An introduction to immunology and immunopathology – Allergy, Asthma & Clinical Immunology

The immune system refers to a collection of cells, chemicals and processes that function to protect the skin, respiratory passages, intestinal nerve pathway and early areas from alien antigens, such as microbes ( organisms such as bacteria, fungi, and parasites ), viruses, cancer cells, and toxins. Beyond, the structural and chemical barriers which protect us from infection, the immune system can be simplistically viewed as having two “ lines of defense ” : unconditioned immunity and adaptive immunity. Innate exemption represents the first channel of defense to an intrude pathogen. It is an antigen-independent ( non-specific ) refutation mechanism that is used by the server immediately or within hours of encountering an antigen. The natural immune answer has no immunological memory and, consequently, it is unable to recognize or “ memorize ” the same pathogen should the body be exposed to it in the future. adaptive unsusceptibility, on the early hand, is antigen-dependent and antigen-specific and, consequently, involves a lag time between exposure to the antigen and maximal response. The authentication of adaptive unsusceptibility is the capacity for memory which enables the horde to mount a more rapid and effective immune answer upon subsequent exposure to the antigen. Innate and adaptive unsusceptibility are not mutually exclusive mechanisms of host defense mechanism, but preferably are complementary, with defects in either system resulting in host vulnerability or inappropriate responses [ 1, 2, 3 ] .

Innate immunity

Innate exemption can be viewed as comprising four types of defensive barriers : anatomic ( clamber and mucous membrane ), physiologic ( temperature, low ph and chemical mediators ), endocytic and phagocytic, and inflammatory. postpone 1 summarizes the non-specific host-defense mechanisms for each of these barriers. Cells and processes that are critical for effective unconditioned exemption to pathogens that evade the anatomic barriers have been widely studied. Innate immunity to pathogens relies on blueprint recognition receptors ( PRRs ) which allow a limited range of immune cells to detect and respond quickly to a wide range of pathogens that share common structures, known as pathogen associated molecular patterns ( PAMPs ). Examples of these include bacterial cell wall components such as lipopolysaccharides ( LPS ) and double-stranded ribonucleic acidic ( RNA ) produced during viral infection .Table 1 Summary of non-specific host-defense mechanisms for barriers of innate immunity [1] Full size postpone An crucial affair of unconditioned immunity is the rapid recruitment of immune cells to sites of infection and ignition through the production of cytokines and chemokines ( little proteins involved in cell–cell communication and recruitment ). cytokine output during unconditioned unsusceptibility mobilizes many defense mechanisms throughout the consistency while besides activating local anesthetic cellular responses to infection or wound. Key inflammatory cytokines released during the early response to bacterial infection are : tumor necrosis factor ( TNF ), interleukin 1 ( IL-1 ) and interleukin 6 ( IL-6 ). These cytokines are critical for initiating cell recruitment and the local inflammation which is essential for clearance of many pathogens. They besides contribute to the development of fever. Dysregulated output of such incendiary cytokines is much associated with inflammatory or autoimmune disease, making them significant therapeutic targets.

