The Human Immune System

Dr. Aspitriani, SpPADepartment of Anatomical Pathology, Medicine Faculty of Sriwijaya University/ Dr. Moh. Hoesin General Hospital Palembang

OVERVIEW

• Innate (natural) immunity• Adaptive (acquired) immunity• Cells, tissues and organs of the immune system• Lymphocytes (B & T cells)

• Macrophage• Dendritic cell• Natural Killer cell• Cytokine• Major histocompatibility complex (MHC) protein

Basic concepts in Immunology

• Organisms and microorganisms• Bacteria, viruses, fungi & parasites

• Infections and diseases Infection == disease

• Mechanisms of defense• The immune system

• Cells & soluble factors

• Immunity and Immunology

Basic Components of the Immune System• Pathogen: Bacteria, Viruses, parasites etc• Leukocytes• Antibodies• Antigens

Immunology

• A broad field encompassing both basic and clinical applications, deals with antigens, antibodies and cell mediated host defense functions, specially as they relate to immunity to disease, hypersensitivity biological reactions, allergies and rejection of foreign tissues.

Pathogens

• Any biological agent that causes illness and/or disease to its host.

Different types of pathogens include the following:

Types of immunity

1. Innate (natural) immunity• Phagocytes etc.• Early, rapid responses, but limited & ‘non-specifc’

2. Adaptive (acquired) immunity• Lymphocytes (B & T cells)• Take time but powerful - ‘specificity + memory’

Immunity: Two Intrinsic Defense Systems

Body defense against exogenous(microbes) and endogenous (tumor cells) agents. It is:

1. Innate (natural, nonadaptive, or nonspecific) system responds quickly and consists of:

A. First line of defense : intact skin and mucosae,Hair, Cilia , Saliva, Tears, Sweat, Digestive tract • prevent entry of microorganismsB. Second line of defense : antimicrobial proteins, phagocytes, and other cells

• Inhibit spread of invaders throughout the body• Inflammation is its hallmark and most important

mechanism

Immunity: Two Intrinsic Defense Systems

2. Adaptive (acquired or specific) defense system• Third line of defense – mounts attack against

particular foreign substances• Occurs after exposure to antigen. • It is mediated by either antibodies (Humeral immunity) or

lymphoid cells (Cellular immunity). • It can be:

A. Passive

B. Active

Epithelial Chemical Barriers• Epithelial membranes produce protective chemicals that

destroy microorganisms:• Skin acidity (pH of 3 to 5) inhibits bacterial growth• Sebum contains chemicals toxic to bacteria• Stomach mucosae secrete concentrated Hcl and protein-digesting

enzymes• Saliva and lacrimal fluid contain lysozyme• Mucus traps microorganisms that enter the digestive and

respiratory systems

Respiratory Tract Mucosae

• Mucus-coated hairs in the nose trap inhaled particles

• Mucosa of the upper respiratory tract is ciliated• Cilia sweep dust- and bacteria-laden mucus

away from lower respiratory passages

Internal Defenses (Second Line of Defense)

The body uses nonspecific cellular and chemical devices to protect itself:

Phagocytes natural killer (NK) cells Inflammatory response enlists macrophages, mast cells,

WBCs, and chemicals Antimicrobial proteins in blood and tissue fluid

• Harmful substances are identified by surface carbohydrates unique to infectious organisms

• The adaptive immune system is a functional system that:• Recognizes specific foreign substances• Acts to immobilize, neutralize, or destroy foreign substances• Amplifies inflammatory response and activates complement

• The adaptive immune system is antigen-specific, systemic, and has memory

• It has two separate but overlapping arms• Humoral or antibody-mediated (B Cell) immunity• Cellular or cell-mediated (T Cell) immunity

Adaptive (Specific) Defenses (Third Line of Defense)

Cells, tissues and organs of the immune system

• Immune cells are bone marrow-derived & distributed through out the body

• Primary lymphoid organs: • Thymus: T cell maturation • Bone marrow (bursa of Fabricius in birds): B cell maturation

• Secondary lymphoid organs: • Lymph nodes• Spleen• MALT (mucosal associated lymph tissue)• GALT (gut associated lymph tissue)• Trap antigen, APC, Lymphocyte Proliferation

• Multiple Afferent Lymphatics• Cortex

• B-cells, Follicular DCs, Makrophage, Germinal Center, Primary Follicles

• Paracortex• TH, Makrophage, DCs

• Medulla• Plasma Cells

• Post Capillary Venule• Allow Lymphocyte Migration From Circulation Into Lymph Node

