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Table of Contents
Introduction ................. Humoral immunity in innate immune system ............ Cellular immunity in the innate immune system ........ Pattern recognition receptors (PRRs) in innate immunity ..... 4 5 6 9
Innate immunity influences adaptive immunity ....... 11 Concluding Remarks ............. 11 References ................... 12
Introduction
mmune system refers to the cells and molecules responsible for immunity, which is a collection of mechanisms within an organism. Healthy individuals protect themselves against diseases by means of an immune system within the body, that functions by identifying and killing a wide variety of pathogens, such as viruses, bacteria, and parasitic worms, as well as tumor cells. The immune system distinguishes foreign material from the organism's normal cells and tissues. Two layers of defense systems are found in organisms, the innate immune system and the adaptive immune system. The innate (also called natural or native) immune system is a front line of defense providing an immediate, but non-specific response found in all plants and animals.[1] A second layer of protection possessed by all vertebrates is provided by the adaptive immune system, which is also called acquired or specific immunity. The adaptive immune system has improved recognition of the pathogen and retains specific responses in the form of an immunological memory that allows the host to mount faster and stronger attacks upon subsequent encounters with pathogens.[2] Both the innate and adaptive immune systems are comprised of both cellular and soluble components (known as humoral immunity) by which they carry out their protective function, but they differ in a number of ways (Table 1). The innate system is thought to constitute an evolutionarily older defense strategy, based on the fact that non-vertebrate organisms use immune systems similar to the vertebrate innate immune system. The major functions of the vertebrate innate immune system include: 1) Recruiting immune cells to sites of infection and inflammation, through the production of specialized chemical mediators, such as cytokines and chemokines. 2) Activation of the complement cascade to identify bacteria, activate cells, and to promote clearance of dead cells or antibody complexes. 3) The identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells. 4) Activation of the adaptive immune system through a process known as antigen presentation. Both humoral and cellular components of innate immunity are required for these protective functions.
Cutaneous & mucosal immune system secreted antibodies Humoral immunity: antibodies Cellular immunity: Lymphocytes
Humoral components
Complement, Mannose-binding lectin Coagulation Platelets Lactoferrin and Transferrin Lysozyme Fibronectin Interferons Interleukin-1 TNF Defensins
Effector function
Opsonization, enhanced phagocytosis, inflammation Chemotactic agents for phagocytic cells, inflammation Antimicrobial substance, e.g. beta-lysin Iron binding, limiting bacterial growth Peptidoglycan hydrolysis, breaking down the cell wall of bacteria Opsonization and phagocytosis Antiviral proteins Fever, Opsonization antiviral, phagocyte activation Antibacterial, antiviral proteins
The complement system is the major humoral component of innate defense mechanism mention.
CLASSICAL PATHWAY Antigen:antibody complexes (pathogen surfaces) C1q, C1r, C1s C4 C2 MB-LECTIN PATHWAY Mannose-binding lectin binds mannose on pathogen surfaces MBL, MASP-1, MASP-2 C4 C2 ALTERNATIVE PATHWAY Pathogen surfaces C3 B D
[3, 4]
C3 convertase Terminal complement components C5b C6 C7 C8 C9 Membrane-attack complex, lysis of certain pathogens and cells
C3a, C5a
C3b
The complement system is a that attacks the surfaces of foreign cells. The term "complement" was introduced by Paul Ehrlich in the late 1890s, who described it is something in the blood which "complements" the cells of the immune system in the killing of pathogens. The complement system is made up of over 25 different serum small proteins and protein fragments, including serum proteins, serosal proteins, and cell membrane receptors. These proteins are synthesized mainly in the liver, and they account for about 5% of the globulin fraction of blood serum. Complement proteins circulate in the blood in an inactive form. Elements of the complement cascade can be found in many species evolutionarily older than mammals including plants, birds, fish , some species of invertebrates[5], as well as in humans. The complement system is not adaptable and does not change over the course of an individual's lifetime; as such it belongs to the innate immune system. However, it can be recruited and brought into action by the adaptive immune system . After complement proteins initially bind to microbes, they activate their protease activity, which in turn activates other complement proteases, and so on. This produces a catalytic cascade that amplifies the initial signal by controlled positive feedback.[6, 7] The cascade results in the production of peptides that attract immune cells, increase vascular permeability, and opsonize (coat) the surface of a pathogen, marking it for destruction. This deposition of complement can also kill cells directly by disrupting the plasma membrane barrier.[3]
Activating enzymes
Membrane-attack proteins
Complement receptors
Complement-regulatory proteins
Figure 1b Functional protein classes in the Three biochemical pathways activate the complement complement system. system: the classical complement pathway, which initiates complement activation via binding to specific antibodies; the alternative complement pathway, which activates via direct binding to pathogen surfaces; and the mannose-binding lectin pathway, which is homologous to the classical complement pathway, but involves a protein that binds to mannose residues and other sugars on multiple pathogens.[5] Figure 1a & b diagrammatically show the major players in all three complement activation pathways of vertebrates [the diagrams are adopted from Janeway CA, Jr. et al (2005). Immunobiology., 6th ed., Garland Science].
