IMMUNE CELLS & AUTOIMMUNITY

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. 

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Neutrophils - The 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.

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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.

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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.

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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).

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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. 

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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.

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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.

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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.