinical features in these patients implies that the unusual detection of this unique autoantibody may not be a coincidence.

A 60-year-old patient presenting with the typical features of progressive sensory neuronopathy and subsequent intestinal pseudo-obstruction was found to have antineuronal nuclear antibodies (ANNA-I or Anti-Hu). These findings were suggestive of a paraneoplastic syndrome, but neither clinically nor at autopsy could a neoplasm be detected. Neuropathological findings were identical with those known for carcinoma-associated forms with marked neuron loss of spinal sensory ganglia and myenteric plexus. Therefore, ANNA-I and intestinal pseudo-obstruction may in rare cases occur without detectable underlying cancer.

Anti-Hu autoantibodies in high titres, as revealed with immunocytochemistry and Western blot, were present in a patient with gastrointestinal pseudo-obstruction and small-cell lung cancer (SCLC) bearing the Hu antigen. Marked neuron and nerve fibre loss were found in the myenteric plexus at postmortem. These findings show that neuronopathic Hu-associated gastrointestinal pseudo-obstruction can occur as the only paraneoplastic neurological symptom in patients with SCLC.

Severe gastrointestinal dysmotility is a newly recognized paraneoplastic syndrome that occurs with small-cell lung carcinoma. Thirty-four patients with small-cell carcinoma, of whom 5 had chronic intestinal pseudoobstruction and 29 had no digestive symptoms, were studied serologically. Four of the 5 patients with gut dysmotility had immunoglobulin G antibodies reactive with neurons of the myenteric and submucosal plexuses of jejunum and stomach in an indirect immunofluorescence assay. Antibodies of this type were not found in any of the 29 patients who had no gut dysmotility, nor were they found in patients with chronic idiopathic intestinal pseudoobstruction (n = 8), ovarian cancer (n = 20), or epilepsy (n = 4) or in normal subjects (n = 9). In 4 of the patients with paraneoplastic pseudoobstruction, antibodies in highly diluted serum (1:4000-1:8000) bound selectively to nuclei and cytoplasm of neuronal elements in the gut. This novel autoantibody activity suggests that intestinal pseudoobstruction occurring in patients with small-cell carcinoma may have an autoimmune basis. From a clinical standpoint, serological testing offers a simple means for determining which patients with gut dysmotility syndromes may have associated small-cell carcinoma, thereby enabling earlier diagnosis and treatment of the tumor.

We studied a group of six patients with clinical, radiological, and/or manometric features of severely abnormal gastrointestinal motility. Symptoms suggestive of esophageal, small bowel, or colonic involvement were present from 1 1/2 to 40 years. All patients had elevated antinuclear antibody (ANA) titers. None had clinical or radiographic features suggestive of progressive systemic sclerosis or other connective tissue diseases. Two patients had pathologic examinations of intestinal specimens, and these did not show changes suggestive of progressive systemic sclerosis. We conclude that patients with severe gastrointestinal motility disorders can have elevated ANA titers without features of progressive systemic sclerosis or other connective tissue diseases.