MLS17-1. Immunologyserology PDF

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BSMLS 3F REVIEWERSmesterMLS 17 - 1 : Immunology & SerologyRMT 2022 (A. 2020-2021)####### Ms. Yvonne Capatayan, RMT1 st cycle: MODULE 8: IMMUNE REGULATION – PART 12ndTOPIC OUTLINE 8. Immune enhancers and suppressors 8. Role of TH in immune response 8. Apoptosis 8. Immune Tolerance LEARNING O...

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MLS 17 17-1: -1: Immunology & Serology

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RMT 2022 (A.Y. 2020-2021) Ms. Yvonne Capatayan, RMT 1st cycle: MODULE 8: IMMUNE REGULATION – PART 1

TOPIC OUTLINE 8.1. Immune enhancers and suppressors 8.2. Role of TH in immune response 8.3. Apoptosis 8.4. Immune Tolerance LEARNING OBJECTIVES 1. Enumerate the different enhancers and suppressors immune response. 2. Identify the central role of T cells in immune regulation. 3. Identify the activators of and mechanisms involved in apoptosis. SOURCE LEGENDS : Module Packets :Text Books  : Lecturer’s Sidenotes [text]: Transcriber’s Sidenotes INTRODUCTION CYTOKINES • As tackled in Module 7, these are chemical messengers that regulate the immune system, orchestrating both innate immunity and the adaptive response to infection. • Cytokines are small proteins produced by several different types of cells that influence the hematopoietic and immune systems through activation of cell bound receptors. • Cytokines are induced in response to the binding of stimuli, such as bacterial lipopolysaccharides, flagellin, or other bacterial products, to specific cell receptors or through the recognition of foreign antigens by host lymphocytes. • The effects of cytokines in vivo include: ✓ regulation by of growth ✓ differentiation ✓ gene expression by many different cell types, including leukocytes. Q: What are cytokines? What produce them? What are their significant functions? • So, cytokines are chemical messengers produced by several types of cells and they have activitymodulating effects on the hematopoietic (if you can recall, we have interleukins in hematopoiesis) and immune systems though activation of cell-bound receptor proteins. Q: How are they produced/induced? • Cytokines are induced in response to stimuli (e.g., Lipopolysaccharides, flagellin) through ligation of cell adhesion molecules or through recognition of foreign antigens by host lymphocytes. [If you could still recall the hormones in endocrine system, hormones are the chemical messengers that mediate different

bodily functions for the immune system. The counterpart of hormones are the cytokines. So, they are produced in response to producing different types of functions as well as that can activate or contribute to total immunity of our body.]

[As you can see in the illustration, inducing stimulus (lipopolysaccharides, flagellin, other bacterial products) binds with cytokine-producing cell. The binding will then trigger the cytokine-producing cell to release cytokines. Cytokines will then bind to its specific target cell receptor. Once bounded, it will signal the gene activation of the target cell which will trigger biological effects. More detailed explanation as you go along.]

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Cytokines act only on cells bearing specific receptors and their expression is highly regulated. [That means, cytokines have specificity in where they would attach and respond firmly on target cells that bear specific receptors (loyal kumbaga). They only attach to the target cells that could only recognize them. ]

MODES OF CYTOKINE ACTION

 Cytokine mechanism action is dependent on signaling mechanism.  If the cytokine signals were secreted and received the cells itself, it is called autocrine action. [That means siya nagproduce/secrete, siya man mabenefit.]

 If the cytokine signals were secreted for another cells or different target cells, it is a paracrine action. [That means different cell ang nag-induce cytokines signal, and the cytokine signals that were released were received by different target cell.]

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 If the cytokine signals secreted traveled first into the general circulation before being received by the target, distant cells then it is an endocrine action. • Cytokines are pleiotropic in nature. One cytokine can have different effects on different cells.

more cytokines combine for a doubled or stronger efficiency of function. For example, IL-4 and IL-5, they combine for a better synergistic effect of their functions in a B-cell. Apart form inducing proliferation and multiplication on B-Ccell, they will induce class switch of the B cell or it will proliferate or differentiate into immunglobulin E. Some cytokines can also antagonize each other. For example, there are some cytokines which function is exactly to inhibit or block the function of the other cytokine. One example is the interferon-gamma in which they usually block or prevent the action of IL-4 on switching B-cell into an immunoglobulin.]

