Dr. Kritika Jangid

MDS- Periodontics

BASICS OF IMMUNITY

IMMUNITY: Resistance to infectious disease

IMMUNE SYSTEM: Collection of cells, tissues and molecules that mediate resistance to infections

IMMUNE RESPONSE: Coordinated reactions of these cells and molecules to infectious microbes

IMMUNOLOGY: Study of immune system and its response to invading pathogens

TERMS ASSOCIATED

IMPORTANCE OF IMMUNE SYSTEM

Role of the Immune System

• Defence against infections

• Recognises and responds to tissue grafts and newly introduced proteins

• Defence against tumors

Implications

• Deficient immunity results in increased susceptibility to infections. Vaccination boosts immune defences and protects against infections

• Immune responses are barriers to transplantation and gene therapy

• Potential for immunotherapy for cancer

OVERVIEW OF IMMUNE SYSTEM

INNATE IMMUNITY

Also called Natural or Native immunity.

Components present before the onset of infection.

Disease resistant mechanisms that are not specific to a particular pathogen

Pathogens must first breach barriers that protect host

INNATE IMMUNITY

Provides the first line defence right after exposure.

Most micro-organisms are readily cleared within a few days by innate immune system before adaptive immune system is activated

INNATE IMMUNITY

Components of innate immunity recognize structures that are shared by various classes of microbes and are not present on the host cells

For eg: Phagocytes express receptors for1. Bacterial LPS (endotoxin)- On cell wall of

many bacterial species2. Terminal mannose residues- Typical of

bacterial gylcoproteins3. Ds RNA- Found in viruses4. Unmethylated CpG oligonucleotide- Common

in microbial DNA

RECOGNITION OF MICROBES

PATHOGEN ASSOCIATED MOLECULAR PATTERNS:The microbial molecules that are targets of innate immunity .Indicates that they are shared by microbes of the same type

PATTERN RECOGNITION RECEPTORS:The receptors of innate immunity that recognize the shared structures.

Recognizes structures of microbes that are often essential for the survival and infectivity of these microbes.

Recognize molecules that are released from stressed or necrotic cells. (Damage associated molecular patterns)

Does not react against the hostEncoded in the germline; not produced by

somatic recombination of genes

Two principal types of defences are:1. Inflammation2. Antiviral defence

...contd

CELLULAR RECEPTORS- LOCATION

Specificity and

functions of TLRs

EPITHLIAL BARRIERS

PHAGOCYTES

DENDRITIC

CELLS

NK CELLSOTHER

LYMPHOCYTES

COMPLEMENT

CYTOKINES

PLASMA PROTEI

NS

COMPONENTS OF

INNATE IMMUNITY

EPITHELIAL BARRIERS

2 types: Neutrophils and monocytes recruited to the site of infection where they recognize and ingest microbes for intracellular killing.

NEUTROPHILS (PMNs): MACROPHAGES

PHAGOCYTES

PMNsMost abundant leukocytes (4000-10,000/µL)Infection: 20,000µL of blood1st cell type to respond to most infections

(particularly bacterial and fungal)Stimulated by cytokines (Colony stimulating

factors) which act on the bone marrow stem cells to produce neutrophil precursors

Ingest microbes in the circulation and rapidly enter extravascular tissues at the site of infection where they ingest microbes and die after a few hours.

NEUTROPHILS

MONOCYTES500-1000/µL of bloodMonocytes that enter extravascular tissues

survive in these sites for long periods

Sequence of events in the migration of blood leukocytes to the site of infection

Phagocytosis and

intracellular killing

of microbes

Initiate T- cell responsesImportant bridge

between innate and adaptive immunity

Respond to microbes by producing cytokines that recruit leukocytes and initiate adaptive immune responses

DENDRITIC CELLS

NK cells

γδ T cells: Present in epitheliaNK-T cells: Present in epithelia and lymphoid

organs. (Recognize microbial lipids bound to a class 1 MHC- related molecule called CD1)

B-1 cells: Most of the antibodies are specific for carbohydrates that are present in the cell walls of many bacteria.

Marginal zone B cells: Responses that are characteristic of adaptive immunity (eg. Antibody production) and have features of innate immunity (eg. Rapid responses and limited diversity of antigen recognition)

OTHER CLASSES OF LYMPHOCYTES

Collection of circulating and membrane associated proteins.

Complement activation involves the sequential activation of proteolytic enzymes sometimes called an enzymatic cascade.

3 pathways:Alternative pathwayClassical pathwayLectin pathway

COMPLEMENT SYSTEM

COMPLEMENT

Pathways of complement activation

Secreted in small amounts in response to an external stimulus and bind to high affinity receptors on target cells

CYTOKINES OF INNATE IMMUNITY

MBL: Plasma Mannose binding lectin: Recognizes microbial carbohydrates and can

coat microbes for phagocytosis or activate the complement cascade by lectin pathway.

Belongs to collectin family of proteins which shares homology to collagen and contain a carbohydrate binding (lectin) domain.

CRP: Binds to phosphoryl-choline on microbes and coats the microbes for phagocytosis.

OTHER PLASMA PROTEINS OF INNATE IMMUNITY

ROLE OF INNATE

IMMUNITY IN

STIMULATING ADAPTIVE

IMMUNE RESPONSES

ADAPTIVE IMMUNITY

Triggered only if microbes or their antigens pass through epithelial barriers and are delivered to the lymphoid organs where they can be recognized by lymphocytes.

