Pamidronate treatment of chronic noninfectious inflammatory lesions of the mandible in children

Noninfectious inflammatory lesions of the mandible occur in chronic recurrent multifocal osteomyelitis (CRMO). Diffuse sclerosing osteomyelitis of the mandible (DSOM) is a condition thought to be a localized form of CRMO. Recently, bisphosphonate therapy, and particularly intravenous pamidronate, has been proposed as a treatment for patients with both CRMO and DSOM who do not improve with nonsteroidal antiinflammatory drug treatment. We report our experience using pamidronate in 2 children with chronic noninfectious osteomyelitis affecting the mandible. We describe the clinical and radiographic features and the treatment, side effects, and clinical and radiographic responses. Our experience suggests that pamidronate is an effective second-line therapy.     

The Dilemma of Chronic Recurrent Multifocal Osteomyelitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare idiopathic inflammatory disease that affects mainly children and young adults, resulting in significant morbidity especially if not diagnosed early. The clinical signs and symptoms are nonspecific, with a consequential delay in diagnosis. Radiological and histopathological criteria are important for its definition. Two cases of CRMO are reported, highlighting the diagnostic challenge and demonstrating the importance of timely investigations.     

Sternocostal involvement in chronic recurrent multifocal osteomyelitis associated with ulcerative colitis

Chronic recurrent multifocal osteomyelitis (CRMO) is a chronic, relapsing, inflammatory, non-infectious disorder of the skeletal system and is of unknown origin. Early diagnosis of the disease is essential to exact treatment. The relationship between inflammatory bowel disease and CRMO is understood as extraintestinal rheumatic manifestations. CRMO associated with ulcerative colitis (UC) is very rarely reported. This case is first report of sternocostal involvement in CRMO associated with UC.     

Association of chronic non-bacterial osteomyelitis with Crohn’s disease but not with CARD15 gene variants

Chronic non-bacterial osteomyelitis (CNO) is an inflammatory, non-infectious disorder of the skeletal system with unknown etiology. Besides bone-inflammation, patients may present with inflammatory involvement of other tissues. Chronic recurrent multifocal osteomyelitis (CRMO) is the most severe form of CNO. We describe the occurrence of Crohn’s disease (CD) in four patients, previously diagnosed with CRMO. Mutations in CARD15, encoding the NOD2 protein, have recently been found in patients with CD. Based on the occurence of CNO and CD in these four and several reported patients, we hypothesized that CD and CRMO might share a common autoinflammatory process. Thus, we searched for CD associated CARD15 gene variants R702W, G908R and 1007fs in 29 CNO patients, 4 of them additionally diagnosed with CD. In the latter one out of the four showed compound heterozygosity for the gene variants R702W and 1007fs. The allele frequency in the 25 patients diagnosed with CNO but not CD was not different from that already reported in healthy people (R702W 4.0%, G908R 2.0%, 1007fs 2.0%). The occurrence of non-bacterial bone inflammation and granulomatous intestinal inflammation seems to represent an extended phenotype of CD, which partly might be explained by potential disease causing mutations in CARD15. However, CNO without intestinal inflammation is not associated with common CARD15 gene variants. Therefore, other variants of genes coding for proteins involved in innate immunity and inflammation might predispose for the occurrence of CNO.     

Chronic Recurrent Multifocal Osteomyelitis Associated with Chronic Inflammatory Bowel Disease in Children

Chronic recurrent multifocal osteomyelitis(CRMO) is a rare disease of children characterized byaseptic inflammation of the long bones and clavicles. Noinfectious etiology has been identified, and CRMO has been associated with a number of autoimmunediseases (including Wegener's granulomatosis andpsoriasis). The relationship between CRMO andinflammatory bowel disease is poorly described. Throughan internet bulletin board subscribed to by 500pediatric gastroenterologists, we identified sixinflammatory bowel disease patients (two with ulcerativecolitis, four with Crohn's colitis) with confirmed CRMO. In all cases, onset of the bony lesionspreceded the onset of bowel symptoms by as much as fiveyears. Immunosuppressive therapy for the bowel diseasegenerally resulted in improvement of the bone inflammation. Chronic recurrrent multifocalosteomyelitis should be considered in any inflammatorybowel disease patient with unexplained bone pain orareas of uptake on bone scan. CRMO may be a rareextraintestinal manifestation of inflammatory bowel disease;alternatively, certain individuals may be geneticallypredisposed to the development of bothdiseases.     

