THE IMMUNE RESPONSE

Thucydides

THE IMMUNE SYSTEM

• “Double Edged Sword”

• Immunity is the protection from diseases and more specifically infectious diseases.

• The collective, coordinated response of the cells and molecules of the immune system is

called Immune Response

TYPES OF IMMUNE DEFENSES

INNATE IMMUNITY

• “Natural or native immunity”• Consists of cellular and biochemical defenses

that are in place before infection and respond rapidly to it.

• Able to distinguish self and non-self but lacks the ability to differentiate between agents.

• Major Components–Epithelial Barriers–Phagocytic Cells (Neutrophils and

Macrophages)–Natural Killer (NK) Cells–Several types of Plasma Proteins–Cytokines

Toll-Like Receptors (TLR)

• The eyes of the immune system, recognize and bind with telltale pathogen markers allowing the effector cells of the immune system to see the pathogens as distinct from self-cells.

• Triggers phagocyte to engulf and destroy

the infections agent• Also triggers

Phagocytic cells to secrete chemical messengers that contribute to inflammation.

Adaptive Immunity• Acquired or specific immunity • Distinguishes among the different, even

closely related molecules and microbes• Components: –White Blood Cells (Lymphocytes T and B)–Antigens

ANTIGENS

• Or Immunogens are substances foreign to the host that can stimulate and immune response.

ANTIGENS

• Recognized by antibodies or immunoglobulins secreted in response to antigens.

• Include components found in bacteria, fungi, viruses, protozoa, and parasites

• Non-microbial elements such as plant pollens, insect venom and transplanted organs.

Basic Antibody Structure

• ANTIGENIC DETERMINANTS OR EPITOPES– It is the unique molecular shape of an epitopes that is

recognized by a specific immunoglobulin receptor found in the surface of the lymphocyte or by an antigen-binding site .

• Single antigen may contain multiple antigenic determinants, each stimulating a distinct clone of lymphocytes to produce a unique type of antibody.

• Haptens are low molecular weight substances (<10,000 Daltons).

• When combined with large protein molecules, they function as antigens.

• HAPTEN –CARRIER COMPLEXES – Allergic response to antibiotic Penicillin

TYPES OF ADAPTIVE IMMUNE RESPONSES

• HUMORAL IMMUNITY – mediated by B cells and is the principal defense against extracellular microbes and toxins.

• CELL-MEDIATED or CELLULAR IMMUNITY – mediated by cytotoxic T cells and defends against intracellular microbes.

• Has the unique ability to “Remember” the pathogen and quickly produce a heightened immune response.

• T cells develop receptors that recognize the viral peptides displayed in the surface of infected cells and then signal destruction of the infected cell.

Cells and Organs of the

Immune System

Immune Cells

TYPES• REGULATORY CELLS – assist is orchestrating

and controlling the immune response.– Helper T lymphocytes

• EFFECTOR CELLS – the final stages of the immune response are accomplished with the elimination of antigens. – Activated T Lymphocytes, Mononuclear

phagocytes and other leukocytes

CLUSTERS OF DIFFERENTIATION

• (CD) molecules aid in the function of immune cells and serve to define functionally distinct subset of cells such as CD4+ helper T cells and CD8 + cytotoxic T cells

• Helped scientist to identify distinct subsets of lymphocytes and study both the normal and abnormal developmental processes displayed by these cells.

MAJOR HISTOCOMPATIBILITY COMPLEX MOLECULES (MHC)• Key recognition molecules essential for

distinguishing self from non-self. • Coded by closely linked genes on

chromosomes 6 were first identified because of their role in organ and tissue

transplantation. • Essential for correct cell-to-cell interaction

among immune and body cells.

CLASS I MHC

• Found on virtually all nucleated cells in the body.

• Involved in the recognition of intracellular antigens.

• Antigen peptides associate with class I molecules in cells that are infected with cellular pathogens (virus)

• MHC antigen complex communicates to cytotoxic T cells that the cell must be destroyed.

CLASS II MHC • Found primarily on Phagocytic cells such as

macrophages, Dendritic cells and B lymphocytes, that engulf extracellular antigen.

