Our Immune System
Our immune system is comprised of many biological structures and processes within our body that protects against disease. To function properly, an immune system must detect a wide variety of agents, known as pathogens, from viruses to parasitic worms, and distinguish them from our body’s own healthy tissue. Our immune system can be classified into subsystems, such as the innate immune system versus the adaptive immune system, or humoral immunity versus cell-mediated immunity.
The Adaptive Immune System
Adaptive immunity is a person’s defense system built on specific cellular targeting. It takes time for the immune system to develop its weaponry (up to 96 hours after infection), but ultimately the adaptive response is far more effective because of its precision.
Once infection is identified, antigen is transported to lymphoid organs where it is recognized by naive B and T cells. Clonal expansion and differentiation of these cells occurs, and then the battle begins. The immune system can take several tacks, depending on the type of infection encountered. Ultimately, the goals of the adaptive response are two-fold: to produce neutralizing antibody, and to flag up infected cells for destruction. This annihilation can be carried out by the cells of both innate and adaptive immunity.
Actions of the Adaptive Immune System
Adaptive immunity is stimulated by the generic actions of innate immunity. Once a foreign organism is identified by the innate immune system, circulating T-cells begin interacting with foreign antigen. Based on their encounter, they can do one of three things: they can kill infected cells directly, they can boost the actions of macrophages to kill infected cells, or they can return to lymph tissue to incite a B cell response. Stimulated B cells will proceed to produce antibody, which can then circulate to fight the infection.
“Antigen” refers to the parts of a foreign organism recognizable by the adaptive immune system. Typically, these are structural proteins, such as the spike proteins of viruses. Antigens can be huge, and are more often identified by epitopes, or smaller fragments of the folded proteins. As such, a single antigen can be recognized by multiple antigen receptors. Antibody has evolved to recognize a dizzying array of antigen epitopes. Antigen can be picked up by lymphocytes in the lymph tissues (T cells and B cells) or the blood stream (T cells only).
T cell receptors (TCR) recognize antigen fragments (that is digestion products) on the surface of cells, whereas B cell receptors (BCR) bind whole antigen in the extracellular fluid. T cells only “see” antigen when it is presented by MHC (Major Histocompatibility Complex) on the cell surface. Antigen digestion and presentation is one of the major functions of the dendritic cells (circulating monocytes) and macrophages. These are referred to as Antigen-Presenting Cells (APCs).
Naive B-cells express IgD and IgM on their cell surfaces, which bind antigen as it is washed into lymph tissue with the afferent lymph fluid. Antigen is presented to B cells by follicular dendritic cells (FDCs), which are also classed as APCs. FDCs can endocytose antigen directly from the afferent lymph or receive them from CD4+ T-cells.
Cellular response: Proliferation and Differentiation
• T cell response
Once T cells recognize antigen presence in the tissues, they go into action. Their first response is always to recruit help, which is accomplished by returning to the nearest lymph node to carry out clonal expansion. Daughter T cells are created with identical TCRs in order to recognize the identified antigen. These daughter cells are then returned to the circulation via the efferent lymph.
T cells can differentiate three different ways, based on their Cluster of Differentiation (CD) number. All T cells are CD3+, and naive circulating T cells will differentiate upon interaction with antigen to become either CD8+ (cytotoxic) or CD4+ (helper) T cells. CD4+ T-cells will initially become CD4-TH0 cells, and must differentiate to TH1 or TH2 depending on the whim of the adaptive response. TH1 and TH2 cells carry out different types of responses: TH1 is responsible for enhancing the macrophage response, whereas TH2 cells enhance the B cell antibody production. Typically, animals produce a balanced response of TH1 and TH2 cells, though this can lead to pathology, as can a skewed response, depending on the nature of the foreign organism.
• B cell response
Naive B cells recognize antigen in the lymph tissue when it is presented to them by Follicular Dendritic Cells (FDCs). They also undergo clonal expansion, creating a germinal center in the follicle as they develop and mature into plasma cells. Once mature, plasma cells in the lymph node migrate to the medullary cords and begin secreting antibody into the efferent lymph. Antibody eventually reaches the circulation in order to wage war on the intruder.
