Immunity Flashcards
What is innate immunity?
This refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen’s appearance in the body. It is hence also known as the non-specific immune system or the inborn immune system.
What are five major functions of innate immunity?
- Acting as a physical and chemical barrier to infectious agents.
- Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines.
- Activation of the complement cascade to identify bacteria, activate cells, and promote clearance of antibody complexes or dead cells.
- Identification and removal of foreign substances present in organs, tissues, blood and lymph, by specialized white blood cells.
- Activation of the adaptive immune system through a process known as antigen presentation.
Discuss innate immunity as a physical and chemical barrier to infectious agents.
✈ The epithelial surfaces form a physical barrier that is impermeable to most infectious agents, acting as the first line of defense against invading organisms.
✈ Desquamation of skin epithelium also helps remove bacteria and other infectious agents that have adhered to the epithelial surfaces.
✈ Lack of blood vessels and inability of the epidermis to retain moisture as well as the presence of sebaceous glands in the dermis provides an environment unsuitable for the survival of microbes.
✈ In the gastrointestinal and respiratory tract, movement due to peristalsis or cilia, respectively, helps remove infectious agents.
✈ Also, mucus traps infectious agents.
✈ The gut flora can prevent the colonization of pathogenic bacteria by secreting toxic substances or by competing with pathogenic bacteria for nutrients or attachment to cell surfaces.
✈ The flushing action of tears and saliva helps prevent infection of the eyes and mouth.
Click on Answer for some notes on IgG and IgM.
IgG (Immunoglobulin G): This is the most common type of antibody found in blood and other body fluids. IgG antibodies protect against bacterial and viral infections by “remembering” which pathogens the body been exposed to before. If those infectious agents manage to infiltrate the body again, the body will know how to attack them. IgG can take time to form after an infection or immunization and is the only antibody that can cross the placenta, providing passive immunity to the fetus.
IgM (Immunoglobulin M): These antibodies are the first to be made by the body when fighting a new infection and are found mainly in blood and lymph fluid. They are the body’s first line of defense against infections. When the body senses an invader, IgM levels will rise for a short time, and then begin to drop as IgG level kicks in to provide long term protection.
Note that IgG and IgM antibodies are not able to bind to just any pathogen. They are highly specific and can only bind to antigens that match their unique antigen-binding sites. Each antibody has a specific structure that allows it to recognize and bind to a particular antigen, much like a lock and key. During an immune response, a diverse array of antibodies is produced, each with a different specificity. This diversity ensures that the immune system can recognize and respond to a wide variety of pathogens. However, each individual IgG or IgM molecule can only bind to an antigen that fits its specific binding site.
What are three key functions of the complement system?
- Opsonization: The complement system enhances phagocytosis of antigens by marking them for recognition and ingestion by phagocytes. This process is known as opsonization and is primarily mediated by the complement protein C3b.
- Promotion of inflammation: Complement proteins help in promoting inflammation, which serves to limit the spread of infection and attract additional immune cells to the site of infection or injury. Inflammatory responses are facilitated by anaphylatoxins such as C3a and C5a, which are produced during complement activation.
- Lysis of pathogens: The complement system can directly lead to the lysis of pathogens through the formation of the membrane attack complex (MAC). The MAC creates pores in the cell membranes of pathogens, causing water and ions to flow into the cells, leading to their destruction.
Click on Answer for some background notes on the Complement System.
✪ there are 9 main complement proteins
✪ named with a C followed by a number
✪ once cleaved, products are given an a or b
- the a fragment is the smaller anaphylatoxin
- the b fragment is the larger binding portion
✪ C2 is the exception to the above
✪ fragments complex together to form enzymes
- when naming a protein complex its fragments are listed in the order in which they bind e.g. C3 convertase = C4b2a = C4b + C2a. When C3b binds to this complex to form C5 convertase, the complex becomes C4b2a3b.
✪ The complement system can be activated through one of three distinct pathways, each of which converges at the step of C3 cleavage, which kicks off the most important effector functions of the complement system.
Discuss the classical pathway of the complement system.
