Basic Immunity

Presented by:-
Raina J. P. Khanam
2nd year
CONTENTS
• Definition
• Types of immunity
• Cells of immune system
• Complement system
• Transendothelial migration
• Leucocytes function
• Specific immune response
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Immunity
It is defined as the resistance exhibited by the host against any
foreign antigen including microorganisms.

Plays a major role in prevention of infectious diseases.

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Immune system
The immune system is a network designed for the homeostasis
of large molecules (oligomers) and cells based on specific
recognition processes.

It is the collection of cells, tissues and molecules that function

to defend us against infectious microbes.

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Types of immunity
1. Innate immunity
2. Adaptive immunity

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Cells of immunity

Cells of the immune system that are important in inflammation and host defenses include
1. mast cells
2. peripheral dendritic cells
3. neutrophils
4. monocytes/macrophages
5. T cells
6. B cells
7. natural killer cells (NK).
Other hematopoietic leukocytes, including basophils, eosinophils, erythrocytes, and
platelets, also participate in certain forms of inflammation or immune function.

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Innate immunity
Innate immunity or non specific immunity is the natural

immunity that a person is born with i.e, it is there at birth.

The cells of innate immunity are phagocytic cells (i.e.,

monocytes, macrophages, neutrophils), which possess a number

of inherently antimicrobial peptides and proteins that kill many

different pathogens rather than one specific pathogen.

 

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1. Mast cells
 Mast cells are important in immediate inflammation.
 More recently, mast cells have been shown to express toll-
like receptors. These receptors allow the innate immune
system to adapt (e.g., express the major histocompatibility
complex (MHC) class II molecules, produce nitric oxide and so
on.

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 Mast cells feature prominent cytoplasmic granules, termed lysosomes,
which store inflammatory mediators such as
1. histamine
2. eosinophil chemotactic factor
3. neutrophil chemotactic factor
4. heparin.

 Mast cells can synthesize, other inflammatory mediators, such as

1. slow-reacting substances of anaphylaxis (SRS-A)
2. tumor necrosis factor alpha (TNF-α)
3. interleukin-6 (IL-6)
4. leukotrienes C4
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2. Peripheral dendritic cells
 Peripheral dendritic cells (DCs) are leukocytes with
cytoplasmic projections, or dendrites.
 Langerhans cells are DCs that reside in the supra-basilar
portions of squamous epithelium.

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Dendritic Cells express high levels of
1. MHC class II molecules
2. intercellular adhesion molecule-1 [ICAM-1]
3. leukocyte function–associated antigen-3 [LFA-3])
4. co-stimulatory factors.

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 3. Neutrophils
Neutrophils, also known as polymorphonuclear
leukocytes (PMNs), are the predominant leukocyte
in blood approx. (4000-8000 cells/mm3).

They possess many lysosomes within their

cytoplasm.

Neutrophils possess receptors for metabolites of

the complement molecule C3 and C5. These
receptors enable neutrophils to
1. Be recruited from the blood
2. locate offending agents
3. Ingest (phagocytose) and kill the offending
agents.
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4. Monocytes
 Monocytes are referred to as macrophages when
they leave the blood.
 They may become greater than 22 μm in
diameter.
 Because macrophages differentiate and live in the
local tissues, they are suited for communicating
with lymphocytes and other surrounding cells.
 Macrophages live long enough to present antigen
to T cells. Together, macrophages and
lymphocytes orchestrate the chronic immune
response.
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Complement system
Complement (C) is an interacting network of about 30
membrane-associated cell receptors and soluble serum
glycoproteins.

 Soluble components of this system account for about 5% (3-4

mg/ml) of the total serum protein.
 The soluble components of the complement system were first
observed to cause bacteriolysis and cytolysis in association with
antibody, and later in the absence of antibody.