Tools of the Adaptive Immune System
Antigen Presenting Cells
• Interdigitating Dendritic Cells
◦ Only IDCs can incite a primary response in naive T-cells
• CD4+ Tcells
Antigen Binding Molecules
• T-cell Receptor (TCR)
• Natural Killer (NK) Cells
Adaptive Immunity to Viruses
• Production of neutralizing antibody
• Antibody-dependent cell mediated cytotoxicity (ADCC)
Antibody-labelled cells can be targeted by NK Cells as another defense against viral infection. Antibody produced against viral protein can attach to infected cells during their budding phase, which effectively labels them for NK targeting. NK cells express Fcγ receptors with which to detect such cells. Once activated, they release a host of enzymes to induce apoptosis of the budding cell.
• CD8+ T-cell mediated killing of virus infected cells
◦ Main cells involved in the immune response to intracellular virus infection
◦ Recognition of MHC I-peptide complex
◦ Infected cells are killed by apoptosis
▪ Perforin and granzymes activate the caspase cascade
▪ Fas-ligand triggers the Fas-mediated apoptosis pathway
▪ Cytotoxic cytokines (especially TNF-α & TNF-β lymphotoxin) act on TNF receptors to induce programmed cell death
Adaptive Immunity to Bacteria
• The adaptive and innate responses work together to destroy bacteria
• The adaptive response ensures the innate response is carried out efficiently
• Complement activation of the classical pathway
◦ Production of IgM and IgG makes the complement system more efficient
• Help for macrophages
◦ IgG production (T-helper type II cells and B cells) which improves phagocytosis by opsonisation
◦ Infected macrophages are rescued by T-helper type I cells when phagocytosis and digestion mechanisms fail to eliminate the pathogen
• Complement and phagocytosis
• B cell and T helper type II cell stimulation
• Production of IgM which activates the classical cascade
• Class switching of IgM to IgG which is a good opsonin and targets bacterial Fcγ receptor expressed by macrophages and neutrophils
• The infected macrophage secretes IL-12
• IL-12 stimulates T-helper type I cells which release IFN-γ
• IFN-γ triggers the macrophages to kill the pathogens inside
The Innate Immune System
The innate immune system is the first barrier of defense to infection. It relies on an older, more generic, and faster acting set of tools than the adaptive system. While the adaptive system is essential for a specific response to infection, it is ultimately the innate system that conquers foreign attackers through means of phagocytosis.
Non-specific protective mechanisms include such innate factors as:
• Physical barriers
◦ Ciliated mucous membranes
◦ Commensal organisms
• Humoral factors
• Cellular mechanisms
• Factors which regulate species specificity
◦ Membrane receptors for pathogens
◦ Nutritional requirements
• Mechanisms of innate immunity are always present and generally unchanging
• Adaptive immunity is acquired only on contact with the infectious agent (antigen) and therefore does not function before first contact with the antigen
Actions of the Innate Immune System
Recognition of Microorganisms
• The innate immune system recognizes components of pathogens which are intrinsically foreign, such as:
◦ Lipopolysaccharides of gram-negative bacteria
◦ Peptidoglycans of gram-positive bacteria
◦ Mannose sugars
◦ D-isoform amino acids
• These are given away as foreign by expressing pathogen-associated molecular patterns (PAMPs)
• PAMPs are recognized by pattern recognition receptors (PRRs) expressed on mammalian cells
◦ Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
◦ Not all are expressed by all cells: different cell types express a different range of PRRs
◦ PRRs are either intracellular, membrane-associated or soluble:
▪ Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
▪ Recognition of pathogens via the humoral PRRs results in various killing mechanisms
• Engagement of PRRs by PAMPs triggers:
◦ The expression of cytokines, which brings about inflammation and other immune responses
Examples of Pattern Recognition Receptors
• Phagocytosis is a very primitive system of defense against infection
◦ Even exists in invertebrates
• Phagocytosis is a form of endocytosis (cell eating), it is the method of removal of bacteria and dead cells by vesicular internalization
◦ The internalized vesicle is referred to as the “phagosome”
◦ Lysosomes, which contain a large range of enzymes, fuse with the phagosome, killing the microbes in an energy-dependent way
▪ Oxygen-Dependent degradation utilizes Oxygen and chlorine free-radicals, Hydrogen peroxide, and Nitric oxide
▪ Oxygen-Independent degradation depends on granules containing proteolytic enzymes such as Defensins, Lysozyme, and cationic proteins
▪ In addition, these granules contain antimicrobial elements such as lactoferrin
◦ Microbes are then digested by a number of different catabolic enzymes
▪ Glycosidases: Digest carbohydrates
▪ Lipases: Digest lipids
▪ Proteases: Digest protein
◦ Waste products of phagocytosis are either exocytosed or further degraded by the phagocyte
• Neutrophils and macrophages are phagocytic
• Opsonins promote and accelerate phagocytosis
• Phagocytic cells target pathogens by using cell membrane receptors (PRRs) that recognize intrinsically foreign components of microorganisms (pathogen-associated molecular patterns; PAMPs)
Tools of Innate Immunity
The simplest way to avoid infection is to prevent microorganisms gaining access to the body. The skin has an external coating of dead cells (cuticle) that, when intact, is impermeable to most infectious agents.
