Immunology 2016-2017

DR.Jassim M.AbdoPhD in Molecular Biology &Immunology

Issued by Ludwig-Maximilians University, Munich, Germany

List of ReferencesEssential Books

•Veterinary Immunology ,An Introduction ,Seven Edition ,Ian R.Tizard 2000•Immunology: A Short Course. 5th Edn. Benjamani, E. Coico, R. & Sunshine G. Wiley Liss,2003.•Immunology. 3rd ed. Kuby, J. Freeman, 1997

History of Veterinary immunology

• 12 th Century the Chinese had observed that those individuals who recovered from smallpox

• Outbreak of Rinderpest in ninth century .• 1754 inoculation may help (Nasal discharge).• 1798 Edward jenner demonstrate that material

frome cow pox lesion could be substituted for smallpox in virolation

• 1879 Louis pasteur investigate fowl cholera • 1882 Discover vacine agains Anthrax

IMMUNOLOGY CONCEPT

Immunology is: the study of host immune system from the moment o birth and sometimes even before that, the body exists in an environment filled with potentially harmful organisms and agents. Over the course of thousand of years of evolution, protective mechanism have developed in human – animal immune system reflects many aspect of this evolution ranging from the innate immunity afforded by the skin and mucous membranes to the highly complex specific response of T -cells and antibodies which recognizes invading pathogens if they are encountered again.

Immunology

Immunology is the study of immunity or protein against infectious or other agents and conditions arising from the mechanisms involved in immunity. Immunity is the protection against infectious agents and other substance.

There are two types of immunity,

1. Non adaptive immune response or Innate immunity. This is the immunity that is not affected by prior contact with the infectious agent or other material involved and is not mediated by lymphocytes.2. Adaptive immune response/ specific immune response/Acquired immunity. This is the immune response that depends on the recognition and the elimination of antigens specific lymphocytes.

Adaptive/acquired Immunity can be natural or artificial, active or passive

Innate (Nonspecific) Immunity

• Innate immunity is the First-Line Defense against infections, its properties

• 1- Does not improve after exposure • 2- Has no memory • 3- Non specific • 4- Act within minute after exposure

Innate HostDefenses Against Infection

•Anatomical barriers–Mechanical factors–Chemical factors–Biological factors•Humoral components–Complement–Coagulation system–Cytokines•Cellular components–Neutrophils–Monocytes and macrophages–NK cells–Eosinophils

Mechanisms of Innate Immunity A. Physical Barriers

Lines (Barriers):

1-mechanical barrier: intact skin *(keratin and epithelial cells) provides mechanical barrier to the invading pathogens, Movement due to cilia or peristalsis, Cough reflex, the trapping effect of mucus and the flushing action of tears, saliva and urine help to protect from invaders

2. Chemical factors: Fatty acids in sebum inhibit the growth of bacteria. Lysozyme and phospholipase found in tears, saliva and nasal secretions can breakdown the cell wall of bacteria and destabilize bacterial membranes.

3. Biological factors: Members of the normal floral competitively exclude pathogens (colonization resistance) and stimulate the host defenses.

B. Tissue factors:

once the infective agent cross the barrier of the body surface, the tissue factors come into play for body defence

• 1. The Complement System (alternative pathway activation)

Complement proteins circulate in the blood and the fluid that batches tissues. The major protective outcomes of complement activation include opsonization, lysis of foreign cells, and initiation of inflammation.

2. Lysozyme, peroxidase, enzymes, lactoferrin, and defensins are antimicrobial substances that inhibit or kill microorganisms

3. Secretory IgA that inhibit attachment of gonococci and Escherichia coli to surface epithelial cells.

4. Type I Interferons: Viral infection induces the expression of antiviral proteins known as interferons. These proteins, called interferon- α (IFN-α) and interferon- β (IFN-β), they induce cells in the vicinity of a virally infected cell to prepare to cease protein synthesis in the event they become infected with a virus (inhibit viral replication)

5. Cytokines:Low molecular weight soluble proteins and peptides secreted by leukocytes and other cells involved in innate immunity, adaptive immunity, and inflammation. Cytokines include interleukins (LLs), colony-stimulating factors (CSFs), tumor necrosis factors (TNFs),chemokines, and interferons.

