3 Immune Response to Bacterial Infection

8/12/2019 3 Immune Response to Bacterial Infection

1/63

Overview of the ImmuneResponse

The Immune System Seen in the Context of

the Response to Infectious Agents/Bacteria

Dr. A.Aziz Djamal MSc.DTM&H.SpMK(K)


2/63

Extracellular Bacteria

Bacteria that replicate outside of host cells

Circulation

Connective tissue

Tissues spaces such as airways and intestinal lumen


3/63


Bacteria that replicate outside of host cells

Examples:

Streptococcus pneumoniae

E. coli

Staphylococcus aureus


4/63


Induce Inflammation

Produce toxins

Endotoxins- products of bacterial cell walls such as LPS

Exotoxins which are actively secreted

cytotoxic

interfere with cell function without deathinduce cytokine production


5/63


Upon exposure to the infectious agent the innate immune system is

activated


6/63


Upon exposure to the infectious agent the innate immune system is

activated

Complement can be directly activated

C1q binds directly to bacteria

Mannan binding lectin binds the pathogen

Alternative pathway


7/63


8/63

Cleavage products of complement function

as opsonins


9/63

C3a , C4a and C5a are anaphylatoxins

Small peptides that causes smooth muscle contractionincreases vascular permeability and mast cell and

basophil degranulation.

C5a is also a chemoattractant and activator of WBC

Also amplify the inflammatory response by inducing

the synthesis of pro-inflammatory cytokines.

Their receptors are present on many cell types

including leukocytes, mast cells, macrophages,

endothelial cells, astrocytes and microglial cells


10/63

Form membrane attack complex: only Gram negative lyse


11/63

Phagocytes have receptors that directly recognize bacteria and

lead to phagocytosis, activation, microbicidal activity and cytokine

secretion

TNF and IL-1: inflammation and leukocyte recruitment

IL-12: TH1 differentiation and IFN-gproduction

Macrophage Has ManyReceptors

LPS

receptor(CD14)

Mannosereceptor

Scavengerreceptos

Fc receptors

CD11b/CD18

Engulfment

Cytokine Secretion

Activation

TLR TLR

Antigen presentation


12/63


13/63

ADAPTIVE IMMUNITY

Adaptive immunity is triggered when an infection eludes the

innate defense mechanism and generates a threshold of antigen.It becomes effective only afterseveral days, the time requiredto haveantigen-specific T and B cells proliferateand differentiate into effector cells.


14/63

The first step is the activation of Tcells in the draining lymphoid organ.

T cells do not become sensitized

in peripheral tissue.

Antigens in tissues are trapped indraining lymph nodes; antigens in the

blood are taken to the spleen where theimmune response in initiated in thewhite pulp.


15/63

Ag uptake by Langerhans' cells

Langerhans' cell leave skin, enter lymphatics and move to

lymph nodes to become dendritic cells expressing B7

B7-positive dendritic cellsstimulate T cells

=APCs


16/63

Naive T cells continually recirculate throughthe lymphoid organs

If a naive T cell recognizes it antigen, LFA-1is activated causing the T cell to adherestrongly to the APC and cease migration


17/63

During the initial response of nave CD4+T cells to Ag,

differentiation into TH1 or TH2 occurs and has a criticalimpact on the outcome of an adaptive immune.

This differentiation is influenced by the cytokines thatare present.


18/63

CD4 T cells develop into TH2cells ifactivated in the presence of IL-4,especially if IL-6 is present . IL-4 and IL-10 inhibit the differentiation of TH1. IL-4from the early response may be fromNK1.1+ CD4 cells.

CD4 T cells develop into TH1cells ifactivated in the presence of IL-12 and

IFN- . INF- inhibits differentiation ofTH2 cells . IL-12 and INF- areproduced by macrophages and NKcells.


19/63

A i i f B ll k l i d l h id


20/63

Activation of B cells takes place in secondary lymphoid organs

B cells specific for protein Ags cannot be activated until they encounter an activated

helper T cell. B cells migrate through peripheral lymphoid organs like T cells. If

they encounter Ag-specific helper T cells, they are activated to proliferate and

differentiate


21/63

Humoral immunity provides the principal

protective immune response against

extracellular bacteria


22/63




Innate:

T independent response against polysaccharide Ags


23/63




Innate:

T independent response against polysaccharide Ags

Adaptive:

T dependent response against protein Ags


24/63

Neutralizationof toxins by high affinity IgG andIgA

Opsonizationthrough Fc receptors

Complementactivation by IgM and some subclassesof IgG


25/63

Receptors for Fcs of IgG and for cleavage produces of complement are

important for the clearance of extracellular bacteria


26/63

Intracellular Bacteria

Eliminated by cell mediated immunity

Examples:

Mycobacterium tuberculosis

Listeria monocytogenes

Mycobacterium leprae


27/63

Intracellular Bacteria

Eliminated by cell mediated immunity

Innate immune response consists mainly of phagocytes

and NK cells

NK cells activated either directly or by IL-12

produced by macrophages


28/63


29/63

The major protective immune response is

cell mediated

Macrophage activation by T cells (IFN- g)

Lysis of infected cells by CTLs

If IL-12 and IFN-gare produced following the initial exposure to thepathogens the response will be dominated by inflammatory T cells


30/63

Both IL-12 and IFN- are critical for defenseagainst an intracellular bacterial infection


31/63

The differential capacity of a pathogen to interact with dendritic cells,macrophages, NK and NK1.1+T cells influences the overall balance

of the cytokines present early in the immune response and thus

determines whether TH1 or TH2 cells develop preferentially

Since inflammatory T cell cytokines make more inflammatory cells and


32/63

Since inflammatory T cell cytokines make more inflammatory cells andhelper make more helper there tends to be amplification


33/63

TH1/TH2 decision can determine the

outcome of infection

For example, most mice mount a TH1 response

toLeishmania majorand clear the infection.

