Immunity to microbes

Overview of the immune system

From Immunology, Todd & Reeves

Range of microbial infections

protozoa

viruses bacteria

worms

fungi

Resolution of adaptive response & establishment of

memory

Normal course of a primary acute infection

Innate/induction of adaptive response

infection adaptive response

time

Leve

l of

mic

robe

t

Immunity to infection requires both innate and acquired immunity

Time

Leve

l of

mic

robe

Mac-/PMN- No innate immunity

Scid/RAG- no T/B cells

Normal immune system

Innate response 1: Inflammation-PPRs

Tissue dwelling macrophages recognize bacterial/viral products as ‘foreign’ via pathogen associated molecular patterns (PAMPs)

PAMPs are conserved products of microbial metabolism

-unique to microbes-invariant between members of a given class-vital for microbial fitness

LPS found in all gram -ve bacteria

Immune system has a range of pattern recognition receptors (PRRs) which recognize PAMPs

Lipopolysaccaride: an example of a PAMP

LPS defective mice

C3H/HeJ sub-strain found to be insensitive to toxic shock syndrome induced by LPS

Mice were also susceptible to infection by certain gram -ve bacteria

Reverse genetics isentified a single point mutation in the cytoplasmic tail of a Toll like receptor

Toll like receptors (TLRs)

Ancient conserved family of PPRs

Transmembrane receptors

Activation leads to induction of various genes responsible for host defense

NFBMAP

CytokineChemokineMHCCo-stimulation

LPS

TLR4

Ligand specificity of human TLRs

Innate response 2: complement

alternative

pro-inflammatory moleculesC3a C3b C5a

cell lysis

classical

Complement activation

• C3a C5a mast cell activation• C3b opsonisation• C5a chemotaxis• C5b-C9 MAC-lysis

LPS

TLR4

N

Bacteria

mast

TNF-IL-1

E&P selectin

VCAMICAM

NC3a

C5a

C3b

Activation of Activation of complementcomplement

NN

NNN

Innate response 3: role of NK cells

Lymphoid originUtilize invariant receptorsVital for early control of viral infectionsRecognize infection as ‘altered self’-e.g. low MHCINK cells are ‘armed’ via IFN- - & IL-12Kill altered cells via secretion of cytotoxic granules (granzyme/perforin)

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Innate response 4: activation of APC

Professional APC reside in tissues

iDCs (e.g. langerhans cells)

Normally endocytose extracellular antigen- tolerance

Activated via: -PPRs (TLRs CD14)-necrotic cell products (HSPs)-viral infection IFN

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Innate response 4: activation of APC

MHCII

•Increased synthesis of MHCII

•Migration to secondary lymphoid organs (chemokines)

CD80CD86CD40

•Upregulation of costimulatory molecules

ICAM-1 -2LFA-1

•Upregulation of adhesion molecules

iDC mDC

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GC

artery

vein

Aquired response 1: activation of naïve lymphocytes

mDC

Tn

CD80CD86CD40

CD28CD40L

ICAM-1 -2LFA-1 -3DC sign

CD2LFA-1ICAM-2

MHCII

TCR

cytokines

Acquired response 1: activation of naïve T lymphocytes

IL-2cytokine

wormsbacteria

Acquired response 2: polarization of naïve T lymphocytes

B

Importance of T cell polarization: Leishmania mouse model

BALB/c

fatal

C57BL/6

recovery

BALB/c

C57BL/6

Th1: IFN-TNF

Leishmania specific T cell responses

Th2: IL-4IL-10IL-13

resistant

susceptible

BALB/c

C57BL/6

Leishmania specific T cell responses

resistant

susceptible

anti-IL-12 ab or IL-12 -/-

anti-IFN- ab of IFN- -/-susceptible

resistant anti-IL-4 ab or IL-4R -/-

Chromatin remodeling

NKM

mDC

Th1

MHCII

TCR

Acquired response 3: role of Th1 cells

Tc

IL-2IFN-

MHCI

Tc

IFN-

NKNKM

Th1 mediated destruction of Leishmania

IgM productionClonal expansionClass switchingAffinity maturationIgG production

Virgin B cell

Th2

IL-4IL-5IL-10IL-13

Acquired response 4: role of Th2 cells

In T cell zone

No

of a

ntig

en s

peci

fic T

cel

ls

in e

ffer

ent

lym

phat

ics

time

Tn

L-selectin-(CD34)

Teff

VLA-4 LFA-1

2 5

Effector T cells migrate from the lymph node to sites of infection

VLA-4 LFA-1

ICAM-1VCAM-1

Teff

TCR

MHCII

INFLAMED TISSUE

TeffTeff

Afferent lymphatics

MAdCAM-1

“addressins”

+ve

Range of effector mechanisms used to clear microbial infections

plasmodium

measles typhoid

Schistozome

Candida

GTcG

Th/M

G

Th/M

GTh/M

Resolution of the effector response

When the infection is removed:

the innate system is no longer activated-inflammation subsides

antigen is cleared in the form of immune complexes-stimulus for T cells is removed

most effector T and B are removed-death by neglect/cytokine starvation

Apoptotic cells are removed by macrophages

Establishment of immunological memory

T BPlasma

cell

Bone marrow LN Spleen

Plasmacell

Plasma cells provide protective memory

Secretion of high affinity antibody

Lifespan of months-years

Re-generated by low level proliferation & differentiation of memory B cells?

B

primary secondary

frequency 1:104-1:105 103

isotype IgM>>IgG IgG IgA

affinity low high

Somatic Mut Low high

Memory B cell responses provide reactive memory

Proliferate and differentiate into plasma cells in response to antigenic stimulation

Memory T cell responses

Relative frequency

1 10

Responsiveness to pep-MHC

low high

Requirement for co-stimulation

high low

Tn Tm

Memory T cell responses

Two distinct populations of memory T cells exist:

-effector memory (Tem) protective memory-central memory (Tcm) reactive memory

Defined by (i) absence or presence of immediate effector function

(ii) expression of homing receptors to enable circulation to2˚ lymphoid organs or non lymphoid tissues

homing Sites of inflamation 2˚ lymphoid organs

distribution Gut lung liver lymphnodes

Proliferative capacity low high

Cytokines production

Th1 Th2 Tc IL-2

Effector function hours days

CCR7 CD62L

TcmTem

CCRs

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Model of T cell differentiation

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Method of immune evasion example

sequestration HIV

disguise S. mansoni

Resistance to complement S. aureus

Inhibition of chemotaxis Streptococci spp.

Cleavage of immunoglobulin T. cruzi

Lymphocyte activation (super Ags) EBV

Lymphocyte supression O. volvulus

HLA expression HSV

Impairment of interferon response Leishmania spp.

Antigenic variation H. influenzae

Methods used by microbes to avoid the immune response

Overview of the immune system

From Immunology, Todd & Reeves