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phagocyte kills viruses

IMMUNE CELLS & AUTOIMMUNITY

THE IMMUNE SYSTEM - BASIC CONCEPTS

ANTIGEN  eg virus, bacteria, chemicals, toxins, food protein 

A FOREIGN SUBSTANCE IN THE BODY THAT GETS EXPOSED TO THE IMMUNE SYSTEM

ANTIGEN PRESENTING CELLS -eg macrophages and dendritic cells in tissues   

ENGULF ANTIGENS & SEND CYTOKINE SIGNALS FOR HELP TO T- HELPER & NATURAL KILLER CELLS.

B CELLS

MAKE ANTIBODIES  (eg IgG, IgE, IgM) - small proteins which attach to the antigen so the immune system can find the antigen quickly (takes 7-14 days).  In autoimmunity these antibodies mistakenly bind to body tissues eg antibodies to joint tissue may lead to arthritis.

T CELLS - KILLER

DESTROY ANTIGENS - CD8+ Cytotoxic Killer T cells (together with Natural Killer cells) locate the antigen (via antibodies) and destroy it.  The more active these killer cells, the more severe a persons autoimmunity may be with more tissue destruction. 

T CELLS - HELPER 

Send messages via cytokines to the immune system i.e. to B cells to make antibodies and to CD8+ and Natural killer cells to destroy the antigen.  Examples of T Helper cells are CD4+T Suppressor Cells and T Regulatory Cells (TRegs).  These cells both modulate and ensure resolution of the immune response to prevent hyper-activation of the immune system and chronic inflammation.  TRegs cells are very important in Autoimmunity, to calm down the immune system.  T-Helper Cells can become polarised into TH1, TH2, TH17 however if they become imbalanced there may be implications for inflammation and Autoimmunity.

IMMUNE BARRIERS

Immune barriers are lined with immune cells that patrol the barrier searching for foreign threats.  When these immune barriers become compromised, they become 'Leaky' and foreign substances or antigens enter into the body. This can trigger or flare the Autoimmune process as it upregulates the immune system.  The activated immune system will make antibodies to the tissues you have antibodies for which will cause a flare and tissue destruction.  Therefore barrier management is a key part to Autoimmunity. The 3 main barriers are:

  • GUT Barrier - The Intestinal Lining which protects the gut

  • Blood Brain Barrier - Protects the brain

  • Lung Epithelium Barrier - protects the lungs

THE IMMUNE CELLS - INNATE AND ADAPTIVE

  • All immune cells come from stem cells in the bone marrow. 

  • The myeloid progenitor stem cell in the bone marrow is the precursor to the innate immune cells: neutrophils, mast cells, eosinophils, basophils, monocytes, dendritic cells, and macrophages.  The first-line, rapid responders. 

  • The lymphoid progenitor stem cell is the precursor to the adaptive immune cells; B cells and T cells, which respond to specific microbes based on immunological memory and previous encounters.

  • Natural killer (NK) cells are also derived from the common lymphoid progenitor and share features of both innate and adaptive immune cells, they provide immediate defence but also retain memory cells.                 


Reference: (Torang, A., Gupta, P. & Klinke, D.J., 2019)

doi.org/10.1186/s12859-019-2994-z

Immune cells

THE INNATE SYSTEM IMMUNE CELLS

The innate immune system is crucial for first line host defence.  However, abnormal activation of the innate immune system may be implicated in the pathogenesis of Autoimmunity.  Research also highlights a growing group of disorders caused by a dysregulation of the innate immune system leading to episodes of systemic inflammation, these are called Autoinflammatory diseases

NeutrophilsThe first white blood cells to migrate into the tissue in response to invading microbes.

  • They kill pathogens with mechanisms such as phagocytosis, generation of reactive oxygen species (ROS),  degranulation of antimicrobials and enzymes. Dysregulation or excess of any of these mechanisms can be pro-inflammatory.

  • Neutrophils also generate an extracellular chromatin fibre, called neutrophil extracellular traps (NETs), which kill extracellular bacteria. Evidence suggests NETs may be involved in the pathogenesis of various diseases, including Autoimmune disorders.

  • At the site of inflammation, neutrophils release cytokines that recruit monocytes for the next stage of the immune process.  Once they have finished their tasks neutrophils die by apoptosis, netosis or necrosis, any dysregulation or clearance of this apoptotic material can be a source of autoantigens (self tissue) in autoimmune diseases.

