Arquivo da tag: Sistema imunológico

New Vessels Found In The Human Body That Connect Immune System And Brain (IFLScience)

June 3, 2015 | by Stephen Luntz

photo credit: Topic / Shutterstock. It used to be thought that the lymphatic system stopped at the neck, but it has now been found to reach into the brain

In contradiction to decades of medical education, a direct connection has been reported between the brain and the immune system. Claims this radical always require plenty of testing, even after winning publication, but this could be big news for research into diseases like multiple sclerosis (MS) and Alzheimer’s.

It seems astonishing that, after centuries of dissection, a system of lymphatic vessels could have survived undetected. That, however, is exactly what Professor Jonathan Kipnis of the University of Virginia claims in Nature.

Old and new representations of the lymphatic system that carries immune cells around the body. CreditUniversity of Virginia Health System

“It changes entirely the way we perceive the neuro-immune interaction,” says Kipnis. “We always perceived it before as something esoteric that can’t be studied. But now we can ask mechanistic questions.”

MS is known to be an example of the immune system attacking the brain, although the reasons are poorly understood. The opportunity to study lymphatic vessels that link the brain to the immune system could transform our understanding of how these attacks occur, and what could stop them. The causes of Alzheimer’s disease are even more controversial, but may also have immune system origins, and the authors suggest protein accumulation is a result of the vessels failing to do their job.

Indeed, Kipnis claims, “We believe that for every neurological disease that has an immune component to it, these vessels may play a major role.”

The discovery originated when Dr. Antoine Louveau, a researcher in Kipnis’ lab, mounted the membranes that cover mouse brains, known as meninges, on a slide. In the dural sinuses, which drain blood from the brain, he noticed linear patterns in the arrangement of immune T-cells. “I called Jony [Kipnis] to the microscope and I said, ‘I think we have something,'” Louveau recalls.

Kipnis was skeptical, and now says, “I thought that these discoveries ended somewhere around the middle of the last century. But apparently they have not.” Extensive further research convinced him and a group of co-authors from some of Virginia’s most prestigious neuroscience institutes that the vessels are real, they carry white blood cells and they also exist in humans. The network, they report, “appears to start from both eyes and track above the olfactory bulb before aligning adjacent to the sinuses.”

Kipnis pays particular credit to colleague Dr. Tajie Harris who enabled the team to image the vessels in action on live animals, confirming their function. Louveau also credits the discovery to fixing the meninges to a skullcap before dissecting, rather than the other way around. This, along with the closeness of the network to a blood vessel, is presumably why no one has observed it before.

The authors say the vessels, “Express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.”

The authors add that the network bears many resemblances to the peripheral lymphatic system, but it “displays certain unique features,” including being “less complex [and] composed of narrower vessels.”

The discovery reinforces findings that immune cells are present even within healthy brains, a notion that was doubted until recently.

Meningial lymphatic vessels in mice. Credit: Louveau et al, Nature.

Anúncios

Bactéria pode ter sistema imune rudimentar, indica estudo (Fapesp)

03 de outubro de 2014

Por Karina Toledo

Agência FAPESP – Um estudo publicado na revista Nature Communications revelou que a bactéria Salmonella enterica é capaz de produzir uma proteína muito semelhante à alfa-2-macroglobulina humana, que desempenha um papel-chave em nosso sistema imunológico.

A hipótese levantada pelos pesquisadores do Instituto de Biologia Estrutural (IBS) de Grenoble, na França, é de que também nas bactérias as macroglobulinas poderiam fazer parte de um sistema de defesa rudimentar. Se a teoria for confirmada por estudos futuros, essas proteínas podem se tornar alvos para o desenvolvimento de novos antibióticos.

“O mais fascinante é que as macroglobulinas são proteínas imensas, formadas por quase 1.700 resíduos de aminoácidos. Para a bactéria sintetizar uma molécula tão grande é porque ela deve ter um papel muito importante”, afirmou a brasileira Andréa Dessen, pesquisadora do IBS e coordenadora, no Laboratório Nacional de Biociência (LNBio), em Campinas, de um projeto apoiado pela FAPESP por meio do programa São Paulo Excellence Chairs (SPEC).

No organismo humano, a missão da alfa-2-macroglobulina é detectar e neutralizar proteases secretadas por microrganismos invasores, disse a pesquisadora. As proteases são enzimas que quebram as ligações entre os aminoácidos das proteínas.

“A macroglobulina impede, dessa forma, que as proteases dos invasores destruam os tecidos do organismo, o que permitiria a infecção de tecidos mais profundos”, explicou.

Além disso, a alfa-2-macroglobulina também se liga a proteases que participam do processo de coagulação sanguínea, evitando que proteínas importantes sejam destruídas indevidamente.

Em estudos anteriores, nos quais o genoma de diversas espécies de bactérias foi sequenciado, pesquisadores alemães já haviam observado a presença do gene da macroglobulina. No IBS, o grupo liderado por Dessen já havia feito a caracterização bioquímica da proteína produzida pelas espécies Escherichia coli e Pseudomonas aeruginosa.

