Wiki Words
The immune system protects individuals from infectious pathogens through two main mechanisms:
Biochemistry Overview
The immune system protects individuals from infectious pathogens through two main mechanisms: innate immunity and adaptive immunity. The biochemical features of innate immunity are the activation of phagocytic cells (neutrophils and macrophages) through transcription factors, cytokines, acute phase proteins, interferons, natural killer cells (NKs), mast cells and basophils, eosinophils, and the complement system. Of adaptive immunity, there are two types, the cell-mediated defense against intracellular microbes (viruses) with T lymphocytes and cytokines, and humoral immunity which protects against extracellular microbes (bacteria) using B lymphocytes and their secreted antibodies.
Innate immunity
Often referred to as the acute phase response, the innate immune system are cells and highly conserved protein domains that are present in all humans from birth. Below are some of the major players involved as first responders for the immune system.
Dendritic Cells in the epidermis (Langerhans cells) are involved in the activation of a delayed-type hypersensitivity response. They serve as antigen-presenting cells, binding with foreign antigens and migrating to lymph nodes where they present the antigen to T cells. The antigen capture is accomplished through phagocytosis (cell eating) and pinocytosis (cell drinking). The dendritic cells then leave the peripheral tissue, travel to lymph nodes via lymph vessels, and upregulate expression of Class II MHC molecules (discussed in detail later) so that they may signal T helper cells to proliferate.
Toll-like Receptors (TLR) are transmembrane proteins with a structural motif of repeating leucines (LRR) which are their ligand binding region. TLRs detect the molecular motifs of common pathogens such as the lipopolysaccharide coat of bacteria, zymosan polysaccharides of fungus, and single/double stranded RNA of certain viruses. The primary response cells of the innate immune system, neutrophils, monocytes, and macrophages bear TLRs, and when a pathogen is recognized, subsequent signaling triggers an engulfing response, and the invader will then either be hydrolyzed or processed for presentation on the cell surface. The graphic below shows the simple protein structure of the hook-like TLR anchored into the cell membrane by the TIR domain.
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Transcription Factors are involved in all cellular machinery, anytime a functional product is required in the cell, transcription factors access the DNA and turn on/off transcription of an mRNA product. The immune system bears many such pathways, but one of particular note is the NF-kB pathway, the main TLR signal transduction pathway. Used often by the innate immune system, NF-kB pathway stimulates microbicidal cytokines which may contribute to local inflammation, leukocyte recruitment, and increased phagocytic activity. Another signaling pathway common to the innate immune system is the MAPk (mitogen-activated protein kinase) cascade. A representative schematic is shown below that shows TNF-alpha, a common immunostimulating cytokine, being produced in response to a Staph aureus bacterium. TNF-alpha is capable of inducing apoptosis in infected cells, stimulating inflammation to bring more white cells to an infected area, it can also inhibit tumor growth and viral replication.
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Complement- Classic, Alternative, and Lectin pathways all activate the membrane attack complex (MAC) and lead to osmotic lysis of the cell. The classic pathway proceeds when IgG and IgM antibodies bound to an antigen trigger the CH2/3 domains and activate C1, leading to C3. The lectin pathway occurs when mannan-binding lectin (MBL) binds to serine proteases, which is similar structurally to C1, leading to C3. The alternative pathway is activated when a microbial surface gets coated with C3b (as they lack the regulatory apparatus of eukaryotic cells to inactivate such proteins) and when they bind with factor B, it creates, again, a C3 convertase.
C3 convertase is the lynch pin that triggers the varied functions of the complement system, the cell lysis by MAC, the inflammation by degranulation of mast cells and basophils, chemotaxis of neutrophils, the opsonization by phagocytes that have C3b receptors and will eat things coated in C3b, and finally the solubilization of immune complexes that may precipitate, they are cleared to the spleen. The diagram below shows the complexity of the protein binding involved to destroy a pathogen through this innate molecular reflex response.
C-reactive protein belongs to a family of pentameric proteins, the pentraxins which look structurally like a flower (below), and responds to an increase in IL-2 in the blood (inflammation). CRP binds to phosphorylcholine on microbes and marks them for phagocytosis. In this way, it brings pathogens into the complement-mediated attack. It is a common clinical measurement of acute inflammation (often as a result of infection, but oftentimes as a cardiovascular barometer, and it is also associated with an increase in some types of cancer (colon)).
