Information

Why do NK cells not destroy bacteria, even though bacteria don't have MHC-I?


Part of the function of NK cells is to destroy cells that are unable to bind their KIR receptors. Or in other words, cells that don't express MHC class I. This is why they can kill MHC supressed infected- or tumor cells, which other immune cells can't.

However bacteria also don't express MHC-I. Yet NK cells are said to have very limited influence one microbial infections. I do not understand why NK cells do not degranulate (kill) bacteria upon finding that they do not have the MHC-I receptor complex.

Could someone elaborate this?


While you're correct that NK cells are often activated (in part) by the absence of MHC-I, they require other signaling events to become fully activated:

The Molecular Mechanism of Natural Killer Cells Function and Its Importance in Cancer Immunotherapy. Paul & Lal. Frontiers in Immunology. 2017.

Activating Receptors on NK Cells

Lack of MHC class I on the target cell is not sufficient to trigger NK cell activation. Full NK cell activation also requires recognition of stress-induced molecules by NK cell activating receptors.

Natural cytotoxicity receptors (NCRs) are another immunoglobulin superfamily of activating receptors that utilize extracellular immunoglobulin-like domain for ligand binding. Human NK cells express three distinct types of NCRs… NCRs recognize a wide variety of ligands on target cells ranging from viral, bacterial and parasite proteins to molecules from tumor cells and other host cells.

Role of natural killer cells in antibacterial immunity. Schmidt et al. Expert Review of Hematology. 2016.

6 Bacteria fight back and inhibit NK cell activities

During evolution, many bacteria have developed survival strategies which counteract NK cell activity.

Both Gram-positive bacteria such as Streptococcus pneumoniae and Gram-negative bacteria such as Salmonella spp and Escherichia coli are able to induce prostaglandin E2 (PGE2), which negatively affects NK cell functions at different levels. PGE2 inhibits the cytolytic activities of NK cells by suppressing their responsiveness to cytokines such as IL-12 and IL-15, and suppresses NK cell mediated activation of macrophages by inhibiting the production of IFN-γ. Similarly, PGE2 has a deleterious effect on homing, migration, and survival of NK cells, as it has been shown in Human Herpes Virus 8 (HHV8) infection. Thus, bacteria are able to inhibit both cytotoxic and immunoregulatory effects of NK cells in various ways.

8 Conclusions

In conclusion, there is a growing body of evidence that NK cells play an important role in the antibacterial host response. NK cells are able to kill bacteria directly, or to modulate the immune system via cytokines and interferons. Further studies are needed to characterize how NK cells are activated by different bacteria. In addition, the role of NK cells among the other arms of the immune system in the defense against bacteria is poorly understood. Last, bacteria are able to inhibit NK cell activities, and a better understanding of this impairment may be the basis to specifically strengthen the antibacterial host response. Therefore, additional in vitro and in vivo data may open new therapeutic strategies using NK cells to fight bacterial infections.

If you'd like a full-text copy of the Schmidt paper, I can share it with you.


Countering Geert Vanden Bossche’s dubious viral open letter warning against mass COVID-19 vaccination

Geert Vanden Bossche is a scientist who published an open letter warning of global catastrophe due to deadly variants of COVID-19 selected for by mass vaccination. His argument sounds a lot like an argument Andrew Wakefield once made for MMR. There’s even grift likely involved!

[Editor’s note: Scott Gavura had circumstances pop up that prevented him from producing a post for today. As a result, I’m posting this. Some of you might have seen it already published elsewhere (although this is an edited/abridged version of the original post). If you haven’t, it’s new to you. A viral “open letter” by Geert Vanden Bossche has gone viral, and antivaxxers have been citing it as slam-dunk evidence that COVID-19 vaccination will lead to global catastrophe. As a result, I thought it worth providing this rebuttal and links to an even better rebuttal, to SBM readers in order to disseminate this information more widely. Enjoy!]

I’ve frequently discussed how in the age of the pandemic, at least in terms of antivaccine misinformation and pseudoscience, everything old is new again. Over the last several months, I’ve listed a number of examples of this phenomenon of antivaxxers recycling hoary tropes to apply them to COVID-19 vaccines for example, claims that vaccines kill, cause infertility, cancer, autoimmune disorders, and Alzheimer’s disease, and are loaded with “toxins“, among several others, such as the claim that they “alter your DNA“. One such claim that I hadn’t yet seen is another favorite antivax claim, although admittedly it’s a rather niche claim in that you don’t hear it too often. Specifically, I’m referring to the abuse of evolutionary theory by antivaxxers to claim that vaccines select for more deadly variants of pathogenic viruses and bacteria, making mass vaccination programs dangerous or even potentially catastrophic. Such claims are generally an offshoot of another favorite antivaccine claim, namely that the diseases being vaccinated against are so innocuous that vaccinating against them is overkill and allowing infection and “natural herd immunity” to occur is better, a trope that has also been resurrected about COVID-19, a disease that’s killed well north of 500K people in just the US in a little over a year. This brings us to our topic, a misinformation-filled “open letter” by a scientist named Geert Vanden Bossche that went viral over the weekend. It’s been accompanied by a video interview posted to—where else?—antivaxxer Robert F. Kennedy, Jr.’s Children’s Health Defense website. Reading the letter, what it reminded me, more than anything else, is an article that Andrew Wakefield wrote about the MMR vaccine and measles, published a few months before the pandemic hit. (Truly, those were simpler times.)