Since leukocytes are able to move freely, part of the inflammatory response is their recruitment to sites of infection. These cells are the main line of defense in the non-specific immune system by interacting, identifying, capturing cellular debris, foreign particles or invading microorganisms, and eliminating the pathogens that might cause infection.[5] Phagocytic cells in the innate immune system utilize a number of processes to carry out their function, including chemotaxis to sites of infection, production of chemicals, enzymes, chemokines and cytokines that initiate inflammation and other immune responses, as well as induce apoptosis and engulf infected cells. [5, 8, 11] In addition, macrophages and dendritic cells also serve as professional antigen-presenting cells (APCs) that display a fragment of foreign antigen complexed with MHC II molecule on their surface. Cells from adaptive immune system, such as T cells, recognize and interact with the antigen-class II MHC molecule complex on the membrane of the antigen presenting cell. An additional co-stimulatory signal such as B7 is then produced by the antigen presenting cell, leading to activation of the T cell which triggers adaptive immunity. [8, 11] Neutrophils, eosinophils and basophils are classified together as granulocytes. Neutrophils are the most common leukocyte type in the blood and are the major responders to inflammation and infection. Eosinophils and basophils along with mast cells are often associated with allergic reactions, but normally carry out protective response in killing pathogens such as parasites. Natural killer (NK) cells also known as large granular lymphocytes (LGL) because they resemble lymphocytes in their morphology, except that they are slightly larger and have numerous granules in their cytoplasm contain special proteins such as perforin and proteases known as granzymes.[5] They can be identified by the presence of CD56 and CD16 and a lack of CD3 cell surface markers. NK cells can nonspecifically kill viral infected cells and tumor cells by releasing perforin that forms pores in the cell membrane of the target cell through which the granzymes and associated molecules can enter, inducing apoptosis of infected cells and preventing the spread of virus. [22] The killing becomes more efficient upon exposure to IL-2 and IFN, wherein NK cells become lymphokine-activated killer (LAK) cells, which are capable of killing malignant cells. Continued exposure to IL-2 and IFN enables the LAK cells to kill transformed as well as malignant cells. It should be noted that anti-viral infection reactions and tumor surveillance of NK cells are not inflammatory responses. For a long time, researchers questioned how NK cells can distinguish a normal cell from a virus-infected or malignant cell. Now we know that NK cells have two kinds of receptors on their surface a killer activating receptor (KAR) and a killer inhibiting receptor (KIR). When the KAR encounters its ligand, a killer activating ligand (KAL) on the target cell, the NK are capable of killing the target. However, if the KIR also binds to its ligand then killing is inhibited even if KAR binds to KAL. The ligands for KIR are MHC class I molecules. So, as long as a target cell expresses class I MHC molecules, it will not be killed by NK or LAK cells even if it expresses KAL. Normal cells constitutively express MHC class I molecules on their surface, however, virus infected and malignant cells down regulate expression of class I MHC. Thus, NK and LAK cells selectively kill virus-infected and malignant cells while sparing normal cells. [29-32] Cells capable of killing foreign and altered self target cells in a non-specific manner are also granted a name, Killer (K) cells. NK cells, activated macrophages and eosinophils belong to this group of cells. Killer cells that carry Fc receptors like NK and macrophages for IgG antibodies and Fc receptor like eosinophils for IgE antibodies can mediate antibodydependent cellular cytotoxicity (ADCC). In ADCC, bound antibodies direct the K cells to the target cells, initiating cell killing. These cells play an important role in the innate immune system. [22] g d T cells are here counted in innate immune system because they exhibit characteristics that place them at the border between innate and adaptive immunity. One on hand, T cells may be considered a component of adaptive immunity in that they rearrange TCR genes to produce junctional diversity and develop a memory phenotype. However, the various subsets may also be considered part of the innate immune system where a restricted TCR or NK receptors may be used as a pattern recognition receptor. [23-28]
