Immunology – VIII

Marcus Peters, marcus.peters@rub.de

Infection & Immunity

Microbes and their associated diseases

Stages of the immune response to infectious

microbes

Conserved structures of pathogens are detected by

„Pattern Recognition Rezeptoren“

www.rndsystems.com

The importance of the TLR signal transduction is apparent in

MyD88 knock out mice

LPS

of gram-

negative

bacteria

IL-1 IL-6TNF-aIL-8

TLR-4

TLR-2

Lipopeptide

of gram-

positive

bacteria

Inflammation

IL-18

Maturation of Interleukin-1 by the Inflammasome

NALP Inflammasom

Pyrin-Domain: 95 amino acids

„death domain superfamily“

Nucleotid binding Domain:

Important for oligomerization!

NACHT associated Domain

Leucin rich repeats-Domain

important as stress sensor!

Caspase Recruitment Domain

Activation of the inflammasom leads to recruitment of Caspase-1

pro IL-1b

pro IL-18

IL-1b

IL-18

binds to Pyrin

Domain after

oligomerization!

Another important group of pattern

recognition receptors are the c-Typ Lectins

- Carbohydrate Recognition Domain

(CRD)

-Type 1 (more than one CRDs)

- Type 2 (only one CRD)

- Binding of sugar is Ca2+ dependent

Quelle: Figdor et al. 2002

Innate Immunity is the basis for induction of the

adaptive immune response.

Chemokines orchestrate the cellular response.

Entry of DCs into inflamed tissue by diapedesis

Chemokine that is most important for attracting DCs:

MIP3a (CCL20) binding to CCR6

Modified from 2002 Decker Intellectual Properties

CCL20

CCR6DC

Am J Respir Crit Care Med Vol 172. pp 530–551, 2005

After activation of DCs at the site of infection cells follow

a chemokine gradient to the lymph node

CCR6↓

CCR7↑

Activated dendritic cells express costimulatory

molecules in the lymph nodes

DC1. DC becomes activated

in the tissue leading to down

regulation of CCR6 and up-

regulation of CCR7

2. DC follows the CCL21

gradient into the lymph node

meanwhile upregulating

expression of costimulatory

molecules

3. DCs interact with T-cells

in the paracortical lymph node

area

APCs must express costimulatory molecules to

Activation of T-lymphocytes in the lymphoid organs

Some of the activated T-cells become memory T-cells

Mechanisms of

the adaptive

immune response

to clear infection

Sepsis

But what when things

went wrong….

Major causes for Sepsis:

-Trauma; Treatment in an intensive care unit

-Systemic or local infection

-Chronic inflammation of skin and mucosa

with endotoxin releasing bacteria

Patient with Sepsis

LPS

of gram-

negative

bacteria

IL-1 IL-6TNF-aIL-8

TLR-4

TLR-2

Lipopeptide

of gram-

positive

bacteria

Inflammation

IL-18

IL-1

TNF-a

IL-8

Adhesion

Macrophages

Neutrophils

Leakage Edema, bleeding

RBCs

Thrombus

TNF, IL-1, 6, 8, 10, 12

Platelet activiting Factor

Prostaglandins

O2 & NO Radicals

Proteasis

From local inflammation to systemic disease

TNF-a

Local effects Systemic effects

Vasodilation,

Vascular leakage

Adhesion of

Platelets,

Cappilary

plugging

Local Inflammation

Vasodilation, Edema,

Hypotonia, Shock

Intravasal blood

clotting, Multiorgan

failure

First: systemic

inflammation, later:

Immune Suppression

TNF-a „knock out“ mice are not prone to sepsis

The systemic effects of TNF-a depend on

the released quantities

Endotoxin induced inflammation

is down regulated by delayed

production of IL-10 und IL-1ra

Regulatory T-cells are induced under

septic conditions

Critical Care Medicine 2010;38(8):1718-1725

Peritoneum Lymph nodes Spleen

Mice were infected with Legionella 15 or 30 days after surviving sepsis.

Mice that survived sepsis show suppression

of immune responses

HIV

Figure 43.20 in Campbell & Reece (2002).

Time course of a HIV Infection

„Anatomy“ of HIV

Figure 11-22Systemic dissemination of HIV

Infection of T-helper cells by HIV

Figure 11-23Infection of T-Lymphotytes by HIV

Figure 11-25Mechanism of replication

Why is a HIV infection not cleared by the

Immune system?

• HIV hides in the genome of immune cells. Therefore the virus cannot be easily recognized by the immune system

• Activation of T-lymphocytes by Interleukin-2 produces new virus

• HIV shows a high mutation rate.

• Immune response of CD8+ cytotoxic T-cells towards HIV infectedcells is weak.

• Produced antibodies do not have neutralizing activity

Figure 11-29

Figure 11-30

Opportunistic infections leading to the disease pattern of AIDS