6. Chemokines: Low-molecular-weight proteins that stimulate leukocyte movement

7. Fever: occurs as a result of certain pro-inflammatory cytokines released by macrophages when their toll-like receptors bind microbial products.

Fever inhibits the growth of many pathogens and increases the rate of various body defenses.

Cellular mechanisms of innate immune system

• Phagocytosis • Is the engulfment and degradation of

microbes by phagocytic cells that secrete cytokines and chemokines to attract and activate other cells of the innate immune system. The oxidative burst, producing several highly reactive oxygen metabolites, and a series of degradation enzymes.

The step of phagocytosis includes

1. chemotaxis attraction of phagocyte to the site of infection by chemotactic agent like C5a and IL-8

2. recognition and attachment which mediated via pattern recognition receptors (PRR) or complement receptors

3. engulfment of particulate material into a vacuole (phagosome) and formation phagolysosome

4. destruction and digestion: intracellular killing of microorganism, and exocytosis.

• Factors Affecting Phagocytosis 1. Opsonization: coating antigen or foreign

particle with antibody or complement or both, in order to enhance its engulfment by phagocytic cells.

2. Solid or rigid medium

InflammationA Coordinated Response to Invasion or Damage

• Swelling, redness, heat, pain and loss of function are the signs of inflammation, the attempt by the body to contain a site of damage, localized the response, and restore tissue function.

• Apoptosis –Controlled Cell Death that circumvent the inflammatory process.

• Apoptosis is a mechanism of eliminating self-cells without evoking an inflammatory response.

The Cell of the innate Immune System :Myeloid lineage

• There are three types of granulocytes- neutrophils, basophila and esinophilis.

• 1. Neutrophils Also called polymorphonuclear leukocytes account for 60% of

blood leukocytes. Short lived cells produced by bone marrow and circulate in blood stream for 6-7 hours. Neutrophils play a critical role during the early stages of inflammation, being the first cell type recruited from the blood stream to the site of damage under the effect of chemoattractant substances.After taking up microorganisms the neutrophil will die.

2. Basophils and mast cells: their granules contain vasoactive amines (like histamine) that cause contraction of smooth muscle, they are important in allergic reactions

3. Eosinophils: important in immunity to parasites

Mononuclear Phagocytes: • 1. Monocytes account for approximately 5-7% of blood

leukocytes,produced by bone marrow, have a longer life span than circulating granulocytic phagocytes. Migrate into the tissues and differentiate into Macrophages.

Macrophages in blood can be activated by various stimulants, including microbes and their products (LPS), antigen-antibody complexes, inflammation, sensitized T lymphocytes, cytokines , and injury. Activated macrophages have an increased number of lysosomes (increased intracellular killing activity)

• Functions: 1. Phagocytose microorganisms 2. Present antigens to T cells 3. cytokine production ( IL-1, which has a wide

range of activity in inflammation. Interleukin-1 participates in fever production and in activation of lymphoid cells), TNF( inflammatory mediator), and IL-8 chemotactic factor

The name of monocyte-derived cells depends upon the tissue they reside in:

• Liver - Kupffer cells • Lung - Alveolar macrophages • CNS - Microglial cells • Bone – Osteoclasts

• 2Dendritic cells: another group of phagocytic cells with both myeloid and lymphoid origins they are so called for their branchlike cytoplasmic projections. Found mainly in the portal of entry of microbes (e.g. skin, lung and GIT), they are professional phagocytes.

