Innate Defenders

The Complement System

The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism.

Learning Objectives

Illustrate the key points of the complement system

Key Takeaways

Key Points

  • Three biochemical pathways activate the complement system–the classical complement pathway, the alternative complement pathway, and the lectin pathway.
  • The following are the basic functions of the complement: Opsonization (enhancing phagocytosis of antigens ); chemotaxis (attracting macrophages and neutrophils); cell lysis (rupturing membranes of foreign cells); and clumping (antigen-bearing agents).
  • The complement system consists of a number of small proteins found in the blood, generally synthesized by the liver, and normally circulating as inactive precursors (pro-proteins).

Key Terms

  • antibodies: An antibody (Ab), also known as an immunoglobulin (Ig), is a large Y-shaped protein produced by B-cells that is used by the immune system to identify and neutralize foreign objects, such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, called an “antigen. “
  • phagocytic: Phagocytosis, meaning “cell,” and -osis, meaning “process,” is the cellular process of engulfing solid particles by the cell membrane to form an internal phagosome by phagocytes and protists.
  • pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
  • classical pathway: a group of blood proteins that mediate the specific antibody response

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, generally 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.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternative complement pathway, and the lectin pathway. The following are the basic functions of the complement: opsonization (enhancing phagocytosis of antigens); chemotaxis (attracting macrophages and neutrophils); cell lysis (rupturing membranes of foreign cells); and clumping (antigen-bearing agents).

The proteins and glycoproteins that constitute the complement system are synthesized by the liver hepatocytes. But significant amounts are also produced by tissue macrophages, blood monocytes, and epithelial cells of the genitourinal tract and gastrointestinal tract. The three pathways of activation all generate homologous variants of the protease C3-convertase. The classical complement pathway typically requires antigen, antibody complexes for activation (specific immune response), whereas the alternative and mannose-binding lectin pathways can be activated by C3 hydrolysis or antigens without the presence of antibodies (non-specific immune response). In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells by opsonization. C5a is an important chemotactic protein, helping recruit inflammatory cells.

C3a is the precursor of an important cytokine (adipokine) named ASP and is usually rapidly cleaved by carboxypeptidase B. Both C3a and C5a have anaphylatoxin activity, directly triggering degranulation of mast cells, as well as increasing vascular permeability and smooth muscle contraction. C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9. MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells and other macrophage cell types help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates, most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

n the classical pathway, C1 binds with its C1q subunits to Fc fragments (made of CH2 region) of IgG or IgM, which forms a complex with antigens. C4b and C3b are also able to bind to antigen-associated IgG or IgM, to its Fc portion.

Such immunoglobulin-mediated binding of the complement may be interpreted, as that the complement uses the ability of the immunoglobulin to detect and bind to non-self antigens as its guiding stick. The complement itself is able to bind non-self pathogens after detecting their pathogen-associated molecular patterns (PAMPs); however, utilizing specificity of antibody, complements are able to detect non-self enemies much more specifically. There must be mechanisms that complements bind to Ig but would not focus its function to Ig but to the antigen.

shows the classical and the alternative pathways with the late steps of complement activation schematically. Some components have a variety of binding sites. In the classical pathway, C4 binds to Ig-associated C1q and C1r2s2 enzyme cleaves C4 to C4b and 4a. C4b binds to C1q, antigen-associated Ig (specifically to its Fc portion), and even to the microbe surface. C3b binds to antigen-associated Ig and to the microbe surface. The ability of C3b to bind to antigen-associated Ig would work effectively against antigen-antibody immune complexes to make them soluble. In the figure, C2b refers to the larger of the C2 fragments.

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Complement Pathways: The classical and the alternative pathways with the late steps of complement activation.

Interferons

Interferons (IFNs) are proteins made and released by host cells in response to the presence of pathogens.

Learning Objectives

Identify interferons and their effects

Key Takeaways

Key Points

  • Interferons are named after their ability to “interfere” with viral replication within host cells.
  • IFNs are divided into three classes: type I IFN, type II IFN, and type III IFNs.
  • IFNs activate immune cells (natural killer cells and macrophages ), increase recognition of infection and tumor cells by up-regulating antigen presentation to T lymphocytes, and increase the ability of uninfected host cells to resist new infection by virus.