• Triggers helper T cells to multiply quickly and direct other immune cells to respond to the invading pathogen through the secretion of cytokines.

• MHC proteins are called Human Leukocyte Antigens (HLA) since they were first detected on White Blood Cells.

• HUMAN Class I MHC – HLA A and HLA B HLA C• Human Class II MHC – HLA DR, HLA DP, HLA-

DQ

• Combination of HLA genes usually is inherited as a unit called haplotype.

• Each inherits one chromosome from each parent and therefore having two HLA haplotypes.

• The identification or typing of HLA molecules is important in tissue or organ transplantation, forensics, paternity evaluations.

• The closer the matching of haplotypes, the greater in probability of identical antigens and the lower the chance of rejection.

MONOCYTES, MACROPHAGES DENDRITIC CELLS

MONOCYTES

• Migrate from the blood to various tissues where they mature into the major tissue

phagocytes, the MACROPHAGES.

• Macrophages are the major scavenger cells of the body. It can be fixed in a tissue or free to migrate from an organ to lymphoid tissues.

• Lungs (i.e. alveolar macrophages)• Liver (i.e. Kupffer cells)• Spleen, lymph nodes, peritoneum, CNS

(i.e. microglial cells)

• Macrophages are activated to engulf and digest antigens that come in contact with their cell membrane.

• The Phagocytic killing of microorganisms help to contain infectious agents until adaptive immunity can be marshaled.

• Phagocytosis?

• Macrophages function early in the immune response to amplify the inflammatory response and initiate adaptive immunity.

• Directs these processes through the secretion of CYTOKINES (e.g. tumor necrosis factor [TNF], interleukin-1 [IL-1] that activates lymphocytes and mediate the different aspects of inflammatory process.

• Influence adaptive immunity as APC’s that break down complex antigens into peptide fragments for association with class II MHC molecules. Macrophages present these complexes to the helper T cells so that self-non-self recognition and activation of the immune response can occur.

DENDRITIC CELLS

• Shares the important task of presenting processed antigen to T lymphocytes.

• Distinct star shaped cells with long extensions of cytoplasmic membrane provide an extensive surface rich in Class II MHC molecules and other membrane molecules important for initiation of adaptive immunity.

• Found in most tissues where antigen enters the body and in the peripheral lymphoid tissues where they function as potent APCs .

• Langerhans cells are specialized dendritic cells in the skin. Follicular dendritic cells are found in the lymph nodes.

T LYMPHOCYTES

• Function in the activation of other T cells and B cells in the control of viral infections, in the rejection of foreign tissue grafts and in delayed hypersensitivity reactions.

• Collectively these immune responses are Cell-mediated immunity

• T cells regulates self-recognition and amplifies the response of B and T lymphocytes.

• Arise from the bone marrow stem cells as pre- T cells and migrate to the thymus for their maturation.

• The immature T lymphocytes undergo rearrangement of the genes needed for expression of a unique T-cell antigen receptor.

2 Types of T CELLS

• CD4+ helper T cells – serves as a master regulator for the immune system

• CD8+ cytotoxic T cells

Subtypes T Helper Cells

• TH1 – differentiation pathway is the response to microbes that infect or activate macrophages and those that induce activation NK cells.

• TH2 – activated in response to allergens and helminths (intestinal parasites) which causes chronic T lymphocyte stimulation, often without significant innate immune response or macrophage activation

B LYMPHOCYTES

• Can be identified by the presence of membrane immunoglobulin that function as the antigen receptor, class II MHC proteins, complement receptors, and specific CD molecules.

• Function as APCs in hummoral response to haptens.

• The antibody responses to haptens- the hapten specific B cell is responsible for recognizing the hapten and the carrier-specific helper T cells for stimulating the differentiation of B cells into immunoglobulin-producing plasma cells.

Immunoglobulins

• Antibodies compromise a class of proteins

• Each immunoglobulin is composed of two identical light (L) chains and two identical heavy (H) chains to for a Y shaped molecule.