The complement system is a biochemical cascade that functions to identify and opsonize ( coating ) bacteria and early pathogens. It renders pathogens susceptible to phagocytosis, a procedure by which immune cells engulf microbes and remove cell debris, and besides kills some pathogens and infect cells immediately. The phagocytic action of the natural immune answer promotes headroom of dead cells or antibody complexes and removes extraneous substances deliver in organs, tissues, blood and lymph. It can besides activate the adaptive immune reception through the mobilization and activation of antigen-presenting cells ( APCs ) ( discussed former ) [ 1, 3 ]. numerous cells are involved in the congenital immune response such as phagocytes ( macrophages and neutrophils ), dendritic cells, mast cells, basophils, eosinophils, natural killer whale ( NK ) cells and innate lymphoid cells. Phagocytes are sub-divided into two main cellular telephone types : neutrophils and macrophages. Both of these cells share a exchangeable function : to engulf ( phagocytose ) microbe and kill them through multiple bactericidal pathways. In addition to their phagocytic properties, neutrophils contain granules and enzyme pathways that assist in the elimination of infective microbes. Unlike neutrophils ( which are ephemeral cells ), macrophages are durable cells that not alone play a character in phagocytosis, but are besides involved in antigen presentation to T cells ( see Fig. 1 ) [ 1 ] .Fig. 1figure 1 Characteristics and function of cells involved in innate immunity [ 1, 3, 4 ]. *Dust cells ( within pneumonic tooth socket ), histiocytes ( connection weave ), Kupffer cells ( liver ), microglial cells ( nervous tissue ), epithelioid cells ( granuloma ), osteoclasts ( bone ), mesangial cells ( kidney ) Full size image Dendritic cells besides phagocytose and function as APCs, initiating the acquired immune response and acting as authoritative messengers between unconditioned and adaptive exemption. Mast cells and basophils plowshare many salient features with each other, and both are implemental in the initiation of acute accent incendiary responses, such as those seen in allergy and asthma. Mast cells besides have important functions as immune “ lookout cells ” and are early producers of cytokines in answer to infection or injury. Unlike mast cells, which by and large reside in the conjunction tissue surrounding blood vessels and are particularly common at mucosal surfaces, basophils reside in the circulation. Eosinophils are granulocytes that posse phagocytic properties and play an significant character in the end of parasites that are much excessively big to be phagocytosed. Along with mast cells and basophils, they besides control mechanisms associated with allergy and asthma. Natural killer ( NK ) cells play a major function in the rejection of tumours and the destruction of cells infected by viruses. end of infect cells is achieved through the release of perforins and granzymes ( proteins that cause lysis of prey cells ) from NK-cell granules which induce apoptosis ( programmed cell death ) [ 4 ]. NK cells are besides an important source of another cytokine, interferon-gamma ( IFN-γ ), which helps to mobilize APCs and promote the development of effective anti-viral unsusceptibility. Innate lymphoid cells ( ILCs ) play a more regulative character. Depending on their type ( i, ILC-1, ILC-2, ILC-3 ), they selectively produce cytokines such as IL-4, IFN-γ and IL-17 that avail to direct the appropriate immune reply to specific pathogens and put up to immune regulation in that tissue. The chief characteristics and functions of the cells involved in the unconditioned immune reaction are summarized in Fig. 1 .

Adaptive immunity

The development of adaptive unsusceptibility is aided by the actions of the congenital immune organization, and is critical when unconditioned immunity is ineffective in eliminating infectious agents. The primary coil functions of the adaptive immune response are : the recognition of specific “ non-self ” antigens, distinguishing them from “ self ” antigens ; the generation of pathogen-specific immunological effecter pathways that rule out specific pathogens or pathogen-infected cells ; and the development of an immunological memory that can promptly eliminate a specific pathogen should subsequent infections occur [ 2 ]. Adaptive immune responses are the basis for effective immunization against infectious diseases. The cells of the adaptive immune system include : antigen-specific T cells, which are activated to proliferate through the action of APCs, and B cells which differentiate into plasma cells to produce antibodies .

T cells and APCs

T cells derive from hematopoietic stem cells in cram marrow and, following migration, mature in the thymus. These cells express a series of singular antigen-binding receptors on their membrane, known as the T-cell receptor ( TCR ). Each T cell expresses a individual type of TCR and has the capacitance to quickly proliferate and differentiate if it receives the appropriate signals. As previously mentioned, T cells require the action of APCs ( normally dendritic cells, but besides macrophages, B cells, fibroblasts and epithelial cells ) to recognize a specific antigen. The surfaces of APCs express a group of proteins known as the major histocompatibility building complex ( MHC ). MHC are classified as either course I ( besides termed human leukocyte antigen [ HLA ] A, B and C ) which are found on all nucleated cells, or class II ( besides termed HLA DP, DQ and DR ) which are found entirely on certain cells of the immune system, including macrophages, dendritic cells and B cells. class I MHC molecules present endogenous ( intracellular ) peptides, while class II molecules on APCs present exogenous ( extracellular ) peptides to T cells. The MHC protein displays fragments of antigens ( peptides ) when a cellular telephone is infected with an intracellular pathogen, such as a virus, or has phagocytosed foreign proteins or organisms [ 2, 3 ].