Key Terms

  • Interferons: 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.
  • pathogens: A pathogen or infectious agent (colloquially known as a germ) is a microorganism (in the widest sense, such as a virus, bacterium, prion, or fungus) that causes disease in its host. The host may be an animal (including humans), a plant, or even another microorganism.
  • immune cells: White blood cells, or leukocytes, are cells of the immune system involved in defending the body against both infectious disease and foreign materials.

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. 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.

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Interferon: The molecular structure of human interferon-alpha.

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.

Based on the type of receptor through which they signal, human interferons have been classified into three major types:

  • Interferon type I: All type I IFNs bind to a specific cell surface receptor complex, known as the IFN-α receptor (IFNAR) that consists of IFNAR1 and IFNAR2 chains. The type I interferons present in humans are IFN-α, IFN-β and IFN-ω.
  • Interferon type II: These bind to IFNGR that consist of IFNGR1 and IFNGR2 chains. In humans this is IFN-γ.
  • Interferon type III: These signal through a receptor complex consisting of IL10R2 (also called CRF2-4) and IFNLR1 (also called CRF2-12). Acceptance of this classification is less universal than that of type I and type II, and unlike the other two, it is not currently included in Medical Subject Headings.

Effects of Interferons

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. In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)—that have roles in combating viruses. They also limit viral spread by increasing p53 activity, which kills virus-infected cells by promoting apoptosis. The effect of IFN on p53 is also linked to its protective role against certain cancers. Another function of interferons is to upregulate major histocompatibility complex molecules, MHC I and MHC II, and increase immunoproteasome activity. Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells. Interferons can inflame the tongue and cause dysfunction in taste bud cells, restructuring or killing taste buds entirely.

By interacting with their specific receptors, IFNs activate signal transducer and activator of transcription (STAT) complexes. STATs are a family of transcription factors that regulate the expression of certain immune system genes. Some STATs are activated by both type I and type II IFNs. However, each IFN type can also activate unique STATs.

STAT activation initiates the most well-defined cell signaling pathway for all IFNs, the classical Janus kinase-STAT (JAK-STAT) signaling pathway. In this pathway, JAKs associate with IFN receptors and, following receptor engagement with IFN, phosphorylate both STAT1 and STAT2. As a result, an IFN-stimulated gene factor 3 (ISGF3) complex forms—this contains STAT1, STAT2 and a third transcription factor called IRF9—and moves into the cell nucleus. Inside the nucleus, the ISGF3 complex binds to specific nucleotide sequences called IFN-stimulated response elements (ISREs) in the promoters of certain genes, known as IFN stimulated genes ISGs. Binding of ISGF3 and other transcriptional complexes activated by IFN signaling to these specific regulatory elements induces transcription of those genes. Interferome is a curated online database of ISGs (www.interferome.org). Additionally, STAT homodimers or heterodimers form from different combinations of STAT-1, -3, -4, -5, or -6 during IFN signaling; these dimers initiate gene transcription by binding to IFN-activated site (GAS) elements in gene promoters. Type I IFNs can induce expression of genes with either ISRE or GAS elements, but gene induction by type II IFN can occur only in the presence of a GAS element.

In addition to the JAK-STAT pathway, IFNs can activate several other signaling cascades. Both type I and type II IFNs activate a member of the CRK family of adaptor proteins called CRKL, a nuclear adaptor for STAT5 that also regulates signaling through the C3G/Rap1 pathway. Type I IFNs further activate p38 mitogen-activated protein kinase (MAP kinase) to induce gene transcription. Antiviral and antiproliferative effects specific to type I IFNs result from p38 MAP kinase signaling. The phosphatidylinositol 3-kinase (PI3K) signaling pathway is also regulated by both type I and type II IFNs. PI3K activates P70-S6 Kinase 1, an enzyme that increases protein synthesis and cell proliferation; phosphorylates of ribosomal protein s6, which is involved in protein synthesis; and phosphorylates a translational repressor protein called eukaryotic translation-initiation factor 4E-binding protein 1 (EIF4EBP1) in order to deactivate it.

Natural Killer Cells

Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system.

Learning Objectives

Describe natural killer cells

Key Takeaways

Key Points

  • NK cells are defined as large granular lymphocytes (LGL).
  • NK cells constitute the third kind of cells differentiated from the common lymphoid progenitor generating B and T lymphocytes.
  • NK cells provide rapid responses to virally infected cells and respond to tumor formation, acting at around 3 days after infection.