Specialized to combat different types of infections:

Antibodies: Eliminate microbes in extracellular fluids

Activated T lymphocytes: Eliminate microbes living inside cells

Protection from an infectious disease agent that is mediated by B- and T- LYMPHOCYTES following exposure to specific antigen, and characterized by IMMUNOLOGIC MEMORY.

Active immunity: Immunity induced in an individual by infection or vaccination

Passive immunity: Immunity conferred in an individual by transfer of antibodies or lymphocytes from an actively immunized individuals

PROPERTIES

OF ADAPTIVE IMMUNE

RESPONSES

TYPES OF

ADAPTIVE IMMUNIT

Y

Antigen receptors of B lymphocytes (Membrane bound antibodies) can recognize a wide variety of macromolecules (proteins, polysaccharides, lipids and nucleic acids) as well as small chemicals in soluble or cell surface associated form.

Most T lymphocytes can see only peptide fragments of protein antigens, and can do so only when these peptides are presented by specialized peptide display molecules on host cells

Antigen capture and Presentation to lymphocytes

CELL MEDIATED IMMUNE RESPONSES

Majority of T lymphocytes recognize peptide antigens that are bound to and displayed by major histocompatibility complex (MHC) molecules of antigen presenting cells (APCs)

Capture of protein antigens by antigen presenting cells (APCs)

Antigen Presentation to T cells MHC (major

histocompatibility complex) 1 all nucleated cellsMHC-encoded alpha

(hvy) chain and beta 2 (lt) microglobulin

Polymorphic alpha 1 and alpha 2 domains for closed binding cleft

Conserved alpha 3 domains = binding site for CD8

Beta 2 interacts noncovalently with alpha 3

MHC-II = dimer of alpha and beta subunitsAPCs Both chains MHC

encodedAlpha 1 and beta 1

domains variable and form open binding cleftMost of variability on

beta chainAlpha 2 and beta 2

folded into Ig domainsB2 Ig domain binds

to CD4

FEATURES OF PEPTIDE BINDING TO MHC MOLECULES

Steps in activation of T lymphocytes

T cells can be distinguished by their different antigen receptors

The definitive T cell linage marker is the T cell antigen receptor (TCR).

2 different types of TCR are:A heterodimer of two disulfide- linked

polypeptides (α and β)A structurally similar heterodimer consisting of

γ and δ polypeptides

90-95% of blood T cells are αβ T cells

T- cells

There are 3 major subpopulations of αβ T cells

Helper T cells (TH) that expresses the CD4 marker (CD4+ T cells) and mainly ‘helps’ or ‘induces’ immune responsesTH1 cells secrete IL2 and IFN γTH2 cells produce IL4. IL5, IL6 and IL10

Regulatory T cells (Treg) that expresses the CD4+ T cells and regulate immune responses.

Cytotoxic T cells (TC) that express the CD8+ T cells- also called as cytotoxic T lymphocytes (CTLs)

Initiation of T cell responses requires multiple receptors on the T cells recognizing ligands on the APCs:The TCR recognizes MHC associated peptide

antigens, CD4 and CD8 c0-receptors recognize the MHC molecules strengthen the binding of T cells to APCs, and receptors for co-stimulators recognize second signals provided by the APCs

The molecules other than antigen receptors that are involved in T cell responses to antigens sometimes are called Accessory molecules of T lymphocytes

Antigen recognition and Co-stimulation

HUMORAL IMMUNE RESPONSES

Humoral immunity is mediated by antibodies and is the arm of adaptive immune response that functions to neutralize and eliminate extracellular microbes and microbial toxins

More important in defending against microbes with capsules rich in polysaccharides and lipids and against polysaccharide and lipid toxins

Phases of humoral immune response

Subset of B cells

PLASMA B CELLSMEMORY B CELLSB1 CELLSB2 CELLS

B Cell Subsets

B cell activation

Antibody Forming Cells

Plasma Cells

B cells differentiate into Antibody Secreting Plasma Cells

glycoprotein molecules that are produced by plasma cells

Immunoglobulins

Major Ig in serumCrosses the placenta

Macrophages, monocytes, PMNs and some lymphocytes have Fc receptors for the Fc region of IgG.

Opsonin

IgG

IgM

Third most common serum IgGood complement fixing IgGood agglutinating IgIgM exists as a monomer and lacks J chain

IgA

2nd most common serum Ig.Major class of Ig in secretions - local

(mucosal) immunity.Does not fix complement, unless aggregated.IgA can binding to some cells - PMN's and

some lymphocytes.

IgD

IgD is found in low levels in serum

IgD is primarily found on B cell surfaces

IgD on the surface of B cells has extra amino acids at C-terminal end for anchoring to the membrane. It also associates with the Ig-alpha and Ig-beta chains.

IgD does not bind complement

IgE

IgE is the least common serum

Involved in allergic reactions - various pharmacological mediators that result in allergic symptoms.

IgE also plays a role in parasitic helminth diseases. Eosinophils have Fc receptors for IgE and binding of eosinophils to IgE-coated helminths results in killing of the parasite.

IgE does not fix complement.

Interactions of TH cells and B cells in lymphoid tissues

Anatomy of humoral immune responses

Antibody Feedback

Basic Immunology 3e By: Abbas and Lichtman

Immunology 8e By: Roitt et. al.Carranza’s Clinical Periodontology 10e, 11e

REFERENCES