Azithromycin: Eine anti-inflammatorische Wirksamkeit im Einsatz bei der chronischen rekurrierenden multifokalen Osteomyelitis? Eine vorläufige Mitteilung

In this preliminary communication we report our experience with Azithromycin in patients with Chronic Recurring Multifocal Osteomyelitis (CRMO). Seven out of 13 patients, mainly teenager, showed a fast clinical improvement after they were started on Azithromycin. The immediate therapeutic effect of Azithromycin in patients with CRMO was surprising and lead us to the hypothesis that Azithromycin could have an antiphlogistic in addition to it's antibiotic effect in this disease setting. In patients with reactive chronic pelvic osteomyelitis Azithromycin obviously had a direct influence on the sympathic coxitis. Half of the patients reported an immediate reduction of pain and a significant improvement in range of movement after they were started on Azithromycin. In all cases the clinical and radiographic signs on MRI showed a reduction of the inflammatory process. Experimental animal models have recently shown that macrolids have independent additional antiinflammatory and immunomodulatory effects. The assumed local immunomodulatory effect of Azithromycin potentially is an additional activity to the already known synergistic antimicrobial and antiinflammatory effect. Right now we are in the process of collecting data from patients with SAPHO Syndrome who underwent bone-biopsies for microbiologic and histomorphologic investigations. All patients with the growth of propionibacterium acnes were started on a long-term antibiotic therapy with Azithromycin. This study will possibly help to answer the question of the additional antiphogistic/immunomodulatory effect of Azithromycin in this disease entity and the related CRMO.     

Inflammasome-independent IL-1β mediates autoinflammatory disease in Pstpip2-deficient mice

