Introduction: Sclerosing mesenteritis is a rare autoimmune disease that eventually evolves into fibrotic changes affecting the adipose tissue around the mesenteric vessels. It can present through a myriad of gastroenterological as well as constitutional symptoms including but not limited to abdominal pain, diarrhea, fever, nausea or vomiting. Although the exact etiology of the disease is yet to be determined, there are several predisposing factors the most common of which is history of previous abdominal trauma and/or surgery. This is a case report of abdominal mesenteric panniculitis that presented with abdominal pain in a middle-aged male with history of cholecystectomy. Case Presentation: The patient was a 53-year-old male with past medical history of hypertension who presented with a 2-week history of intolerance to food and liquids and abdominal pain, colicky in nature, radiating to both flanks with no alleviating or relieving factors. One year before, the patient had cholecystectomy due to biliary dyskinesia. His hospital stay at that time was complicated by biliary leak treated with biliary stenting. He later also developed multiloculated abscess collection in the gallbladder fossa that was managed with external drainage and IV antibiotics. In the ER his vital signs were as the following: BP between 120-130/70-80, HR 70s, temperature 97, oxygen saturation was more than 95%. On physical examination, he had abdominal tenderness in all four quadrants with no rigidity, rebound tenderness, masses or skin changes. CBC showed WBC of 7K with no shift to the left, hemoglobin of 15.6 and platelets of 107. CMP showed Na of 142, K 4.2, Chl 19, Glu 99, Ca 9.5, AG 18, lactic acid 1, lipase 50, phos 2.7, beta-hydroxybutyrate 0.12 and Mg of 1.9. urine analysis and Troponins were within normal limits. EKG showed sinus rhythm. Urine drug screen was negative. CRP and ESR were within normal limits. Porphyria workup was negative. Alpha-1-antitrypsin was 123. Ceroluplasmin level was 17. Actin antibody was negative as well as mitochondria M2 antibody. CT angiogram of the abdomen showed patent mesenteric vessels. However, fat stranding was noticed especially at the root of the mesenteric vessels. The patient was placed on prednisone 40mg once daily and tamoxifen. His abdominal pain greatly improved after 2 days. He was discharged with a prolonged prednisone taper. He was scheduled for an appointment with his primary care at discharge but didn’t show up and was lost to follow up. Conclusion: Mesenteric panniculitis is a rare cause of abdominal pain. it is divided based on histological features into sclerosing (retractile) mesenteritis, mesenteric panniculitis and mesenteric lipodystrophy. Diagnoses is usually rarely inferred from the clinical presentation and is often suggested by radiological features. Distinctive findings on CT include fat ring sign and pseudotumor capsule. Although radiological characteristics are helpful, histological proof is essential for definitive diagnosis, especially with an atypical clinical and radiological appearance. There is no consensus on the optimal treatment option but prolonged steroid taper has been used with various degrees of success.

Sclerosing mesenteritis is a rare autoimmune disease that eventually evolves into fibrotic changes that usually affect the adipose tissue around the mesenteric vessels. It can present through a myriad of gastroenterological as well as constitutional symptoms, including but not limited to abdominal pain, diarrhea, fever, nausea, or vomiting. Although the exact etiology of the disease is yet to be determined, there are several predisposing factors, the most common of which is a previous history of abdominal trauma and/or surgery. Several case series have reported the association of sclerosing mesenteritis with prior abdominal surgery ranging from as low as 24% to as high as 53%.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22341号 / 医博第4582号 / 新制||医||1042(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 羽賀 博典, 教授 伊藤 貴浩 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Prior immunity to a related or unrelated pathogen greatly influences the host’s immune response to a subsequent infection and can cause a dramatic difference in disease course, a phenomenon known as heterologous immunity. Heterologous immunity can influence protective immunity, immunopathology and/or immune deviation of cytokine-producing T cell subsets. Examples of heterologous immunity have been well documented in mouse models, as well as during human infections. For example, prior immunity to lymphocytic choriomeningitis virus (LCMV) provides partial protection against vaccinia virus (VV), as LCMV-immune mice show reduced VV titers and increased survival upon lethal dose VV infection. Heterologous protection against VV challenge, as a result of LCMV immunity, is mediated by LCMV-specific CD4 and CD8 T cells, as transfer of LCMV-specific memory T cells can mediate this protective effect in naïve mice. The recognition of a single TCR with more than one MHC-peptide complex is referred to as T cell cross-reactivity. A VV Kb-restricted epitope a11r198 was identified to be able to induce cross-reactive responses from LCMV-specific CD8 T cells. During VV infection, LCMV-specific memory T cells that are cross-reactive to VV epitopes produce IFN-γ early in VV infection. IFN-γ is essential for mediating the protection against VV in LCMV-immune mice, as this heterologous protection is absent in IFN-γR-/-and IFN-γ blocking antibody-treated LCMV-immune mice. In addition to protective immunity, cross-reactive LCMV-specific memory