Immune system

The Human Immune System

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What is the immune system?

The body’s defense against disease causing organisms, malfunctioning cells, and foreign particles

Role of the immune system

Defense against microbes Defense against the growth of tumor cells kills the growth of tumor cells Homeostasis destruction of abnormal or dead cells (e.g. dead red or white blood cells, antigen-antibody complex)
immune system consist of : cells Antibodies Complement Cytokines Interleukines Interferons

IMMUNE SYSTEM:(1) ORGANS

Tonsils and adenoidsThymusLymph nodesSpleenPayer’s patchesAppendixLymphatic vesselsBone marrow IMMUNE SYSTEM:(2) CELLS
Lymphocytes T-lymphocytes B-Lymphocytes, plasma cells natural killer lymphocytes Monocytes, Macrophage Granulocytes neutrophils eosinophils basophils
3:1 With TCR CD4,CD8
No TCR
Surface IgM



Components of Human Immune System

The cells of Immune System

Definitions
Immune system = cells, tissues, and molecules that mediate resistance to infections Immunology = Derived from latin (immunis)means free of burden( internal & external threats) , branch of biology ,study of structure and function of the immune system Immunity = resistance of a host to pathogens and their toxic effects Immune response = collective and coordinated response to the introduction of foreign substances in an individual mediated by the cells and molecules of the immune system

Antigen: Definitions & features

A molecule that can react with antibody. Where as immunogens is a molecule that induce an immune response some antigen is not immunogenic by itself but can react with antibody( haptin) a Features of immunogenicity:Foreignness(non self)( muramic acid, DAPA) (PAMP)Molecular size(↑10.000)M.WStructural complexity( homoplymer less antigenic than heteropolymerAntigenic determinant( epitopes):the smallest unit of antigen capable to bind to antibody immunogen must be multivalent

Innate immunity: mechanisms

If failed

Two types of immunity

Innate (non-adaptive) first line of immune response relies on mechanisms that exist before infection( pre existing) Non specific Acquired (adaptive) Second line of response (if innate fails) relies on mechanisms that adapt after infection several days handled by T- and B- lymphocytes one cell determines one antigenic determinant Produce memory cells response strongly in second exposure

Innate immunity

Based on genetic make-up Relies on already formed components Rapid response: within minutes of infection Not specific same molecules / cells respond to a range of pathogens Has no memory same response after repeated exposure Does not lead to clonal expansion

Has 4 Characteristics Memory Diversity Antigenic Specificity Self/nonself recognition

Adaptive Immunity

Innate (Non-Specific) Immunity

Innate Immunity Made Up Of 4 Forms Anatomical, physiological, phagocytic and inflammatory Anatomical: skin, epidermis (densely packed dead cells) Flow of Mucus Prevents Bacterial Entry By Washing Them Away Normal Flora Colonize Epithelial Cells Of Mucosal Surfaces, Pathogens Compete With Them For Attachment Sites

The First Line of Defense Mechanical barriers~Skin~

The dead, outer layer of skin, known as the epidermis, forms a shield against invaders and secretes chemicals that kill potential invaders You shed between 40 – 50 thousand skin cells every day!

As you breathe in, foreign particles and bacteria bump into mucus throughout your respiratory system and become stuck Hair-like structures called cilia sweep this mucus into the throat for coughing or swallowing
The First Line of Defense~Mucus and Cilia~
Don’t swallowed bacteria have a good chance of infecting you?

The First Line of Defense Chemical barriers~Saliva~

Saliva contains many chemicals that break down bacteria Thousands of different types of bacteria can survive these chemicals, however


Swallowed bacteria are broken down by incredibly strong acids in the stomach that break down your food
The First Line of Defense~Stomach Acid~

The Second Line of Defense~White Blood Cells~

If invaders actually get within the body, then your white blood cells (WBCs) begin their attackWBCs normally circulate throughout the blood, but will enter the body’s tissues if invaders are detected Video


These white blood cells are responsible for eating foreign particles by engulfing them Once engulfed, the phagocyte breaks the foreign particles apart in organelles called ________
White Blood Cells ~Phagocytes~
Lysosomes
Where could invaders hide from phagocytes?

Phagocytosis

Phagocytosis is a process by which phagocytic cells ingest extracellular particulate material, including whole pathogenic microorganisms. The phagocytic cells involved in innate immune responses such as (neut., mono., macr.) Unlike adaptive immunity Phagocytic cells are designed to recognize only a few highly conserved structures present in many different microorganisms Called: pathogen-associated molecular patterns PAMPs are molecular components common to a variety of microorganisms but not found as a part of eukaryotic cells


• lipopolysaccharide (LPS) from the Gram-negative cell wall • peptidoglycan, lipotechoic acids from the Gram positive cell wall • mannose (common in microbial glycolipids and glycoproteins but rare in humans)• bacterial DNA • N-formylmethionine found in bacterial proteins • double-stranded RNA from viruses • glucans from fungal cell walls. pattern-recognition receptors and Toll-like receptors PRRs on APC
pathogen-associated molecular patterns PAMP