• Very few pathogens are capable of penetrating the thick stratified squamous epithelium of the skin.
◦ Infection becomes a problem when there is:
▪ Skin loss: e.g. burns
▪ A break in the skin: e.g. wounds
2. Mucus Membranes
• Thin epithelial surfaces are necessary for the normal physiological functions of the body’s mucus membranes (ie absorption and gas exchange).They are therefore more susceptible to infection
◦ The body uses alternative protective mechanisms in these areas:
▪ The mucociliary escalator of the respiratory tract (assisted by coughing and sneezing)
▪ Peristalsis, vomiting & diarrhea when necessary removes microorganisms from the GIT
• Lactic and fatty acids in sweat and sebaceous secretions are directly bacteriocidal
• Enzymes e.g. lysozyme in saliva, sweat & tears and Gastric acid denature microorganisms
• Mucus itself is acidic, indigestible and traps microorganisms
• Out-compete pathogens at mucosal and epithelial surfaces and produce natural antibiotics
• When commensals are disturbed, infection with opportunistic organisms is increased
• Lysozyme is one of the major bactericidal agents in secretions
• Helps to protect vulnerable sites such as the eyes and nasal passages
• Exerts bactericidal effects by digesting bacterial cell walls
◦ Gram-positive bacteria are more sensitive to lysozyme action than gram-negative bacteria
◦ The outer membrane of gram-negative bacteria helps to protect them
• The Complement system is a group of about 30 proteins within the body fluids of all vertebrates and some invertebrates
• Complement promotes phagocytosis or causes lysis of an invading organism
• Complement acts as a cascade, like the blood clotting system
◦ The early enzymes in the cascade are bound to invading bacteria and fungi
▪ They have an affinity for components of microbial cell membranes
◦ This binding initiates a cascade so that the binding of one molecule will eventually lead to the fixation of millions of later molecules
• The early components act as targets for phagocytes
• The later components punch holes in bacteria, causing their lysis
• Lysozyme and complement have only marginal effects on virus infections because these are intracellular
◦ The body has evolved non-specific mechanisms to protect against viruses
▪ The most notable of these is the interferons
• Interferons are small polypeptides produced mainly by virus-infected cells
◦ Interact with uninfected cells and render them resistant to infection
▪ This resistance is mainly due to the production of enzymes that digest viral nucleic acids
• If pathogens breach the barriers formed by the skin and mucus membranes, they must be detected and destroyed by cellular and humoral means
• The cells involved with innate protection are:
◦ Blood granulocytes, or Polymorphonuclear Cells
▪ Notable for their multi-lobed nuclei
▪ Neutrophils: phagocytose bacteria
▪ Eosinophils: kill parasites by the release of granules
▪ Basophils / mast cells: kill parasites by the release of granules
◦ Blood monocytes: phagocytose bacteria
◦ Tissue mast cells and macrophages: phagocytose bacteria
• Effectively, innate cellular response seeks to hold off the infection until the adaptive response can back it up with a more specific attack
• The role of macrophages in Innate Immunity is to act as primary phagocytes
• Macrophages are present within tissues and take the form of distinct, tissue-specific populations:
◦ Alveolar macrophages
◦ Tissue histiocytes
◦ Glomerular macrophages
◦ Hepatic Küpffer cells
◦ CNS microglia
◦ Sinus-lining macrophages of the lymph nodes and spleen
• Monocytes (immature macrophages) are circulating phagocytes
◦ Circulate for 6-8 hours
◦ Can function as phagocytes within the blood and as newly migrated cells in tissues
◦ Chiefly function to replace the various tissue macrophage populations
• Neutrophils are the principal, highly active phagocytes in the blood
◦ Comprise 30-70% of white blood cells depending on species