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 The complement system is a central component of
inflammation that enables endothelium and leukocytes to
recognize and bind foreign substances for which they lack
receptors. Complement promotes inflammation by
generating the following:
1. A Vasoactive substance, termed kinin-like, C2a, which induces pain
and increases vascular permeability and dilation.
2. Molecules, termed anaphylatoxins, C3a and C5a, which produce
anaphylaxis by inducing mast cell secretion.
3. A chemotaxin, C5a, which attracts leukocytes and stimulates
phagocyte secretion.
4. An opsonin, C3b, covalently bound to molecular aggregates, particles,
or cells, which enables phagocytes to ingest them.

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C3 is the most important component of complement system.
A sequestered, internal thioester bond is the essential feature of C3,
and it shares this feature with the related molecule, C4.
Splitting of C3 forms C3a and C3b and exposes the internal thioester
bond residing within the C3b fragment.
Two main pathways result in the splitting of C3: the alternative and
classical pathways.
Both the alternative pathway and the classical pathway lead to
inflammation and phagocytosis through an enzyme that is designated a
bound C3 convertase.
The alternative pathway leads to the hydrolysis of C3b by larger
structures (designated R), including the hydroxyls and amines on
macromolecules and bacterial cell surfaces. The resulting covalent
structure,
21 C3b-R, leads to the bound C3 convertase (R-C3bBb).
 
 The classical pathway is initiated in response to the presence of some
irritant.

 Irritants include antibody-antigen complexes, certain membranes, or

suspicious polymers.

 This pathway involves the activation of a serine protease (e.g., C1qrs) that
has attached to an irritant.

 The protease serves as a C4/C2 convertase and leads to formation of a C3

convertase covalently bound to R (R-C4bC2b), with release of the vasoactive
kinin-like substance C2a.
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Two main processes can occur with the formation of bound C3
convertase.

First, amplification occurs, and second, the membrane attack

complex is formed.

Amplification is an exponential increase in the formation of C3b.

Membrane attack complex is initiated after approximately 100

molecules of C3b are formed.

These new complexes can bind and cleave both C3 and C5; thus
they are called C3/C5 convertase.
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 The C5 convertase activity is monumentally slow
(one of the slowest enzymatic activities known).

 C5 produces two important fragments, C5a and

C5b.

 The C5a fragment is the main leukocyte

chemoattractant derived from complement and
is an important anaphylatoxins.

 The C5b component associates with C6, C7, C8,

and C9, forming a membrane attack complex
that can kill certain bacteria and cells by forming
a large pore in the target cell membrane.
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Transendothelial migration
Transendothelial migration is a selective interaction between leukocytes and
endothelium that results in the leukocyte pushing its way between
endothelial cells to exit the blood and enter the tissues.

 The blood contains only 2% of all lymphocytes at any given time.

In a local inflammatory response, transendothelial migration occurs in the
following sequential phases
1. Rolling
2. Complement activation
3. signaling the endothelium
4. increased rolling
5. signal for rolling arrest
6. strong adhesion
7. zipper phase
8. Basement membrane degraded
9. Chemotaxis

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 Leukocytes use the lectin (a non-enzymatic carbohydrate-binding
protein) designated L-selectin to interact with carbohydrate molecules
known as vascular addressin on the luminal surface of endothelial cells.

 A local insult triggers the release of a variety of inflammatory signals

(e.g., interleukin-1β, tumor necrosis factor alpha) from cells in the
tissue, especially from resident leukocytes such as mast cells .

 IL-1β, TNF-α, C5a, and lipopolysaccharides can stimulate endothelial

cells to express P selectin and E-selectin on their luminal surfaces. This
appears microscopically as an increase in number of leukocytes attached
to the luminal surface of the endothelium, or increased rolling.
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 The stimulated endothelium also
releases chemokines.

Chemokines are small peptide

cytokines, first recognized for their
chemoattractant activities, which
play a fundamental role as selective
signals for leukocytes to exit the
blood. Chemokines function as a signal
for rolling arrest.