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Cascade effect, cytokines production of other cytokines.

can

stimulate

the

[So, even if we only have one cytokine, they can still have different effects in different cells. For example, interleukin-4, it has different actions and functions in several cells. Other interleukins can induce activation, proliferation, and differentiation in B-cells. Thymocytes or T-cells can also induce proliferation, mast cells can also induce development and proliferation]

• Cytokines can be redundant. [Meaning, even if cytokines have different origins, they can have the same effects or actions or functions.]

[So, remember when we say pleiotropic it means one cytokine have different effects to different cells. This time is redundancy of cytokines, meaning different cytokines with the same effects or function. For example, most interleukins in the form of interleukin-2,4,5, all of them have the same effects on the Bcells where they induce proliferation. That is redundancy, different cytokines respond on one cell inducing the same functions. Also, take note of the three cytokines mentioned. All of them can cause proliferation and multiplication of B cells.]

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 Cascade effect sounds familiar because in Module 4, we have there the complement cascade, which both have same mechanism. [If you could recall the complement system, starting with the activation and the cleavage of the complement proteins, they usually stimulate the activation of different kinds of complements. So if you can recall, C4 cleaves to C4a and C4b, C2 cleaves to C2a and C2b, then C4a will bind to C2b forming C4a2b, then it will activate cleavage of C3 to C3a and C3b and then so on and so forth. In other words, cascade is a chain reaction. One cytokine activates other cytokine to activate or react with the target cell eventually causing a reaction of another cytokine. In a more simple and shortened explanation, they help the activation of each other.]

Cytokines can synergize with each other.

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[Take note of the word “synergize”, that means some cytokines combine with another cytokine to combine their effect on a certain cell. When we say “synergistic” or “synergism”, two or

2 CLASSIFICATION OF CYTOKINES Structural Grouping ✓ Interferons ✓ Tumor Necrosis Factor ✓ Interleukins (IL-1 to IL-32) ✓ Transforming Growth Factors (TGF) ✓ Colony Stimulating Factors (CSF)

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Functional Grouping

Mediators and regulators of innate immunity

Act on endothelial cells and leukocytes to stimulate eary innate response. [ mostly cytokines that have

IL-1 • • • •

contributions to the innate immunity]

Mediators and regulators of adaptive immunity

Stimulators of hematopoiesis

Act on lymphocytes to stimulate and regulate adaptive responses to specific things.

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Act on the bone marrow to stimulate grwoth and differentiation of leukocytes and lymphocytes.

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CYTOKINES OF INNATE IMMUNE SYSTEM ✓ Type 1 IFN (IFN-α, IFN-β) ✓ IL-1 ✓ IL-6 ✓ IL-12 ✓ IL-15 ✓ IL-18 ✓ TNF-α ✓ TGF-β ✓ Chemokines IFN- α and IFN- β • Interferes with viral replication and cell division. • Activates NK cells and enhances Class I MHC expression, thus increasing the recognition and killing of virus-infected cells. • Origin: ▪ IFN- α: Leukocytes ▪ IFN- β: Fibroblasts, epithelial cells [Once you hear the word “interferon”, that means to interfere. So alpha and beta interferons are cytokines that: 1. Interferes viral replication and cell division 2. Activates NK cells and enhances Class I MHC expression which in result increases virus-infected cells recognition and killing.

IL-1 family consists of IL-1β, IL-1α, and IL-1RA Origin: monocytes and macrophages Acts as an endogenous pyrogen Induces fever in acute phase response through its actions in the hypothalamus [So, your IL-1 are subclassified into three including IL1B, IL-1a, and IL-1RA which originates from the monocytes and macrophages that act as an endogenous pyrogen in which during acute phase immune response acts in the hypothalamus inducing a fever.]

[mostly cytokines that have contributions to the adaptive immunity]

[As mentioned, these are cytokines with direct involvement in the bone marrow; They have effects to the quicker super cells that will eventually cascade into the hematopoietic stem cells; They also help in the differentiation of naïve cells.]

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Induces the production of vascular cell-adhesion molecules as well as chemokines and IL-6. IL-1RA acts as an antagonist to IL-1 by blocking the IL-1 receptor and limiting the availability of the receptor for IL-1. This helps to regulate the physiological response when no longer needed.

ILA-1RA makes sure that there is no overproduction of IL1.  If the body doesn’t need the action of IL-1, the IL-1RA take in charge so there will be no abusive or overstimulation of the different interleukins .