Dr. Vanden Bossche has publicized his letter on Twitter:

In this open letter I am appealing to the @WHO and all stakeholders involved, no matter their conviction, to immediately declare such action as THE SINGLE MOST IMPORTANT PUBLIC HEALTH EMERGENCY OF INTERNATIONAL CONCERN. Please read and share: https://t.co/0Fupw9JInP #COVID19 pic.twitter.com/I24mSjpVKM

&mdash Geert Vanden Bossche (@GVDBossche) March 6, 2021

More recently, he set up his own website to publicize his letter:

We've put together a website to gather all information, scientific documents and interviews I've posted on this public health emergency. We'll try to work on further translations and regular updates. https://t.co/DPYKE7kxmM

&mdash Geert Vanden Bossche (@GVDBossche) March 15, 2021

Along with science, maa-aan!

The science behind the catastrophic consequences of thoughtless human intervention in the Covid-19 pandemic. Read full document here: https://t.co/DPDFlg4U45 pic.twitter.com/TISexYqyTq

&mdash Geert Vanden Bossche (@GVDBossche) March 13, 2021

He’s also started making rounds on the podcast/vlog interview circuit:

You can watch yesterday's interview with Philip McMillan here: https://t.co/sx9fxpsyHg Thanks for all your support, we will need it. #COVID19 #openthedebate

&mdash Geert Vanden Bossche (@GVDBossche) March 7, 2021

Before I get to Vanden Bossche’s open letter and his “warning to the world” that mass vaccination with the current COVID-19 vaccines is likely to lead to a global catastrophe due to the proliferation of ever-more-transmissible COVID-19 variants (as if the COVID-19 pandemic itself hasn’t been a global catastrophe!), let’s just review what Wakefield claimed about the MMR vaccine back in 2019. Central to the concept in his article, published via the in-house journal of the American Association of Physicians and Surgeons (AAPS), an organization I like to refer to as the John Birch Society of medical societies given its penchant for conspiracy theories and pseudoscience, was that the MMR vaccine, by selecting for more aggressive measles strains, could result in a “sixth extinction event”. (I kid you not.) He even entitled his nonsensical screed “The Sixth Extinction: Vaccine Immunity and Measles Mutants in a Virgin Soil“.

As I go through Dr. Vanden Bossche’s open letter, I’ll point out the similarities, while also noting differences when they occur. By the time I get through this, I suspect you’ll understand why the misinformation that Dr. Vanden Bossche is selling (and I use the word “selling” intentionally, as I suspect there’s grift involved) is nonsense and nothing more than repackaged antivax tropes.


Patho II Exam 2

A. They are the receptors for interleukin-2, which is produced by macrophages when they attack the donor cells.

B. They are recognized by helper T cells, which then activate cytotoxic T cells to kill the donor cells.

C. They induce the production of blocking antibodies that protect the graft.

C. CD4-positive T lymphocytes.

C. phagocytosis of IgE-coated bacteria.

A. B cells that can kill without complement.

C. increased by immunization.

A. a humoral immune response has occurred.

B. a cell-mediated immune response has occurred.

C. both the T and B cell systems are functional.

A. from the same host infected with any virus.

B. infected by virus A and identical at class I MHC loci of the cytotoxic T cells.

C. infected by virus A and identical at class II MHC loci of the cytotoxic T cells.

D. infected with a different virus and identical at class I MHC loci of the cytotoxic cells.

A. enzymatic digestion of the cell membrane.

B. activation of adenylate cyclase.

C. insertion of complement proteins into the cell membrane.

C. helper T cells and macrophages.

A. It is unlikely that the patient has encountered this organism previously.

B. The patient is predisposed to IgE-mediated hypersensitivity reactions.

C. The information given is irrelevant to previous antigen exposure.

A. Perforins from cytotoxic T cells lyse the red cells.

B. Neutrophils release proteases that lyse the red cells.

C. Interleukin-2 binds to its receptor on the red cells, which results in lysis of the red cells.

C. T cell-B cell interaction.

B. lyse virus-infected target cells.

C. activate cytotoxic T cells.

A. matching the complement components of donor and recipient

B. administering alpha interferon

C. removing mature T cells from the graft

Possible Answers:
part of immunological memory

derivatives of natural killer (NK) cells

part of the innate immune system

Possible Answers:
A deficiency of B-cells, with a relative abundance of T-cells

Deficiency of both T-cells and B-cells

A deficiency of T-cells, with a relative abundance of B-cells

Excess production of both T-cells and B-cells

Possible Answers:
Mast cells

Possible Answers:
T-cells could not be generated

T3 and T4 levels would decrease

Hypothyroidism would occur

B-cells would not be able to mature

In the muscle fibers, the effects of the disease can be exacerbated by auto-immune interference. Weakness of the sarcolemma leads to damage and tears in the membrane. The body's immune system recognizes the damage and attempts to repair it. However, since the damage exists as a chronic condition, leukocytes begin to present the damaged protein fragments as antigens, stimulating a targeted attack on the damaged parts of the muscle fiber. The attack causes inflammation, fibrosis, and necrosis, further weakening the muscle.

Studies have shown that despite the severe pathology of the muscle fibers, the innervation of the muscle is unaffected.

Which of the following does not play a key role in the adaptive immune response?