◦ Kill and digest microbes in a similar way as macrophages
• Neutrophils can also cause extracellular bacterial killing by disrupting bacterial membranes
◦ Secrete small antibacterial peptides
▪ E.g. defensins and bactenecins
• Neutrophils produce vasoactive peptides
◦ E.g. histamine and bradykinin
◦ Cause a great increase in extravasation of blood granulocytes and monocytes and plasma proteins at the site of infection
• Neutrophils are the archetypal cell associated with acute inflammation
◦ Are attracted to sites of inflammation by:
▪ Complement activation
▪ Cytokine production
▪ Changes to vascular endothelium
◦ Neutrophil activation in an inflammatory lesion results in the release of prostaglandins
▪ Responsible for vasoactive changes and for pain
• The accumulation of dead and dying neutrophils at the site of infection is called pus
◦ Their removal from the site after the removal of infection is an important step in the resolution of the lesion
• Eosinophils are less common than neutrophils, and they are not phagocytic
◦ Make up <5% of the leukocytes in normal blood
• Eosinophil numbers are increased:
◦ Slightly during the resolution phase of inflammation
◦ Many-fold in parasite-infected animals
▪ The presence of a large proportion of eosinophils in a blood smear is highly indicative of parasitemia
• Mainly function by targeting the surface of parasites by means of specific antibody or complement
◦ Release a large range of toxic molecules that break down the parasite integument
• Prominent in allergic (anaphylactic) reactions
Basophils / Mast Cells
• Basophils/mast cells are principally localized at epithelial surfaces
◦ Very small numbers are present in blood
▪ Less than 0.5% circulating leukocytes
• They have two principal functions:
1 Induction of acute inflammation
▪ Trauma and/ or bacterial infection causes the production of cytokines by the mast cells that induce a classical acute inflammatory response
2 Response to parasite infection
▪ Specific IgE binds cells
▪ Subsequent contact with antigen causes the mast cells to degranulate
▪ Release enzymes and vasoactive substances that can result in a high level of mucus secretion and smooth muscle contraction
• Also produce factors that influence local host cell physiology
◦ Various mediators increase the ratio of phagocyte to microbe
Innate Immunity to Viruses
Because viruses invade host cells to take over a host’s cellular machinery, the innate system has a more difficult time detecting viruses as foreign agents. However, there is a give-away element of the viral attack that the innate system can recognize: the double-stranded RNA (dsRNA) produced by a virus in its replication phase. Because mammalian cells only ever produce single-stranded RNA, the presence of dsRNA signals a foreign intruder. dsRNA can be detected by TLR-3R on the cell surface or intracellularly by the presence of dsRNA-dependent protein kinase.
The innate response to viral attack also depends on the presence of Type-1 Interferons, which are produced by all cells on recognition of a viral attack. Interferons serve to increase degradation of mRNA, inhibit protein synthesis, and increase the effectiveness of the adaptive response by increasing antigen presentation to antibody.
Lastly, the final line of defense for the innate response to viruses lies in the actions of Natural Killer (NK) cells]]. These warriors monitor the production of MHC (Major Histocompatibility Complex) on the surface of cells, which is produced as part of the adaptive response. A cell whose cellular machinery is compromised by viral infection will experience a drop in the amount of MHC it produces. When a cell’s MHC production drops, NK cells are triggered to phagocytose these cells. As such, this is a non-specific targeting based simply on the ability of a cell to function normally, which also lends them to playing a role in targeting malignant cells. NK cells are incapable of directly targeting viral infection.