Chronic recurrent multifocal osteomyelitis (CRMO) is a human autoinflammatory disorder that primarily affects bone. Missense mutation (L98P) of proline-serine-threonine phosphatase-interacting protein 2 (Pstpip2) in mice leads to a disease that is phenotypically similar to CRMO called chronic multifocal osteomyelitis (cmo). Here we show that deficiency of IL-1RI in cmo mice resulted in a significant reduction in the time to onset of disease as well as the degree of bone pathology. Additionally, the proinflammatory cytokine IL-1β, but not IL-1α, played a critical role in the pathology observed in cmo mice. In contrast, disease in cmo mice was found to be independent of the nucleotide-binding domain, leucine-rich repeat-containing family, pyrin domain-containing 3 (NLRP3) inflammasome as well as caspase-1. Neutrophils, but not bone marrow-derived macrophages, from cmo mice secreted increased IL-1β in response to ATP, silica, and Pseudomonas aeruginosa compared with neutrophils from WT mice. This aberrant neutrophil response was sensitive to inhibition by serine protease inhibitors. These results demonstrate an inflammasome-independent role for IL-1β in disease progression of cmo and implicate neutrophils and neutrophil serine proteases in disease pathogenesis. These data provide a rationale for directly targeting IL-1RI or IL-1β as a therapeutic strategy in CRMO.Chronic recurrent multifocal osteomyelitis (CRMO) is a sterile inflammatory disorder that affects children and presents with bone pain due to sterile osteomyelitis (1). The etiology of the disease is unknown, but it is associated with Crohn disease, inflammatory arthritis, and psoriasis in affected individuals and their close relatives, suggesting a shared pathophysiology and supporting a genetic contribution to disease (2). There are two autosomal recessive disorders that present with neonatal- or infant-onset sterile osteitis that are histologically similar to the bone disease in CRMO and clinically improve with IL-1 blockade (3, 4). Majeed syndrome, caused by mutations in LPIN2, presents with CRMO, congenital dyserythropoietic anemia, and sterile neutrophilic dermatosis (5). Deficiency of the IL-1 receptor antagonist (DIRA) is caused by mutations in IL1RN, which encodes the IL-1 receptor antagonist (3), resulting in dysregulation of the IL-1 pathway. Affected individuals present with neonatal-onset cutaneous pustulosis, marked elevation of inflammatory markers, sterile multifocal osteitis, and periostitis (3).There are two autosomal recessive murine models of CRMO both due to mutations in proline-serine-threonine interacting protein 2 (Pstpip2) (6–8). The mutation (L98P) present in the chronic multifocal osteomyelitis (cmo) model results in no detectable expression of Pstpip2, a protein expressed predominantly in the cells of the myeloid lineage, and leads to disease that resembles human CRMO (6, 9). The development of osteomyelitis in the cmo mouse is hematopoietically driven and develops in the absence of lymphocytes, consistent with an autoinflammatory mechanism of disease (9). Although it is known that cmo mice have a dysregulated innate immune system, it is not clear what inflammatory pathway is critical for disease.Mutations within NLRP3 (also known as NALP3 or cryopyrin) are associated with the autoinflammatory Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and neonatal-onset multisystem inflammatory disease, collectively known as cryopyrin-associated periodic syndrome (10). These NLRP3 mutations result in a constitutively active form of NLRP3 that leads to increased inflammasome activation with a resultant increase in secretion of IL-1β (10). A diverse array of agonists has been identified that are capable of activating NLRP3, which results in the assembly of the NLRP3 inflammasome composed of NLRP3, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), and caspase-1 (11). The activation of the inflammasome leads to the activation of caspase-1, with the resultant processing of pro-IL-1β and pro-IL-18 to their mature and secreted forms (12). However, the role of the NLRP3 inflammasome in the pathogenesis of cmo remains unknown.Given the evidence that IL-1 is important in the pathogenesis of sterile bone inflammation in humans (3, 4), we investigated the role of IL-1 in the pathogenesis of sterile osteomyelitis in the cmo mouse. Here we demonstrate that deficiency of IL-1RI (interleukin-1 receptor type I) or IL-1β in cmo mice resulted in delayed onset of disease and an attenuation of disease severity. In contrast, disease progression in cmo mice was found to be independent of the NLRP3 inflammasome, and in vitro findings support a role for neutrophil serine proteases in the abnormally increased secretion of IL-1β. Taken together these data demonstrate an inflammasome-independent role for the IL-1 pathway in the disease pathogenesis of cmo.     

Das SAPHO-Syndrom: Klinisch-rheumatologische und radiologische Differenzierung und Klassifizierung eines Krankengutes von 86 Fällen