However BALB/c mice mount a TH2 response

and die of disseminated disease.

However, note as pointed out in class Leismania

is a protozoan parasite, not a bacterium.

Nevertheless, the immune issues remain the

same.


34/63

Thankyou


35/63

Viruses

Replicate within cells

Cytopathic - cause cell lysis

Noncytopathic - latent


36/63

Response immune

against viral infection

Dr. A.Aziz DjamalMSc.DTM&H.SpMK(K)


37/63

Innate Immunity to Viruses

Inhibition of infection by type 1 IFNs

double stranded RNAs engage Toll-like

receptors and trigger production

NK cell-mediated killing

Recognize stress-induced proteins

Viral infection frequently decreases class I

MHC expression


38/63

Adaptive Immunity to Viruses

Antibodies

block virus binding and entry into cell

CTLs

eliminate the infection by killing infected cells


39/63


Antibodies- effective during extracellular stage

neutralizing Abs prevent virus attachment

and entry

opsonize viral particles and promote clearance

by phagocytes through Fc or C3b receptors


40/63



effective in containing the spread of a virus

during acute infection and in protecting

against reinfection

complement activation may promote direct lysis

of viruses with lipid envelopes

sIgA in mucosal secretions plays an important

role by blocking viral attachment to mucosalepithelial cells


41/63



While antibodies block viral infection of cellsand spread of viruses from cell to cell, once

the virus enters the cell it is inaccessible to

antibodies and infected cells must be eliminated

by CTLs



42/63

Adaptive Immunity to VirusesCTLs

CD8+T cells recognize cytosolic, usually

endogenously synthesized viral Ags in

association with class I MHC



43/63





CTL activation requires co-stimulation.

If the virally infected cell is not a

professional APC, it may be

phagocytosed by one.



44/63





full differentiation of CTLs requires

cytokines produced by CD4+helper

cellsCTL activation requires co-stimulation.If the virally infected cell is not a

professional APC, it may be

phagocytosed by one


45/63

Activated CTLs differentiate

into effectors CTLs that can kill any infected

nucleated cell (Ag specific)


46/63


CTLs

In some viral infections, especially with non-

cytopathic viruses, CTLs may be responsiblefor tissue injury

T-cell deficient mice become chronic carriers of

LCMV

Normal mice develop meningitis because

virus-specific CTLs kill infected meningeal cells


47/63

Immunity to Parasites

There is a wide range of animal parasitesincluding protozoa (which are small) and the

helminths (large worms)


48/63

Immunity to Parasites

Parasites currently account for greater morbidityand mortality than any other class of infectious

organism, particularly in developing countries

30% of the worlds population suffers from

parasitic infection

Malaria alone affects more than 100 million

people, killing 1 million annually

I t I it t P it


49/63

Innate Immunity to Parasites

Principal innate response is phagocytosis; however

many parasites are resistant to phagocytosis and

may even replicate within macrophages

I t I it t P it


50/63

Innate Immunity to Parasites

Phagocytes attack helminthic parasites and secrete

microbicidal substances to kill organisms too large

to be phagocytosed

Although some helminths activate the alternative

pathway of complement, many appear to have

developed resistance to complement-mediated lysis

Many helminths have thick teguments that makethem resistant to cytocidal mechanisms of

neutrophils and macrophages

Ad ti I it t P it


51/63

Adaptive Immunity to ParasitesDifferent parasites elicit distinct adaptive immune

responses

Pathogenic protozoa have evolved to live within

host cells.

The principal defense mechanism againstprotozoa that survive within macrophages

is cell mediated immunity, particularly macrophage

activation by TH1-derived cytokines


52/63

Mice resistant toLeishmaniaproduce large amounts of IFN-g.

BALB/c, which are susceptible, respond toLeishmaniainfection

with the production of IL-4.


53/63

Immunity to trypanosomes is mediated by antibodies.

Trypanosomes have developed the ability to change the expression

of their surface antigen, thereby evading the immune response


54/63

Protozoa such as malaria that replicatewithin host cells and lyse these cells

stimulate specific antibody and CTL

responses


55/63

The defense against many helminthic infections is mediated by theactivation of TH2 cells which results in the production of IL-4 and

IL-5 leading to IgE production and eosinophil activation


56/63

Eosinophils attached through Fcereceptors are activated to secretegranule enzymes that destroy the parasites


57/63

Protective Immunity

Immunity to re-infection

Immune reactants such as Ab

Armed effector T cells


58/63

Protective Immunity

Immunity to polio requires pre-existing Ab toprevent neuron infection

Specific IgA on epithelial surfaces canneutralize a virus before it enters the body


59/63


60/63

Immunization

Immunologic Memory

IgG

IgM

IgG

IgM


61/63

Are slightly increased in number relative to what is seen before

Immunization

Express markers characteristic of activated cells such as CD44

The isoform of CD45 that is expressed changes

CD45RA is on nave T cells

CD45RO is present on memory cells


62/63


63/63

Documents

3 Immune Response to Bacterial Infection