Immunology Lecture
Lymphatic System:
Network of vessels that penetrate every tissue, and a collection of tissues & organs that produce immune cells
It has 3 main functions:
1.Fluid recovery
2. Immunity
3. Fat absorption ( Lacteals )
Lymphoid Organs
1.Primary : Thymus , BM
2.Secondary : LN , Tonsils( Nodules ), Peyer Patches( at last segment of small intestine) & spleen
Have well defined anatomical sites & capscule
3.Mucosa Associated Lymphatic tissue MALT
LYMPHOID TISSUES
Secondary Primary
(Sites for Ag contact and response) (Responsible for maturation of Ag-reactive cells)
Spleen Lymph node BM Thymus
(T-cell maturation)
Similar to lymph nodes but part of blood circulation. Collects blood-borne Ags (Expansion of lymphatic system, separate from blood circulation. Deep cortex harbors mostly T-cells, superficial cortex harbors mostly B-cells) (B-cell maturation) (T-cell maturation)
Principles
• The immune system defends the body against invading agents, participates in autoimmune and hypersensitivity disorders, and determines transplant tissue reactions.
• The ability to recognise foreign antigens allows destruction and removal of invading organisms by various effector mechanisms.
• Inappropriate immune reactions against self-antigens or host cells result in autoimmune disorders.
• Overt responses to an antigen result in hypersensitivity disorders.
Cells of Lymphatic System:
Immune responsive cells can be divided into five groups based on
i) the presence of specific surface components
ii) function:
B-cells (B lymphocytes), T-cells (T lymphocytes), Accessory cells (Macrophages and other antigen-presenting cells), Killer cells (NK and K cells), and Mast cells.
Functions Surface components Cell group
Direct antigen recognition Differentiation into ABproducing plasma cells
Antigen presentation within Class II MHC Surface Ig(Ag\recognition) ImmunoglobulinFc,receptor Class II Major Histocompatability Complex (MHC) molecule (Ag presentation) B-lymphocytes
Involved in both humoral and cell-mediated responses CD3 molecule
T-cell receptor (TCR, Ag recognition) T-lymphocytes
Recognizes antigen presented within Class II MHC
Promotes differentiation of B-cells and cytotoxic T-cells Activates macrophages CD4 molecule Helper T-cells (TH)
Downregulates the activities of other cells CD8 molecule Suppressor T-cells (TS)
Recognizes antigen presented within Class I MHC
Kills cells expressing appropriate antigen CD8 molecule Cytotoxic T-cells (CTL)
Phagocytosis and cell killing Variable Accessory cells
Bind Fc portion of Ig (enhances phagocytosis) Bind CC C3b (enhances phagocytosis) Antigen presentation within Class II MHC
Secrete IL-1 (macrokine) promoting T-c differentiation and proliferation Can be "activated" by T-cell lymphokines
ImmunoglobulinFc\receptor Complement\componentC3b receptor ,
Class II MHC molecule Macrophages
APCwithin Class II MHC Class II MHC molecule Dendritic cells
Bind Fc portion of Ig (enhances phagocytosis) Bind CC C3b (enhances phagocytosis) Immunoglobulin Fc receptor Complement component C3b receptor Polymorphonuclear cells (PMNs)
Direct cell killing Variable Killer cells
Kills variety of target cells (e.g. tumor cells, virus-infected cells, transplanted cells) Unknown NK cells
Bind Fc portion of Ig Kills antibody-coated target cells (antibody-dependent cell-mediated cytotoxicity, ADCC) Immunoglobulin Fc receptor K cells
Bind IgE and initiate allergic responses by release of histamine High affinity IgE Fc receptors Mast cells
( 1 ) T cells ( Thymus Dependent )
( 2 ) B Cells Lymphocytes : changed into plasma cells when activated & produce AB the protective Ig in tissue fluids
( 3 ) Macrophage : Derived from monocytes of the blood . ( - phogocyte foreign matter Antigens , - “Display’’ frogments antigen to certain T cells alerting immune system to the presence of Enemy ,
Works as part of APC with other cells
( 4 ) Dendritic cells are APCs in the epidermis & mucus membrane and lymphatic organs ( in the skin is called Langerhan’s cell )
( 5 ) Reticular cells : stoma or connective tissue network in lymphoid organs and in the thymus can works as APCs
Thymus Gland
A gland that has lymphoid & endocrine functions , house developing lymphocytes and secrete their activating hormones
Located in the superior mediastinum between the sternum & aortic arch
It is large in the Fetus & grows slowly during childhood ,when it is most active , after 14 begins to shrink ( involution ) where in adults its very small and in elderly replaced by fibrous and fatty tissues making it indistinguishable from surrounding tissues .