Lymphocytes Lymphocytes, which include 1. B cells, T cells are involved in adaptive immunity. 2. Natural Killer (NK) cells Non-T, non-B cells, large granular

lymphocyte (LGL) account for 5-10% of blood lymphocyte. No classical antigen receptors. Part of the innate immune system. Recognise and kill abnormal cells such as tumour cells.

Directly induce apoptosis in virus infected cells by pumping proteases through pores that they make in target cells. Similar cytolytic mechanisms to cytotoxic T lymphocytes (CTL)

Involved in antibody-dependent cellular cytotoxicity (ADCC)

Cells of Immune SystemStem cells of bon marrow

differentiate into

cytokines (IL-&, IL-3) colony stimulating factor

Lymphoid series Myeloid series

B-lymphocytes T-lymphocytes NK

monocytee-macrophages dendritic cells eosinophils mast cells

Hematopoiesis

All blood cells arise from a type of cell called the hematopoietic

stem cell (HSC). Stem cells are cells that can differentiate into other cell types; they are self-renewing—they maintain their population level by cell division. In humans, hematopoiesis, the formation and development of red and white blood cells, begins in the embryonic yolk sac during the first weeks of development.

Hematopoiesis• Begins with hematopoietic stem cells (HSC)

– Few in # in bone marrow; difficult to culture– Pluripotent; able to produce RBC’s, WBC’s, megakaryocytes

• HSC differentiates to become:either a) Myeloid progenitor cell or b) Lymphoid progenitor cell

Myeloid RBC’s and WBC’s and dendritic cellsLymphoid B and T cells and dendritic cells

Mononuclear Phagocytes

Granulocytes Neutrophils: Phagocytes First to arrive at problem Eosinophils: Phagocytes Defense against parasites? Basophils: Nonphagocytic Allergies

Dendritic cells: Diverse functions Antigen capture Antigen presentation

Cell Communication Surface Receptors bind ligands that are on the outside of the cell,

enabling the cell to detect that the ligand is present. Adhesion Molecules 1. Adhesion molecules allow cells to adhere to other cells. Sensor Systems: Pattern recognition receptors: receptor of innate

immune system that recognize structures called pathogen-associated molecular pattern produced by microbes but not mammalian cellsand essential for survival of microbes eg. CD14 on macrophage that bind to bacterial endotoxin and activated it.

Toll-Like Receptor:Toll-like receptor a receptor located on the immune cell enables cells to detect molecules that signify the presence of microbe.

Factors affecting innate immunity

1. Age: two extremes of life, neonate and elderly animals are more susceptible to infectous diseases

2. Hormonal influence, e.g. diabetes mellitus there is high incidence of staphylococcal sepsis due to altered metabolism and elevated level of CHO in tissues

3. Nutrition: malnutrition predispose to bacterial infection like T.B., septicemia

2. Acquired immunity. Adaptive immunity,

which occurs after exposure to an antigen (eg, an infectious agent) is specific and is mediated by either antibody or lymphoid cells. Cells of adaptive have long-term memory. Improve after exposure and act effectively after several days of exposure.

Adaptive/acquired Immunity can be active or passive natural or artificial,

Adaptive ImmunityAdaptive immunity is capable of recognizing and selectivelyeliminating specific foreign microorganisms and molecules(i.e., foreign antigens). Unlike innate immune responses,adaptive immune responses are not the same in all membersof a species but are reactions to specific antigenic challenges.Adaptive immunity displays four characteristic attributes:• Antigenic specificity• Diversity• Immunologic memory• Self/nonself recognition

Acquired Immunity

Key Features:• 1.Antigen Specificity• 2.Diversity• 3.Immunologic memory• 4.Self/nonself recognition

Antigens• Antigenicity is the ability to bind to Ig or immune cells; animmune response need not result• Immunogenicity is the capacity to induce an immuneresponse by foreign, complex, high molecular weightcompounds• Therefore an antigen may not be an immunogen but animmunogen is an antigen!• Epitope Discrete site on immunogen recognised byimmune cells

Components of adaptive Immune response1. B cells2. T cells3. Antigen Presenting Cells (APC)

Strategy of the Adaptive Immune Response

1. Humoral immunity is mediated by B.cells; in response to extracellular antigens, these may be triggered to proliferate and then differentiate into plasma cells that function as antibody producing factories.

