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The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime.
However, it can be recruited and brought into action by the adaptive immune system.The complement system consists of a number of small proteins found in the blood, in general synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).
When stimulated by one of several triggers, proteases in the system cleave specific proteins to release cytokines and initiate an amplifying cascade of further cleavages. The end-result of this activation cascade is massive amplification of the response and activation of the cell-killing membrane attack complex.
Over 25 proteins and protein fragments make up the complement system, including serum proteins, serosal proteins, and cell membrane receptors. They account for about 5% of the globulin fraction of blood serum and can serve as opsonins.
Endocytosis is an energy-using process by which cells absorb molecules (such as proteins) by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane.
The binding of macrophage receptors to their microbial ligands initiates the process called receptor-mediated endocytosis, in which the receptor-bound pathogen is surrounded by the macrophage membrane and internalized into a membrane-bounded vesicles called an endosome or phagosome.
Phagosome is a vesicle formed around a particle absorbed by phagocytosis. The vacuole is formed by the fusion of the cell membrane around the particle. A phagosome is a cellular compartment in which pathogenic microorganisms can be killed and digested. Phagosomes fuse with lysosomes in their maturation process, forming phagolysosomes.Some bacterial pathogens that enter cells inside phagosomes either reproduce inside of the formed phagolysosome or escape into the cytoplasm before the phagosome fuses with the lysosome.Many mycobacteria, including Mycobacterium tuberculosis and Mycobacteria avium paratuberculosis , manipulate the host macrophage to prevent nitrous acid-containing lysosomes from fusing with phagosomes and creating mature phagolysosomes. Such incomplete maturation of the phagosome maintains an environment favorable to the pathogens inside it.
Phagosomes that fused with cellular organelles called lysosome is called phagolysosomes, vesicle that are loaded with degradative enzyme and toxic substances that destroy the pathogen.
The process of facilitation of phagocytosis by coating of protein is called opsonization.
Opsonization is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively charged molecules on the membrane. Molecules that activate the complement system are also considered opsonins.
Both the membrane of a phagocytosing cell and its target have a negative charge (zeta-potential), making it difficult for the two cells to come close together. Once the opsonins attach to the target, the negative charge is masked. Take note that the negative charge of the target doesn't disappear. The opsonin simply overrides the charge, making it easier for white blood cells (phagocytic cells) to carry out phagocytosis.
chemokines are messegers that direct the flow of leukocyte traffic; they differ in the type of cell or tissue that makes the and in the type of cell they attract.
Some chemokines, including CXCL8, attract leukocytes into the sites of tissue damage or infection. Others direct the traffic of leukocytes during their development and during recirculation through lymphoid tissue.
Cells are attracted from the blood into infected tissue by following the concentration gradient of chemokine produced by the cells within the infected site.
The principal function of CXCL8, a CXC chemokine, it to recruit neutrophils from the blood into the infected area.
Chemotaxis is chemically prompted taxis, in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food (for example, glucose) by swimming towards the highest concentration of food molecules, or to flee from poisons (for example, phenol).
Positive chemotaxis occurs if the movement is toward a higher concentration of the chemical in question. Conversely, negative chemotaxis occurs if the movement is in the opposite direction.
Neutrophils is a phagocytic cell. They are short lived dedicated killer is the blood awaiting a call from the macrophage to enter infected tissue.
Neutroophils are a type of granulocyte, having numerous granules in the cytoplasm. They are the most abundant white blood cell, a healthy adult having some 50 billion in circulation at any time.
They have a a short lifespan, less than 2 days, it means that 60% of the hematopoietic activity of the bone marrow is devoted to neutrophil production. Mature neutrohils are kept in the bone marrow for about 5 days before being released to the circulation.
The cleavage of C3 and C5 produces two small fragments:C3a and C5a. These bind to receptors on several cells to produce inflammation at the site of infection.
Inflammatory response or inflammation is a result of the innate immune response. In rare occasions, these molecules spread throughout the body and produce systemic inflammatory response called as anaphylactic shock. These peptides are therefore called anaphylatoxins. They bind to phagocytes, endothelial cells, mast cells. By binding to receptors on these cell types they produce, contraction of smooth muscles and release of histamine from mast cells and basophils, resulting in enhanced capillary permeability.