Innate Immunity to Bacteria
The innate response to bacterial infection lies in its first-response role of detection of a foreign organism. By using the above described tools of Pattern-Recognition Receptors (PRRs), the innate response flags up problems while the adaptive response gets itself organized. Once a foreign organism is detected, the innate system responds by engaging in cell warfare via phagocytosis and triggering the inflammatory response. The release of inflammatory cytokines will cause an increase in vasodilation, vascular permeability and an influx of white blood cells. Neutrophils take on their primary role as phagocytes in this phase. In addition, systemic effects of inflammatory cytokines will sustain a rise in core temperature (fever), the release of acute phase proteins from the liver, and bone marrow mobilization as the need for white blood cells production is increased. Acute phase proteins will bind to bacterial cell walls, enhancing neutrophil, macrophage, and complement-initiated phagocytosis.
According to Dr. Andrew Weil, Chronic Inflammation is a disease. The system has gotten hung up, and instead of protecting the organism (our bodies) it starts to kill the organism, slowly but surely. Today modern medicine is starting to admit that chronic inflammation is the MAIN contributing factor to all chronic degenerative diseases and the real cause of the two greatest killers in America: Cancer and Heart Disease. Indeed, chronic inflammation might just be the real cause of all degenerative disease.
Chronic Inflammation depresses the immune system and helps promote the formation of cancerous tumors. The longer inflammation persists, the higher risk of associated carcinogenesis.
Chronic inflammation destroys nerve cells in the brains, a primary cause of Alzheimers
It is the real source of all autoimmune disorders with over 100 named conditions.
The chronic inflammation, misused or misread signaling pathways, and improper growth factors and apoptosis, creates the “perfect storm” for degenerative disease.
1. The Cancer Research Institute states that “Chronic Inflammation plays a multifaceted role in carcinogenesis”
2. Center for Disease Control and Prevention 2011 states “of the ten leading causes of mortality in the United States, Chronic low level inflammation contribute to the pathogenesis of at least seven. [heart disease/cancer/Chronic lower respiratory disease/stroke/Alzheimer/diabetes/nephritis]. Their findings conclude that Chronic Inflammation to be a major factor in the development of degenerative disease and loss of youthful functions — Aging—
3. Symptoms from Chronic Fatigue Syndrome, Epstein Barre and other conditions go undiagnosed and ignored because of lack of medical understanding of the destructive power of Chronic Inflammation.
4. Chronic Inflammation, allowed to persist, leads to deregulation, altered, and distorted cell communication and specific growth and survival—related pathways. This results in:
• Aberrant IFN expression is associated with a large number of auto-inflammatory, autoimmune diseases.
• Disrupted JAK-STAT functionality can result in immune deficiency syndromes and cancers
• Errors in cellular information processing are responsible for diseases such as cancer, autoimmunity and diabetes.
• When you combine Chronic Inflammation, misread and distorted signaling pathways, as well as overgrowth and deregulated apoptosis, you get cancer that is immortalized and degenerative conditions that are unalterable.
Cytokines are small proteins that are essential for cell signaling and communication. They are released by cells and effect the behavior of other cells. They modulate the balance between immune responses.
• Tumor necrosis factor (TNF)
Primary & Signaling Pathways – JAK STAT (Janus Kinase Signal Transducer and Activator of Transcription) signaling pathway transmits information from chemical signals outside a cell (Cytokines), through the cell membrane to the DNA & mRNA transcription in the activity in a cell nucleus. This is called Transduction and is a major actuator of on/off switching of proteins. Since JAK-STAT signaling pathways are expressed through white blood cells (source of all immune cellular activity). They are central & crucial to regulation of the immune system.
Secondary Message System
• cAMP — cyclic adenosine monophosphate
• cGMP — cyclic guanosine monophosphate
• Calcium signaling
• Mitochondrion – is the powerhouse within the cell producing, ATP (Adenosine triphosphate) the energy currency of all cell activity.