• Two forked ends that bind antigen is the Fab fragments.

• Tail of the molecule Fc fragment determines the biologic properties that are characteristics of a particular class of immunoglobulins.

IgG

• Gamma globulin. • Most abundant in body fluids and enters

tissues.• Crosses the placenta and transfers immunity

from mother to fetus.

• Subtypes: IgG1, IgG2, IgG3 and IgG4

• Some have restrictions in their response to certain antigens. – IgG2 is responsive to Streptococcus

pneumoniae, Haemophilus influenzae and Neisseria meningitidis

IgM

• Forms a polymer of five basic immunoglobulin units.

• First to appear in response to an antigen and the first antibody made by a newborn

• Diagnostically useful, detects infection in the infant by a specific pathogen.

IgA

• Secretory immunoglobulin, found in the saliva, tears, colostrum, in the bronchial, gastrointestinal, prostatic, and vaginal secretions.

• Primary defense against local infections in mucosal tissue.

IgD

• Found on the cell membranes of B lymphocytes and serves as an antigen receptor for initiating differentiation of B cells.

IgE

• Involved in inflammation, allergic responses and combating parasitic infections.

• Binds to mast cells and basophils to release HISTAMINE

NATURAL KILLER CELLS

• Lymphocytes that are functionally and phenotopically distinct from T cells, B cells, and monotype-macrophages.

• An effector cell important in innate immunity that can kill tumor cells, virus-infected cells or intracellular microbes.

• They are called “natural” because unlike cytotoxic T cells, they do not recognize a specific antigen before being activated.

• Believed to be one of the immune surveillance for cancerous or virus infected cells.

• Present in large numbers in the central and peripheral lymphoid organs.

• Central lymphoid organs: BONE MARROW and THYMUS

• Peripheral lymphoid organs: – Lymph nodes– Spleen– Tonsils–Appendix–Peyer’s patches in the intestine–Mucosa-associated lymphoid tissues in the

respiratory, GIT and reproductive systems

THYMUS• An elongated,

bilobed structure that is located in the neck region above the heart.

• Generates mature immunocompetent T lymphocytes.

• A fully developed organ at birth weighing 15-20 g• At puberty thymus begins regressing and is

replaced by adipose tissue.• Some thymus tissue persists into old age.

Pre-T cells enter the thymus as immature T cells

Thymic Hormones and Cytokines

T cells mature and multiply and acquires T-cell

Receptors

Undergoes THYMIC SELECTION95% of thymocytes die when they do not produce appropriate type of self-

antigens

Mature Immunocompetent T cells leave the thymus in 2-3 days and enters the peripheral lymphoid tissues via blood stream

Surface markers that distinguish among the

types of T cells and antigens that distinguish

self from non-selfOnly T cells able to recognize foreign antigen and not

react to self antigens are allowed to

mature

LYMPH NODES• Small aggregates of the

lymphoid tissue located along lymphatic vessels throughout the body.

• Many lymph nodes are in the axillae, groin, along great vessels of the neck, thorax, and abdomen.

• Two Functions:1. Remove foreign material from lymph

before it enters the bloodstream 2. Centers of proliferation of immune cells.

• Bean-shaped tissue surrounded by a connective tissue capsule.

• Lymph enters the node through afferent channels and leaves through efferent lymph vessels located in the deep indentation of the hilus

• Lymphocytes and macrophages flow slowly through the node, allows trapping and interaction of antigen and immune cells.

• This reticular meshwork serves as a surface where macrophages can more easily phagocytize antigens.

• Dendritic cells also permeates lymph nodes and aid antigen presentation.

SPLEEN • A large ovoid secondary

lymphoid organ located high in the left abdominal cavity

• Filters antigens from the blood and is important in the response of systemic infections.

• Composition:– RED PULP

• Supplied with arteries and is the area where senescent and injured RBCs are removed

– WHITE PULP• Contains concentrated

areas of B and T cells permeated by macrophages and Dendritic cells.

MUCOSA-ASSOCIATED LYMPHOID TISSUES

• Nonencapsulated clusters of lymphoid tissues in the membranes lining the respiratory, digestive, urogenital tracts.