• One Efferent Lymphatic• Rich In Abs and Lymphocytes

Lymph Node

• Mucous Membrane: Most Common Pathogen Entry Site

• Mucous Membrane Protected by MALT• GI Tract, IEL Unique TCRs• Lamina Propia (below epithelium): Makrophage,

B cells, TH

• M Cell Allows Ag Entry, Unique Architecture

Mucosal Associated Lymphoid Tissue (MALT)

• Bilobed Organ on Top of Heart• Reaches Max. Size During Puberty

• 70 mg 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

Leukocytes (White Blood

Cells)

lymphocytes

T cells B Cells NK Cells

Other Types ofWBC

Eosinophils Macrophages

White Blood Cells

Haematopoiesis

• Two types of lymphocytes• B lymphocytes – oversee humoral immunity• T lymphocytes – non-antibody-producing cells that

constitute the cell-mediated arm of immunity• Antigen-presenting cells (APCs):

• Do not respond to specific antigens• Play essential auxiliary roles in immunity

Cells of the Adaptive Immune System

• Lymphoid Cells• B-cells, T-cells and Null cells (NK cells)• 20-40% of body’s leukocytes• 99% of lymph node• If inactivated said to be naïve• Nucleus occupies almost entire cell• 6 m diameter

Cells of the Immune System

• Immature lymphocytes released from bone marrow are essentially identical

• Whether a lymphocyte matures into a B cell or a T cell depends on where in the body it becomes immunocompetent• B cells mature in the bone marrow• T cells mature in the thymus

Lymphocytes

• T cells mature in the thymus under negative and positive selection pressures• Negative selection – eliminates T cells that are

strongly anti-self• Positive selection – selects T cells with a weak

response to self-antigens, which thus become both immunocompetent and self-tolerant

T Cells

Major Types of T Cells

T cells!

T cells

Helper T cell (Th)

Memory T cell

Helper T cell

Killer T cell

Suppressor T cell

Killer T cell (Tk)

Suppressor T cells- in charge of slowing and stopping the immune response after the foreign substance is destroyed.

Helper T cells- secrete lymphokines that direct B cells into producing antibodies and also direct the Killer T cells as to which cell they get to eliminate.

Killer T cells- They find specifically coded infected cells, and then destroy them with cytotoxins. They may be directed by Helper T cells

Memory T cells- derived from Helper T cells, have the same properties as their parent cell, and circulates until the body encounters the pathogen its parent cells were designer for.

• B cells become immunocompetent and self-tolerant in bone marrow

• Some self-reactive B cells are inactivated (anergy) while others are killed

• Other B cells undergo receptor editing in which there is a rearrangement of their receptors

B Cells

B cellsB Plasma Cells• when the B cell produces the

antibody for a specific antigen, it begins to clone itself into B plasma cells, that produce more of that particular binding antibody.

• These cells release immunoglobulin, or antibodies

• B plasma cells have a 5 to 7 day life-span

• all its protein synthesis energy is going into the production of Antibodies, not self preservation

B Memory Cells• These are the same as B plasma

cells, except they remain inactive until the secondary immune response

• Secondary immune response is considered anytime the body encounters a pathogen after the first time. Quicker response time.

• Primary response is the first time the body encounters a specific pathogen, Lag period before B cells respond.

Red bone marrow

1

2

3

Immunocompetent, but still naive, lymphocyte migrates via blood

Mature (antigen-activated) immunocompetent lymphocytes circulate continuously in the bloodstream and lymph and throughout the lymphoid organs of the body.

Key: = Site of lymphocyte origin

= Site of development of immunocompetence as B or T cells; primary lymphoid organs

= Site of antigen challenge and final differentiation to activated B and T cells Immature

lymphocytesCirculation in blood 1

1 Lymphocytes destined to become T cells migrate to the thymus and develop immunocompetence there. B cells develop immunocompetence in red bone marrow.

Thymus

Bonemarrow

Lymph nodes, spleen, and other lymphoid tissues

2 2 After leaving the thymus or bone marrow as naive immunocompetent cells, lymphocytes “seed” the lymph nodes, spleen, and other lymphoid tissues where the antigen challenge occurs.