IL-6 • Origin: macrophages, T cells, osteoblasts • It is part of the cytokine cascade released in response to lipopolysaccharide and plays an important role in acute phase reactions and the adaptive immune response. IL-6 is a cytokine cascade which is released during a lipopolysaccharide infection.  Recap: if an invading microorganism has a lipopolysaccharide on their cell surface, what complement pathway will be triggered? Alternative Pathway  Likewise, IL-6 will be released in terms of lipopolysaccharide detection by the antigen. 

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IL-6 is expressed by a variety of normal and transformed cells, including T cells and B cells, monocytes, and macrophages, fibroblasts, hepatocytes, keratinocytes, astrocytes, vascular endothelial cells and various tumor cells. Stimulates B cells to proliferate and differentiate into plasma cells and induces CD4+ T cells to produce greater quantities of both pro- and anti-inflammatory cytokines.

 Apart from that they help in the innate immunity. They are also release or stimulated during inflammation or inflammatory responses.

IL-12 (NK Stimulatory factor) • Origin: B cells and macrophages. • Stimulates the production of IFN-gamma by NK and T cells, stimulating the differentiation of naïve T cells into Th1 cells and enhancing cytolytic functions of activated NK cells and CD8+ Tc cells.

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Recall, one of the subtypes of T lymphocytes is T helper cells or CD4+ cells. Th or CD4+ cells have further subtypes, Th1 and Th2 cells. So, IL-12 helps the naïve Th cells to differentiate into Th1 cells. Growth factor for activated NK-LAK cells .

• IL-15 • Origin: T cells • It is produced in response to viral infection and other signals that trigger innate immunity. • Promotes proliferation of NK cells • Produces survival signals for memory lymphocytes • Acts as synergist in LAK cell induction process • Increases antitumoral activities of T-killer and NK cells and can be chemoattraction for T lymphocytes. • Endogenous IL-15 is the key condition for IFNgamma synthesis  

Main triggering factor is viral infections Other signals that trigger innate immunity also involve IL15.  So, during viral infections IL-15 combines with LAK-cell which increases the antitumoral activities of T-killer and NK cells. It promotes proliferation of NK cells as well as the production of survival signal for the memory lymphocytes.

IL-18 • Origin: macrophages • Acts as synergist with IL-12 which stimulates the production of IFN-gamma by NK and T cells. • High IFN-gamma production under integrated effect of IL-18 and IL-12 suppresses tumor growth. TNF- α (Cachectin) • Origin: macrophages • Activates T cells through its ability to induce expression of MHC class II molecules, vascular adhesion molecules, and chemokines. • When secreted at higher levels, TNF can have deleterious systemic effects, leading to: septic shock, causing a decrease in blood pressure, reduced tissue perfusion, and disseminated intravascular coagulation. The latter may lead to uncontrolled bleeding. 

TNF is an inflammatory chemical mediator or also responds to in terms of inflammation of the body.  However, over-excessive or too much production can lead to ill effect or harmful effects, particularly septic shock that can cause bleeding .

TGF-β • Origin: T cells • Active TGF- is primarily a regulator of cell growth, differentiation, apoptosis, migration, and the inflammatory response. Thus, it acts as a control to help downregulate the inflammatory response when no longer needed. • Inhibitory cytokine • TGF- β regulates the expression of CD8 in CD4– CD8– thymocytes and acts as an autocrine inhibitory factor for immature thymocytes. • It inhibits the activation of macrophages and the growth of many different somatic cell types and functions as an anti-inflammatory factor for mature T cells. • TGF- β blocks the production of IL-12 and strongly inhibits the induction of IFN-γ 

It is important that there are molecules that function is to regulate to ensure the over-excessive production.  Transforming growth factor acts as an inhibitory cytokine in innate system which prevents most of the cytokines once they reach the hemostasis or proper response of the body.

CHEMOKINES • Family of cytokines that enhance motility and promote migration of many types of white blood cells toward the source of the chemokine (chemotaxis) • Target cells are macrophages. • Structural grouping: C Chemokines, CC Chemokines, CXC Chemokines and CX3C Chemokines Are cytokines and chemokines similar? • Cytokines are signaling molecules produced by cell for specific biological functions. • Cytokine is a general term used for all signaling molecules while chemokines are specific cytokines that functions by attracting cells to sites of infection or inflammation. [So cytokines and chemokines are similar but cytokines are in general term, whereas chemokines are specific group of cytokines.]