Thymus Gland Structure
Fibrous capscule sends trabeculae , which divide the parenchyma into several angular lobules each lobule is divided into Cortex and Medulla that populated by Lymphocytes
Reticular Epithelial cells seal off the cortex from the medulla and surrounding blood vessels and lymphocytes cluster in the cortex,( Blood – Thymus Barrier ) which isolates developing lymphocytes from forieng antigens
There is no Blood – Thymus Barrier in the medulla and T cells develops in the cortex and leaves the cortex to the medulla & spend during this period 3 weeks .The reticular epithelial form WHORL called Thymic HASSAL corpuscles , their function is unknown and serete the hormones Thymosin & Thymopoitin which promote development & activation of T lymphocytes
Spleen
The parenchyma divided into White pulp & Red pulp ( red pulps are sinuses engorged with concentrated RBCs, and the White pulps are lymphocytes and macrophages that accumulate like a sleeve along the small branches of splenic artery .What is the function of the spleen ?
Immune resistance & defence
Immune defences are normally categorised into:
1)Innate immune response( Non specific )which provides immediate protection against an invading pathogen, and
2) Adaptive or acquired immune response, which takes more time but confers exquisite specificity and long-lasting protection.
PROPERTIES OF IMMUNE RESPONSES
Innate Adaptive
Immediate slow, Amplification
No memory Memory, Self Recognition
Immuune Response:
Host defense is present in many forms. Overall, the Immune Response (IR) can be divided into two major classifications; humoral and cell-mediated. While these responses are not mutually exclusive, they provide distinctly different avenues for dealing with pathogenic organisms or altered host cells.
Immune Response
CMIR Humoral
(Cytotoxicity) (Antibody)
DEFINITIONS:
Antigen (Ag): A molecule which elicits a specific immune response when introduced into an animal. More specifically, antigenic (immunogenic) substances are:
1. Generally large molecules (>10,000 daltons in molecular weight),
2. Structurally complex (proteins are usually very antigenic),
3. Accessible (the immune system must be able to contact the molecule), and
4. Foreign (not recognizable as "self").
Antibody (Ab): A glycoprotein produced in response to an antigen that is specific for the antigen and binds to it via non-covalent interactions. The term "immunoglobulin" is often used interchangeably with "antibody". We will use the term "immunoglobulin" to describe any antibody, regardless of specificity, and the term "antibody" to describe an antigen-specific "immunoglobulin". Immunoglobulins (Igs) come in different forms (IgA, IgD, IgE, IgG, IgM) that reflect their structure. More information can be found here.
Antibody kinetics: The above figure illustrates the production of antibody in response to antigenic substances. In this figure, an animal was injected with Antigen A at day 0. Antigen A invokes a primary response beginning about day 4, as indicated by a rise in the specific antibody titer (titer = measure of the amount of antibody in the animal s serum per unit volume). Initially, this antibody is mostly IgM (and some IgG). After a peak titer between days 7 and 10, the response decreases rapidly. If the animal is then reinjected with Antigen A at day 28, the production of antibody begins almost immediately and reaches a level 1000-fold greater that that seen in the primary response. This is known as the secondary response and the principal antibody produced is IgG. If a second antigen (Antigen B) is also injected at the same time as the reinjection of Antigen A, however, only a primary response to Antigen B is observed. These results demonstrate that:
1. The immune response is specific.
2. The immune response has memory.
Clonal selection hypothesis (Jerne and Burnet): The clonal selection hypothesis attempts to explain the findings described above by suggesting the following:
1. Animals contain numerous cells called lymphocytes,
2. Each lymphocyte is responsive to a particular antigen by virtue of specific surface receptor molecules,
3. Upon contacting its appropriate antigen, the lymphocyte is stimulated to proliferate (clonal expansion) and differentiate,
4. The expanded clone is responsible for the secondary response (more cells to respond) while the differentiated ("effector") cells secrete
REGULATION OF THE HUMORAL RESPONSE
Regulation of the immune response is possibly mediated in several ways.
First, a specific group of T-cells, suppressor T-cells, are thought to be involved in turning down the immune response. Like helper T-cells, suppressor T-cells are stimulated by antigen but instead of releasing lymphokines that activate B-cells (and other cells), suppressor T-cells release factors that suppress the B-cell response. While immunosuppression is not completely understood, it appears to be more complicated than the activation pathway, possibly involving additional cells in the overall pathway.Other means of regulation involve interactions between antibody and B-cells. One mechanism, "antigen blocking", occurs when high doses of antibody interact with all of the antigen s epitopes, thereby inhibiting interactions with B-cell receptors.