Synovitis (inflammatory arthritis), acne (pustulosa), pustulosis (psoriasis, palmoplantar pustulosis), hyperostosis (acquired), and ostitis (bland osteomyelitis) are symptoms forming the acronym SAPHO, which is a syndrome of nosologic heterogeneity. All entities forming the SAPHO syndrome are connected by a non-obligate dermatoskeletal association with an aseptic pustulous character. 86 cases were analyzed clinically, radiologically and by histology/histopathology. 31 adult patients showed the typical triad of pustulosis palmo-plantaris (psoriatica, PPP), sterno-costo-clavicular hyperostosis (SCCH), and "productive" spondylopathy, which we define as entity I. spondarthritis hyperostotica pustulopsoriatica (Spond.hyp.pp). Twelve adolescent and 13 adult patients showed entity no. II: chronic recurrent multifocal osteomyelitis (CRMO), being characterized by non-purulent osteomyelitis of plasma-cell sclerotic type, potentially being a reactive inflammatory process. 50% of the adult patients with CRMO showed PPP. Differentiation between these two entities is possible by detection of ossifying enthesiopathy in cases of Spond. hyp.pp and primarily chronic osteomyelitis in cases of CRMO. Two more entities or abortive forms of group I and II are III: the inflammatory syndrome of the anterior chest-wall (ACW syndrome) and IV: the more productive form of isolated sterno-costoclavicular hyperostosis (SCCH). Both are connected quite frequently to HLA-B-27-independent forms of spondarthritis and to pustulous dermatosis. More rarely we find osteo-articular symptoms in cases of acne pustulosa, which form group V: acne-associated spondarthritis and CRMO in the case of acne. Adult forms of CRMO with different forms of appearance (lumosacro-iliac hyperostosis with retroperitobeal fibrosis, pelvic type with affection of the hip-joint) are described. The immunologic theory of a "reactive osteomyelitis" potentially triggered by saprophytes is described. The inverse acne triad is brought in a context of skin symptoms. A case of intercurrent postpartum symptoms together with ulcerative colitis is described. Three cases of patients with Crohn's disease are described. Clinical features, radiological findings, and histopathological elements are brought together to determine the connections between the different entities and the possibilities of differentiation. With these elements together with bone-scan, it is often not necessary to obtain a bone specimen. Therapeutical possibilities, especially concerning CRMO, are discussed. "SAPHO syndrome" is more a sign-post on the way to a more subtle diagnosis when it comes to hyperostotic, skin-associated diseases, and it needs interdisciplinary work to clear the situation.     

Serum biomarkers for the diagnosis and monitoring of chronic recurrent multifocal osteomyelitis (CRMO)

Chronic recurrent multifocal osteomyelitis (CRMO), the most severe form of chronic nonbacterial osteomyelitis, is an autoinflammatory bone disorder. A timely diagnosis and treatment initiation is complicated by the absence of widely accepted diagnostic criteria and an incomplete pathophysiological understanding. The aim of this study was to determine biomarkers for the diagnosis and follow-up of CRMO. Serum of 56 CRMO patients was collected at the time of diagnosis. As controls, sera from treatment-naïve age-matched patients with Crohn’s disease (N = 62) or JIA (N = 28) as well as healthy individuals (N = 62) were collected. Multiplex analysis of 25 inflammation markers was performed. Statistical analysis was performed using Kruskal–Wallis and Mann–Whitney U tests, canonical discriminant analysis, and mixed model variance analysis. Mostly monocyte-derived serum proteins were detectable and differed significantly between groups: IL-1RA, IL-2R, IL-6, IL-12, eotaxin, MCP-1, MIP-1b, RANTES. Multicomponent discriminant analysis allowed for the definition of algorithms differentiating between CRMO, Crohn’s disease, and healthy controls. Persistently high levels of MCP-1, IL-12, sIL-2R correlated with incomplete remission in follow-up samples from CRMO patients. Discrimination algorithms allow differentiation between patients with CRMO or Crohn’s disease, and healthy individuals. IL-12, MCP-1, and sIL-2R can act as markers for treatment response. Though confirmation of our findings in larger multiethnical cohorts is warranted, they may prove valuable to differentiate between otherwise healthy individuals or Crohn’s disease patients with “bone pain” and CRMO patients. The elevation of mainly monocyte-derived pro-inflammatory serum proteins supports the hypothesis of pro-inflammatory monocyte/macrophages driving inflammation in CRMO.     

Chronic non-bacterial osteomyelitis in children

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) in children is a chronic non-suppurative inflammation involving multiple sites. Some children affected by chronic non-bacterial osteomyelitis (CNO) do not have multiple lesions or a recurrent course. OBJECTIVE: To characterise the long term outcome of children with the full spectrum of CNO. METHODS: 30 children diagnosed with CNO were followed up for a mean of 5.6 years and their disease assessed using a clinical score, multiple imaging, and a diagnostic biopsy, including extensive microbial analysis. RESULTS: 9 patients had unifocal non-relapsing disease, 3 unifocal lesions with relapses, 9 multifocal lesions without relapses, and 9 multifocal lesions with relapses (CRMO). Granulocytes were present significantly more often in CRMO than in unifocal and non-recurrent lesions. Pustulosis was more common in multifocal cases regardless of recurrence. Mean duration of treatment in 15 children with a single occurrence was 9.2 months. Naproxen treatment was generally effective. Naproxen treatment in 12 patients with relapses lasted 25 months. However, 7 of these were not effectively treated with naproxen alone. Five were treated with oral glucocorticoids for 27 days in addition to naproxen, which induced remission in four, lasting for at least 1.5 years. Longitudinal growth of affected bones was not altered, except for the development of hyperostosis. CONCLUSION: CNO is a spectrum of inflammatory conditions, with CRMO being the most severe. Most children with CNO have a favourable outcome of the disease. Oral glucocorticoids may be necessary in severe recurrent cases.     