T cells have a wide roll of unique TCRs which can bind to specific extraneous peptides. During the development of the immune system, T cells that would react to antigens normally found in our body are largely eliminated. T cells are activated when they encounter an APC that has digested an antigen and is displaying the correct antigen fragments ( peptides ) tie to its MHC molecules. The opportunities for the correct T cells to be in contact with an APC carrying the appropriate peptide MHC complex are increased by the circulation of T cells throughout the body ( via the lymphatic system and blood stream ) and their accumulation ( together with APCs ) in lymph nodes. The MHC-antigen building complex activates the TCR and the T cellular telephone secretes cytokines which further control the immune reaction. This antigen presentation serve stimulates T cells to differentiate chiefly into either cytotoxic T cells ( CD8+ cells ) or T-helper ( Th ) cells ( CD4+ cells ) ( see Fig. 2 ). CD8+ cytotoxic T cells are chiefly involved in the destruction of cells infected by foreign agents, such as viruses, and the kill of tumor cells expressing appropriate antigens. They are activated by the interaction of their TCR with peptide bounce to MHC class I molecules. clonal expansion of cytotoxic T cells produces effector cells which release substances that induce apoptosis of target cells. Upon resolution of the contagion, most effector cells die and are cleared by phagocytes. however, a few of these cells are retained as memory cells that can cursorily differentiate into effector cells upon subsequent encounters with the lapp antigen [ 2, 3 ] .Fig. 2figure 2 ( design adapted from images available at : hypertext transfer protocol : // : B_cell_activation.png and hypertext transfer protocol : // : Antigen_presentation.svg ) Adaptive immunity: T-cell and B-cell activation and function. APC antigen-presenting cell, TCR T-cell sense organ, MHC major histocompatibility complex Full size prototype CD4+ Th cells play an significant role in establishing and maximizing the immune answer. These cells have no cytotoxic or phagocytic natural process, and can not directly kill infect cells or well-defined pathogens. however, they “ mediate ” the immune response by directing other cells to perform these tasks and regulate the type of immune answer that develops. Th cells are activated through TCR recognition of antigen adhere to course II MHC molecules. once activated, Th cells free cytokines that influence the natural process of many cell types, including the APCs that activate them. several types of Th cell responses can be induced by an APC, with Th1, Th2 and Th17 being the most frequent. The Th1 reception is characterized by the production of IFN-γ which activates the bactericidal activities of macrophages and enhances anti-viral unsusceptibility angstrom well as unsusceptibility to early intracellular pathogens. Th1-derived cytokines besides contribute to the differentiation of B cells to make opsonizing antibodies that enhance the efficiency of phagocytes. An inappropriate Th1 response is associated with certain autoimmune diseases. The Th2 answer is characterized by the passing of cytokines ( IL-4, 5 and 13 ) which are involved in the development of immunoglobulin E ( IgE ) antibody-producing B cells, a well as the growth and recruitment of mast cells and eosinophils that are all-important for effective responses against many parasites. In addition, they enhance the production of certain forms of IgG that care in combatting bacterial contagion. As mentioned earlier, mast cells and eosinophils are implemental in the initiation of acute incendiary responses, such as those seen in allergy and asthma. IgE antibodies are besides associated with allergic reactions ( see Table 2 ). Therefore, an asymmetry of Th2 cytokine production is associated with the development of atopic ( allergic ) conditions. Th17 cells have been more recently described. They are characterized by the production of cytokines of the IL-17 syndicate, and are associated with ongoing inflammatory responses, peculiarly in chronic infection and disease. Like cytotoxic T cells, most Th cells will die upon settlement of infection, with a few remaining as Th memory cells [ 2, 3 ] .Table 2 Major functions of human Ig antibodies [5] Full size table A subset of the CD4+ T cell, known as the regulative T cell ( T reg ), besides plays a function in the immune reception. T reg cells limit and suppress immune responses and, thereby, may function to control aberrant responses to self-antigens and the development of autoimmune disease. T reg cells may besides help in the resolving power of normal immune responses, as pathogens or antigens are eliminated. These cells besides play a critical function in the development of “ immune permissiveness ” to certain foreign antigens, such as those found in food.

B cells

B cells arise from hematopoietic shank cells in the bone marrow and, following festering, leave the marrow expressing a unique antigen-binding receptor on their membrane. Unlike T cells, B cells can recognize antigens immediately, without the need for APCs, through unique antibodies expressed on their cell surface. The chief serve of B cells is the output of antibodies against alien antigens which requires their further specialization [ 2, 3 ]. Under sealed circumstances, B cells can besides act as APCs. When activated by extraneous antigens to which they have an appropriate antigen particular sense organ, B cells undergo proliferation and differentiate into antibody-secreting plasma cells or memory B cells ( see Fig. 2 ). memory B cells are “ durable ” survivors of past infection and continue to express antigen-binding receptors. These cells can be called upon to respond cursorily by producing antibodies and eliminating an antigen upon re-exposure. Plasma cells, on the other hand, are relatively ephemeral cells that much undergo apoptosis when the incite agent that induced the immune response is eliminated. however, these cells produce big amounts of antibody that enter the circulation and tissues providing effective protection against pathogens. Given their routine in antibody production, B cells play a major function in the humoral or antibody-mediated immune response ( as opposed to the cell-mediated immune response, which is governed primarily by T cells ) [ 2, 3 ] .

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