• In the Tonsils, Peyer’s Patches in the intestine and the appendix , organized structures are evident.

• Immunity at the mucosal layers helps to exclude many pathogens and thus protects the vulnerable internal organs.

CYTOKINES AND THE IMMUNE RESPONSE

CYTOKINES• Low molecular weight proteins made by cells

that affect the behavior of other cells.

• Made primarily by and act primarily on immune cells, especially activated helper T cells and macrophages.

• Name of cytokines were derived from their biological properties.– Interleukins (IL) – made of leukocytes and

act on leukocytes– Interferons (IFNs) – were found to interfere

with virus multiplication

• Cytokines modulate reactions of the host to foreign antigens and injurious agents by regulating movement, proliferation and differentiation of leukocytes and other cells.

• Actions of cytokines affects more than one cell type and have more than one biologic effect. E.g. INFN-γ –inhibits virus replication and a potent activator of macrophages and NK cells.

• Cytokines have biologic activities that overlap which maximizes the immune response and protection against detrimental mutations in a single cytokine.

• Excessive Cytokine production may lead to serious adverse effects associated with septic shock, food poisoning and types of cancer.

• Cytokine secretion is brief and a self-limited event. – This short half-life of cytokines ensures that

excessive immune responses and systemic activation do not occur.

• Production of cytokines occurs in a cascade. Some function as antagonists to inhibit biologic effects of earlier cytokines.– Functions as appropriate control of cytokine

synthesis and subsequently of the immune response.

Major Functional Groups

• Pro inflammatory – produces fever and acute phase response and by activating phagocytes.

• Evident in local inflammation, systemic inflammation, or even septic shock

• Maturation factors for hematopoesis of white or red blood cells. – IL -3, GM-CSF

• Recombinant CSF molecules are being use to increase rates of bone marrow transplantations.

• Function in adaptive immunity as intracellular communication molecules among T cells, B cells, macrophages and other immune cells

• IL 2 therapy for several malignancies has lead to some clinical success.

EFFECTOR RESPONSES OF

THE IMMUNE SYSTEM

• Humoral and cell-mediated immune responses

• Active and Passive Immunity• Complement System

ACTIVE VS PASSIVE Immune Responses

• ACTIVE IMMUNITY – acquired through immunization or having a disease

• Depends on the antigen by the person’s immune system.

• Long lasting, though requires a few days to weeks after first exposure before the immune response is sufficiently developed.

• IMMUNIZATION – the process of acquiring the ability to respond to an antigen after administration by vaccines.

• PASSIVE IMMUNITY – Transferred from another source. – Infant receiving antibodies from the mother • Maternal IgG

– Infant is protected from 3 to 6 mos. – Can be artificially provided by transfer of

antibodies produced by other people or animals through injection of hyperimmune serum with high concentrations of antibodies for a specific disease.

• Produces short-term protection that lasts weeks to months.

HUMORAL IMMUNITY

• Depends on the maturation of B lymphocytes into the plasma cells which produce and secrete antibodies.

• Combination of antigen with antibody can result in several effector responses:– Precipitation of antigen-antibody complexes– Agglutination or clumping of cells– Neutralization of bacterial toxins and viruses– Lysis and destruction of pathogens or cells– Adherence of antigen to immune cells– Facilitation of phagocytosis and complement

activation.

PRIMARY IMMUNE RESPONSE

• Occurs when an antigen is first introduced in the body.

• There is a latent period or lag before the antibody can detect the serum. – During this lag the B cells are activated to

proliferate and differentiate into antibody-secreting plasma cells and memory cells.

• Recovery from infectious diseases occur when the primary response is at its peak.

SECONDARY IMMUNITY• Occurs on the second or subsequent

exposures to the antigen.• The rise in antibody occurs sooner and

reaches a higher level because of the available memory cells. – Booster immunization given in Infectious diseases

CELL-MEDIATED IMMUNITY• Provides protection against viruses,

intracellular bacteria, and cancer cells.

• Actions of T lymphocytes and effector macrophages predominate.