Adaptive immunity
Adaptive immunity is more commonly referred to as the secondary response of the immune system. It is faster, more specific, and more complicated genetically and biochemically than the innate immune mechanisms. There are two divisions of the adaptive immune response, the humoral response which refers to the secretion of antigen specific immunoglobulin antibodies from plasma cells, and the cell-mediated response, which refers to a complicated dance between T helper cells and B cells as they collaborate to activate a B cell response. Both processes involve a myriad of ligand/receptor interactions, co-stimulatory systems, signal transduction to the nucleus to elicit cytokine release, and the alteration of DNA through somatic hypermutation and gene rearrangement to achieve specificity. An overview of these processes is summarized below.
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Cell-Mediated Immunity
T lymphocytes from thymus. Each T cell is genetically programmed to recognize a specific cell-bound antigen with its T-cell receptor.
The antigen-presenting cells display the antigen on the major histocompatibility complex (MHC). So that this immune response does not depend on a hair-trigger, two signals are actually required for activation. There are several T-cell membrane-associated glycoproteins that serve as co-receptors in T-cell activation. For the antigen to present, CD4 molecules bind to class II MHC molecules and CD8 bind to class I MHC molecules. In addition, the second signal required is the interaction of CD80/86 on the antigen-presenting cell with CD28 on the T cell. As soon as all of the pieces are connected, cytokines (interleukin-2, etc) are released and the antigen-specific T cell proliferates to go out and bind with other cells that have processed an alert signal (antigen) that says they have been invaded by a pathogen.
MHC molecules, Class I, II.
There is incredible diversity among major histocompatibility complex (MHC) genes, also known as human leukocyte antigens (HLA), with hundreds of alleles and polymorphic loci. This contributes uniquely to allow recognition of "self" (but also makes it challenging for those in need of transplantation). MHC alleles are codominant, both are expressed, and are often referred to as "haplotypes."
MHC I and II are both transmembrane glycoproteins. MHC Class I is expressed by all nucleated cells, creates a binding cleft with two domains of a heavy alpha chain and a noncovalently bonded beta-microglobulin component. The peptide it presents comes from the cytosol of the presenting cell itself, and then MHC I exclusively binds with CD8+, cytotoxic T cells (tumor suppressor cells), which then lyse the 'sick cells' by similar mechanisms as NK cells. MHC Class II shows up most typically in B cells, macrophages, epithelial cells of the thymus, or on activated T cells. It is a bit larger than the Class I MHC, it has similar heavy chains to the Ig constant domain, and its binding cleft is formed with alpha and beta domains that are a bit further apart. Class II complexes present peptides that are extracellular pathogens or antigens within vesicles. MHC Class II is the antigen presentation context necessary for CD4+, helper T cells, to recognize and then respond with cytokine release or proliferation.
There are genes that encode Class III region, but the products from this region are not HLA complexes. From the Class III region complement proteins are made (without which systemic lupus erthymatosis has been observed), tumor necrosis factor (TNF) and heat shock proteins, which aid in regulating inflammatory rheumatoid arthritis.
Humoral Immunity
B cells come from bone marrow. They recognize extracellular antigen through the B cell receptor complex, IgM and IgD. The B cell also has antigen specificity from somatic rearrangement of its B cell receptor. After it binds an antigen in the germinal center of a secondary lymph nodule, the B cell is stimulated to release immunoglobulins, IgG, IgA, and IgE antibodies (structures below). A more detailed discussion of this process is outlined in the Selected Clinical Case section under B cell Biochemistry.
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Follicular dendritic cells also have a role in the humoral response as they have Fc receptors for IgG, for C3b, and can trap antigen bound to antibodies. They can present antigens to B cells and aid T helper cells in selecting and releasing into circulation the B cells that have the highest affinity.
Effector Phases of Immune Response
Macrophages
Opsonization (humoral) is a promotion of phagocytosis of antigens by macrophages and neutrophils and is made possible by the presence of Fc receptors on the cell surfaces. When antibodies complex on invading antigens and their Fc tails are pointing out in all directions, they can cross-link with the FcR that initiates a signal pathway to phagocytize the whole antigen-antibody complex. Inside the macrophage, the pathogen is digested by enzymes and oxidative damage.
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