Mendedikasikan pengenalan pola reseptor membantu dgn pemberian

kekebalan sel - neutrofil, makrofag, dendritik

sel, dan sel mast - dengan kemampuan untuk

mengenali mikroba, toll-like receptor intraseluler

9 (TLR9), misalnya, mengidentifikasi mikroba

DNA dalam wadah endosomal. germline-

dikodekan pengenalan pola reseptor

tidak secara klonal didistribusikan. Semua sel yang mengekspresikan

mereka segera mengidentifikasi patogen terkait

Pola-molekul mengungkapkan mikroba sebagai potensi

ancaman. Mereka memulai peradangan, mensekresi

sitokin dan kemokin, yang memperingati

dan menarik leukosit lainnya, sehingga fokus mereka

destruktif potensial pada tempat infeksi.

Mitokondria adalah organel membran-terikat

yang menghasilkan energi di hampir semua eukariotik

sel. Mereka telah berevolusi dari sebuah endosimbion

alpha-proteobacterium (seorang kerabat Brucella dan

rickettsia). Mitokondria memiliki DNA sendiri,

diperkaya hypomethylated CpG yang mengandung urutan,

yang diduplikasi ketika mitokondria

membelah. Asal dari sel eukariotik adalah

masih kontroversial, dan bentuk peralihan antara

prokariota dan eukariota belum

persuasif documented.3 The penggabungan dari

dua prokariota atau penggabungan dari prokariota yang

dengan sel eukariotik yang perintis

kemungkinan skenario. Apapun, penggabungan akan

terjadi jauh sebelum adanya suatu

sistem kekebalan tubuh, yang menurut definisi adalah fitur

yang unik untuk organisme multiseluler.

Zhang et al. Oleh karena itu, berdasarkan mereka

asal usul evolusi, mitokondria mungkin diakui

oleh pola-pengenalan reseptor dan dengan demikian

mungkin memulai peradangan. Acara ini tampaknya

mungkin terjadi pada jaringan sehat, di mana

membran-terikat mitokondria yang terkandung

Mitochondria and the Immune ResponseBy: Laura Vargas-Parada, Ph.D. (Biology Dept., School of Sciences, National University of Mexico) © 2010 Nature

Education 

Citation: Vargas-Parada, L. (2010) Mitochondria and the Immune Response. Nature Education 3(9):15

Due to their similarities to bacteria, mitochondria can actually trigger severe illness in humans. How can organelles inside our bodies suddenly become a threat?From biology courses in school, many of us know that mitochondria are the organelles in charge of providing energy to the

cells in our bodies. They provide energy through their ability to convert glucose into adenosine triphosphate, or ATP, which

is the main energy source for cellular functions. Interestingly, scientists have learned that mitochondria evolved

from bacteria a long, long time ago. Due to their similarities to bacteria, mitochondria can actually trigger severe illness in

humans. How can organelles inside our bodies suddenly become a threat?

The Origin of Mitochondria as Cellular Organelles: Endosymbiotic Theory

Figure 1:   Endosymbiosis

Mitochondria originated following endocytosis of a proteobacteria by another prokaryotic cell.

© 2004 Nature Publishing Group Timmis, J. N. et al.Endosymbiotic gene transfer: organelle genomes forge

eukaryotic chromosomes. Nature Reviews Genetics 5, 123–135 (2004) doi:10.1038/nrg1271. All rights reserved. 

In the late nineteenth century, botanist Andreas Schimper first suggested the idea that some organelles evolved from the

symbiotic union of two different organisms. As he was observing chloroplast division in green plants, he noticed the

resemblance of chloroplasts with free-living cyanobacteria. In the early decades of the twentieth century, another botanist,

Konstantin Mereschkowski, gave voice to Schimper's idea by proposing the theory of symbiogenesis, which suggested that

chloroplasts originated from symbiotic cyanobacteria. Meanwhile, Ivan Emanuel Wallin proposed that mitochondria arose

from bacteria. Their ideas were largely ignored until the 1960s, when the theory finally resurged. By then, scientists had

electron microscopes at their disposal to study cells in greater detail. Scientists could now view cellular organelles and

entities that were as small as a few microns. With this revolutionary visual aid, researchers discovered that mitochondria

have their own DNA located inside the organelle in the form of circular chromosomes, an observation that was later

confirmed by biochemical methods (Nass & Nass 1963; Haslbrunner, Tuppy, & Schatz 1964).

