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1.
Cell ; 187(4): 897-913.e18, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38280374

RESUMO

Canonically, the complement system is known for its rapid response to remove microbes in the bloodstream. However, relatively little is known about a functioning complement system on intestinal mucosal surfaces. Herein, we report the local synthesis of complement component 3 (C3) in the gut, primarily by stromal cells. C3 is expressed upon commensal colonization and is regulated by the composition of the microbiota in healthy humans and mice, leading to an individual host's specific luminal C3 levels. The absence of membrane attack complex (MAC) components in the gut ensures that C3 deposition does not result in the lysis of commensals. Pathogen infection triggers the immune system to recruit neutrophils to the infection site for pathogen clearance. Basal C3 levels directly correlate with protection against enteric infection. Our study reveals the gut complement system as an innate immune mechanism acting as a vigilant sentinel that combats pathogens and spares commensals.


Assuntos
Complemento C3 , Mucosa Intestinal , Microbiota , Animais , Humanos , Camundongos , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Neutrófilos , Complemento C3/metabolismo , Células Estromais/metabolismo
2.
Immunity ; 57(4): 876-889.e11, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38479384

RESUMO

Concentrations of the secondary bile acid, deoxycholic acid (DCA), are aberrantly elevated in colorectal cancer (CRC) patients, but the consequences remain poorly understood. Here, we screened a library of gut microbiota-derived metabolites and identified DCA as a negative regulator for CD8+ T cell effector function. Mechanistically, DCA suppressed CD8+ T cell responses by targeting plasma membrane Ca2+ ATPase (PMCA) to inhibit Ca2+-nuclear factor of activated T cells (NFAT)2 signaling. In CRC patients, CD8+ T cell effector function negatively correlated with both DCA concentration and expression of a bacterial DCA biosynthetic gene. Bacteria harboring DCA biosynthetic genes suppressed CD8+ T cells effector function and promoted tumor growth in mice. This effect was abolished by disrupting bile acid metabolism via bile acid chelation, genetic ablation of bacterial DCA biosynthetic pathway, or specific bacteriophage. Our study demonstrated causation between microbial DCA metabolism and anti-tumor CD8+ T cell response in CRC, suggesting potential directions for anti-tumor therapy.


Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Camundongos , Animais , Ácidos e Sais Biliares , Ácido Desoxicólico/farmacologia , Linfócitos T CD8-Positivos
3.
Cell Mol Gastroenterol Hepatol ; 18(2): 101350, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38704148

RESUMO

BACKGROUND & AIMS: Gut bacterial sphingolipids, primarily produced by Bacteroidetes, have dual roles as bacterial virulence factors and regulators of the host mucosal immune system, including regulatory T cells and invariant natural killer T cells. Patients with inflammatory bowel disease display altered sphingolipids profiles in fecal samples. However, how bacterial sphingolipids modulate mucosal homeostasis and regulate intestinal inflammation remains unclear. METHODS: We used dextran sodium sulfate (DSS)-induced colitis in mice monocolonized with Bacteroides fragilis strains expressing or lacking sphingolipids to assess the influence of bacterial sphingolipids on intestinal inflammation using transcriptional, protein, and cellular analyses. Colonic explant and organoid were used to study the function of bacterial sphingolipids. Host mucosal immune cells and cytokines were profiled and characterized using flow cytometry, enzyme-linked immunosorbent assay, and Western blot, and cytokine function in vivo was investigated by monoclonal antibody injection. RESULTS: B fragilis sphingolipids exacerbated intestinal inflammation. Mice monocolonized with B fragilis lacking sphingolipids exhibited less severe DSS-induced colitis. This amelioration of colitis was associated with increased production of interleukin (IL)-22 by ILC3. Mice colonized with B fragilis lacking sphingolipids following DSS treatment showed enhanced epithelial STAT3 activity, intestinal cell proliferation, and antimicrobial peptide production. Protection against DSS colitis associated with B fragilis lacking sphingolipids was reversed on IL22 blockade. Furthermore, bacterial sphingolipids restricted epithelial IL18 production following DSS treatment and interfered with IL22 production by a subset of ILC3 cells expressing both IL18R and major histocompatibility complex class II. CONCLUSIONS: B fragilis-derived sphingolipids exacerbate mucosal inflammation by impeding epithelial IL18 expression and concomitantly suppressing the production of IL22 by ILC3 cells.