Key Terms

  • Natural killer cells (or NK cells): Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response.
  • lymphocyte: A type of white blood cell or leukocyte that is divided into two principal groups and a null group: B-lymphocytes, which produce antibodies in the humoral immune response, T-lymphocytes, which participate in the cell-mediated immune response, and the null group, which contains natural killer cells, cytotoxic cells that participate in the innate immune response.
  • innate immune system: This is the initial line of defense that entails a cascade of cells and mechanisms that protect the host from infection by different organisms in an indeterminate pattern.

Place in the Immune System

Natural killer cells (or NK cells) are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is similar to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virally infected cells and to tumor formation, beginning around three days after infection. Typically immune cells detect MHC that is present on infected cell surfaces, triggering cytokine release and causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named “natural killers” because of the initial notion that they do not require activation in order to kill cells that are missing “self” markers of major histocompatibility complex (MHC) class 1.

NK cells are defined as large granular lymphocytes (LGL) and constitute the third kind of cell differentiated from the common lymphoid progenitor generating B and T lymphocytes. NK cells are known to differentiate and mature in the bone marrow, lymph node, spleen, tonsils, and thymus, where they then enter into the circulation. NK cells differ from Natural Killer T cells (NKT) phenotypically, by origin, and by respective effector functions. Often NKT cell activity promotes NK cell activity by secreting IFNγ. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or Pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. Up to 80% of human NK cells also express CD8.

Mechanism

NK cells paralyze target cells using the cytolytic protein perforin and a variety of protease enzymes. An NK cell will first use perforin to create pores in a target cell, allowing it to inject granzymes through an aqueous channel. The granzymes then break down the target cell, inducing death by either apoptosis or osmotic cell lysis.

NK cells also alert the greater immune system by secreting chemicals that are taken as a message that a threat has arrived.

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Schematic diagram indicating the complementary activities of cytotoxic T-cells and NK cells.: Schematic diagram indicating the complementary activities of cytotoxic T-cells and NK cells.

Natural Killer Cells Play Other Roles

Natural killer cells are not only effectors of innate immunity; recent research has also uncovered information on both activating and inhibitory NK cell receptors, which play roles in maintaining self-tolerance and sustaining NK cell activity. NK cells also play a role in the adaptive immune response. Numerous experiments have demonstrated their ability to adjust to the immediate environment and formulate antigen-specific immunological memory, which is fundamental for responding to secondary infections with the same antigen. The ability for NK cells to act in both innate and adaptive immune response is becoming increasingly important in research utilizing NK cell activity in potential cancer therapies.

NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis after binding to ligands that directly indicate infection of a cell. The MHC dependent receptors (described above) use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation—for example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited. Similarly, if the activating signal is dominant, then NK cell activation will result.

Functions of NK cells include: Cytolytic Granule Mediated Cell Apoptosis; Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC); Cytokine induced NK and CTL activation; Missing ‘self’ hypothesis; Tumor cell surveillance; NK cell function in adaptive response; NK cell function in pregnancy; and NK cell evasion by tumor cells.

Toll-Like Receptors

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system.

Learning Objectives

Summarize Toll-like receptors

Key Takeaways

Key Points

  • TLRs are a type of pattern recognition receptor (PRR).
  • TLRs recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs).
  • TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway.

Key Terms

  • Toll-like receptor: Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes.
  • innate immune system: This is the initial line of defense that entails a cascade of cells and mechanisms that protect the host from infection by different organisms in an indeterminate pattern.
  • signaling pathway: Signal pathways occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response. There are two stages in this process:A signaling molecule activates a specific receptor protein on the cell membrane.A second messenger transmits the signal into the cell, eliciting a physiological response.In either step, the signal can be amplified. Thus, one signaling molecule can cause many responses.

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system as well as the digestive system. They are single, membrane-spanning, non-catalytic receptors that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses.

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TLR3: The curved leucine-rich repeat region of Toll-like receptors, represented here by TLR3

TLRs are a type of pattern recognition receptor (PRR) and recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs). TLRs together with the Interleukin-1 receptors form a receptor superfamily, known as the “Interleukin-1 Receptor/Toll-Like Receptor Superfamily”; all members of this family have in common a so-called TIR (Toll-IL-1 receptor) domain.