• Phagocytes and Macrophages becomes activated after exposure to T-cell cytokines, especially IFN-γ

• Helper T cells become activated after antigen recognition and by induction with IL-12

• Activated helper T cells then synthesizes IL-2 and IL-4

• These molecules drive and the multiplication of helper T cells which amplifies the response

• Further differentiation of helper T cells leads to production of additional cytokines which enhance the activity of cytotoxic T cells and effector macrophages.

• Contact dermatitis due to poison ivy sensitivity is an example of cell-mediated hypersensitivity caused by hapten-carrier complexes.

THE COMPLEMENT SYSTEM

• Primary mediator of both innate and adaptive immunity that enables the inflammatory response, lyse foreign cells and increase phagocytosis

• Consist of group of proteins (C1 – C9) present in the circulation and functionally inactive precursors.

• For a complement reaction to occur, complement components must be activated in proper sequence.

• Each enzyme or molecule activated be one step can generate multiple activated enzyme molecules at the next step.

• Complement activation is inhibited by proteins that are present on the normal host cells, thus, its actions are limited to microbes and other antigens that lack these inhibitory proteins.

3 Phases of the Complement System

1. INITIAL ACTIVATION PHASE- 3 Pathways for recognizing microbes and activating the complement system:

• ALTERNATIVE PATHWAY – activated on microbial cell surfaces in the absence of antibody and is a component of innate immunity.

• CLASSIC PATHWAY – activated by types of antibodies bound to antigen and is part of Humoral immunity.

• LECTIN PATHWAY – activated by plasma lectin that binds to mannose on microbes and activates the classic system pathway in the absence of an antibody.

2. EARLY STEP INFLAMMATORY RESPONSE- The Activation of the complement protein C3 and its enzymatic cleavage into a large C3b and a smaller C3b fragment.

-Smaller 3a acts stimulates inflammation by acting as a chemoattractant for neutrophils

- Large 3b attach to microbes and acts as an opsonin for phagocytosis

- Also acts as an enzyme to cleave C5 into 2 components C5a which produces vasodilatation and increases vascular permeability and C5b leads to late step membrane attack responses

• LATE STEP MEMBRANE ATTACK – C3b binds to other complement proteins to form

an enzyme that cleaves C5, generating C5a and C5b fragments

– C5a stimulates the influx of neutrophils, and the vascular phase of acute inflammation.

– C5b initiates the formation of complex of complement proteins C6, C7, C8 and C9 into membrane attack protein or pore that allows fluids and ions to enter and cause cell lysis.

DEVELOPMENTAL ASPECTS OF THE IMMUNE SYSTEM

• Immune system develops 5-6 weeks as the fetal liver becomes active in hematopoesis.

• Middle of the first trimester – development of primary lymph organs (i.e. thymus and bone marrow) begins and secondary lymphoid organs (i.e. spleen, lymph nodes, and mucosa-associated lymphoid tissues) develop soon after.

• The thymus at birth is the largest lymphoid tissue relative to body size and normally two thirds of its mature weight which it achieves during the first year of life.

MOTHER TO INFANT

• The largest amount of IgG crosses the placenta during the last weeks of pregnancy and is stored in fetal tissues.

• The infant begins producing IgM antibodies shortly after birth in response to immense antigenic stimulation of new environment

• At approximately 6 days the IgM rises sharply ang continues to 1 year of age when the adult level is achieved

• IgA is detected 13 days after birth. Adult levels are reached between the 6th and 7th year.

• Maternal IgA also is transferred in the colostrum or milk by breast-feeding.

In the Elderly

• Aging – characterized by the declining ability to adapt to environmental stresses.

• Decline of the immune response: – Decrease in the size of the thymus glands– Slight decrease of proportion of T cells to other

lymphocytes and decrease in CD4+ and CD8+ cells.

• Increasing proportion of lymphocytes become unresponsive.

• The range of antigens that can be recognized by B cells does not diminish. If anything autoreactive B cell clones increases to the extent, the B cells begin to recognize some self-antigens as foreign antigens