Monocytes/Macrophages - Monocytes migrate to the inflammatory site in the tissue and transform into tissue macrophages.  Macrophages detect and phagocytose harmful organisms or dead cells. They can also present antigens to T cells and initiate inflammation by releasing cytokines. Macrophages can drive innate and adaptive immune responses by complicated cross-talk with other cells, including Natural killer and Dendritic Cells.

Macrophages are subdivided in two main phenotypes:

1) M1 macrophages - produce proinflammatory cytokines, phagocytise microbes, and initiate an immune response. They can cause tissue destruction.

2) M2 macrophages - involved with immune regulation, wound healing and tissue repair, elimination of parasites and allergic diseases. However, if the  initial insult persists chronic activation of M2 leads to exacerbation of fibrosis and eventual tissue scarring as is often seen in Autoimmunity.

Dendritic Cells - The professional antigen presenting cells.  The function of dendritic cells is activation of CD4+ T Helper Cells to initiate adaptive immune responses, a crucial step in the development of Autoimmunity if 'self tissue' is being presented.  Dendritic cells have a tolerance function, which is important to promote in autoimmunity.  Dendritic cells can become over-active (especially in the gut) due to constant bombardment from antigens.

Eosinophils

Present in the respiratory, gastrointestinal, and urinary tract.  The main function of these cells is to destroy microbial pathogens, mainly parasites.  They release pro-inflammatory mediators, which are toxic, cationic proteins so they can also be damaging as part of the inflammatory process of allergic disease.  There is evidence of a pathogenic role of eosinophils in several autoimmune diseases.

 

Mast cells and basophils

Basophils are not phagocytic in nature and are found in the blood. Mast cells are located in tissues, mainly in mucosa, they release a variety of cytokines that enhance the inflammatory process, they are involved in allergic and viral processes.  Mast cells and basophils share features in common, especially in that they contain: 

• histamine-containing granules 

• high-affinity receptors for immunoglobulin E (IgE, an antibody type that is involved in allergic disease).

Natural Killer (NK) Cells

NK cells are best known for killing virally infected cells and detecting and controlling early signs of cancer.  NK cells secrete cytokines which act on other immune cells like Macrophage and Dendritic cells to enhance the immune response.  They also exert a regulatory role through secretion of immuno-regulatory cytokines thus, NK cells may be important target in the pathogenesis of autoinflammatory diseases, disorders associated with a cytokine storm or where immune cells are highly activated. 

Inflammasomes

Inflammasomes are large multiprotein complexes that assemble within the cytosol of the cell in response to both pathogens during microbial infection and danger signals released from damaged or dying cells.  Dysregulated inflammasome signalling is linked with a growing number of autoimmune and autoinflammatory diseases.

Myeloid-derived suppressor cells (MDSC)

MDSCs are a group of immune cells from the myeloid lineage. MDSCs have been known as suppressors of T cells, particularly CD8+ Killer T cells and  growing evidence indicates that MDSCs are involved in the pathogenesis of Autoimmune diseases and cancers.

Apoptosis of Immune Cells

Apoptosis is the physiological process of cell death.  After an immune response is completed, the majority of antigen responsive cells must be removed in order to prepare for the next immune challenge faced by the organism. Removal of immune cells without causing inflammation and tissue damage is achieved by inducing the unwanted cells to undergo apoptosis. Apoptosis is important in the immune system, and plays a significant role in regulation of the immune response and especially in Autoimmunity through deletion of unwanted immune cells recognising self-antigens.  Dysregulation of apoptosis can cause problems such as Autoimmune diseases.

Immune Cells: Text

Interactions between innate and adaptive immune systems

'When pathogens invade the body, the innate immune system is activated first and participates in the initial attack against the pathogens. Among the cells involved in innate immunity, dendritic cells act as antigen-presenting cells and migrate from the infected tissue to the regional lymph nodes where they present the antigens to T cells. Subsequently, the adaptive immune system is activated, and antibody production and killer T cells are induced. The resulting antibodies and killer T cells specifically attack the pathogens'.