Die chronische rekurrierende multifokale Osteomyelitis in Assoziation mit chronisch entzündlichen Darmerkrankungen: Die enteropathische CRMO

The enterogenic reactive arthritides and entheropathic spondyloarthropathies are well-known entities. The so-called gut iteropathy concept offers an interesting working hypothesis to link the gut inflammation and the lymphocytic infiltration of the synovium. However, the association of rheumatic diseases belonging to the entity of the SAPHO syndrome with inflammatory bowel diseases (IBD) has only been rarely described in the literature. Among 138 cases of our (heterogenic) SAPHO cohort, we detected 5 patients (1 male, 4 females) with a proven association of SAPHO syndrome with IBD (in 4 cases Crohn's disease, in 1 case ulcerative colitis). Two patients belonged to the juvenileadolescent form and 3 to the adult form of SAPHO syndrome. In all cases the underlying osteoarticluar disease was classified as chronic recurrent multifocal osteomyelitis (CRMO), 2 of them presenting as inflammatory anterior chest wall syndrome. There was a strong association with psoriatic pustular dermatitis. Thus, we present 5 cases of "enteropathic CRMO" demonstrating several analogies to the enteropathic spondyloarthropathies. Both disease entities have in common i) metachronic development with osteoarticluar manifestations often preceding the gastrointestinal disease; ii) Crohn's like lesions that may develop from the stomach to the colon; iii) concomittent or intermittent skin pustulosis which mostly resolves; iiii) the gastrointestinal disease that often dominates the whole syndrome namely in the longterm follow-up. We suggest to transfer the hypothesis of the gut-synovium axis of enteropathic spondyloarthropathies to the entity of CRMO. This concept offers an opportunity to link the target organs gut mucosa, bone marrow and the skin via homing of antigen specific lymphocytes. This concept may help to better understand the pathogenesis of the "Skibo" (i. e., skin-bone) disease CRMO.     

Role of Melanocortin Receptors in the Regulation of Gouty Inflammation

Gouty arthritis is a form of acute joint inflammation provoked by joint deposition of urate crystals. Although this acute pathology resolves after a few days, the marked degree of inflammation in the joint and—possibly more important to the patient—the excruciating pain it causes require proper therapeutic management. Often deemed a “poor sibling” of chronic joint pathologies such as rheumatoid arthritis and psoriatic arthritis, the increasing incidence of gout makes it a more palatable disease for novel drug discovery programs. This fact, associated with novel insights into the molecular mechanisms activated by the urate crystal deposition, is at the basis of new therapeutics under clinical development for gout, a valid example being the effective targeting of the proinflammatory cytokine interleukin-1. Here we briefly review the current status of antigout drug development and propose another target; our focus is on melanocortin receptor agonists as novel therapeutics for gout and inflammatory arthritides, a prototype of which, the adrenocorticotropic hormone, is already used in clinical settings.     

Psoriatic arthritis: Current topics

Psoriatic arthritis is a common inflammatory arthropathy that occurs in approximately 25% of psoriasis patients. Due to significant advances in therapeutics—mainly the advent of biologic therapy—the disease has been subject to intense investigation recently. This review summarizes recent investigations of disease pathogenesis and clinical treatment. Clinical responses to tumor necrosis factor-blocking agents appear robust and superior to traditional disease-modifying drug responses, whereas other interventions, such as costimulation blockade, require more investigation. The pathogenesis of the disease appears related to T helper 17-polarized immune responses that target skin, joints, and the enthesial compartment. Finally, new insights into the disorder’s genetic antecedents are emerging as more cohorts of patients undergo advanced genetic screening methods.     