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 The interaction of a chemokine, interleukin-8 (IL-8), with the leukocyte
receptor CXCR2 causes the leukocyte to shed L-selectin and upregulate the
integrin leukocyte function–associated antigen-1 (LFA-1).
 LFA-1 binds intercellular adhesion molecule-2 (ICAM-2), which is expressed
constitutively by endothelium. This results in rolling arrest because the
phagocyte becomes firmly associated with the endothelium.
 CD31 (platelet-endothelial cell adhesion molecule-1) is a transmembrane
glycoprotein present at the intercellular borders of endothelial cells facing into
lumen and on all leukocytes.
 Once the leukocyte locates the inter-endothelial junction, it uses its own CD31
as a zipper.
 This zipper effect has been proposed as a mechanism of minimizing the leakage
of fluid. As the endothelium unzips its CD31, the leukocyte rapidly “zips”
between the endothelial cells.
 Leukocytes possess several proteases, including uro-kinase plasminogen activator
receptor (uPAR). The uPAR leads to the activation of collagenase, which then
degrdae
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the basement membrane and enable the leukocyte to enter the
connective tissue.
LEUKOCYTE FUNCTIONS
1. Chemotaxis
2. Phagocytosis
3. Antigen processing and presentation
1. Chemotaxis
 Once the leukocyte enters the connective tissue, it must be able to locate
and migrate to the site of insult.

 This is accomplished by chemotaxis, which depends on the leukocyte’s

ability to sense a chemical gradient across its cell body and migrate in the
direction of increasing concentration.

 The phagocyte senses only a limited number of chemicals: chemotaxins for

which it has receptors.

 The receptors for chemotaxis belong to a family called the G-protein

coupled family.

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2. Phagocytosis
 Phagocytosis is the process by which cells ingest particles of a size visible
to light microscopy.

 Neutrophils and monocytes/macrophages are the only cells efficient

enough at phagocytosis to be considered “professional phagocytes.”

 Phagocytosis results of a pathogen within a membrane-delimited

structure, the phagosome.

 The immune system has evolved mechanisms of coating the pathogen with
a few recognizable ligands, which enable the phagocyte to bind and ingest
the pathogen. This is referred to as opsonization.

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Once a microbe has been ingested, it may be killed. Phagocytes kill bacteria
through two broad categories of killing mechanisms.

1. Oxidative mechanisms require

 The presence of oxygen and
 An oxidation reduction potential.

2. Non-oxidative mechanisms requires

 phagosome-lysosome fusion
 Each neutrophil possesses two main types of lysosomes, or granules:
 Specific granules, designed for both extracellular and intra phago-lysosomal secretion.
 Azurophil granules, designed mainly for intra phago-lysosomal secretion.

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Specific granules contain microbiocidal components like
 Lysozymes
 Lactoferrin
 Lactoferricin

Azurophil granules contain antimicrobial peptides

 α-defensins
 Serprocidins
 Cathepsin-G
 Lysozymes
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 They are primitive pattern recognition
PRRs (Pattern Recognition receptor.
Receptor) These receptors identify specific structural
patterns.
Discriminates between self and non-self.

One of the primary challenges of the

innate system is the discrimination On the basis of function PRRs are classified as:
of pathogens from host.. 1. Signaling PRRs
 Toll-like receptors
 NOD receptors (Nucleotide-Oligomerization
This challenge is met by recognition domain)
of the evolutionary structures:
The PRRs. 2. Endocytic PRRs

On the basis of location PRRs are classified as:

1.Membrane bound PRRs
2.Cytoplasmic PRRs
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3.Secreted PRRs
 TOLL-LIKE RECEPTORS
 Toll-like receptors are the gate keepers of innate immunity.

 These are a class of Pattern Recognition Receptor (PRRs) that recognises Microbiota
associated molecular patterns (MAMPs) and that signals cytokine secretion in innate cells.