3 3

Activated immunocompetent B and T cells recirculate in blood and lymph

Immunocompetent B or T cells

• Major roles in immunity are:• To engulf foreign particles• To present fragments of antigens on their own surfaces, to be

recognized by T cells• Major APCs are dendritic cells (DCs), macrophages, and activated

B cells• The major initiators of adaptive immunity are DCs, which actively

migrate to the lymph nodes and secondary lymphoid organs and present antigens to T and B cells

Antigen-Presenting Cells (APCs)

Mononuclear Cells• Monocytes in Blood, Macrophage in Tissues

• Monocytes 5-10 times smaller than Macrophage• Macrophage Increases Phagocytic Ability• Secretes cytokines and Produces Hydrolytic

Enzymes• Named Based on Tissue They Reside

• Alveolar (lungs), Kupffer (liver), Microglial (brain), Osteoclasts (bone)

• Activated By Phagocytosis or Cytokines (IFN)• Antigen Presenting Capacity Thru MHC II

Mononuclear Cells

Dendritic cell(sentinel)

Monocyte vs Macrophage

• Secrete soluble proteins that activate T cells• Activated T cells in turn release chemicals that:

• Rev up the maturation and mobilization of DCs• Prod macrophages to become activated

macrophages, which are insatiable phagocytes that secrete bactericidal chemicals

Macrophages and Dendritic Cells

• Professional APCs• Several Types

• Langerhans (LC) found in skin• Circuilating DCs

• Myeloid (MDC1 and MDC2)• Plasmacytoid

• Interstitial DCs, populate organs such as heart, lungs, liver, intestines

• Interdigitating DCs, T-cell areas of lymph nodes and Thymic medulla

Dendritic Cells

Developmental Pathway of DCs

• Do Not Express MHC II Molecules• Found in Lymph Follicles (Rich in B Cell)• Express FcR For Antibodies and Complement• Ag-Ab Complex Shown To Last Very Long (weeks

to months)

Follicular DCs

Natural Killer (NK) Cells• Cells that can lyse and kill cancer cells and virus-

infected cells• Natural killer cells:

• Are a small, distinct group of large granular lymphocytes

• React nonspecifically and eliminate cancerous and virus-infected cells

• Kill their target cells by releasing perforins and other cytolytic chemicals

• Secrete potent chemicals that enhance the inflammatory response

Interferon Family• Interferons are a family of related proteins each

with slightly different physiological effects• Lymphocytes secrete gamma () interferon, but

most other WBCs secrete alpha () interferon• Fibroblasts secrete beta () interferon• Interferons also activate macrophages and

mobilize NKs • FDA-approved alpha IFN is used:

• As an antiviral drug against hepatitis C virus• To treat genital warts caused by the herpes virus

Eosinophils and Macrophages

• Macrophage, “Big Eaters,” a form of White Blood Cell.

• Operates in both the Non-specific and Specific Immune Systems

• Also a Phagocyte, which means it engulfs pathogens and cellular debris, and then proceeds to digest it, this process is known as Phagocytosis.

Macrophage

Eosinophils are a type of White Blood Cell.

They fight infection and parasites.

They also play a role in Allergic reactions.

Eosinophils produce Interleukin 1 and Interleukin 2

• Primary immune response – cellular differentiation and proliferation, which occurs on the first exposure to a specific antigen• Lag period: 3 to 6 days after antigen challenge• Peak levels of plasma antibody are achieved in

10 days• Antibody levels then decline

Immunological Memory

• Secondary immune response – re-exposure to the same antigen• Sensitized memory cells respond within hours• Antibody levels peak in 2 to 3 days at much

higher levels than in the primary response • Antibodies bind with greater affinity, and their

levels in the blood can remain high for weeks to months

Immunological Memory

Primary and Secondary Humoral Responses

The Immune Recognition Molecules of the Adaptive Immune System

1. Immunoglobulin (Ig)- B Cell Receptor (BCR)- Antibody (Ab)

2. T Cell Receptor (TCR)

3. Major Histocompatibility Complex (MHC)

• B cells encounter antigens and produce antibodies against them• Naturally acquired – response to a bacterial or

viral infection• Artificially acquired – response to a vaccine of

dead or attenuated pathogens• Vaccines – spare us the symptoms of disease,

and their weakened antigens provide antigenic determinants that are immunogenic and reactive

Active Humoral Immunity

• Differs from active immunity in the antibody source and the degree of protection• B cells are not challenged by antigens• Immunological memory does not occur• Protection ends when antigens naturally

degrade in the body• Naturally acquired – from the mother to her

fetus via the placenta• Artificially acquired – from the injection of

serum, such as gamma globulin

Passive Humoral Immunity

Types of Acquired Immunity

Antibodies & Antigens

• Antibodies are produced by B cells, when stimulated by lymphokines from helper T cells. The antibody attaches to the antigen, completing the signal, coding the infected cells for destruction.