The classical pathway begins with a protein complex called C1. C1 is made up of three distinct subunits: C1q, C1r and C1s. C1r and C1s are proteases i.e. enzymes that cleave proteins [Diagram 1] [Diagram 2]. They are inactive during normal conditions. During an infection however, circulating C1q can bind directly to some bacterial surfaces, antibodies bound to a pathogen [the antibodies involved are specifically IgG or IgM], or to an acute phase protein called C-reactive protein that also binds to bacterial surfaces [C1q has six globular heads that recognize and bind to the Fc region of the antibodies].
C1q binding causes a conformational change, resulting in autocatalytic activation of C1r. Activated C1r then cleaves and activates C1s.
Once C1 is activated, it cleaves circulating complement proteins C4 and C2. C4b covalently binds to the pathogen’s surface or to pathogen-bound antibodies and C2a binds to C4b, forming the C4b2a complex. This complex is known as the C3 convertase, and it cleaves circulating C3 into C3a and C3b.
[Diagram]
Further notes:
What is the Fc region of an antibody? The Fc region, or fragment crystallizable region, is the tail part of an antibody that interacts with cell surface receptors known as Fc receptors, as well as some proteins of the complement system. This region is crucial for the antibody’s ability to activate the immune system. For example, through binding of Fc receptors, it mediates different phyisological effects of antibodies, such as detection of opsonized particles, cell lysis, and degranulation of mast cells, basophils and eosinophils.
What is degranulation?
Degranulation refers to the process where cells, particularly those involved in the immune response, release the contents of their granules into the extracellular space. These granules contain a variety of substances, such as enzymes, antimicrobial peptides, and other cytotoxic molecules, which play a role in the body’s defense mechanisms. For example, mast cells, upon activation, undergo degranulation to release histamine and other mediators that contribute to inflammation and allergic responses. Similarly, eosinophils degranulate to release substances that combat parasitic infections. Neutrophils also degranulate to release antimicrobial substances that help in controlling infections.
Discuss the lectin pathway of the complement system.
Lectins are proteins that can recognize and bind to specific carbohydrate groups. Some lectins play homeostatic roles within the host, while others act as pattern recognition receptors (PRRs) for pathogen sugars, such as those found on bacterial cell walls or adorning yeast cell surface proteins. There are four lectins that activate the complement system: mannose-binding lectin (MBL), ficolin 1, ficolin 2 and ficolin 3.
MBL is made in the liver and circulates in the bloodstream. It is a multimeric protein with multiple binding sites. It recognizes fructose, mannose, and N-acetylglucosamine. These sugar groups are commonly exposed on microbial polysaccharides but not on host cells. The ficolins are structurally similar to mannose binding lectin except that they bind acetylated sugars instead of mannose groups.
The lectin pathway is triggered when MBP or one of the ficolins binds to its respective sugar on a pathogen. The lectin will then complex with the circulating proteins MASP-1 and MASP-2, which are protease zymogens [homologous to C1r and C1s in the classical pathway]. MASP-1 and MASP-2 become activated and they cleave C4 and C2. C4b and C2a combine to form the C4b2a complex, known as the C3 convertase.
Discuss the alternative pathway of the complement system.
✈ The alternative pathway is initiated spontaneously when C3b directly binds to a microbe or pathogen surface. [Unlike the classical or lectin pathways, it does not rely on antibodies or lectins for activation.]
✈ Circulating Factor B then binds to C3b, and this allows another plasma protein called Factor D to cleave Factor B, resulting in a complex known as C3bBb.
✈ This complex acts as the C3 convertase in the alternative pathway.
✈ [Diagram]
Discuss the common pathway of the complement system.
Various pathways lead to the formation of the complex C3 convertase, which leaves C3 into two parts: C3a and C3b. C3a is an anaphylatoxin that promotes inflammation [it recruits neutrophils and other phagocytes to the site of infection]. C3b can do one of two things:
(1) many molecules of C3b can bind to the surface of the pathogen, coating it in a process called opsonization. This marks the pathogen for destruction by phagocytes e.g. macrophages. Phagocytes have receptors that recognize C3b.