2. Cellular Immunity: Effector T- cytotoxic cells are able to induce apoptosis in ‘self” cells that present abnormal protein that signify danger. Effector T-helper orchestrates the various response of cellular and humoral immunity.

Strategy of the Adaptive Immune Response

• The Humoral Immunity• Humoral immunity is mediateds by B.cells; in

response to extracellular antigens, these maybe triggered to proliferate and then differentiate into plasma cells that function as antibody producing factories.

• Cellular Immunity• Effector T- cytotoxic cells are able to induce

apoptosis in ‘self” cells that present abnormal protein that signify danger. Effctor T-helper orchestrates the various response of cellular and humoral immunity.

Immunoglobulin contd……

• Terminal regions of H & L chains are the variable regions• The variable region is the site where Ig combines withantigen• This region’s variability is responsible for wide range ofantigen specificity• The 5 classes of Ig are:– IgM– IgA– IgD– IgG– IgE

Anatomy of the lymphoid system Lymphatic Vessels. Lymph, which may contain antigens that have entered tissues,

flows in the lymphatic vessels to the lymph nodes. • Secondary lymphoid organs Secondary lymphoid organs are the sites at which lymphocytes

gather to contact antigens; they facilitate the interactions and transfer of cytokines between the various cells of the immune system.

• Primary Lymphoid Organs 1. Primary lymphoid organs are the sites where B.cells and

T.cells mature.

60

Lymphocytesthe primary cells of the lymphoid system

• Respond to:– Invading organisms– Abnormal body cells, such as virus-infected cells or

cancer cells– Foreign proteins such as the toxins released by

some bacteria• Types of lymphocytes– T cells (thymus-dependent)– B cells (bone marrow-derived)– NK cells (natural killer)

The primary lymphoid organs

The primary lymphoid organs provide sites where lymphocytes mature and become antigenically committed. T lymphocytes

mature within the thymus, and B lymphocytesarise and mature within the bone marrow of

humans, mice, and several other animals, but not all vertebrates.

• Bilobed Organ on Top of Heart• Reaches Max. Size During Puberty– 70g infants, 3 g in adults

• 95-99% Of T Cells Die in Thymus– self reactivity or no reactivity to Ag

• Consists of Cortex and Medulla• Rat Thymocytes Sensitive to Glucorticoids

Thymus

Thymus

• Mucous Membranes S.A=400m2

• Mucous Membr. Most Common Pathogen Entry Site• M.M Protected by MALT• Organization Varies (most organized P.P, Tonsils,

appendix• GI Tract, IEL Unique TCRs• Lamina Propia (below epithelium) M, B cells, TH

• M Cell Allows Ag Entry, Unique Architecture

Mucosal Associated Lymphoid Tissue (MALT)

secondary lymphoid

There are several types of secondary lymphoid tissue:lymph nodes, spleen, the loose clusters of follicles, andPeyer’s patches of the intestine, and cutaneous-

associated lymphoid tissue. Lymph nodes trap antigen from lymph, spleen traps blood-borne antigens, intestinal-associated lymphoid tissues (as well as other secondary lymphoid tissues) interact with antigens that enter the body from the gastrointestinal tract, and cutaneous-associated lymphoid tissue protects epithelial tissues.

• Multiple Afferent Lymphatics• Cortex

– B-cells, Follicular DCs, M, GCs, Primary Follicles• Paracortex

– TH, M, DCs• Medulla

– Plasma Cells• Post Capillary Venule

– Allow Lymphocyte Migration From Circuilation Into Lymph Node• One Efferent Lymphatic

– Rich In Abs and Lymphocytes

Lymph Node

Lymph Node