• Antibodies are constructed of DNA fragments, making them so unique and almost innumerable.

• Also called immunoglobulins • Constitute the gamma globulin portion of

blood proteins• Are soluble proteins secreted by activated B

cells and plasma cells in response to an antigen • Are capable of binding specifically with that

antigen• There are five classes of antibodies: IgD, IgM,

IgG, IgA, and IgE

Antibodies

• IgD – monomer attached to the surface of B cells, important in B cell activation

• IgM – pentamer released by plasma cells during the primary immune response

• IgG – monomer that is the most abundant and diverse antibody in primary and secondary response; crosses the placenta and confers passive immunity

• IgA – dimer that helps prevent attachment of pathogens to epithelial cell surfaces

• IgE – monomer that binds to mast cells and basophils, causing histamine release when activated

Classes of Antibodies

• Consists of four looping polypeptide chains linked together with disulfide bonds• Two identical heavy (H) chains and two

identical light (L) chains• The four chains bound together form an

antibody monomer• Each chain has a variable (V) region at one end

and a constant (C) region at the other• Variable regions of the heavy and light chains

combine to form the antigen-binding site

Basic Antibody Structure

Basic Antibody Structure

• Neutralization: e.g. toxins, viruses

• Opsonization: bind pathogens for recognition by other immune cells (e.g. phagocytes)

Antibody functions

Antibodies & Antigens• Antigens= a fragment of a protein or peptide from the

pathogen, taken to the surface of the infected cell and bound in an MHC (major histocompatibility complex) molecule.

• The class 1 MHC complex molecule and the foreign peptide form the antigen, which can be read by the receptors on Killer T cells.

CellClass 1 MHC moleculeAntigen

Pathogen

Antigenic Determinants

• Since antibodies are useless against intracellular antigens, cell-mediated immunity is needed

• Two major populations of T cells mediate cellular immunity• CD4 cells (T4 cells) are primarily helper T cells (TH) • CD8 cells (T8 cells) are cytotoxic T cells (TC) that

destroy cells harboring foreign antigens• Other types of T cells are:

• Suppressor T cells (TS)• Memory T cells

Cell-Mediated Immune Response

• T cells recognize and respond only to processed fragments of antigen displayed on the surface of body cells

• T cells are best suited for cell-to-cell interactions, and target:• Cells infected with viruses, bacteria, or

intracellular parasites• Abnormal or cancerous cells• Cells of infused or transplanted foreign tissue

Importance of Cellular Response

TH cells play a central role in the immune system

• Our cells are dotted with protein molecules (self-antigens) that are not antigenic to us but are strongly antigenic to others (reason for transplant rejection)

• One type of these, MHC proteins, mark a cell as self

• The two classes of MHC proteins are:• Class I MHC proteins – found on virtually all

body cells• Class II MHC proteins – found on certain cells in

the immune response

Self-Antigens: MHC Proteins

• Immunocompetent T cells are activated when the V regions of their surface receptors bind to a recognized antigen

• T cells must simultaneously recognize:• Nonself (the antigen)• Self (a MHC protein of a body cell)

Antigen Recognition and MHC Restriction

• Both types of MHC proteins are important to T cell activation

• Class I MHC proteins• Always recognized by CD8 T cells• Display peptides from endogenous antigens

MHC Proteins

• Endogenous antigens are:• Degraded by proteases and enter the

endoplasmic reticulum• Transported via TAP (transporter associated

with antigen processing)• Loaded onto class I MHC molecules• Displayed on the cell surface in association

with a class I MHC molecule

Class I MHC Proteins

Class I MHC Proteins

• Class II MHC proteins are found only on mature B cells, some T cells, and antigen-presenting cells

• A phagosome containing pathogens (with exogenous antigens) merges with a lysosome

• Invariant protein prevents class II MHC proteins from binding to peptides in the endoplasmic reticulum

Class II MHC Proteins

• Class II MHC proteins migrate into the phagosomes where the antigen is degraded and the invariant chain is removed for peptide loading

• Loaded Class II MHC molecules then migrate to the cell membrane and display antigenic peptide for recognition by CD4 cells