Reference: (Shizuo Akira, 2011)

doi.org/10.1098/rstb.2011.0106

Innate and adaptive cells

THE ADAPTIVE SYSTEM IMMUNE CELLS

Adaptive immunity involves an antigen-specific cell mediated response which is adapted to the specific pathogen and regulated by crosstalk between immune cells. The Adaptive immune response is characterised by secretion of antibodies by B cells or activation of T cells, several days following the initial encounter with the pathogen.  Adaptive immune cells have evolved with a repertoire of cell receptors which can recognise specific antigens and discriminate between self- and non self-antigens.  Immunologic memory is the ability of the adaptive immune system to identify a previously encountered antigen and develop an efficient immune response.  This is why Autoimmune diseases may not be curable as the immune system will remember an antigen whether it is 'self' or 'non self'.

B Lymphocytes (B Cells)

In the adaptive humoral immune system B cells are responsible for the production of antigen-specific immunoglobulins (Ig) directed against invasive pathogens, typically known as antibodies.  There are five classes of antibodies, IgM, IgG, IgD, IgE, and IgA. IgG is the most abundant and is distributed throughout the body.  IgA is mostly located in the mucosa at the immune barriers.  On encountering a foreign substance (antigen) the B cell differentiates into a plasma cell which secretes antibodies. B cells also play an important role in antigen presentation and cytokine production.  Not all B cells positively regulate immune responses. Regulatory B cells negatively regulate immune responses by production of anti-inflammatory cytokines to dampen the immune response.  Regulatory B cells are been found to be decreased and/or functionally impaired in various autoimmune diseases.  B cells also produce pro-inflammatory cytokines, which may contribute to the pathogenesis of autoimmune diseases.  B cells play a significant role in many autoimmune diseases. ​

T Lymphocytes (T Cells)

Most T cells are produced in the thymus and resident in the lymph nodes or spleen, a small amount are present in the blood.  Naïve CD4+ T cells are activated for the first time in the lymph node by antigens presented to their cell receptors, this sets off an intracellular cascade of signalling causing T cell functional polarisation.  This is the ability of the adaptive immune system to promote a specific type of immune response as required for that antigen.  These processes take several days to achieve. The best-described polarisation of T-cell responses are:

  • ​CD8+ [cytotoxic T cells kill antigens]

  • CD4+ [T cells become polarised according to their function i.e. T helper cells can become TH1, TH2 etc see below]

  • Memory CD4+ [memory T cells are important in the context of autoimmune diseases because of their long-lived nature, efficient responses to antigens, and unique potential to mediate recurring autoimmune responses] 

T Helper Cells explained

Research on understanding exactly how helper T cells respond to immune challenges is of major interest in immunology, and research is ongoing.  Currently there are a number of T Helper polarisations identified but four important polarisations for Autoimmunity are:


T Helper 1 (TH1)

Pro-inflammatory, organises killing of bacteria, fungi, viruses, activates macrophages to kill intracellular bacteria, instructs cytotoxic T cell responses.

T Helper 2 (TH2)

Pro-inflammatory, organises killing of parasites by recruiting eosinophils, promotes antibody responses, especially switching to IgE.

T Helper 17 (TH17)

Pro-inflammatory, causes tissue destruction in autoimmune conditions.  TH17 is activated by inflammatory triggers such as reactive food proteins (eg gluten, Casein, Soy), reactive chemicals, stress, lack of sleep and overtraining.

Regulatory T Cells (Treg)

Regulates inflammation, maintain homeostasis and tolerance within the immune system as they balance out TH1 TH2 and TH17 cells.  TRegs can be activated with nutraceuticals, healthy emotional relationships, sleep, exercise etc 

If the TH1/TH2 or TRegs/TH17 balance is disturbed there can be severe implications for Autoimmune conditions.  Immune balance or tolerance may be achieved with the help of TReg cells.  The key to controlling Autoimmunity based on current research concepts is to Reduce Immune Triggers (TH17) and Improve Immune Tolerance (TRegs).  Balancing these immune cells can be achieved with lifestyle and nutrition factors as per evidence based research and clinical trials.

Immune Cells: Text

T Cell Polarisation

'A summary of CD4 T helper cell fates: their functions, their unique products, their characteristic transcription factors, and cytokines critical for their fate determination'.  


Reference: (Jinfang Zhu, William E. Paul, 2008)

doi.org/10.1182/blood-2008-05-078154

Please Note - Since this Research in 2008,  it has been determined that TH1 does not cause Autoimmunity, please bear that in mind when reviewing this diagram.

T cell polarisation
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