C3a and C5a also bind to local blood vessels. Thechanges results in passage of cells and plasma proteins to extracellular spaces leading to swelling and redness.
Defensins are peptides of 35-40 amino acids in length with antimicrobial properties. They are of two types: a-defensins and b-defensins. The defensins have both Hydrophobic and hydrophilic surfaces, a property used to penetrate microbial surface membranes and disrupt membrane integrity. Bacteria, fungi and enveloped viruses are destroyed by defensis by this mechanism
The a-defensins are secreted by neutrophils and the specialized epithelial cells of the intestine (Paneth cells).
b-defensins are secreted by epithelial cells of urogenital tract, skin and the respiratory tract. The defensins are activated in the acidic pH of gut, tears and sweat.
Cytokines are a broad and loose category of small proteins that are important in cell signaling. They are released by cells and affect the behavior of other cells, and sometimes the releasing cell itself.
Cytokines include chemokines, interferons, interleukins, lymphokines, tumour necrosis factor but not generally not hormones or growth factors.
Cytokines are produced by broad range of cells, including immune cells like macrophages, B lymphocytes and T lymphocytes, mast cells, as well as endothelial cells, fibroblasts, and various stromal cells; a given cytokine may be produced by more than one type of cell.
They act through receptors, and are especially important in the immune system; cytokines modulate the balance between humoral and cell-based immune responses, and they regulate the maturation, growth, and responsiveness of particular cell populations. Some cytokines enhance or inhibit the action of other cytokines in complex ways.
cytokines that induce innate immune responses and inflammation at the site of infection are known as inflammatory cytokines.
Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens such as viruses, bacteria, parasites or tumor cells. They allow for communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.
IFNs belong to the large class of glycoproteins known as cytokines. Interferons are named after their ability to "interfere" with viral replication within host cells. IFNs have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase recognition of infection or tumor cells by up-regulating antigen presentation to T lymphocytes; and they increase the ability of uninfected host cells to resist new infection by virus. Certain symptoms, such as aching muscles and fever, are related to the production of IFNs during infection.About ten distinct IFNs have been identified in mammals; seven of these have been described for humans.
They are typically divided among three IFN classes: Type I IFN, Type II IFN, and Type III IFN. IFNs belonging to all IFN classes are very important for fighting viral infections.
All interferons share several common effects; they are antiviral agents and can fight tumors. As an infected cell dies from a cytolytic virus, viral particles are released that can infect nearby cells. However, the infected cell can warn neighboring cells of a viral presence by releasing interferon. The neighboring cells, in response to interferon, produce large amounts of an enzyme known as protein kinase R (PKR). This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. Another cellular enzyme, RNAse L—also induced following PKR activation—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. Inhibited protein synthesis destroys both the virus and infected host cells.
NK (Natural Killer ) lymphocyte
The cytokine IL-12 serves to activate a class of lymphocyte called NK lymphocyte, which enters infected sites soon after the infection. NK cells are lymphocyte of innate immunity that specialized in defense against viral infection.
Toll-like receptors (TLRs) recognize pathogen derived products and transmit signals to contain infection. There are ten types of TLRs expressed in various cell types.
They are transmembrane proteins. The extracellular domain recognizes the pathogen and the intracellular domain transmits the signal to initiate signaling pathways in the cytoplasm.
These pathways translocate the transcription factor nuclear factor k B (NFkB) to the nucleus,resulting in synthesis and secretion of cytokines.
Depending on the type of infection, bacteria (extracellularor intracellular) or virus, different cytokines are producedby the activation of TLRs. Thus, inflammatory cytokine production and release into extracellular spaces controls extracellular bacteria whereas interferon production eliminates virus infection.
Macrophage initiated inflammation
Macrophage activation through the TLRs induces cytokine secretion. These cytokines recruit effector cells such as neutrophils and natural killer cells (NK cells) and cause inflammation.
