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INFEPERIUMâ„¢

A breakthrough Immunotherapy and why it is different!

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Innate and Acquired Immune Systems

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 Recognition
"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
    â€¢    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
    â€¢    Macrophages
    â€¢    Interdigitating Dendritic Cells
    â—¦    Only IDCs can incite a primary response in naive T-cells
    â€¢    CD4+ Tcells
    â€¢    B-cells
Antigen Binding Molecules
    â€¢    Immunoglobulins
    â€¢    T-cell Receptor (TCR)
    â€¢    Natural Killer (NK) Cells


Adaptive Immunity to Viruses
Humoral
    â€¢    Production of neutralizing antibody
    â€¢    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.

Cell-Mediated
    â€¢    CD8+ T-cell mediated killing of virus infected cells
    â—¦    Main cells involved in the immune response to intracellular virus infection
    â—¦    Recognition of MHC I-peptide complex
    â—¦    Infected cells are killed by apoptosis
    â–ª    Perforin and granzymes activate the caspase cascade
    â–ª    Fas-ligand triggers the Fas-mediated apoptosis pathway
    â–ª    Cytotoxic cytokines (especially TNF-α & TNF-β lymphotoxin) act on TNF receptors to induce programmed cell death


Adaptive Immunity to Bacteria
    â€¢    The adaptive and innate responses work together to destroy bacteria
    â€¢    The adaptive response ensures the innate response is carried out efficiently
Humoral
    â€¢    Complement activation of the classical pathway
    â—¦    Production of IgM and IgG makes the complement system more efficient
Cell-Mediated
    â€¢    Help for macrophages
    â—¦    IgG production (T-helper type II cells and B cells) which improves phagocytosis by opsonisation
    â—¦    Infected macrophages are rescued by T-helper type I cells when phagocytosis and digestion mechanisms fail to eliminate the pathogen

Extracellular Infection
    â€¢    Complement and phagocytosis
    â€¢    B cell and T helper type II cell stimulation
    â€¢    Production of IgM which activates the classical cascade
    â€¢    Class switching of IgM to IgG which is a good opsonin and targets bacterial Fcγ receptor expressed by macrophages and neutrophils

Vesicular Infection
    â€¢    The infected macrophage secretes IL-12
    â€¢    IL-12 stimulates T-helper type I cells which release IFN-γ
    â€¢    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
    â—¦    Skin
    â—¦    Ciliated mucous membranes
    â—¦    Commensal organisms
    •    Humoral factors
    â—¦    Lysozyme
    â—¦    Complement
    â—¦    Interferons
    •    Cellular mechanisms
    â—¦    Phagocytosis
    •    Factors which regulate species specificity
    â—¦    Membrane receptors for pathogens
    â—¦    Nutritional requirements
    â—¦    Temperature
    â—¦    pH
    •    Mechanisms of innate immunity are always present and generally unchanging
    â€¢    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
    â€¢    The innate immune system recognizes components of pathogens which are intrinsically foreign (i.e. not present on normal mammalian cells), such as:
    â—¦    Lipopolysaccharides of gram-negative bacteria
    â—¦    Peptidoglycans of gram-positive bacteria
    â—¦    Mannose sugars
    â—¦    D-isoform amino acids
    â€¢    These are given away as foreign by expressing pathogen-associated molecular patterns (PAMPs)
    â€¢    PAMPs are recognized by pattern recognition receptors (PRRs) expressed on mammalian cells
    â—¦    Pattern recognition receptors are expressed on many different cell types, not just on phagocytes
    â—¦    Not all are expressed by all cells: different cell types express a different range of PRRs
    â—¦    PRRs are either intracellular, membrane-associated or soluble:
    â–ª    Recognition of pathogens via the cellular PRRs results in phagocytosis and inflammation
    â–ª    Recognition of pathogens via the humoral PRRs results in various killing mechanisms
    â€¢    Engagement of PRRs by PAMPs triggers:
    â—¦    Phagocytosis
    â—¦    The expression of cytokines, which brings about inflammation and other immune responses.

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