In 1967, Lynn Margulis (then Lynn Sagan) gathered diverse microbiological observations to support what is now known as

the endosymbiotic theory. Her publication is now a landmark paper on the origin of eukaryotic cells (cells with a nucleus, like

those of plants and animals). However, at the time, her article was rejected by fifteen scientific journals before it was

accepted for publication in the Journal of Theoretical Biology. According to the endosymbiotic theory proposed by Margulis,

mitochondria evolved from ancient symbiotic prokaryotes (organisms without nuclei, such as bacteria) that were absorbed

into other free-living prokaryotes (Sagan 1967) (Figure 1). As you might suspect from the problems Margulis faced when

trying to publish her article, this theory did not immediately receive wide acceptance. Indeed, it took decades for mainstream

scientists to accept her hypothesis and begin calling it a theory.

The EvidenceWhat evidence did Margulis use to support her idea? Remember that at that time, scientists could examine cells under the

microscope, lyse them, and study the chemistry of cellular components, but they could not examine DNA sequences.

Margulis used a number of pieces of evidence to support her theory. She noted that mitochondria are self-replicating bodies.

Mitochondria are surrounded by two or more membranes, and the innermost of these membranes is very similar

in composition to bacteria. Both mitochondria and chloroplast have their own DNA, which by then was known to contain the

hereditary material of organisms. Mitochondrial DNA has a simple circular structure, which is structurally similar to bacteria

DNA and is more or less the same size. Mitochondrial ribosomes, enzymes, and transport systems are all similar to those of

bacteria. Moreover, mitochondria are approximately the same size as bacteria.

With the advent of molecular biology methodologies, the amount of evidence supporting the endosymbiotic theory has

grown. For example, by using genomic sequencing and phylogenetic analysis, scientists have shown that mitochondrial

DNA share similar structural motifs with bacterial DNA and that mitochondrial genes originated within proteobacteria (a

group of gram-negative bacteria that share common ribosomal RNA sequences) (Gray, Burger, & Lang 2001; Andersson et

al. 2003). In an exciting recent development, the endosymbiotic theory crossed fields of knowledge to help physicians solve

a mystery that they had been observing for years in the emergency room. What follows is the story of how mitochondria are

related to immune inflammatory responses in critical care patients.

A Mystery in the Emergency Room: Mitochondria and the Inflammatory ResponseFor years, physicians working in critical care units have observed similarities between two different phenomena: systemic

inflammatory responsesyndrome (SIRS) and sepsis. Patients who survive a severe trauma or physical injury may develop

SIRS, a complication that can be life-threatening. SIRS is characterized by a fever, increased heart rate, and low blood

pressure, resulting in generalized shock and compromised function of several organs. Sepsis, on the other hand, is a well-

characterized phenomenon that occurs during the systemic inflammatory response to severe infection.

Physicians noted that SIRS and sepsis had many of the same symptoms, and both conditions showed clinical similarities.

But what was the physiological basis for these similarities? At first glance, the two conditions seem to be very different. In

SIRS, the inflammatory response — the body's defense to any type of lesion — is triggered by a physical injury or trauma.

Meanwhile, the response in sepsis is caused by infections by diverse pathogens. Scientists proposed that the innate

immune system recognizes certain molecules or "stimulators" through specialized receptors known as pattern-recognition

receptors (PRRs), leading to molecular signaling pathways that result in an inflammatory response (Iwasaki & Medzhitov

2010). So, what are the "stimulators" in sepsis and in SIRS?

Scientists have now discovered that the innate immune system uses PRRs as "microbial sensors" to detect a set of

evolutionarily conserved molecules found in a variety of pathogens. These molecules are collectively known as pathogen-

associated molecular patterns (PAMPs), and they are expressed in a wide variety of microorganisms, including those that do

not cause disease. In patients with severe infections such as sepsis, PAMPs are the major external "stimulators" of the

inflammatory response

In 1994, Polly Matzinger proposed that the immune system does not only respond to pathogens, but it also responds to

intracellular alarms that are activated when endogenous molecules are released in the body (Matzinger 1994). In the

following years, scientists have experimentally shown that several endogenous molecules are released from damaged

tissues, and these molecules were collectively named damage-associated molecular patterns (DAMPs). DAMPs are capable

of initiating an inflammatory response similar to that produced by PAMPs (Lotze et al. 2007), even when there are no

microbial infections present. So, why are the signaling pathways triggered by PAMPs in sepsis (external "stimulators") and

DAMPs in SIRS (internal or endogenous "stimulators") so similar, and do these pathways overlap?

It turns out that our knowledge of mitochondria — that they were evolutionarily derived from bacteria and share conserved

structural motifs with prokaryotes — can explain why the signaling pathways activated by external and internal triggers are

so similar. With this idea in mind idea, Qin Zhang and his colleagues proposed a new and intriguing hypothesis: They

suggested that mitochondrial DNA and proteins may act as DAMPs, triggering the same pathways activated by bacterial

PAMPs. This hypothesis would explain the similarities observed between the immune response to infection and the immune

response to trauma (Zhang et al. 2010).