T cells and IFN-γ also induce an altered immunopathology during heterologous VV challenge. LCMV-immune mice show moderate to severe levels of inflammation of the fat tissue, known as panniculitis, in the visceral fat pads upon VV challenge. In humans, panniculitis is a painful condition, most commonly presenting as erythema nodosum. Erythema nodosum is a disease of unknown etiology with no known treatment. It may occur following intracellular bacterial and viral infections, and occasionally happens after vaccination with VV for smallpox. During infections there can be a delicate balance between the ability of immune responses to provide protective immunity, and the tendency to induce immunopathology. By using the mouse model of heterologous immunity between LCMV and VV, we tried to understand how the immunity to LCMV biased the balance between the protective immunity and immunopathology, and what effector molecules were responsible for the pathogenesis of panniculitis in this system. TNF is a pleiotropic cytokine, which is required for normal innate and adaptive immune responses. Its functions range from inducing proliferative responses including cell survival, to destructive responses such as promoting apoptosis and programmed necrosis. In response to inflammatory stimuli, activated macrophages/ monocytes produce large amounts of TNF, and upon activation, T cells, B cells and NK cells also produce TNF. In vitro and in vivo studies have shown that TNF in synergy with IFN-γ plays an important role in mediating host defense against pathogens, such as Listeria monocytogenesand poxviruses in mice and hepatitis B virus and human immunodeficiency virus in humans. However, inappropriate expression of TNF often results in tissue damage. Considering the important role TNF plays in both host defense and mediating autoimmune diseases, we hypothesized that TNF was required for mediating both protective and pathogenic effects in the heterologous immunity between LCMV and VV. We first examined whether TNF was involved in mediating protective heterologous immunity. LCMV-immune mice, that were TNF-deficient as a consequence of genetic deletion (TNF-/-) or receptor blockade by treatment with etanercept (TNFR2: Fc fusion protein), were challenged with VV. These TNF-deficient mice showed normal recruitment and selective expansion of cross-reactive LCMV-specific memory CD8 T cells. They also exhibited efficient clearance of VV similar to LCMV-immune mice with normal TNF function. Thus, we concluded that neither TNF nor lymphotoxin (LT), which uses the same receptors as TNF, was required in mediating protective heterologous immunity against VV. Indeed, prior immunity to LCMV could completely compensate for the role of TNF in protection of naïve mice against VV infection, even under conditions of lethal dose inoculum. Thus, heterologous immunity may help explain why treatment of humans with etanercept is reasonably well tolerated with relatively few infectious complications. One of the histological characteristics of panniculitis is necrosis of adipose tissue. It is known that three members in the TNF superfamily, i.e. TNF/LT, FasL and TRAIL are able to induce necrosis of a target cell. It is also known that TNF is able to induce VV-infected cells to go through necrosis, when apoptosis is blocked in these cells by VV protein. Furthermore, TNF and FasL have already been shown to be associated with some skin and fat pathology. Thus, we hypothesized that TNF, FasL and TRAIL were involved in the pathogenesis of panniculitis in VV infected LCMV-immune mice. By using blocking antibodies or genetically deficient mice, we demonstrated that both TNF/LT and FasL were crucial for inducing panniculitis. Although TNFR1 has been reported to induce programmed necrosis, our data indicated that TNFR2, not TNFR1, was involved in mediating tissue damage in the fat pads of LCMV-immune mice infected with VV. We also found that TNF signaled through TNFR2 to up-regulate the expression of Fas on adipocytes. Thus, the engagement of Fas on the adipocytes with FasL expressed on activated VV-specific and cross-reactive LCMV-specific CD8 T cells in the fat pads could lead to panniculitis. Thus, our data may identify a potential mechanism in the pathogenesis of human panniculitis, and may suggest a possible treatment for this painful disease. Recent reports suggest that heterologous immunity may contribute to the tremendous variation in symptoms between individuals, from subclinical to death, upon viral infection. Even in genetically identical mice, variations in immunopathology from none to life-threatening levels of pathology are observed in LCMV-immune mice during VV infection. By adoptive transfer of splenocytes from a single LCMV-immune donor into two recipients, we showed that similar levels of pathology were generated in mice receiving the same splenocytes. However, the level of pathology varied among recipients receiving splenocytes from different LCMV-immune donors. The difference in levels of VV-induced pathology observed in individual LCMV-immune mice was a reflection of the private specificity of the T cell repertoire, which is a unique characteristic of each individual immune host. The goal of this doctoral thesis is to understand how heterologous immunity contributes to the pathogenesis of panniculitis. Our data demonstrate that TNF/LT and FasL directly contribute to development of panniculitis in LCMV-immune mice during VV infection, and suggest that anti-TNF treatment might be a useful treatment for diseases, such as erythema nodosum and lupus-induced acute fatty necrosis in humans.