Possible Answers:
dendritic cells

Possible Answers:
Macrophages use isolation as their main defense, and wall off pathogens

Macrophages produce antibodies to target pathogens

Macrophages use reactive oxygen species after ingesting pathogens

Macrophages only recruit other cells that are then able to kill pathogens

I. They present their antigens on major histocompatibility complex molecules.

II. They migrate to lymph nodes to present their antigens to B-cells and T-cells.

III. Antigen-presenting cells form a link between the innate and adaptive immune systems.


Clinical trials of NK cells for cancer

Sarah Cooley , Jeffrey S. Miller , in Natural Killer Cells , 2010

Thinking beyond KIRs

While KIRs are the best characterized family of MHC class I-recognizing NK cell receptors, other MHC-recognizing receptors, including NKG2A (binds HLA-E) and LIR-1 (binds HLA-G and other low affinity HLA ligands), may also be involved in tumour eradication. Their functional importance should not be overlooked because in addition to KIRs, NKG2A is expressed in approximately 50 percent of PB NK cells, and it is the dominant NK cell receptor expressed on NK cells reconstituting in the first six months after HCT. Furthermore, LIR-1 is expressed on approximately one-third of PB NK cells and is more likely to be co-expressed on KIR + NK cells than KIR − NK cells. A series of experiments using primary AML and ALL target cells was performed using blocking antibodies to inhibitory KIRs, NKG2A and LIR-1 to understand the relative individual contribution of each to NK cell-mediated killing ( Godal et al., 2008 ). In both cytotoxicity and CD107a degranulation assays, the blockade of a single inhibitory receptor led to slight increases in killing. However, the addition of an LIR-1 blockade to either the KIR blockade or NKG2A blockade consistently increased killing of all targets sensitive to the pan-HLA blockade. Interestingly, KIR − NK cells that did express NKG2A or LIR-1 were potently alloreactive against primary leukemia targets but only upon the dual blockade of NKG2A and LIR-1. These findings have important implications for potential efficacy of current NK cell-based therapies. Both KIR + and KIR − NK cell subsets exhibit significant potential for cytotoxicity of killing primary AML and ALL blasts. The potent effector function of the KIR − NK cells demonstrates that they can be licensed via receptors other than KIRs. Preliminary clinical testing of anti-KIR or anti-NKG2A monoclonal antibodies to block inhibitory receptor interactions demonstrated increases in NK-mediated antitumour killing ( Koh et al., 2001 ). Further trials are warranted.


The Acquired or Adaptive Immune System

The acquired, adaptive, or specific immune system develops during our life as we are exposed to pathogens or after we receive vaccinations. The components of this system are more specialized than the components of the innate system. They take longer to react to a pathogen and are antigen-specific.

The acquired system is able to identify specific fungi, bacteria, viruses, and other potentially harmful items. It also has a memory component. This allows the body to quickly attack a pathogen when it&aposs exposed to the invader for a second or subsequent time after the initial exposure.

The combination of the rapid but generalized innate system and the slower but specialized acquired system is very often an effective way to protect the body from infection or to help the recovery from one.

NK, B, and T cells are known as lymphocytes because they are found in lymph (as well as blood). The lymphatic system contains vessels that collect excess fluid from the tissues and return it to the bloodstream. The system also fights invaders. The lymph nodes in the lymphatic system are important centers in the fight.


Scientists use Doppler to peer inside cells

Doppler radar improves lives by peeking inside air masses to predict the weather. A Purdue University team is using similar technology to look inside living cells, introducing a method to detect pathogens and treat infections in ways that scientists never have before.

In a new study, the team used Doppler to sneak a peek inside cells and track their metabolic activity in real time, without having to wait for cultures to grow. Using this ability, the researchers can test microbes found in food, water, and other environments to see if they are pathogens, or help them identify the right medicine to treat antibiotic-resistant bacteria.

David Nolte, Purdue's Edward M. Purcell Distinguished Professor of Physics and Astronomy John Turek, professor of basic medical sciences Eduardo Ximenes, research scientist in the Department of Agricultural and Biological Engineering and Michael Ladisch, Distinguished Professor of Agricultural and Biological Engineering, adapted this technique from their previous study on cancer cells in a paper released this month in Communications Biology.

Using funding from the National Science Foundation as well as Purdue's Discovery Park Big Idea Challenge, the team worked with immortalized cell lines -- cells that will live forever unless you kill them. They exposed the cells to different known pathogens, in this case salmonella and E. coli. They then used the Doppler effect to spy out how the cells reacted. These living cells are called "sentinels," and observing their reactions is called a biodynamic assay.

"First we did biodynamic imaging applied to cancer, and now we're applying it to other kinds cells," Nolte said. "This research is unique. No one else is doing anything like it. That's why it's so intriguing."

This strategy is broadly applicable when scientists have isolated an unknown microbe and want to know if it is pathogenic -- harmful to living tissues -- or not. Such cells may show up in food supply, water sources or even in recently melted glaciers.

"This directly measures whether a cell is pathogenic," Ladisch said. "If the cells are not pathogenic, the Doppler signal doesn't change. If they are, the Doppler signal changes quite significantly. Then you can use other methods to identify what the pathogen is. This is a quick way to tell friend from foe."

Being able to quickly discern whether a cell is harmful is incredibly helpful in situations where people encounter a living unknown microorganism, allowing scientists to know what precautions to take. Once it is known that a microbe is harmful, they can begin established protocols that allow them to determine the specific identity of the cell and determine an effective antibiotic against the microorganism.

Another benefit is the ability to quickly and directly diagnose which bacteria respond to which antibiotics. Antibiotic resistance can be a devastating problem in hospitals and other environments where individuals with already compromised bodies and immune systems may be exposed to and infected by increasingly high amounts of antibiotic resistant bacteria. Sometimes this results in a potentially fatal condition called bacterial sepsis, or septicemia. This is different from the viral sepsis that has been discussed in connection with COVID-19, though the scientists say their next steps will include investigating viral sepsis.