C-reactive protein act as a soluble PRR bind to bacteria to promote phagocytosis • α1-Antitrypsin neutralizes proteases released by bacteria, activated polymorphonuclear leukocytes • Mannose-binding protein functions as a soluble PRR and activates the lectin complement pathway to promote inflammation and attract phagocytes. Chemical Mediators Of Inflammation Acute phase protiens

interferon

Interferon: glycoproteins, comprises a group of cytokines that mediate innate immunity and includes : (beta inter. From V. infec.cell ) that protect against viral infection (alpha IF from mono.& fibro.) that initiate inflammatory reactions (gamma IF from T cell). that protect against bacterial pathogens by enhance phagocytosis

~ (NK cells)~

T-Cells, often called “natural killer” cells, recognize infected human cells and cancer cellsT-cells will attack these infected cells, quickly kill them, and then continue to search for more cells to kill

NK cells

Large granular lymphocytesLack TCR,CD3,IgM,IgD.Developed normally in the absence of thymusActive prior to exposureKill virus infected cell& tumor cellsNon specificKilling activated by down regulation of MHC Ɩ by cellKill by garaenzyme,Perforin & fas-fas ligand

NK cell

It consists of at least 30 components – enzymes, regulators and membrane receptors – which interact in an ordered and tightly regulated manner to bring about phagocytosis or lysis of target cells. (augment the effect of immune system) Complement components are normally present in body fluids as inactive precursors.Two pathways for complement activation :Alternative pathway AgClassical pathway Ag-Ab complex Mannose binding lectin pathwayComplement factor C3 is the central component of both the classical and alternative pathways Complement

Alternative pathway

decay-accelerating factor (DAF), membrane cofactor protein (MCP), (factor H), CR1 and factor I.

Classical pathway

Membrane attack complex

Complement path ways

Function of complement

1- Opsonization Ag-Ab comlex & viruse (C3b have R.on the surfase of phagocytes) 2-Chemotaxis ( C5a , C6a,C7a) component attract neutrophils 3-Anaphylatoxin(C3a,C4a,C5a) degranulation of mast cell release histamin vascular permeability smooth muscle contraction, bronchspasim 4- Cytolysis by MAC 5-Enhance Ab production By C3b which bind to IgM on Bcell

Cytokines

Cytokines are low-molecular-weight hormone-like glycoproteins secreted by leukocytes and various other cells in response to a number of stimuli, which are involved in communication between cells, particularly those of the immune system. Lymphocyte-derived cytokines are known as lymphokines, interleukins (ILs), cytokins secreted by some leukocytes and act upon other leukocytes. Their action is mediated by binding to specific receptors on target cells. Chemokines are a family of low-molecular-weight, structurally related cytokines that promote adhesion of cells to endothelium, chemotaxis and activation of leukocytes.

Cytokines

Close collaboration Macrophages can secret cytokines that affect the type of adaptive immunity Macrophages/DCs Present Antigen Lymphocytes Increase Effectiveness of Macrophages
Innate and Adaptive Immunity Collaborate



Number of Cells capable of Antigen Presentation Dendritic Cell (DC) professional APC Macrophages B cells Besides Antigen They Provide Co-stimulation
Antigen Presenting Cells

function of Macrophages

1- phagocytosis 2-Ag presentation 3- Cytokine production : 1- IL1 (endogenous pyrogene) activate many immune cells 2-TNF inflamm.mediator 3- IL12


MHC
The major histocompatibility complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules, which in turn determines histocompatibility. The main function of MHC molecules is to : bind to Ag. derived from pathogens display them on the cell surface for recognition by the appropriate T cell Clonal deletion (-ve selection ) & +ve selection Bind only to peptide Ag.

Types of MHC

MHC class II found on professional antigen-presenting cells (APCs): macrophages, B cells, and especially dendritic cells (DCs) MHC class I occurs on all nucleated cells . It presents epitopes to killer T cells, also called cytotoxic T lymphocytes (CTLs). A CTL expresses CD8 receptors, in addition to TCRs. When a CTL's CD8 receptor docks to a MHC class I molecule, if the CTL's TCR fits the epitope within the MHC class I molecule, the CTL triggers the cell to undergo programmed cell death by apoptosis.


First Protein Antigens Must Be Broken Down Form Complexes With MHC I or II Exogenous Antigens Antigens Processed Through Endocytic Pathway Binding of Ags To MHC II Expression of MHC II+Ags On Surface CD4 T Cells Recognize Ag Thru Class II MHC Endogenous Antigens Antigens Processed Thru Cytosolic Pathway Produced Within Cell, Ex. Virus Ag, Cancer Ag MHC I Molecules Bind Ag in ER CD8 T Cells Recognize Ag Thru MHC I

Processing and Presentation of Antigens

Processing and Presentation of Antigens

The adaptive immune system

The Third Line of Defense  1- Humoral or Ab mediated immunity 2 -Cell Mediated Immune Response

B cells are highly efficient APCs. They receive 1 signal for activation by binding antigen, to the BCR proceed to internalize antigen and process peptides on to MHC II molecules for presentation to T-helper cells They are then induced to express co-stimulatory B7 and can therefore provide signal 2 for T-helper cell activation through CD28
B cell activation

B cell activation

Activated T-helper cells are induced to express CD40L for binding to B cell CD40. Interaction between these two molecules induces B cell activation, Ig production and isotype switching. IL-12 is not usually the dominant cytokine at the site of B–TH interaction, so T-helper cells induced by B-APC will generally be of the TH2 type, secreting IL-4, IL-5 and IL-10. These lymphokines further promote B cell proliferation, activation and isotype switching.