Class II MHC Proteins

Class II MHC Proteins

• 20 or so proteins that circulate in the blood in an inactive form

• Proteins include C1 through C9, factors B, D, and P, and regulatory proteins

• Provides a major mechanism for destroying foreign substances in the body

• Amplifies all aspects of the inflammatory response• Kills bacteria and certain other cell types (our cells are

immune to complement)• Enhances the effectiveness of both nonspecific and

specific defenses

Complement

• Complement can be activated by two pathways: classical and alternative

• Classical pathway is linked to the immune system • Depends on the binding of antibodies to

invading organisms • Subsequent binding of C1 to the antigen-

antibody complexes (complement fixation)• Alternative pathway is triggered by interaction

among factors B, D, and P, and polysaccharide molecules present on microorganisms

Complement Pathways

• Each pathway involves a cascade in which complement proteins are activated in an orderly sequence and where each step catalyzes the next

• Both pathways converge on C3, which cleaves into C3a and C3b

• C3b initiates formation of a membrane attack complex (MAC)

• MAC causes cell lysis by interfering with a cell’s ability to eject Ca2+

• C3b also causes opsonization, and C3a causes inflammation

Complement Pathways

Complement Pathways

Figure 21.5

Interleukins• A form of cytokine, they act like neurotransmitters for

the immune system, relaying messages.

Interleukin 1:

-Responsible for fever response

-Controls some lymphocytes

-Increases the number of bone marrow cells

-Causes degeneration of joints between bones

Interleukin 2:

- Key in discriminating between Self and foreign cells

- Secreted by the binding of T cells to an antigen

- Stimulates growth, differentiation, and survival of killer T cells.

Interleukin 6:

- Secreted by macrophages, and sent to liver to produce Mannose, which is a protein that binds to sugars.

- Helps with inflammation, especially from burns

Specific Immune Response

• Also known as “Adaptive Immune System”• Breaks down into two categories: Antibody-Mediated Immune Response (AMIR) Cell-Mediated Immune Response (CMIR)

Antibody Mediated Immune Response

• Also known as Humoral Immune Response

• The antibodies secreted by the B cells in AMIR attach to antigens and effectively “tag” specific cells for destruction, sparing the lives of the healthy cells.

Flow of AMIRMacrophages roam body, engulfing infected extracellular materials

Degrades engulfed material into peptides

Class II MHC presents the infected peptideAs an Antigen

Macrophage returns to lymph nodes w/ antigen

Antigen received by Helper T cells

Th Cells secrete lymphokines

Lymphokines direct B cells to release antibodiesAnd directs Tk cells to infected cells.

Tk kills infected cells tagged by antibodies

Flow of CMIR

Host cells carry class 1 MHC molecules to outside of cell

MHC binds to and displays peptide/protein fragment of pathogen

Parasite and MHC form antigenAntigen recognized by Killer T cell antigen receptors

Killer T cell releases cytotoxins into infected cells, and kills them

The Immune System presented differently

Immunological memory

CMIR

AMIR

Interferon Response

• As the name suggests, they interfere with viral replication!

• Once the virus infects the cell, the cell creates a chemical protein called Interferon!

• Interferon inhibits viral reproduction between cells by binding to the receptors of uninfected cells.

Allergic reactions

• The allergy is the immune systems response to a harmless foreign substance, such as pollen or dust.

• Since the immune system is based primarily off of DNA, then it can be inferred that allergies are hereditary.

Fever Response• The response to toxins in the body, produced by

bacteria, is to increase the internal temperature of the body.

• This affect is enhanced when cells release Pyrogen, a cytokine that resets the bodies temp. Also known as Interleukin 1.

Self vs. Not Self

• Like most systems things can go wrong, such as when the immune system attacks itself, not recognizing the proteins that code a cell as “self.” When this happens it is known as an autoimmune disease.

• In the case of tissue implants, they may be rejected if the tissue cells don’t have the proper proteins to inactivate the complement system in a different humans body. So the complement kills the cells!

• In order for tissues to be accepted they also must have the proper MHC complex to pass as human cells, these proteins must be on the surface of the cells, as either of the two classes.

Immunological Memory• The reason why vaccines make sense, and we eventually build

a tolerance to certain diseases

It’s because after every encounter with a pathogen, both the T cells and the B cells differentiate into an inactive form of their parent cell. They remain inactive until the second immune response for that specific pathogen.

Vaccination is an introduction of a dormant or dead pathogen, which allows are body to do its primary immune response without the risk of actual sickness.

Now, the pieces come together…Immune System

Non-specific Response

Complement System

Interferon Response

Inflammatory Response

Fever Response

Specific Response

Anti-body Mediated Response

Cell Mediated Response

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