 Among the 10 human toll-like receptors identified so far, toll-like receptor-2 and toll-
like receptor-4 are the most defined members.
 Toll-like receptor-2 is mostly involved in the recognition of a variety of different
bacterial cell components, such as peptidoglycans and lipoproteins.
 Toll-like receptor-4 has been shown to specifically recognize lipopolysaccharide of Gram-
negative bacteria and acts in cooperation with several protein components, such as
lipopolysaccharide-binding protein and CD14.
 The gingiva is constantly exposed to microbes present in plaque biofilm, toll-like receptors
signaling plays an important role in the innate immune response and maintenance of
periodontal
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health. However, over-production of pro-inflammatory cytokines due to
chronic stimulation of toll-like receptors, they may lead to tissue destruction.
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TLR signaling pathway……
 The Toll-Like Receptors are single-pass transmembrane proteins
characterized by an N-terminal leucine-rich recognition domain and an
intracellular C-terminal Toll/IL-1 receptor signaling domain (TIR).

 TIR domains of TLRs act as a scaffold to recruit various TIR domain-

containing adaptor proteins:
1. Myeloid differentiation primary-response protein 88 (MYD88)
2. MYD88-adaptor-like protein (MAL)
3. TIR domain-containing adaptor protein inducing IFN-β (TRIF)
4. TRIF-related adaptor molecule (TRAM).
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 With the exception of TLR-3, all TLRs engage the
MyD88 adapter protein.

 TLR-3 and TLR-4 uniquely interact with the

TRIF adapter protein.

 Engagement of the adapter proteins at the TIR

domain of TLRs initiates signal transduction that
involves interactions between the adaptor
molecules, IL-1 receptor– associated kinases
(IRAKs) and TNF receptor–associated factors
(TRAFs).

 In the case of TLR-2 localized to the plasma

membrane, MyD88-dependent downstream
activation of transforming growth factor-beta
(TGF-β), activated kinase 1 (TAK-1)
simultaneously induces mitogen- activated
protein
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(NF-κB) signaling.
 NF-κB translocates to the nucleus, and MAPK cascades activate activator protein
1 (AP-1), ultimately resulting in the expression of proinflammatory cytokine
genes.

 When TLR-4 translocates to endosomes, TRIF-dependent signaling leads to the

activation of NF-κB and IFN-regulatory factor (IRF)-3, resulting in the expression
of proinflammatory cytokine and type I IFN genes.

 Concerning TLR- 9 localized to the endo lysosomal membrane, MyD88-

dependendent signaling leads to the activation of IRF-7, which up-regulates the
expression of type I IFN genes.

 The TLR signaling pathways highlights the potential for synergy or amplification
effects modulating the host immune response.
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ANTIGEN PRESENTATION

 Cellular interaction is very important for the recognition and presentation

of antigens to the immune system by antigen presenting cells.
 Antigens are macromolecules which are presentable and recognizable so
that the antigen processing and presenting cells digest them into smaller
fragments which are then presented on their surfaces (APCs) using MHC
molecules and CD1 clusters.
 The three main professional APCs are
1. Peripheral DCs,
2. Monocyte derivatives,
3. B cells (these are both antigen receiving and presenting cells).

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 However, binding of T-lymphocytes to MHC/ or CD1 cluster alone does not activate the T-
lymphocytes into action.

 So in order to become activated T-cell must receive a second signal from APC.

 This second signal is called as co-stimulation. It is mediated by a variety of transmembrane

molecules of the tumor necrosis factor (TNF) superfamily.

 Co-stimulation performs three functions:

1. Makes the T cell resistant to apoptosis
2. Increase the proliferation of T-cells
3. Decreases the amount of time needed to trigger the T cell response (also referred to as amplification)

 B –cell also require co-stimulation to proliferate further after initial recognization and binding
to the antigen.
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Adaptive immunity
 The adaptive immune system is also known as the acquired
immune system/specific immune system.
 It is activated by the non specific innate immune system.
 Lymphocytes (e.g., T cells, B cells) get stimulated through
their B and T cell antigen receptors (BCRs and TCRs)
present on the cell membranes which facilitates the specific
targets.

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1. T Cells

 T cells are responsible for cell mediated immunity.