Because of the specificity of Toll-like receptors (and other innate immune receptors) they cannot easily be changed in the course of evolution, these receptors recognize molecules that are constantly associated with threats (i.e., pathogen or cell stress) and are highly specific to these threats (i.e., cannot be mistaken for self molecules). Pathogen-associated molecules that meet this requirement are usually critical to the pathogen’s function and cannot be eliminated or changed through mutation; they are said to be evolutionarily conserved. Well-conserved features in pathogens include bacterial cell-surface lipopolysaccharides (LPS), lipoproteins, lipopeptides, and lipoarabinomannan; proteins such as flagellin from bacterial flagella; double-stranded RNA of viruses; or the unmethylated CpG islands of bacterial and viral DNA; and certain other RNA and DNA. For most of the TLRs, ligand recognition specificity has now been established by gene targeting (also known as “gene knockout”): a technique by which individual genes may be selectively deleted in mice. See the table below for a summary of known TLR ligands.

TLRs are believed to function as dimers. Though most TLRs appear to function as homodimers, TLR2 forms heterodimers with TLR1 or TLR6, each dimer having a different ligand specificity. TLRs may also depend on other co-receptors for full ligand sensitivity, such as in the case of TLR4’s recognition of LPS, which requires MD-2. CD14 and LPS-Binding Protein (LBP) are known to facilitate the presentation of LPS to MD-2.

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Signaling pathway: Signaling pathway of Toll-like receptors. Dashed grey lines represent unknown associations.

The adapter proteins and kinases that mediate TLR signaling have also been targeted. In addition, random germline mutagenesis with ENU has been used to decipher the TLR signaling pathways. When activated, TLRs recruit adapter molecules within the cytoplasm of cells in order to propagate a signal. Four adapter molecules are known to be involved in signaling. These proteins are known as MyD88, Tirap (also called Mal), Trif, and Tram.

TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK 4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKKβ. On binding, TAK1 phosphorylates IKKβ, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription.

Both TRL3 and TRL4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TRL3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIP1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Type I interferons. Meanwhile, activation of RIP1 causes the polyubiquination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.

TLR signaling ultimately leads to the induction or suppression of genes that orchestrate the inflammatory response. In all, thousands of genes are activated by TLR signaling, and collectively, the TLRs constitute one of the most pleiotropic yet tightly regulated gateways for gene modulation.

Toll-like receptors bind and become activated by different ligands, which, in turn, are located on different types of organisms or structures. They also have different adapters to respond to activation and are located sometimes at the cell surface and sometimes to internal cell compartments.

Iron-Binding Proteins

Iron binding proteins of the innate immune system include lactoferrin and transferrins.

Learning Objectives

Describe Iron-Binding proteins

Key Takeaways

Key Points

  • Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family.
  • Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions.
  • Transferrins are iron -binding blood plasma glycoproteins that control the level of free iron in biological fluids.

Key Terms

  • transferrin: A glycoprotein, a beta globulin, in blood serum that combines with and transports iron
  • Lactoferrin: Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa. It is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions.
  • iron: Iron is a chemical element with the symbol Fe (from Latin: ferrum) and atomic number 26. It is a metal in the first transition series.

Iron-binding proteins are proteins generally used to play roles in metabolism. They are carrier proteins (those used to move ions and molecules across membranes) and more generally metalloproteins (those which contain a metal ion cofactor). Iron-binding proteins are serum proteins, found in the blood, and as their name suggests, are used to bind and transport iron.

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Lactoferrin: Richardson diagram of recombinant human lactoferrin. Based on PDB (Protein Data Bank) 1b0l

Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa. It is widely represented in various secretory fluids such as milk, saliva, tears, and nasal secretions. Lactoferrin is also present in secondary granules of PMN (Polymorphonucler neutrophil) and is secreted by some acinar cells. Lactoferrin can be purified from milk or produced recombinantly. Human colostrum (“first milk”) has the highest concentration, followed by human milk, and then cow milk (150 mg/L).

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Transferrin: PDB (Protein Data Bank) rendering based on 1a8e.

Lactoferrin is one of the components of the immune system of the body. It has antimicrobial activity (bacteriocide, fungicide) and is part of the innate defense, mainly at mucoses. In particular, lactoferrin provides antibacterial activity to human infants. Lactoferrin interacts with DNA and RNA, polysaccharides and heparin, and shows some of its biological functions in complexes with these ligands.