(2) C3b may also bind to existing C3 convertase, creating a C5 convertase. C5 convertase cleaves C5 into C5a and C5b. C5a is released into circulation to recruit phagocytes [anaphylatoxin], while C5b initiates the assembly of membrane attack complex (MAC), leading to pathogen lysis.
Discuss the cascade that leads to the formation of the membrane attack complex.
☯︎ The process begins when C5 convertase cleaves C5 into two fragments: C5a and C5b.
☯︎ C6 then binds to C5b, forming the C5b6 complex.
☯︎ C7 binds to the C5b6 complex. Binding causes a conformational change in C7, which exposes a hydrophobic site on C7, allowing it to insert into the pathogen’s phospholipid bilayer.
☯︎ C8 binds to the complex, and this induces a conformational change that allows C8 to insert into the pathogen’s plasma membrane.
☯︎ This causes 10 to 16 molecules of C9 polymerize within the cell membrane to form a pore that allows water and solutes to flow out of the cell, hence killing it.
[Diagram 1] [Diagram 2] [Diagram 3] [Diagram 4] [Diagram 5]
Compare humoral and cellular immunity.
(a) Humoral immunity is antibody-mediated whereas cellular immunity is cell-mediated.
(b) Humoral immunity eliminates extracellular pathogens whereas cellular immunity eliminates intracellular pathogens.
(c) In humoral immunity, B cells play a major role whereas T cells play a major role in cellular immunity.
Discuss the inner workings of humoral immunity.
- Recognition: When a pathogen enters the body, it is recognized by its antigens, which are specific proteins or polysaccharides on the pathogen’s surface.
- Antibody production: B lymphocytes (B cells) are the primary cells responsible for humoral immunity. They can recognize antigens directly or with the help of antigen-presenting cells and helper T cells.
- B cell activation: Once a B cell recognizes an antigen, it becomes activated. This activation can be T cell dependent or T cell independent, depending on the nature of the antigen.
- Proliferation and Differentiation: Activated B cells proliferate and differentiate into plasma cells, which are specialized cells that produce antibodies specific to the recognized antigen.
- Primary and Secondary Response: The primary immune response occurs upon the first encounter with an antigen and it is relatively slow. The secondary immune response, however, is faster and more robust due to the presence of memory B cells created during the primary response.
- Antibody functions: The antibodies produced by plasma cells circulate in the blood and lymphatic system, binding to the antigens on pathogens. This binding can neutralize the pathogen, promote phagocytosis, or activate the complement system, which can lead to the lysis of the pathogen.
- Memory: After the pathogen is cleared, some of the activated B cells become memory B cells, which remain in the body and can quickly respond to future infections by the same pathogen.
Discuss the physiology of toll-like receptors.
Toll-like receptors are a class of proteins that play a key role in the innate immune system. They are expressed on cells such as macrophages and dendritic cells, and recognize structurally conserved molecules derived from molecules. Their functions include:
(1) Recognition of pathogens: TLRs can recognize both invading pathogens and endogenous molecules released from dying cells and damaged tissues. They are able to identify pathogens that cause cell injury and distinguish them from harmless microbes.
(2) Activation of immune responses: Once these microbes have breached physical barriers such as the skin or intestinal tract mucosae, they are recognized by TLRs, which activate immune cell responses. The binding of ligands to the TLR marks the key molecular events that ultimately lead to innate immune responses and the development of antigen-specific acquired immunity.
(3) Signal transduction: Upon, activation, TLRs recruit adaptor proteins within the cytosol of the immune cell to propagate the antigen-induced signal transduction pathway. These recruited proteins are then responsible for the subsequent activation of other downstream proteins, including protein kinases that further amplify the signal and ultimately lead to the upregulation or suppression of genes that orchestrate inflammatory responses and other transcriptional events.
(4) Production of cytokines: Some of these events lead to cytokine production, proliferation, and survival, while others lead to greater adaptive immunity.
(5) Phagocytosis: If the ligand is a bacterial factor, the pathogen might be phagocytosed and digested, and its antigens presented to CD4+ T cells.
(6) Apoptosis: In the case of a viral factor, the infected cell may shut off its protein synthesis and may undergo programmed cell death.