Mitochondria and Bacteria Use the Same Mechanisms to Trigger Immune Responses

Figure 2: PAMPs and DAMPs in the inflammatory response

Similar to the release of bacterial DNA following sepsis, the mitochondrial DNA released by severe trauma can also act

through the toll-like receptor-9 (TLR9) to activate neutrophils by activating p38 MAP kinase (MAPK). Similarly, formylated

peptides released from bacteria and mitochondria activate the formyl peptide receptor-1 (FPR1) and attract neutrophils by

the process of chemotaxis to sites of inflammation and injury. In both cases, the outcome may be acute lung injury, which is

part of the systemic inflammatory response syndrome (SIRS). DAMPs, damage-associated molecular patterns; PAMPs,

pathogen-associated molecular patterns.

© 2010 Nature Publishing Group Calfee, C. S. & Matthay, M. A. Clinical immunology: Culprits with evolutionary

ties. Nature 464, 41–42 (2010) doi:10.1038/464041a. All rights reserved. 

To gather evidence to test their hypothesis, Zhang and his colleagues observed whether mitochondrial DAMPs were

released by trauma patients after severe injury. Assuming that mitochondria evolved from bacteria, they looked for two

known bacterial PAMPs: DNA and formyl peptides. In one experiment, they measured the release of mitochondrial DNA into

the circulation of major trauma patients. As they expected, they found very high levels of mitochondrial DNA in the trauma

patients' blood compared with that of control volunteers (who suffered no injury). They also detected high levels of

mitochondrial DNA in bones after fractures were repaired by orthopedists. Both of these postinjury measurements confirmed

that signature mitochondrial DAMPs are released into the circulation after major bodily injury.

Where do these mitochondria come from? It is very likely that injuries cause cell lysis, degradation, and tissue breakdown

(necrosis), which release the contents of cells, including broken mitochondria. Because each cell contains dozens of

mitochondria and there are thousands of cells within our tissues, severe trauma can result in the release of large amounts of

mitochondrial DAMPs into the blood.

In another experiment, Zhang's group analyzed how mitochondrial-derived DAMPs activate the immune response. Only

bacteria and mitochondria have their proteins N-formylated; therefore, they are the only known sources of N-formyl peptides

in nature. Formyl peptides can attract neutrophils, a type of white blood cell that is essential for the innate immune system.

They can also activate neutrophils by specifically binding to the formyl peptide receptor-1 (FPR1), which is found on the

surface of these cells. The activation of neutrophils promotes the inflammatory response by releasing chemical mediators

and activating several enzymes known as MAP kinases. Using mitochondrial-derived DAMPs, the scientists were able to

activate FPR1 and MAP kinases, which confirmed the presence of formyl peptides in mitochondrial DAMPs. Mitochondrial

DNA can also bind to neutrophils through a specific receptor called the toll-like receptor 9 (TLR9) located on their surfaces.

TLR9 is a member of the PRRs. By binding to TLR9, mitochondrial DNA can also activate the MAP kinases (Figure 2).

Zhang's group concluded that the immune response to injury "mimic sepsis" because mitochondrial DAMPs activate

neutrophils through PRRs and FPR1, which normally would be activated by bacterial PAMPs.

Perhaps the most interesting question Zhang and his colleagues asked was if circulating mitochondrial DAMPs could cause

neutrophil-mediated organ injury. To answer this question, they intravenously injected mitochondrial DAMPs into rats to see

if they could produce organ injury in vivo. After exposure to the DAMPs, the animals were sacrificed, and samples of their

organs were stained and observed under the microscope. They found that mitochondrial DAMPs produced systemic

inflammation in several tissues, including a "marked-inflammatory lung injury," which is a major cause of respiratory failure in

critically ill patients (such as those with severe trauma). In contrast, the control rats showed no evidence of inflammation.

In scientific research, a new discovery often opens the door to even more questions. Are there additional DAMPs associated

with mitochondrial components that can trigger an immune response to trauma? Does the quantity of mitochondrial DAMPs

released after trauma determine a patient's clinical outcome? In addition, can high amounts of circulating DAMPs be used as

a marker to predict the severity of the inflammatory response and mortality? 

SummaryMitochondria are not only the "powerhouses" of our cells, they also play a significant role in triggering severe illnesses.

Zhang and his colleagues provided evidence indicating that mitochondria are the missing link to explain the observed

similarities between SIRS and sepsis. Severe trauma releases mitochondrial DAMPs into the blood where they are

recognized by innate immunity through PRRs and FPR1, which also sense bacteria. Because mitochondrial DAMPs have

evolutionarily conserved similarities to bacterial PAMPs, the release of mitochondrial DAMPs results in a "sepsis-like" state.