Transferrins are iron-binding blood plasma glycoproteins that control the level of free iron in biological fluids. Human transferrin is encoded by the TF gene. Transferrin glycoproteins bind iron very tightly, but reversibly. Although iron bound to transferrin is less than 0.1% (4 mg) of the total body iron, it is the most important iron pool, with the highest rate of turnover (25 mg/24 h). Transferrin has a molecular weight of around 80 KDa and contains two specific high- affinity Fe(III) binding sites. The affinity of transferrin for Fe(III) is extremely high (1023 M−1 at pH 7.4), but decreases progressively with decreasing pH below neutrality. When not bound to iron, it is known as “apotransferrin” (see also apoprotein).

Antimicrobial Peptides

Antimicrobial peptides are an evolutionarily conserved component of the innate immune response and are found among all classes of life.

Learning Objectives

Describe the role of antimicrobial peptides in host defense

Key Takeaways

Key Points

  • Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure.
  • The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components.
  • Antimicrobial peptides have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection.

Key Terms

  • antimicrobial peptide: Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life.
  • innate immune: The innate immune system, also known as non-specific immune system and first line of defense, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.
  • molecules: A molecule is an electrically neutral group of two or more atoms held together by covalent chemical bonds. Molecules are distinguished from ions by their lack of electrical charge. However, in quantum physics, organic chemistry, and biochemistry, the term molecule is often used less strictly, also being applied to polyatomic ions.

Antimicrobial peptides (also called host defense peptides) are an evolutionarily conserved component of the innate immune response and are found among all classes of life. Fundamental differences exist between prokaryotic and eukaryotic cells that may represent targets for antimicrobial peptides. These peptides are potent, broad spectrum antibiotics which demonstrate potential as novel therapeutic agents. Antimicrobial peptides have been demonstrated to kill Gram negative and Gram positive bacteria (including strains that are resistant to conventional antibiotics), mycobacteria (including Mycobacterium tuberculosis), enveloped viruses, fungi and even transformed or cancerous cells. Unlike the majority of conventional antibiotics, it appears as though antimicrobial peptides may also have the ability to enhance immunity by functioning as immunomodulators.

Antimicrobial peptides are a unique and diverse group of molecules, which are divided into subgroups on the basis of their amino acid composition and structure. Antimicrobial peptides generally consist of between 12 and 50 amino acids. These peptides include two or more positively charged residues provided by arginine, lysine or, in acidic environments, histidine, and a large proportion (generally >50%) of hydrophobic residues. The secondary structures of these molecules follow 4 themes, including:

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Various AMPs: These are various antimicrobial peptide structures.

  1. α-helical
  2. β-stranded due to the presence of 2 or more disulfide bonds
  3. β-hairpin or loop due to the presence of a single disulfide bond and/or cyclization of the peptide chain
  4. Extended

Many of these peptides are unstructured in free solution, and fold into their final configuration upon partitioning into biological membranes. It contains hydrophilic amino acid residues aligned along one side and hydrophobic amino acid residues aligned along the opposite side of a helical molecule. This amphipathicity of the antimicrobial peptides allows the partition of the membrane lipid bilayer. The ability to associate with membranes is a definitive feature of antimicrobial peptides, although membrane permeabilisation is not necessary. These peptides have a variety of antimicrobial activities ranging from membrane permeabilization to action on a range of cytoplasmic targets.

The modes of action by which antimicrobial peptides kill bacteria is varied and includes disrupting membranes, interfering with metabolism, and targeting cytoplasmic components. The initial contact between the peptide and the target organism is electrostatic, as most bacterial surfaces are anionic, or hydrophobic, such as in the antimicrobial peptide Piscidin. Their amino acid composition, amphipathicity, cationic charge, and size allow them to attach to and insert into membrane bilayers to form pores by ‘barrel-stave’, ‘carpet’ or ‘toroidal-pore’ mechanisms. Alternately, they may penetrate into the cell to bind intracellular molecules which are crucial to cell living. Intracellular binding models include inhibition of cell wall synthesis, alteration of the cytoplasmic membrane, activation of autolysin, inhibition of DNA, RNA, and protein synthesis, and inhibition of certain enzymes. However, in many cases, the exact mechanism of killing is not known. One emerging technique for the study of such mechanisms is dual polarisation interferometry. In contrast to many conventional antibiotics these peptides appear to be bacteriocidal (bacteria killing) instead of bacteriostatic (bacteria growth inhibiting). In general the antimicrobial activity of these peptides is determined by measuring the minimal inhibitory concentration (MIC), which is the lowest concentration of drug that inhibits bacterial growth.