Resistin and visfatin: are they valuable enough to be the differential diagnosis in familial Mediterranean fever with acute appendicitis?

Familial Mediterranean fever (FMF) is an autosomal recessive disease which predominantly affects certain ethnic groups mainly Sephardic Jews, Turks, Arabs, and Armenians. Differential diagnosis of an attack of FMF with appendicitis could be difficult in patients presenting with acute abdomen. Circulating levels of resistin and visfatin have been shown to increase in several inflammatory conditions. In this study we aimed to investigate the role of resistin and visfatin in diseases activity by monitoring these adipokines’ levels in patients with FMF (attacks and attack-free period) and acute appendicitis. The study involves four groups: group 1—31 FMF patients at attack (M/F, 14/17), group 2—27 FMF patients at attack-free period (M/F, 9/18), group 3—29 acute appendicitis patients (M/F, 16/13), and group 4—20 healthy controls (M/F, 10/10). Erythrocyte sedimentation rate, C-reactive protein, white blood cell count, fibrinogen, resistin, visfatin, interleukin-1β, interleukin-6, interleukin-10, TNF-α, and IFN-γ were evaluated concurrently. Resistin level could be a useful test in diagnosis of FMF patients in attacks period but not in acute appendicitis as differential diagnosis. Measuring visfatin levels would not give additional information neither for attacks and attack-free period nor FMF attack and appendicitis.     

Current Status of Understanding the Pathogenesis and Management of Patients With NOMID/CINCA

Neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic, cutaneous, and arthritis (CINCA) syndrome is the most severe clinical phenotype in the spectrum of cryopyrin- (NLRP3/NALP3) associated periodic syndromes (CAPS). The study of patients with NOMID/CINCA has been instrumental in characterizing the extent of organ-specific inflammatory manifestations and damage that can occur with chronic interleukin (IL)-1β overproduction. Mutations in CIAS1/NLRP3 lead to constitutive activation of the “NLRP3 inflammasome,” an intracellular platform that processes and secretes increased amounts of IL-1β. The pivotal role of IL-1β in NOMID/CINCA has been demonstrated in several clinical studies using IL-1—blocking agents that lead to rapid resolution of the inflammatory disease manifestations. NOMID/CINCA is a monogenic autoinflammatory syndrome; and the discovery of the role of IL-1 in NOMID has led to the exploration in the role of IL-1 in other disorders including gout and Type II diabetes. The inflammation in NOMID/CINCA is continuous with intermittent flares, and organ manifestations encompus the central nervous system, eye, inner ear, and bones. This review discusses updates on the pathogenesis of NOMID/CAPS, emerging long term-outcome data regarding IL-1—blocking agents that have influenced our considerations for optimal treatment, and a monitoring approach tailored to the patient’s disease severity and organ manifestations.     

Genetic aspects of inflammatory bowel disease: How far have we come, and where are we heading?

Crohn's disease and ulcerative colitis are related complex genetic disorders, with gene—gene and gene—environment interactions that are critical to their pathogenesis. Multiple genetic loci have been implicated through genome-wide searches. Of these, a locus on Crohn's disease has been definitively established in the pericentromeric region of chromosome 16. Multiple candidate gene studies have been forwarded, and functionally significant variants in immuneassociated genes will provide additional insight. Characterization of the genetic variation responsible for causing inflammatory bowel disease will result in development of novel therapeutic approaches as well as in tailoring of specific therapies to individual patients based on their specific molecular pathogenesis.     