Treating sepsis is challenging. Giving the patient broad-spectrum antibiotics, which sounds like a good idea, might not help and could make the situation worse for the next patient. Letting bacteria come into close contact with antibiotics that do not kill them only makes them more resistant to that antibiotic and more difficult to fight next time.

Culturing the patient's tissues and homing in on the correct antibiotic to use can take time the patient does not have, usually eight to 10 hours. This new biodynamic process allows scientists to put the patient's bacterial samples in an array of tiny petri dishes containing the tissue sentinels and treat each sample with a different antibiotic. Using Doppler, they can quickly notice which bacterial samples have dramatic metabolic changes. The samples that do are the ones that have reacted to the antibiotic -- the bacteria are dying, being defeated and beaten back by antibiotics.

"When we treat with antibiotics, the bacteria don't have to multiply much before they start to affect the tissue sentinels," Nolte explained. "There are still too few bacteria to see or to measure directly, but they start to affect how the tissues behaves, which we can detect with Doppler."

In less than half the time a traditional culture and diagnosis takes, doctors could tell which antibiotic to administer, bolstering the patient's chances for recovery. The researchers worked closely with the Purdue Research Foundation Office of Technology Commercialization to patent and license their technologies. They plan to further explore whether this method would work for tissue samples exposed to nonliving pathogenic cells or dried spores, and to test for and treat viral sepsis.


Benefits and Examples

Chemoimmunotherapy is now being used—both via approved therapies and in clinical trials—for a number of different types of cancer. We will discuss only a few of these here, but it's likely that more trials will be developed in the near future for cancers that have not yet been approached with this combination.

Lung Cancer

The first combination of first-line chemotherapy and immunotherapy for non-small cell lung cancer (specifically lung adenocarcinoma) was approved in 2017. The trial leading to approval used a combination of the immunotherapy drug (a type of checkpoint inhibitor) Keytruda (pembrolizumab) with the two chemotherapy drugs Paraplatin (carboplatin) and Alimta (premetrexed), to show that the combination was both safe and more effective than chemotherapy alone.  

Since that time, other combinations have been used and there are several clinical trials in place looking at the combination.

For people who are receiving immunotherapy either with or without chemotherapy, it's important to be aware of the phenomena of pseudoprogression. Unlike what is seen with chemotherapy, early responses to immunotherapy are not as dramatic (it takes more time to get the immune system working to fight cancer). Imaging tests (such as CT scans) can also look "worse" early on, even if a tumor is responding.   When immune cells surround and infiltrate a tumor, it can make the tumor look larger on a scan, something referred to as pseudoprogression. Even though the tumor appears larger, it actually may be smaller.

Of interest, is that radiation therapy, particularly SBRT (stereotactic body radiotherapy) to treat metastases, has also been found to enhance the effectiveness of immunotherapy for some people. Via something that has been coined the "abscopal effect," radiation given to one area of the body may sometimes stimulate the immune system such that the treatment results in reduction of a tumor in a different region of the body away from the site of radiation.  

Breast Cancer

Despite sometimes dramatic responses to immunotherapy with some solid tumors (such as lung cancer and melanoma), results of studies using immunotherapy in people with breast cancer have been disappointing. Unlike some tumors, breast cancers often have a "lower mutational burden," meaning that they look less abnormal to the immune system.

In one setting, however, combining immunotherapy with chemotherapy has been quite effective, specifically, with advanced triple-negative breast cancer. A 2018 study compared the effectiveness of Tecentriq (atezolizumab) and the chemotherapy drug Abraxane (nab-paclitaxel), to that of the chemotherapy drug alone.   The overall median survival was 25.0 months for the group also given the immunotherapy drug (a checkpoint inhibitor) compared with 15.5 in the chemotherapy alone group.

Research is in progress looking for ways to "wake up" the immune system in people who do not respond to immunotherapy, and some evidence suggests that chemotherapy may have a role in the future.

Lymphoma

Combinations of cancer treatments have long been used to treat different types of lymphoma, and in 2019 the first chemotherapy regimen for people with relapsed diffuse large B-cell lymphoma was approved. The drug, PolivyPolivy (polatuzumab vedotin-piiq), in combination with the chemotherapy drug Bendeka (bendamustine) and a rituximab medication further advanced the treatment of this challenging disease.  

Other Cancers

Combinations of immunotherapy (checkpoint inhibitors as well as other types) and chemotherapy are being evaluated for many different types of cancer. As of June 2019, there were more than 170 clinical trials investigating checkpoint inhibitors and chemotherapy (chemoimmunotherapy) in different types of cancer.  

A Word From Verywell

The combination of immunotherapy and chemotherapy (chemoimmunotherapy) to treat cancer is an exciting advance in options for at least some people with cancer. These newer treatment approaches differ from those in the past (coined "slash, poison, burn" by some), and uses knowledge of the biology of cancer rather than trial and error as a basis. This precision medicine, may not only lead to more effective treatments, but with fewer side effects. There are still many unanswered questions, but many clinical trials are currently in place that promise to bring more insight in the near future.