In addition to killing bacteria directly, they have been demonstrated to have a number of immunomodulatory functions that may be involved in the clearance of infection, including the ability to:

  • Alter host gene expression
  • Act as chemokines and/or induce chemokine production,
  • Inhibit lipopolysaccharide induced pro-inflammatory cytokine production
  • Promote wound healing
  • Modulate the responses of dendritic cells and cells of the adaptive immune response

Animal models indicate that host defense peptides are crucial for both prevention and clearance of infection. It appears as though many peptides initially isolated and termed as “antimicrobial peptides” have been shown to have more significant alternative functions in vivo (e.g. hepcidin).

Several methods have been used to determine the mechanisms of antimicrobial peptide activity. In particular, solid-state NMR studies have provided an atomic-level resolution explanation of membrane disruption by antimicrobial peptides.

The Complement System and Heart Disease

In autoimmune heart diseases, the body’s immune defense system mistakes its own cardiac antigens as foreign, and attacks them.

Learning Objectives

Identify autoimmune heart diseases

Key Takeaways

Key Points

  • The commonest form of autoimmune heart disease is rheumatic heart disease, or rheumatic fever.
  • The typical mechanism of autoimmunity involves auto-toxic T-lymphocyte, and the complement system.
  • Inflammatory damage leads to the following: pericarditis, myocarditis, and endocarditis.

Key Terms

  • autoimmune: Autoimmunity is the failure of an organism in recognizing its own constituent parts as self, which allows an immune response against its own cells and tissues. Any disease that results from such an aberrant immune response is termed an autoimmune disease. Autoimmunity is often caused by a lack of germ development of a target body, and as such the immune response acts against its own cells and tissues.
  • immune: Immunity is a biological term that describes a state of having sufficient biological defences to avoid infection, disease, or other unwanted biological invasion. In other words, it is the capability of the body to resist harmful microbes from entering it. Immunity involves both specific and non-specific components.
  • antigen: A substance that induces an immune response, usually foreign.

Causes

Autoimmune heart diseases result when the body’s own immune defense system mistakes cardiac antigens as foreign, and attacks them, leading to inflammation of the heart as a whole, or in parts. The most common form of autoimmune heart disease is rheumatic heart disease, or rheumatic fever.

A typical mechanism of autoimmunity is autoantibodies, or auto-toxic T-lymphocyte mediated tissue destruction. The process is aided by neutrophils, the complement system, and tumor necrosis factor alpha.

Aetiologically, autoimmune heart disease is most commonly seen in children with a history of sore throat caused by a streptococcal infection. This is similar to the post-streptococcal glomerulonephritis. Here, the anti-bacterial antibodies cross react with the heart antigens causing inflammation.

Pericarditis, Myocarditis, and Endocarditis

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Viral myocarditis: Histopathological image of myocarditis at autopsy in a patient with acute onset of congestive heart failure

Inflammatory damage can lead to pericarditis, myocarditis, and endocarditis.

Pericarditis: Here the pericardium gets inflamed. Acutely, it can cause pericardial effusion leading to cardiac tamponade and death. After healing, there may be fibrosis and adhesion of the pericardium with the heart, leading to constriction of the heart and reduced cardiac function.

Myocarditis: Here the muscle bulk of the heart gets inflamed. Inflamed muscles have reduced functional capacity. This may be fatal if left untreated, as is in a case of pancarditis. On healing, there will be fibrosis and reduced functional capacity.

Endocarditis: Here the inner lining of the heart is inflamed, including the heart valves. This may cause a valve prolapse, adhesion of the adjacent cusps, of these valves, and occlusion of the flow tracts of blood through the heart, which causes disease known as valve stenosis.

Treatment

Specific clinical manifestations depend on the amount of inflammation. Therapy will involve intensive cardiac care and immunosuppressives, including corticosteroids, which are helpful in the acute stage of the disease. The chronic phase consists of mainly debility control and supportive care options.