Are cytokines and interleukins similar? • The main difference between cytokines and interleukins is that cytokines are small proteins involved in cell signaling, whereas interleukins are a group of cytokines that regulate the immune and inflammatory responses. [ Again, when we say cytokine it is more general in terms whereas when we say interleukins and chemokines they are more specific. So, chemokines and interleukins are all cytokines. Since cytokines are chemical messengers, so as your interleukins and chemokines.]

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FUNCTIONAL GROUPING Homeostatic chemokines: control the migration of cells during the normal development and maintenance of tissues and lymphoid organs. [Here, there is still migration of immune cells and WBCs, however they have an impact in development, maturation and differentiation of precursor cells, tissues, and organs.]

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Inflammatory chemokines: produced in response to infection or injury and direct the migration of leukocytes into the infected or damaged site. [So, these types of chemokines tell WBCs and immune cells to migrate in response to infection and injury infected or damaged sites. They are responsible for transporting immune cells during inflammation and injury.]

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Angiogenic chemokines: promote the development of blood vessel (pro-angiogenic) other prevent the development of blood vessels (anti-angiogenic) [So, we have two types of angiogenic chemokines, when it promotes development of blood vessel, they are pro-angiogenic, whereas when they prevent development of blood vessel, they are anti-angiogenic.] [They also stimulate or induce chemotaxis wherein there is migration of WBCs or immune cells towards the site of inflammation or infection.]

CYTOKINES OF AADAPTIVE IMMUNE SYSTEM • IFN-γ Th1 cytokines • IL-2 • IL-4 Th2 cytokines • Il-10 • IL-5* • IL-13* [Interferon-gamma and IL-2 are cytokines that mediate or initiate differentiation of Th cells to Th1 cells, whereas IL-4 and IL-10 are cytokines that mediate differentiation of Th cells into Th2 cells. Lastly IL-5 are cytokines that mediate eosinophilic inflammation and T-cell activation, and IL-13 are the important mediator of allergic inflammation and disease.] More detailed explanations will be explained as you go along.

IFN-γ • Origin: Th1 cells • Actions: ✓ Regulation and activation of CD4 Th1 cells, CD8 cytotoxic lymphocytes, NK cells, bactericidal activities, IL-12R and IL-18R. ✓ Stimulates antigen presentation by MHC I and MHC II molecules. ✓ Stimulator of macrophages and boosts their tumoricidal activity. IL-2 (T-cell growth factor) • Origin: Th cells (CD4+) • Actions: ✓ Drives the growth and differentiation of both T and B cells.

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✓ Induces lytic activity in NK cells. ✓ IL-2 and IFN induce the development of Th1 cells, which, in turn, induces macrophage activation and delayed type hypersensitivity. ✓ IL-2 alone can activate proliferation of Th2 cells and helps in generating IgG1 and IgE producing cells. [IgG and IgE are antibodies and the only cells that produce them is the plasma B cells. So, that means IL-2 are mediators for the differentiation of B-cells into plasma B cells that produces antibodies when need arise.]

IL-4 • Origins: T cells & mast cells • Actions: ✓ Induces differentiation of naïve helper T cells (Th0 cells) to Th2 cells. [ Remember, when we say “naïve” that means they are virgin or cells that have not gone through differentiation or maturation.]

✓ Promotes the production of IgG2a and IgE. ✓ Along with IL-5, they drive the differentiation and activation of eosinophils in both allergic immune response and they respond to parasitic infections. [So as mentioned, your IL-4 and IL-5 works together to drive the differentiation and activation of eosinophils during allergic inflammations and parasitic infections. Since they work together, that means they follow the synergism effect. Also if you can recall, once there is allergic inflammation and parasitic infections, your eosinophil is the main blood cell involved, but they need activation through the IL-4 and IL-5.]

IL-10 • Origin: monocytes, macrophages, CD8+ T cells and Th2 CD4+ t CELLS. • Actions: ✓ Inhibits activated macrophages. ✓ Displays potent abilities to suppress antigenpresenting of APCs. ✓ Released by Tc cells to inhibit the action of NK cells during immune response to viral infection. ✓ Predominantly an inhibitory cytokine. [If you can recall in Module 7, we have there the Regulatory T cells which are cells that suppresses the immune respon...