Summary and Conclusion

NK cells play crucial roles in regulation of chronic inflammatory diseases such as tissue fibrosis and cancer. Thus, the understanding of NK-mediated immunoregulation would provide insight into designing therapeutics against viral infection and inflammatory diseases. NK cells have a protective role in the development of liver fibrosis in the model of NAFLD development where they regulate the tight balance between liver inflammation and repair through macrophage polarization. Thus, the identification of NK cells as upstream regulators of macrophage function provides a new cellular target to modulate macrophage-mediated inflammation in chronic liver diseases. Further exploration of the interplay between myeloid cells and NK cells may thus help identify key molecular regulators that can resolve chronic inflammation and restore immune homeostasis.


Contents

Anatomical barrier Additional defense mechanisms
Skin Sweat, desquamation, flushing, [2] organic acids [2]
Gastrointestinal tract Peristalsis, gastric acid, bile acids, digestive enzyme,
flushing, thiocyanate, [2] defensins, [2] gut flora [2]
Respiratory airways and lungs Mucociliary escalator, [3] surfactant, [2] defensins [2]
Nasopharynx Mucus, saliva, lysozyme [2]
Eyes Tears [2]
Blood-brain barrier endothelial cells (via passive diffusion/ osmosis & active selection). P-glycoprotein (mechanism by which active transportation is mediated)

Anatomical barriers include physical, chemical and biological barriers. The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line of defense against invading organisms. [2] Desquamation (shedding) of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces. Lack of blood vessels, the inability of the epidermis to retain moisture, and the presence of sebaceous glands in the dermis, produces an environment unsuitable for the survival of microbes. [2] In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious agents. [2] Also, mucus traps infectious agents. [2] The gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces. [2] The flushing action of tears and saliva helps prevent infection of the eyes and mouth. [2]

Inflammation is one of the first responses of the immune system to infection or irritation. Inflammation is stimulated by chemical factors released by injured cells and serves to establish a physical barrier against the spread of infection, and to promote healing of any damaged tissue following the clearance of pathogens. [4]

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendritic cells, histiocytes, Kupffer cells, and mast cells. These cells present receptors contained on the surface or within the cell, named pattern recognition receptors (PRRs), which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). At the onset of an infection, burn, or other injuries, these cells undergo activation (one of their PRRs recognizes a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation.

Chemical factors produced during inflammation (histamine, bradykinin, serotonin, leukotrienes, and prostaglandins) sensitize pain receptors, cause local vasodilation of the blood vessels, and attract phagocytes, especially neutrophils. [4] Neutrophils then trigger other parts of the immune system by releasing factors that summon additional leukocytes and lymphocytes. Cytokines produced by macrophages and other cells of the innate immune system mediate the inflammatory response. These cytokines include TNF, HMGB1, and IL-1. [5]

The inflammatory response is characterized by the following symptoms:

    , due to locally increased blood circulation
  • heat, either increased local temperature, such as a warm feeling around a localized infection, or a systemic fever
  • swelling of affected tissues, such as the upper throat during the common cold or joints affected by rheumatoid arthritis
  • increased production of mucus, which can cause symptoms like a runny nose or a productive cough
  • pain, either local pain, such as painful joints or a sore throat, or affecting the whole body, such as body aches and
  • possible dysfunction of the organs or tissues involved.

The complement system is a biochemical cascade of the immune system that helps, or “complements”, the ability of antibodies to clear pathogens or mark them for destruction by other cells. The cascade is composed of many plasma proteins, synthesized in the liver, primarily by hepatocytes. The proteins work together to:

  • trigger the recruitment of inflammatory cells
  • "tag" pathogens for destruction by other cells by opsonizing, or coating, the surface of the pathogen
  • form holes in the plasma membrane of the pathogen, resulting in cytolysis of the pathogen cell, causing the death of the pathogen
  • rid the body of neutralised antigen-antibody complexes.

There are three different complement systems: Classical, alternative, Lectin

  • Classical: starts when antibody binds to bacteria
  • Alternative: starts "spontaneously"
  • Lectin: starts when lectins bind to mannose on bacteria

Elements of the complement cascade can be found in many non-mammalian species including plants, birds, fish, and some species of invertebrates. [6]

All white blood cells (WBCs) are known as leukocytes. Most leukocytes differ from other cells of the body in that they are not tightly associated with a particular organ or tissue thus, their function is similar to that of independent, single-cell organisms. Most leukocytes are able to move freely and interact with and capture cellular debris, foreign particles, and invading microorganisms (although macrophages, mast cells, and dendritic cells are less mobile). Unlike many other cells in the body, most innate immune leukocytes cannot divide or reproduce on their own, but are the products of multipotent hematopoietic stem cells present in the bone marrow. [7]

The innate leukocytes include: natural killer cells, mast cells, eosinophils, basophils and the phagocytic cells include macrophages, neutrophils, and dendritic cells, and function within the immune system by identifying and eliminating pathogens that might cause infection. [1]

Mast cells Edit

Mast cells are a type of innate immune cell that resides in connective tissue and in mucous membranes. They are intimately associated with wound healing and defense against pathogens, but are also often associated with allergy and anaphylaxis (serious allergic reactions that can cause death). [4] When activated, mast cells rapidly release characteristic granules, rich in histamine and heparin, along with various hormonal mediators and chemokines, or chemotactic cytokines into the environment. Histamine dilates blood vessels, causing the characteristic signs of inflammation, and recruits neutrophils and macrophages. [4]

Phagocytes Edit

The word 'phagocyte' literally means 'eating cell'. These are immune cells that engulf, or 'phagocytose', pathogens or particles. To engulf a particle or pathogen, a phagocyte extends portions of its plasma membrane, wrapping the membrane around the particle until it is enveloped (i.e., the particle is now inside the cell). Once inside the cell, the invading pathogen is contained inside a phagosome, which merges with a lysosome. [1] The lysosome contains enzymes and acids that kill and digest the particle or organism. In general, phagocytes patrol the body searching for pathogens, but are also able to react to a group of highly specialized molecular signals produced by other cells, called cytokines. The phagocytic cells of the immune system include macrophages, neutrophils, and dendritic cells.