A second mechanism, "receptor cross linking", results when antibody, bound to a B-cell via its Fc receptor, and the B-cell receptor both combine with antigen. This "cross-linking" inhibits the B-cell from producing further antibody.
Another means of regulation that has been proposed is the idiotypic network hypothesis. This theory suggests that the idiotypic determinants of antibody molecules are so unique that they appear foreign to the immune system and are, therefore, antigenic. Thus, production of antibody in response to antigen leads to the production of anti-antibody in response, and anti-anti-antibody and so on. Eventually, however, the level of [anti]n-antibody is not sufficient to induce another round and the cascade ends
Immunity & Resistance
• Pathogens are toxins ,living organisms & other agents that can cause damage or disease
• Body contains 10,000 times bacteria as we do human cells
• Body’s 3 lines of defence against pathogens include :
1. External Barriers
2. Anti microbial protein , Inflammation , Fever & other
3. Specific Immune mechanism ( Humeral & Cellular )
Non specific resistance
• Skin & mucus membrane ( in skin contains surface keratin and Antimicrobials chemical e.g. Definsins produced by surface neutrophils and Lactic acid as surface coat inhibits bacterial growth )
• Mucus membrane( Cilia , Mucus , Lysozymes , tears , Saliva , urine ,and areolar tissue Hyaluronic acid viscous consistency )
• Microbial growth is inhibited by physiological factors such as low pH and low oxygen tension, and sebaceous glands secrete hydrophobic oils that further repel water and microorganisms
• Within the respiratory tract, cilia directly trap pathogens and contribute to removal of mucus, assisted by physical manoeuvres such as sneezing and coughing.
• In the gastrointestinal tract, hydrochloric acid and salivary amylase chemically destroy bacteria, while normal peristalsis and induced vomiting or diarrhoea promote clearance of invading organisms.
• Cells involved in innate resistance ( Leucocytes & Macrophages ) as phagocytes system in the body can attack pathogens that penetrate the skin and mucus membrane .
Cells in non specific immunity :
• Neutrophils Highly mobile cells , spending most of their time wandering in tissues & kill bacteria by two ways : ( 1.Phagocytosis & digestion .2. Respiratory Burst )
• Eosinophils less phagocytic than neutrophils
• Basophils secrete products that aids other cell ( Heparin ,Histamine )
• Monocytes system & Lymphoid – Macrophage in various tissues in the body
Anti microbial proteins in Innate system
• Complements
• Interferones & other cytokines that play IMPORTANT roles IN REGULATION OF THE IMMUNE RESPONSE
• These provide short term & non specific resistence to viral & bacterial infections
Interferon
A polypeptide secreted by cells that had been infected by viruses non specific,for,a,particularvirus Activate NK cells,Macrophages&CD8+ T cells Also promotes destruction of cancer cells
IFN types
Types Sources Functions Potentialclinical uses
INF ? Macrophage Antiviral HepatitisB&C HCL,CML,Kaposi’s Sarcomas,
INF beta Fibroblast Antiviral Multiple Sclerosis
INF gama T cells Antiviral Activate Macrophag Increase antimycobactericidal activity TB,Leprosy , Leishmaniasis,CGD ,
Complement
The complement system is a group of more than 20 tightly regulated, functionally linked proteins ( Beta globulins )that act to promote inflammation and eliminate invading pathogens, proteins are continually present in blood plasma & must be activated by pathogens to exert their effects .
Three mechanisms by which the complement cascade may be triggered 1 . The classical pathway is initiated when IgM or IgG antibody binds to antigen, forming immune complexes.This induces a conformational change in the antibody, exposing a binding site for the first protein in the classical pathway, Antibodies bind to pathogens then bind a complex of three complement protein C1, C2 ,and C4 – Complement fixing .
2. The alternative pathway is directly triggered by binding of C3 to bacterial cell wall components such as lipopolysaccharide of Gram-negative bacteria and teichoic acid of Gram-positive bacteria. It begins with 3 complement proteins Factor B ,D & P . Both pathways 1 & 2 converge on step where complement C3 is splits into 2 fragments C3a & C3b
3 . The lectin pathway is activated by the direct binding of mannose-binding lectin to microbial cell surface carbohydrates( Mannose binding – Lectine pathway )
Complement help destruction of Pathogens in 3 ways
Chemotaxis & enhences inflammation :C3a stimulates mast cells & Basophils to secrete chemicals that enhence inflammation
Opsonization : C3b
Direct cell lysis ( MAC )
References :
1. Roitt Immunology
2. Cecil Textbook of Medicine 2008
3. Kumar & Clark
4. Pass Final Carty
5. Immunology 4th Ed Richard Hyde
6. Immunology a short course Eli
7. Lecture Notes on Immunology by Gordin
8. Immunological disorder by David Edger