Function
against pathogens, wound healing, allergy and anaphylaxis, recruits neutrophils and macrophages, dilates blood vessels
Product
histamine heparin chemokines, or chemotactic cytokines
Location
connective tissue and mucous membranes
Reported Markers
Reference
[9-10]
Activation
IgE:allergen attachment
Receptors
FcRI SCF receptor (ckit, Cd117)
CD9, CD33, CD43, CD45, CD54, CD117 (c-kit, SCF receptor), HLA-class I, IgE Fcg Rs, CD11c,CD14, CD16/CD32, CD68, CD82, CD163 HLADM, MHC class
Macrophages
Large phagocytic cells, chemotaxis, phagocytosis destroy bacteria through respiratory burst, inflammation, apoptosis, antigen presentation
reactive oxygen species, Cathepsins, lysozyme, PLA2, iNOS, MMPs (1, 2, 7, 9, 12), chemokines/cytoki nes (IL-8, Rantes, MIP1a, MIP1b, MIP-2, IP-10, IFN, IL-1a, IL-1b, TNF, IL-6, IL-12, TGFb, PDGF, FGFb, VEGF, IGF), Fas Ligand oxidizing agents including hydrogen peroxide, free oxygen radicals and hypochlorite, Defensins and the serine proteases neutrophil elastase and cathepsin G
MHC class II, Fcg receptors (I-III), B7-1, B7-2, Scavenger receptors, Complement receptors, MSPR,TLR4, IFNg Rs, CXCRs, IL-4Ra, IL-13Ra1
b 2-integrins, Fcg receptors, lselectin, complement receptor 1 (CR-1), C5a receptor, decay-accelerating factor (DAF), intercellular adhesion molecule-1 (ICAM-1) and ICAM-3
Dendritic cells [Myeloid dendritic cells (mDC), Plasmacytoid dendritic cells (pDC)]
phagocytic cells, phagocytosis, antigen presentation (TH cell activators) serving as a link between the innate and adaptive immune systems
CD1a, CD11c, CD40, TLR 2 & TLR 4 (mDC), TLR 7 & TLR 9 (pDC) The markers BDCA-2, BDCA-3, and BDCA-4 for discriminate among the types
MHC class II, B7s, TLRs, LTb Rs TLRs, BDCA-2, BDCA-3, BDCA-4, CD40LTb Rs
Basophils Eosinophils
killing bacteria and parasites, allergic reactions attack and destroy tumor cells, and virally infected cells by inducing apoptosis bridge between innate and adaptive responses
Infectin site
g d T cells
[23-28]
PRR: Vg 9/V2
In mammals, there are about 13 TLRs reported so far[34-36], each of which, specializes in a subset of PAMPs. See Table 4 for the summary of known Mammalian Toll-like Receptors.
Table 4 : Summary of Mammalian Toll-like Receptors
Receptor
TLR 1
Ligand(s)
triacyl lipoproteins lipoproteins; gram positive peptidoglycan; lipoteichoic acids; fungi; viral glycoproteins
Target Pathogen(s)
Adapter(s)
MyD88/MAL
Location
cell surface cell surface
TLR 2
MyD88/MAL
TLR 3
Viruses
TRIF
cell compartment
TLR 4
MyD88/MAL/TRIF/TRAM
cell surface
TLR 5
flagellin
MyD88
cell surface
MyD88/MAL
cell surface
TLR 7
MyD88
cell compartment
TLR 8
MyD88
cell compartment
TLR 9
MyD88
cell compartment
TLR 10
unknown
unknown
cell surface
Profilin
Protozoans (Apicomplexa)
MyD88
cell surface
unknown
unknown
unknown
unknown
unknown
unknown
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Concluding remarks
he innate immune system, as a first line of defense against pathogens, involves a diverse collection of molecules and mechanisms that include chemicals, enzymes, cytokines, chemokines, and effector cells (see tables 1-4). Overall, many different cellular processes are involved, including cell signaling via receptors, phagocytosis, targeted cell killing, and apoptosis. BioLegend provides a variety of reagents, antibodies, and tools for study of the innate immune system including leukocyte phenotyping, cytokine and chemokine measurements, receptor detection, measurement of apoptosis and cell signaling molecules.