This new model provides clues to better understand how the systemic inflammatory response develops. What scientists still

do not know is if both SIRS and sepsis can be alleviated or prevented by inhibiting these pathways with pharmaceutical

compounds. More research will be needed to answer these questions.

References and Recommended Reading

Andersson, S. G. et al. On the origin of mitochondria: A genomics perspective. Philosophical Transactions of the Royal

Society of London, Series B: Biological Sciences 358, 165–177 (2003).

Gray, M. W., Burger, G. & Lang, B. F. The origin and early evolution of mitochondria. Genome Biology, 2(6), reviews1018.1–

1018.5 (2001) 

Haslbrunner, E., Tuppy, H. & Schatz, G. Deoxyribonucleic acid associated with yeast mitochondria. Biochemical and

Biophysical Research Communications 15, 127–132 (1964) .

Iwasaki, A. & Medzhitov, R. Regulation of adaptive immunity by the innate immune system. Science 327, 291–295 (2010).

Lotze, M. T. et al. The grateful dead: Damage-associated molecular pattern molecules and reduction/oxidation regulate

immunity. Immunological Reviews220, 60–81 (2007).

Matzinger, P. Tolerance, danger, and the extended family. Annual Review of Immunology 12, 991–1045 (1994).

Nass, M. M. & Nass, S. Intramitochondrial fibers with DNA characteristics . Journal of Cell Biology 19, 593–629 (1963) 

Sagan, L. On the origin of mitosing cells. Journal of Theoretical Biology 14(3), 255–274 (1967).

Zhang, Q. et al. Circulating mitochondrial DAMPs cause inflammatory response

Imunitas atau kekebalan adalah sistem mekanisme pada organisme yang melindungi tubuh terhadap

pengaruh biologis luar dengan mengidentifikasi dan membunuh patogen serta sel tumor. Sistem ini

mendeteksi berbagai macam pengaruh biologis luar yang luas, organisme akan melindungi tubuh

dari infeksi, bakteri, virus sampai cacing parasit, serta menghancurkan zat-zat asing lain dan

memusnahkan mereka dari sel organisme yang sehat dan jaringan agar tetap dapat berfungsi seperti

biasa. Deteksi sistem ini sulit karena adaptasi patogen dan memiliki cara baru agar dapat menginfeksi

organisme.

Untuk selamat dari tantangan ini, beberapa mekanisme telah berevolusi yang menetralisir patogen.

Bahkan organisme uniselular sepertibakteri dimusnahkan oleh sistem enzim yang melindungi

terhadap infeksi virus. Mekanisme imun lainnya yang berevolusi pada eukariotakuno dan tetap pada

keturunan modern, seperti tanaman, ikan, reptil dan serangga. Mekanisme tersebut termasuk peptida

antimikrobialyang disebut defensin, fagositosis, dan sistem komplemen.[1] Mekanisme yang lebih

berpengalaman berkembang secara relatif baru-baru ini, dengan adanya evolusi vertebrata. Imunitas

vertebrata seperti manusia berisi banyak jenis protein, sel, organ tubuh dan jaringan yang berinteraksi

pada jaringan yang rumit dan dinamin. Sebagai bagian dari respon imun yang lebih kompleks ini, sistem

vertebrata mengadaptasi untuk mengakui patogen khusus secara lebih efektif. Proses adaptasi

membuat memori imunologis dan membuat perlindungan yang lebih efektif selama pertemuan pada

masa depan dengan patogen tersebut. Proses imunitas yang diterima adalah basis dari vaksinasi.

Jika sistem kekebalan melemah, kemampuannya untuk melindungi tubuh juga berkurang,

membuat patogen, termasuk virus yang menyebabkan penyakit. Penyakit defisiensi imun muncul ketika

sistem imun kurang aktif daripada biasanya, menyebabkan munculnya infeksi. Defisiensi imun

merupakan penyebab dari penyakit genetik, seperti severe combined immunodeficiency, atau diproduksi

oleh farmaseutikal atau infeksi, seperti sindrom defisiensi imun dapatan (AIDS) yang disebabkan

oleh retrovirus HIV. Penyakit autoimunmenyebabkan sistem imun yang hiperaktif menyerang jaringan

normal seperti jaringan tersebut merupakan benda asing. Penyakit autoimun yang umum

termasuk rheumatoid arthritis, diabetes melitus tipe 1 dan lupus erythematosus. Peran

penting imunologi tersebut pada kesehatan dan penyakit adalah bagian dari penelitian.