Phagocytosis of the hosts’ own cells is common as part of regular tissue development and maintenance. When host cells die, either by programmed cell death (also called apoptosis) or by cell injury due to a bacterial or viral infection, phagocytic cells are responsible for their removal from the affected site. [7] By helping to remove dead cells preceding growth and development of new healthy cells, phagocytosis is an important part of the healing process following tissue injury.

Macrophages Edit

Macrophages, from the Greek, meaning "large eaters", are large phagocytic leukocytes, which are able to move outside of the vascular system by migrating through the walls of capillary vessels and entering the areas between cells in pursuit of invading pathogens. In tissues, organ-specific macrophages are differentiated from phagocytic cells present in the blood called monocytes. Macrophages are the most efficient phagocytes and can phagocytose substantial numbers of bacteria or other cells or microbes. [1] The binding of bacterial molecules to receptors on the surface of a macrophage triggers it to engulf and destroy the bacteria through the generation of a “respiratory burst”, causing the release of reactive oxygen species. Pathogens also stimulate the macrophage to produce chemokines, which summon other cells to the site of infection. [1]

Neutrophils Edit

Neutrophils, along with two other cell types (eosinophils and basophils see below), are known as granulocytes due to the presence of granules in their cytoplasm, or as polymorphonuclear cells (PMNs) due to their distinctive lobed nuclei. Neutrophil granules contain a variety of toxic substances that kill or inhibit growth of bacteria and fungi. Similar to macrophages, neutrophils attack pathogens by activating a respiratory burst. The main products of the neutrophil respiratory burst are strong oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite. Neutrophils are the most abundant type of phagocyte, normally representing 50-60% of the total circulating leukocytes, and are usually the first cells to arrive at the site of an infection. [4] The bone marrow of a normal healthy adult produces more than 100 billion neutrophils per day, and more than 10 times that many per day during acute inflammation. [4]

Dendritic cells Edit

Dendritic cells (DCs) are phagocytic cells present in tissues that are in contact with the external environment, mainly the skin (where they are often called Langerhans cells), and the inner mucosal lining of the nose, lungs, stomach, and intestines. [7] They are named for their resemblance to neuronal dendrites, but dendritic cells are not connected to the nervous system. Dendritic cells are very important in the process of antigen presentation, and serve as a link between the innate and adaptive immune systems.

Basophils and eosinophils Edit

Basophils and eosinophils are cells related to the neutrophil (see above). When activated by a pathogen encounter, histamine-releasing basophils are important in the defense against parasites and play a role in allergic reactions, such as asthma. [1] Upon activation, eosinophils secrete a range of highly toxic proteins and free radicals that are highly effective in killing parasites, but may also damage tissue during an allergic reaction. Activation and release of toxins by eosinophils are, therefore, tightly regulated to prevent any inappropriate tissue destruction. [4]

Natural killer cells Edit

Natural killer cells (NK cells) are a component of the innate immune system that does not directly attack invading microbes. Rather, NK cells destroy compromised host cells, such as tumor cells or virus-infected cells, recognizing such cells by a condition known as "missing self." This term describes cells with abnormally low levels of a cell-surface marker called MHC I (major histocompatibility complex) - a situation that can arise in viral infections of host cells. [8] They were named "natural killer" because of the initial notion that they do not require activation in order to kill cells that are "missing self." For many years, it was unclear how NK cell recognize tumor cells and infected cells. It is now known that the MHC makeup on the surface of those cells is altered and the NK cells become activated through recognition of "missing self". Normal body cells are not recognized and attacked by NK cells because they express intact self MHC antigens. Those MHC antigens are recognized by killer cell immunoglobulin receptors (KIR) that, in essence, put the brakes on NK cells. The NK-92 cell line does not express KIR and is developed for tumor therapy. [9] [10] [11] [12]

Γδ T cells Edit

Like other 'unconventional' T cell subsets bearing invariant T cell receptors (TCRs), such as CD1d-restricted Natural Killer T cells, γδ T cells exhibit characteristics that place them at the border between innate and adaptive immunity. On one hand, γδ T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a pattern recognition receptor. For example, according to this paradigm, large numbers of Vγ9/Vδ2 T cells respond within hours to common molecules produced by microbes, and highly restricted intraepithelial Vδ1 T cells will respond to stressed epithelial cells.

The coagulation system overlaps with the immune system. Some products of the coagulation system can contribute to the non-specific defenses by their ability to increase vascular permeability and act as chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation system are directly antimicrobial. For example, beta-lysine, a protein produced by platelets during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic detergent. [2] Many acute-phase proteins of inflammation are involved in the coagulation system.

Also increased levels of lactoferrin and transferrin inhibit bacterial growth by binding iron, an essential nutrient for bacteria. [2]

The innate immune response to infectious and sterile injury is modulated by neural circuits that control cytokine production period. The inflammatory reflex is a prototypical neural circuit that controls cytokine production in the spleen. [13] Action potentials transmitted via the vagus nerve to spleen mediate the release of acetylcholine, the neurotransmitter that inhibits cytokine release by interacting with alpha7 nicotinic acetylcholine receptors (CHRNA7) expressed on cytokine-producing cells. [14] The motor arc of the inflammatory reflex is termed the cholinergic anti-inflammatory pathway.