“Agora, de maneira inédita, estudamos a estrutura tridimensional da macroglobulina secretada pela Salmonella enterica por uma técnica conhecida como cristalografia de raios X, que permite visualizar detalhes em nível atômico. E pudemos confirmar que, de fato, ela é muito parecida com a macroglobulina humana”, contou Dessen.

De acordo com a pesquisadora, a descoberta reforça a hipótese de que a alfa-2-macroglobulina tem o papel de proteger a bactéria das proteases secretadas por outras bactérias ou pelo organismo do hospedeiro que ela tenta infectar.

“Em um modelo de camundongo, pesquisadores canadenses mostraram que cepas da bactéria Pseudomonas aeruginosa que não produzem macroglobulina têm menor capacidade de causar doença, ou seja, são menos virulentas. A proteína parece dar uma vantagem à bactéria na hora de colonizar o hospedeiro, mas ainda não sabemos exatamente por quê”, disse.

Desdobramentos

Em um braço da pesquisa que está sendo conduzido no LNBio, com apoio da FAPESP e orientação de Dessen, a pós-doutoranda francesa Samira Zouhir investiga a estrutura da macroglobulina sintetizada por bactérias da espécie Pseudomonas aeruginosa – causadora de diversos casos de infecção hospitalar.

“Se conseguirmos desvendar a estrutura tridimensional da proteína, isso nos dará pistas sobre sua função no processo infeccioso”, disse Dessen.

Quando o papel das macroglobulinas estiver bem compreendido em diferentes espécies de bactérias, acrescentou, essas proteínas poderão se tornar alvo para o desenvolvimento de novos antibióticos.

“Também há pesquisas interessantes em modelo de camundongo mostrando que a aplicação de alfa-globulina humana pode oferecer proteção contra a sepse. Há várias possibilidades de tratamento a serem exploradas”, avaliou a pesquisadora.

O artigo Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity (doi: 10.1038/ncomms5917), pode ser lido em www.nature.com/ncomms/2014/140915/ncomms5917/full/ncomms5917.html.

Gene Variants in Immune System Pathways Correlated With Composition of Microbes of Human Body (Science Daily)

Oct. 24, 2013 — Human genes in immunity-related pathways are likely associated with the composition of an individual’s microbiome, which refers to the bacteria and other microbes that live in and on the body, scientists reported today, Oct. 24, at the American Society of Human Genetics 2013 annual meeting in Boston.

Bacterial colonies on an agar plate. This study is the first genome-wide and microbiome-wide investigation to identify the interactions between human genetic variation and the composition of the microbes that inhabit the human body. (Credit: © anyaivanova / Fotolia)

“These genes are significantly enriched in inflammatory and immune pathways and form an interaction network highly enriched with immunity-related functions,” said Ran Blekhman, Ph.D., Assistant Professor, Department of Genetics, Cell Biology, and Development at the University of Minnesota, Minneapolis.

The study is the first genome-wide and microbiome-wide investigation to identify the interactions between human genetic variation and the composition of the microbes that inhabit the human body.

The skin, genital areas, mouth, and other areas of the human body, especially the intestines, are colonized by trillions of bacteria and other microorganisms. “Shifts in the composition of the species of the microbes have been associated with multiple chronic conditions, such as diabetes, inflammatory bowel disease and obesity,” noted Dr. Blekhman.

Dr. Blekhman and his collaborators found evidence of genetic influences on microbiome composition at 15 body sites of 93 people surveyed. “We found in our study that genetic variation correlated with the microbiome at two levels,” he said.

At the individual level, the mathematical procedure known as principal component analysis demonstrated that genetic variation correlated with the overall structure of a person’s microbiome.

At the species level, potential correlations between host genetic variation and the abundance of a single bacterial species were identified, said Dr. Blekhman, who conducted much of the research while a scientist in the lab of Andrew G. Clark, Ph.D., the Jacob Gould Schurman Professor of Population Genetics in the Department of Molecular Biology and Genetics at Cornell University, Ithaca, NY. Dr. Clark is the senior author of the abstract.

To identify the bacterial species that inhabited each human body site, the researchers mined sequence data from the Human Microbiome Project (HMP), an international program to genetically catalog the microbial residents of the human body.

Using a systems-level association approach, the researchers showed that variation in genes related to immune system pathways was correlated with microbiome composition in the 15 host body sites.

To shed light on the evolutionary history of the symbiosis between humans and their microbiomes, the researchers analyzed sequencing data from the 1000 Genomes Project, which is designed to provide a comprehensive resource on human genetic variation.

They found that the genes in the pathways linked to the composition of an individual’s microbiome vary significantly across populations. “Moreover, many of those genes have been shown in recent studies to be under selective pressure,” said Dr. Blekhman.

“The results highlight the role of host immunity in determining bacteria levels across the body and support a possible role for the microbiome in driving the evolution of bacteria-associated host genes,” he added.

Dr. Blekhman is currently investigating the combined role of host genetics and the microbiome in influencing an individual’s susceptibility to such diseases as colon cancer. His goal is to unravel the interaction between host genomic variation and the gut microbiome in colon cancer incidence, evolution and therapeutic response.