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References
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21. Komiya A (2006) Expression and Function of Toll-Like Receptors in Human Basophils International Archives of Allergy and Immunology 2006;140 (Suppl. 1):23-27. 22. Bots M, Medema JP (2006). "Granzymes at a glance". J. Cell. Sci. 119 (Pt 24): 5011-4. 23. Holtmeier W, Kabelitz D. T cells link innate and adaptive immune responses. Chem Immunol Allergy. 2005;86:151-183. 24. Born WK, Reardon CL, O'Brien RL. The function of T cells in innate immunity. Curr Opin Immunol. 2006;18:3138. 25. Morita CT, Mariuzza RA, Brenner MB. Antigen recognition by human T cells: pattern recognition by the adaptive immune system. Springer Semin Immunopathol. 2000;22:191-217. 26. Eberl M, Hintz M, Reichenberg A, Kollas AK, Wiesner J, Jomaa H. Microbial isoprenoid biosynthesis and human T cell activation. FEBS Lett. 2003;544:4-10. 27. Girardi M. Immunosurveillance and immunoregulation by T cells. J Invest Dermatol. 2006 Jan;126:25-31. 28. Thedrez A, Sabourin C, Gertner J, Devilder MC, Allain-Maillet S, Fournie JJ, Scotet E, Bonneville M. Self/non-self discrimination by human T cells: simple solutions for a complex issue? Immunol Rev. 2007;215:123-135. 29. Lieto LD (2006) The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B Genes and Immunity 7, 3643. 30. Makrigiannis AP (2001) Class I MHC-binding characteristics of the 129/J Ly49 repertoire. J Immunol. 2001 Apr 15;166(8):5034-43. 31. Butsch Kovacic et al. (2005) Variation of the Killer Cell Immunoglobulin-Like Receptors and HLA-C Genes in Nasopharyngeal Carcinoma. Cancer Epidemiol Biomarkers Prev 14 (11): 2673. 32. Gonen-Gross et al. (2005) 175 (8): 4866. The CD85J/Leukocyte Inhibitory Receptor-1 Distinguishes between Conformed and _2-Microglobulin-Free HLA-G Molecules. The Journal of Immunology 175: 48664874. 33. Lemaitre,B., Nicolas,E., Michaut,L., Reichhart,J.M., and Hoffmann,J.A. 1996. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86:973-983. 34. Du,X., Poltorak,A., Wei,Y., and Beutler,B. 2000. Three novel mammalian toll-like receptors: gene structure, expression, and evolution. Eur. Cytokine Netw. 11:362-371. 35. Chuang,T.H., and Ulevitch,R.J. 2000. Cloning and characterization of a sub-family of human toll-like receptors: hTLR7, hTLR8 and hTLR9. Eur. Cytokine Netw. 11:372-378. 36. Tabeta,K., Georgel,P., Janssen,E., Du,X., Hoebe,K., Crozat,K., Mudd,S., Shamel,L., Sovath,S., Goode,J. et al 2004. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc. Natl Acad. Sci. U. S. A 101:3516-3521. 37. Yamamoto,M., Sato,S., Hemmi,H., Hoshino,K., Kaisho,T., Sanjo,H., Takeuchi,O., Sugiyama,M., Okabe,M., Takeda,K. et al 2003. Role of adapter TRIF in the MyD88-independent Toll-like receptor signaling pathway. Science 301:640-643. 38. Yamamoto,M., Sato,S., Hemmi,H., Uematsu,S., Hoshino,K., Kaisho,T., Takeuchi,O., Takeda,K., and Akira,S. 2003. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat. Immunol. 4:1144-1150. 39. Yamamoto,M., Sato,S., Hemmi,H., Sanjo,H., Uematsu,S., Kaisho,T., Hoshino,K., Takeuchi,O., Kobayashi,M., Fujita,T. et al 2002. Essential role for TIRAP in activation of the signalling cascade shared by TLR2 and TLR4. Nature 420:324-329.
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