 T cells recognize diverse antigens using a low-affinity
transmembranous complex, the T-cell antigen receptor (TCR).
 The T cells are of the following types:
1. Helper T cells (CD4 cells).
2. Cytotoxic T cells (CD8 cells).
3. Regulatory (Suppressor).
4. Memory T cells.
5. Natural killer T cells (NK T cells).
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 Helper T cells/ CD4 cells are responsive to MHC class II molecules found on the
dendritic cells, macrophages and B lymphocytes.
 Cytotoxic T cells/CD8 cells are cytotoxic and kills virus infected cells eg. HIV
infected CD4+ T cells, cells infested with bacteria or protozoa, allograft eg.
Transplanted kidney, heart, lungs, etc. and cancer cells.
 Regulatory/ suppressor T cells maintain immunological tolerance and regulate
effects and continuation of the immune response.
 Memory T cells live for a long time after an infection has been settled. Upon re-
exposure by the same microbe, they quickly expand the number of effector T cells
and effects the specific immune response.
 Natural Killer T cells/ NKT cells are a heterogeneous group of T cells that share
properties of both T cells and Natural killer cells. Dysfunction or deficiency of NKT
cells is believed to lead to the development of autoimmune diseases eg. Diabetes,
cancer, etc.
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2. B Cells

 B cells are primarily responsible for humoral immunity.

 B cells work chiefly by secreting soluble substances called antibodies into

the body fluids.

 B cells recognize diverse antigens using the B-cell antigen receptor

(BCR), which is a high-affinity antigen receptor.

 The high-affinity interaction between BCR and antigen enables the B cell
to bind and ingest the antigen without antigen presentation. Ingested
antigen is degraded and presented to T cells.

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3. Natural Killer (NK) Cells

• NK cells recognize and kill certain tumor and virally infected cells.

• The NK cells possess several classes of antigen receptors, including killer

inhibitory receptor (KIR) and killer activating receptor (KAR).
• NK cells have small granules containing proteases, perforin, etc in their
cytoplasm.

• These receptors also recognizes the antigens.

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 SPECIFIC IMMUNE RESPONSES
 Following events that take place are:
1. Clonal selection – selection and activation of specific lymphocytes which are
capable of recognizing specific Antigen.
2. Clonal expansion – increase in the number of activated lymphocytes (up to
5000 times).
3. Clonal contraction – apoptosis of activated lymphocytes after completing their
job.
4. Memory – maintenance of these activated lymphocytes in small number till the
time body encounters the same antigen again. These cells will cause rapid
immune response (secondary immune response). 

 When the body encounters the same antigen again the memory cells
will induce clonal expansion at a rapid phase (1 to 3 days).
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T-CELL RESPONSES

 After receiving co-stimulation, cytokines receptors are activated and

produce cytokines. Once activated, the T cell undergoes proliferation and
differentiation, leading to one of several possible mature T-cell
phenotypes.

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 B-CELL RESPONSES AND ANTIBODIES
 B cells produce immunoglobulins at the site of infection from local and systemic tissue
sources.

 An immunoglobulin that binds a known antigen is known as antibody.

 Immunoglobulin accounts for about 20% to 25% (15 mg/ml) of the total serum protein
(60-70 mg/ml).

 Humans possess nine genetically distinct isotypes of immunoglobulins: IgM, IgD, IgG1, IgG2,
IgG3, IgG4, IgA1, IgA2, and IgE.

 The ability of B cells to respond to antigen depends on the B-cell antigen receptor (BCR).
The51BCR is formed partly by immunoglobulin molecules on the B-cell surface, which serve
as highly specific antigen receptors.
 B cells are capable of responding to certain antigens in the absence of T cells.
This is referred to as T-independent B-cell antibody response.

 However, in some situations B-cells are activated by the T-cells. This is known
to be T cell dependent antibody response.

 In this pathway B cell bind soluble antigens and then they are ingested and
processed. Thus mechanism of binding antibody to antigen results in
protection via:-
1. Neutralization
2. Agglutination
3. Opsonization
4. Complement activation
5. Enhanced NK cells

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