Schnitzler-Syndrom

Schnitzler syndrome is a rare systemic inflammatory disease characterized by the presence of chronic urticarial skin rash and a monoclonal immunoglobulin M (IgM) gammopathy, combined with further, variable disease symptoms. The term refers to a young disease entity which has recently gained increasing acknowledgement and attention, also due to the availability of interleukin-1 (IL-1) blockade as an effective therapeutic option. Insights into the pathophysiology of the disease have resulted in the assumption of Schnitzler syndrome being a special form of an autoinflammatory disease with late onset or an acquired genesis. This article provides an overview on the clinical appearance, current knowledge of pathophysiology and available therapeutic options.     

Genetic factors in the pathogenesis of gastroesophageal reflux disease

Multiple factors play a role in the pathogenesis of gastroesophageal reflux disease (GERD). Two landmark studies showing higher concordance of disease in monozygotic than dizygotic twin pairs suggested the role of host genetic factors in its pathogenesis. Recent studies have shown that genetic polymorphism in genes influencing host’s inflammatory response, drug metabolism, cell cycle regulation, xenobiotic pathways, DNA repair, mutagenesis, esophageal sensory function and gene silencing are associated with risk of GERD and its sequelae—Barrett’s esophagus and esophageal adenocarcinoma. However, more studies on larger sample size are needed before reaching a definite conclusion on the role of an individual gene.     

Alterations of the mucosal immune system in inflammatory bowel disease

The normal intestinal immune system is under a balance in which proinflammatory and anti-inflammatory cells and molecules are carefully regulated to promote a normal host mucosal defense capability without destruction of intestinal tissue. Once this careful regulatory balance is disturbed, nonspecific stimulation and activation can lead to increased amounts of potent destructive immunologic and inflammatory molecules being produced and released. The concept of balance and regulation of normal mucosal immune and inflammatory events is indicative of how close the intestine is to developing severe inflammation. The normal intestinal mucosal immune system is constantly stimulated by lumenal contents and bacteria. The stimulatory molecules present in the intestinal lumen that activate and induce subsequent mucosal immunologic and inflammatory events include bacterial cell wall products, such as peptidoglycans and lipopolysaccharides, as well as other chemotactic and toxic bacterial products that are produced by the many different types of bacteria within the gastrointestinal tract. These highly stimulatory bacterial cell wall products are capable of activating macrophages and T lymphocytes to release potent proinflammatory cytokines, including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor α (TNF-α). IL-1, IL-6, and TNF-α increase the presence of human leukocyte antigen (HLA) class II antigen-presenting molecules on the surfaces of epithelial cells, endothelial cells, macrophages, and B cells, thus increasing their ability to present lumenal antigens and bacterial products. The proinflammatory cytokines IL-1 and TNF-α also increase the ability of epithelial cells, endothelial cells, macrophages, and fibroblasts to secrete potent chemotactic cytokines, such as interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), which serve to increase the movement of macrophages and granulocytes from the circulation into the inflamed mucosa. Thus, through lumenal exposure to potent, nonspecific stimulatory bacterial products, the state of activation of the intestinal immune system and mucosal inflammatory pathways are markedly up-regulated. This raises the question of whether there is a deficiency in effective down-regulation through the absence of normally suppressive cytokines such as interleukin-10 (IL-10), transforming growth factor-β (TGF-β), interleukin-4 (IL-4), and IL-1 receptor antagonist. Normally, the turning off of the active and destructive immunologic and inflammatory events should occur following the resolution of a bacterial or viral infection that has been appropriately defended against and controlled by the mucosal immune system. In inflammatory bowel disease (IBD), however, the down-regulatory events and processes that should turn off the immunologic and inflammatory protective processes, once the pathogenic agent has been cleared, appear to be deficient or only partially effective. We may find that we ultimately are dealing with disease processes that have more than one genetic or cellular basis. The improved understanding of the immunopathophysiology of IBD will allow exploration of novel immunologic and genetic approaches, such as gene replacement therapy, administration of a suppressor cytokine or an altered cell surface antigen, the administration ofhumanized monoclonal antibodies directed against proinflammatory cytokines, or the development of newer strategies against fundamenial cell biologic mechanisms such as adhesion molecules.