B cell activation

Fate of Antigen-Antibody Complexes
Ag-Ab complexes engulfed into the B-cell and partially digested Antigen is displayed on the B-cell surface by a special receptor protein (MHC II) fo recognition by helper T-cells B-cell is activated by the helper T-cell to divide and produce secreted antibodies Abs circulate in the serum and lymph Some B-cells become memory cells to produce antibody at a low rate for a long time (long term immunity) They respond quickly when the antigen is encountered again

Clonal Selection of B Cells is Due to Antigenic Stimulation

Antibodies, or immunoglobulins (Igs), are the secreted products of B lymphocytes, which have become activated following binding of antigen to their B cell receptors (BCRs). The specificity for antigen of the secreted antibody is the same as that of the BCR, so they will bind to the same antigen that induced their production. The formation of the antigen–antibody complex may result in: • neutralization of the antigen (e.g. soluble toxins, viruses) • removal of the complex by phagocytic cells, which bind via Fc receptors (FcRs) to the Ig constant region • killing of antigen-bearing cells by the membrane attack complex of complement or by natural killer (NK) cells, monocyte/macrophages or granulocytes, which bind antibody-coated cells via FcRs. ~Antibodies~

Classes of Antibodies (Immunoghlobulins)

Monomer or dimer

Immuoglobulin G (IgG)

Humoral Immune Response to Antigen
First exposure to antigen "A”:begin to make low levels of antibody in about a weekSecond exposure to antigen "A”:produces a much faster response, andseveral orders of magnitude higher levels of antibody. Ability of antibody to bind antigen also increases dramatically in the secondary response. Injecting a new antigen "B” with "A" Elicits only a primary responseShows that a memory or prior exposure is required for the accelerated response.

Primary & Secondary immune response

Cell mediated immune response
Primary response production of specific clones of effector T cells and memory clones develops in several days does not limit the infection Secondary response more pronounced, faster more effective at limiting the infection

First stimulus

Time
Second stimulus
Antibody titer
IgM
IgG
Anamnestic response
Primary & secondary response
IgM

T helper cell CD4

The nature of the immune effector response is largely determined by the range of lymphokines secreted by activated T-helper cells. depending on the type of APC If the APC is a macrophage or dendritic cell, it will normally be stimulated to produce IL-12 during T-helper cell activation&IFN-γ, which stimulates the TH1 and suppresses the TH2 secretion If the APC is a non-IL-12 producing cell, such as a B cell, or if TH0 activation takes place in an environment containing IL-4-secreting cells IL-4 stimulates production of TH2- and suppresses TH1-type lymphokines.

Functions of T helper cell

Activate the Ag specific helper cell to produce clone of these cells(IL2) Activate CTC by (IL2) Activate B cell by IL4- &IL5 Activate Macrophage

T helper cell CD4

AAb mediated immunity
Acell mediated immunity

CTC Activation Mode of action

Cytotoxic T cells carrying CD8, activated via the endogenous antigen presentation pathway, are able to recognize and kill target cells, such as virus-infected cells, expressing MHC I + foreign peptide Both CD8 and various adhesion proteins are important in enhancing and maintaining target cell–effector cell contact. When a cytotoxic T cell makes contact with its specific target, cytoplasmic granules polarize to the contact point and are released into the narrow gap between the cells.

Cytotoxic granules contain perforin and granzymes. Perforin is polymerize on the target cell surface, forming transmembrane channels. Granzymes are granular proteases, which gain entry into the target cell through perforin pores. Granzymes activate the target cell’s suicide programme (apoptosis), which leads to nuclear fragmentation and packaging of products of nuclear disintegration into apoptotic bodies, which are efficiently removed by phagocytosis. Target cell apoptosis can also be induced by binding of Fas ligand (FasL), induced during activation of cytotoxic effector T cells, with the death receptor Fas (CD95) on target cell.

Cell Mediated Immune System: T lymphocytes

T-cells mature in the thymus (thus the name T-cell) Act on antigens appearing on the surface of individual cells. Over a million different kinds of T-cells Each produces a different receptor in the cell membrane Each receptor is composed of 1 molecule each of two different proteins Each receptor binds a specific antigen but has only one binding site Receptor only recognizes antigens which are "presented" to it within another membrane protein of the MHC type (major histocompatibility complex).

T Cells and their Functions

Have a specific receptor for a fragment of antigen Cytotoxic T-cells: Contain a surface protein called CD8 Destroy pathogen infected cells, cancer cells, and foreign cells (transplanted organs) Helper T-cells: Contain a surface protein called CD4 Regulate both cellular and humoral immune systems This regulation reduces autoimmunity.
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Adaptive Immunity: active and passive