The parts of the innate immune system have different specificity for different pathogens.

  • Listeria monocytogenes
  • Legionella
  • Mycobacterium
  • Rickettsia
  • Staphylococcus
  • Streptococcus
  • Neisseria
  • Salmonella typhi
  • Plasmodium malariae
  • Leishmania donovani
  • Entamoeba histolytica
  • Giardia lamblia
  • Candida
  • Histoplasma
  • Cryptococcus

Cells of the innate immune system prevent free growth of microorganisms within the body, but many pathogens have evolved mechanisms to evade it. [19] [20]

One strategy is intracellular replication, as practised by Mycobacterium tuberculosis, or wearing a protective capsule, which prevents lysis by complement and by phagocytes, as in Salmonella. [21] Bacteroides species are normally mutualistic bacteria, making up a substantial portion of the mammalian gastrointestinal flora. [22] Some species like B. fragilis for example are opportunistic pathogens, causing infections of the peritoneal cavity inhibit phagocytosis by affecting the phagocytes receptors used to engulf bacteria. They may also mimick host cells so the immune system does not recognize them as foreign. Staphylococcus aureus inhibits the ability of the phagocyte to respond to chemokine signals. M. tuberculosis, Streptococcus pyogenes, and Bacillus anthracis utilize mechanisms that directly kill the phagocyte. [ citation needed ]

Bacteria and fungi may form complex biofilms, protecting from immune cells and proteins biofilms are present in the chronic Pseudomonas aeruginosa and Burkholderia cenocepacia infections characteristic of cystic fibrosis. [23]

Viruses Edit

Type I interferons (IFN), secreted mainly by dendritic cells, [24] play a central role in antiviral host defense and a cell's antiviral state. [25] Viral components are recognized by different receptors: Toll-like receptors are located in the endosomal membrane and recognize double-stranded RNA (dsRNA), MDA5 and RIG-I receptors are located in the cytoplasm and recognize long dsRNA and phosphate-containing dsRNA respectively. [26] When the cytoplasmic receptors MDA5 and RIG-I recognize a virus the conformation between the caspase-recruitment domain (CARD) and the CARD-containing adaptor MAVS changes. In parallel, when toll-like receptors in the endocytic compartments recognize a virus the activation of the adaptor protein TRIF is induced. Both pathways converge in the recruitment and activation of the IKKε/TBK-1 complex, inducing dimerization of transcription factors IRF3 and IRF7, which are translocated in the nucleus, where they induce IFN production with the presence of a particular transcription factor and activate transcription factor 2. IFN is secreted through secretory vesicles, where it can activate receptors on both the same cell it was released from (autocrine) or nearby cells (paracrine). This induces hundreds of interferon-stimulated genes to be expressed. This leads to antiviral protein production, such as protein kinase R, which inhibits viral protein synthesis, or the 2′,5′-oligoadenylate synthetase family, which degrades viral RNA. [25]

Some viruses evade this by producing molecules which interfere with IFN production. For example, the Influenza A virus produces NS1 protein, which can bind to host and viral RNA, interact with immune signaling proteins or block their activation by ubiquitination, thus inhibiting type I IFN production. [27] Influenza A also blocks protein kinase R activation and establishment of the antiviral state. [28] The dengue virus also inhibits type I IFN production by blocking IRF-3 phosophorylation using NS2B3 protease complex. [29]

Prokaryotes Edit

Bacteria (and perhaps other prokaryotic organisms), utilize a unique defense mechanism, called the restriction modification system to protect themselves from pathogens, such as bacteriophages. In this system, bacteria produce enzymes, called restriction endonucleases, that attack and destroy specific regions of the viral DNA of invading bacteriophages. Methylation of the host's own DNA marks it as "self" and prevents it from being attacked by endonucleases. [30] Restriction endonucleases and the restriction modification system exist exclusively in prokaryotes. [31]

Invertebrates Edit

Invertebrates do not possess lymphocytes or an antibody-based humoral immune system, and it is likely that a multicomponent, adaptive immune system arose with the first vertebrates. [32] Nevertheless, invertebrates possess mechanisms that appear to be precursors of these aspects of vertebrate immunity. Pattern recognition receptors are proteins used by nearly all organisms to identify molecules associated with microbial pathogens. Toll-like receptors are a major class of pattern recognition receptor, that exists in all coelomates (animals with a body-cavity), including humans. [33] The complement system, as discussed above, is a biochemical cascade of the immune system that helps clear pathogens from an organism, and exists in most forms of life. Some invertebrates, including various insects, crabs, and worms utilize a modified form of the complement response known as the prophenoloxidase (proPO) system. [32]

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response found among all classes of life and represent the main form of invertebrate systemic immunity. Several species of insect produce antimicrobial peptides known as defensins and cecropins.