Assuntos
Bacteroides fragilis , Colite , Sulfato de Dextrana , Interleucina 22 , Interleucinas , Esfingolipídeos , Animais , Esfingolipídeos/metabolismo , Interleucinas/metabolismo , Camundongos , Colite/imunologia , Colite/patologia , Colite/induzido quimicamente , Colite/microbiologia , Colite/metabolismo , Sulfato de Dextrana/toxicidade , Bacteroides fragilis/imunologia , Modelos Animais de Doenças , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/patologia , Mucosa Intestinal/microbiologia , Mucosa Intestinal/metabolismo , Fator de Transcrição STAT3/metabolismo , Camundongos Endogâmicos C57BL
4.
Porto Alegre; AMGH; 19 ed; 2017. 2 v. (xxxviii, 2770 ; índice i-200) p. ilus, tab, graf.
Monografia em Português | Coleciona SUS | ID: biblio-943848
5.
Porto Alegre; AMGH Editora Ltda; 18 ed; 2013. 1796 p. graf, ilus, tab.
Monografia em Português | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Tatuapé | ID: sms-11707
6.
Porto Alegre; AMGH Editora Ltda; 18 ed; 2013. 1811 p. graf, ilus, tab, mapas.
Monografia em Português | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Tatuapé | ID: sms-11708
7.
New York; McGraw Hill Medical; 17th ed; 2008. 2754 p. ilus, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-3471

RESUMO

The seventeenth edition of Harrison’s has a full-color format that draws from and extends the excellent appearance of the sixteenth edition to make the content more accessible and pleasant to read. The placement of color illustrations within the chapters rather than in the separate atlas was very favorably received by our sixteenth edition readers and has been continued in the current edition. Many changes to the design of this edition have been made in order to speed the reader’s navigation through the textual and visual materials. For example, tables have been shaded for ease of reading, citations in tables and illustrations are now more instantly notable and in color, and our Treatment sections in each chapter have been redesigned to allow even faster access. The new global icons call greater attention to key epidemiologic and clinical differences in the practice of medicine throughout the world. The seventeenth edition has been enriched by the addition of a new editor, Joseph Loscalzo, MD, PhD, who joined with our most senior editor Eugene Braunwald, MD, in contributing to and/or editing of chapters in the Parts on Disorders of the Cardiovascular System, Disorders of the Respiratory System, and Disorders of the Kidney and Urinary Tract. The addition of Dr. Loscalzo provides a smooth editorial transition in preparation for the upcoming retirement from Harrison’s of Dr. Braunwald who has served as an esteemed editor for 12 editions


Assuntos
Humanos , Doença , Doenças Transmissíveis , Doenças Vasculares , Doenças Respiratórias , Medicina Interna
8.
Porto Alegre; AMGH Editora Ltda; 18 ed; 2013. 1811 p.
Monografia em Português | LILACS | ID: biblio-870615
9.
Porto Alegre; AMGH Editora Ltda; 18 ed; 2013. 1796 p.
Monografia em Português | LILACS | ID: biblio-870616
10.
Porto Alegre; Artmed; 17 ed; 2011. 1244 p. ilus, tab.
Monografia em Português | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Tatuapé | ID: sms-10723
12.
Rio de Janeiro; Mc Graw Hill; 16 ed; 2006. 1565 p. graf, ilus, tab.
Monografia em Português | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Tatuapé | ID: sms-11117
13.
New York; McGraw-Hill; 13 ed; 1994. 1332 p. ilus, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-5964
14.
New York; McGraw-Hill; 13 ed; 1994. 1540 p. ilus, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-5965
15.
Rio de Janeiro; McGraw-Hill; 13 ed; 1995. 1438 p. ilus.
Monografia em Português | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-5966
16.
Rio de Janeiro; McGraw-Hill; 13 ed; 1995. 1392 p. ilus.
Monografia em Português | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-5967
17.
Rio de Janeiro; McGraw-Hill; 14 ed; 1998. 1572 p. ilus.
Monografia em Português | Sec. Munic. Saúde SP, Hospital do Servidor Público Municipal-Acervo | ID: sms-5970
18.
New York; McGraw-Hill; 13 ed; 1994. 1352 p. ilus, mapas, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Campo Limpo | ID: sms-2477
19.
New York; McGraw-Hill; 15 ed; 2001. 1442 p. ilus, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Campo Limpo | ID: sms-2489
20.
New York; McGraw-Hill; 15 ed; 2001. 1187 p. ilus, tab.
Monografia em Inglês | Sec. Munic. Saúde SP, Autarquia Hospitalar Municipal-Acervo, AHM-Acervo Campo Limpo | ID: sms-2490
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