Cytokines act on local blood capillaries and cause increase in diameter of blood vessels (vasodilation), decrease in blood flow and increased permeability of blood vessels. This results in increased movement of plasma and blood cells to the tissue surrounding the infection causing fluid retention, swelling, reddening and pain.
The macrophages release cytokines:IL-1, IL-6CXCL8, IL-12 and tumor necrosis factor-a (TNF-a). The cytokine CXCL8 is also called as chemokine as it attracts leukocytes into sites of tissue damage or infection.
Chemokine CXCL8 attracts neutrophils from the circulating blood to the pathogen infected tissue. Neutrophils express two receptors CXCR1 and CXCR2 which bind to the ligand CXCL8, altering the adhesive property of the neutrophils and causing the cells to migrate toward the site of infection along a gradient of chemokine.
An epitope, also known as antigenic determinant, is the part of an antigen that is recognized by the immune system, specifically by antibodies, B cells, or T cells. The part of an antibody that recognizes the epitope is called a paratope. Although epitopes are usually non-self proteins, sequences derived from the host that can be recognized are also epitopes.
The epitopes of protein antigens are divided into two categories, conformational epitopes and linear epitopes, based on their structure and interaction with the paratope. A conformational epitope is composed of discontinuous sections of the antigen's amino acid sequence. These epitopes interact with the paratope based on the 3-D surface features and shape or tertiary structure of the antigen. The proportion of epitopes that are conformational is unknown. By contrast, linear epitopes interact with the paratope based on their primary structure. A linear epitope is formed by a continuous sequence of amino acids from the antigen.
Major Histocompatibility Complex - Antigen processed and to be presented are carried to the cell surfaced by binding to the glycoproteins call MHC molecules.
Each MHC molecule binds to one peptide and carries itto the surface of the cell. The circulating T cells recognize these peptides. The MHC proteins are transcribed from stable genes without rearrangement as in T Cell receptor genes or immunoglobulin genes. There are several gene families coding the MHC proteins.The heterogeneity of MHC proteins is achieved by genetic polymorphisms within the population
MHC Class 1
MHC Class I Molecules present intracellular pathogens. These pathogens live inside cells and replicate in the cells. (Example: Virus). The CytotoxicT cells recognize these antigens.
MHC Class 2
MHC Class 2 presents pathogens that are extracellular (living and replicating in the spaces between cells) are processed and presented by Class 2 MHC molecules.The T helper cells recognize these antigens
Antigen processing enzyme.
In the normal tissue,enzymes of the proteasome complex degrade proteins that are damaged or misfolded.
In cells infected with pathogens, proteasome complex enzymes are modified to process proteins of pathogen origin into small peptides.
These peptides are delivered to the endoplasmic reticulum with the help of a protein (Transporter associated with antigen processing or TAP). The MHC1 molecules bind to the peptides in the endoplasmic reticulum. The subunits of MHC1 bind with peptides and complete the protein folding. MHC1 bound with peptides are transported to the cell membrane.
Transporter associated with antigen processing (TAP) delivers cytosolic peptides into the endoplasmic reticulum (ER), where they bind to MHC class I molecules.
Expression of MHC class 1 and MHC class 2 molecules.
MHC class 1 molecules are expressed by all cells of the body, except the red blood cells. As all cells are prone to infection by intracellular pathogens, expressionof MHC class 1 molecules makes the infected cells to be attacked and destroyed by CD8 T cells.
MHC class 2 molecules are primarily expressed on antigen processing cells such as dendritic cells and macrophages, activated T cells, thymic epithelial cells and B cells.
Constitutive expression of MHC class 1 and 2 are elevated during the course of an immune reaction. The increase in expression enhances immunes response. The cytokine interferon gamma(IFN-g) induces MHC class 2 expression on cells that do not normally express it.
Cell-adhesion molecules are involved in lymphocyte interactions. The main classes are: selectins, integrins ,members of immunoglobulin superfamily and mucin-like molecules.
Adhesion molecules are involved in interactions between naïve T cells and antigen presenting cells (APCs), interactions between effector T cells and their target cells ,entry of monocytes and leukocytes into tissues and T-cell and B-cell interactions.
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