Proteolytic cascades Edit

In invertebrates, pattern recognition receptors (PRRs) trigger proteolytic cascades that degrade proteins and control many of the mechanisms of the innate immune system of invertebrates—including hemolymph coagulation and melanization. Proteolytic cascades are important components of the invertebrate immune system because they are turned on more rapidly than other innate immune reactions because they do not rely on gene changes. Proteolytic cascades have been found to function the same in both vertebrate and invertebrates, even though different proteins are used throughout the cascades. [34]

Clotting mechanisms Edit

In the hemolymph, which makes up the fluid in the circulatory system of arthropods, a gel-like fluid surrounds pathogen invaders, similar to the way blood does in other animals. There are various different proteins and mechanisms that are involved in invertebrate clotting. In crustaceans, transglutaminase from blood cells and mobile plasma proteins make up the clotting system, where the transglutaminase polymerizes 210 kDa subunits of a plasma-clotting protein. On the other hand, in the horseshoe crab species clotting system, components of proteolytic cascades are stored as inactive forms in granules of hemocytes, which are released when foreign molecules, like lipopolysaccharides enter. [34]

Plants Edit

Members of every class of pathogen that infect humans also infect plants. Although the exact pathogenic species vary with the infected species, bacteria, fungi, viruses, nematodes, and insects can all cause plant disease. As with animals, plants attacked by insects or other pathogens use a set of complex metabolic responses which lead to the formation of defensive chemical compounds that fight infection or make the plant less attractive to insects and other herbivores. [35] (see: plant defense against herbivory).

Like invertebrates, plants neither generate antibody or T-cell responses nor possess mobile cells that detect and attack pathogens. In addition, in case of infection, parts of some plants are treated as disposable and replaceable, in ways that very few animals are able to do. Walling off or discarding a part of a plant helps stop spread of an infection. [35]

Most plant immune responses involve systemic chemical signals sent throughout a plant. Plants use pattern-recognition receptors to recognize conserved microbial signatures. This recognition triggers an immune response. The first plant receptors of conserved microbial signatures were identified in rice (XA21, 1995) [36] [37] and in Arabidopsis (FLS2, 2000). [38] Plants also carry immune receptors that recognize highly variable pathogen effectors. These include the NBS-LRR class of proteins. When a part of a plant becomes infected with a microbial or viral pathogen, in case of an incompatible interaction triggered by specific elicitors, the plant produces a localized hypersensitive response (HR), in which cells at the site of infection undergo rapid programmed cell death to prevent the spread of the disease to other parts of the plant. HR has some similarities to animal pyroptosis, such as a requirement of caspase-1-like proteolytic activity of VPEγ, a cysteine protease that regulates cell disassembly during cell death. [39]


Dıscussıon and Conclusıon

Being under focus of immunologists for decades, NK cells, their biology, functions as well as their contributions in the pathogenesis of a number of diseases are being better illuminated day by day. There is strong evidence that the innate immune system, specifically NK cells, influence subsequent adaptive immune responses. Thanks to their ability to rapidly kill abnormal cells and produce cytokines and chemokines, NK cells are positioned for a key role in regulation of autoimmune responses, and can either suppress or augment autoimmunity, directly or indirectly. NK cells could play roles with functional alterations in autoimmune conditions ( Figure 2 ).

Contribution of NK cells in autoimmune disorders: NK cells have roles in underlying pathogenesis of a number of diseases with autoimmune and autoinflammatory etiology. NK cells could have both predisposing and also protective roles in these disorders thanks to their altered functional competencies and also their variable cytokine productions. The alterations in NK cell numbers and functions in Beh๾t’s disease, systemic lupus erythematosus, ankylosing spondylitis, autoimmune diabetes, psoriasis, rheumatoid arthritis and multiple sclerosis are summarized.

Activating and inhibitory receptors of the NK cells are essential for the regulation of NK activity and some of these NK cell receptor related genes are strongly associated with autoimmunity (330). Inhibitory receptor signals are usually generated by the binding of the MHC-class I molecules. Therefore, the functions of these receptors are especially prone to be affected in MHC-class I molecule related diseases (MHC-I-opathies) such as ankylosing spondylitis, psoriasis, and Beh๾t’s disease (331). Certain activating KIR receptor polymorphisms can also cause susceptibility to autoimmunity. Activating receptors KIR2DS1 and KIR2DS2 are implicated in the pathogenesis of autoimmune diseases such as in the examples of RA and psoriasis (332, 333). The expression of the ligands of the activating receptors, such as MICA also contributes to the disease pathogenesis such that alternated receptor affinty may lead to activaiton in predisposed individuals, observed in various autoimmune diseases including RA, BD and type 1 diabetes (334�). Finally, certain KIR/HLA combinations reduce the activation threshold of the NK cells and can be protective against some infections, while the same KIR/HLA combination may also predispose autoimmunity. Individuals with HIV have a slower progression to AIDS and reduced viral loads, when they express KIR3DS1 and HLA-B Bw4-801 (337). However, the same genetic combination also causes susceptibility to autoimmunity such as in the examples of BD and AS (338, 339). The delicate balance of the activating and inhibitory KIR molecules and their ligands are important in NK cell homeostasis. Genetic and environmental factors affecting this delicate balance can potentially induce autoimmunity in susceptible individuals.

Further investigations are needed in order to unravel the roles played by NK cells, as a bridge between innate and adaptive immunity in the onset of autoimmune diseases. Expression of different subsets of NK and also ILC subsets might serve as a biomarker in the follow-up of different autoimmune diseases. The TCR-NK cells operate with a mechanism that is distinct from CAR-T cells. They can target molecules located not only on the surface of cancer cells, but inside them as well, meaning that they can reach places that are inaccessible to CAR-T cells. This technology can be adapted to target any other form of cancer and also to autoimmune diseases.

Briefly, NK cells harbor great potential both for being biomarkers and also for utilization in a number of therapeutic interventions, especially in autoimmune diseases and in cancer, all of which warrants more intense investigations to be carried out.