Relazione tra: eziologia, patogenesi, manifestazioni … tra: eziologia, patogenesi, manifestazioni morfo-funzionali e Complicazioni in 4 tipi di malattie. Infiammazione •! Che cosa

Relazione tra: eziologia, patogenesi, manifestazioni morfo-funzionali e

Complicazioni in 4 tipi di malattie.

Infiammazione

•! Che cosa è: processo reattivo (morboso) locale, base delle malattie

•! Sede: vascolo-connettivale (microcircolo)

•! Nomenclatura: suffisso “ITE” con il nome dell’organo interessato,

polmonite, pancreatite, gastrite….

•! Andamento stereotipato. Per effetto dei mediatori, nonostante la diversità degli stimoli.

•! Fenomeni elementari costanti: vasodilatazione, variazione

permeabiltà, migrazione cellulare.

•! Decorso: variabile per quantità e diversità stimoli, e delle reattività

dell’ospite ( danno variabile).

INFIAMMAZIONE

Ippocrate: individua fenomeni quali rossore e gonfiore

Celso: definisce i 4 punti cardinali della infiammazione

Galeno introduce il concetto della “funzione lesa”

Hunter: non si tratta di una malattia ma di una risposta agli stimoli

E. Metchnicoff: scopre i macrofagi

Lewis: scopre il ruolo dell’Istamina

Definizione generale

L’Infiammazione è il più importante processo morboso reattivo

locale che forma la base patologica delle malattie

Infiammazione acuta (sintesi)

•! Classificazione: acuta e cronica

•! Acuta: fenomeni vascolari prevalenti (essudativa), con migrazione

cellulare Neu e Mon , esito benevolo e guarigione completa.

•! Acuta: due fasi

•! Fase 1- Vasodilatazione e aumento permeabilità, con azione sulle

arteriole e sugli endoteli ( azione dell’istamina).

•! Fase 2- i fenomeni cellulari diventano prevalenti, si forma l’essudato

e con il procedere della perdita dei fluidi si arriva al rallentamento

ematico e alla fase di iperemia passiva. Marginazione dei granulociti

neutrofili e formazione di “rouleaux” di globuli rossi

What is inflammation?

Rubor Tumor Calor Dolor

(redness) (swelling) (heat) (pain)

What sort of things induce this inflammation?

Four basic symptoms (known since ancient Greek & Roman times)

EXOGENOUS FACTORS which can induce inflammation:

•! Mechanical (traumatic injury – wounding, fracture etc)

•! Physical (low or high temperature, ionising irradiation, microwaves)

•! Chemical (venoms, caustic agents, poisons etc)

•! Nutritive (deficiency of oxygen, vitamins & basic nutrients)

•! Biological (viruses, microorganisms, unicellular & multicellular parasites)

ENDOGENOUS FACTORS like autoantigens may also induce inflammation.

So, these induce inflammation but what is inflammation?

Inflammation is a general term for the local

accumulation of fluid, plasma proteins, and white

blood cells.

This is also known as an inflammatory response.

It’s a process whereby molecules and cells of the

immune system are concentrated at a site of tissue damage or infection.

These molecules and cells come from the blood.

How is the blood supply to the damaged site improved?

Inflammation is achieved by:

1.! Vasodilation – an increased blood supply.

3.! Increased capillary permeability caused by retraction of the

endothelial cells, allowing larger molecules than usual to

escape.

3.! Leukocyte migration out of the capillaries into the tissue.

Earliest stages – neutrophil migration predominates.

Later – monocytes and lymphocytes also migrate

into tissue.

So increased vascular permeability has a central role in

inflammation because it allows access of serum components

and blood cells to the challenged tissues.

Vascular permeability (leakiness) is promoted by many

inflammatory mediators.

Endothelial cells

lining blood vessel

Complement

Immunoglobulin

What’s the advantage in leaking complement and immunoglobulin at the

inflamed site?

3 main ways in which antibodies

protect the host from infection

Inflammatory mediators

Phases of inflammation (using a skin scratch as an example)

try it, but don’t draw blood 1.! Initial transient blanching due to vasoconstriction (immediate)

2.! Thin red line as capillaries dilate (usually within seconds)

3.! Flush in immediate area as arterioles dilate (usually within 1 minute).

4.! A wheal, or swollen area, as fluid leaks from the capillaries (usually

within a few minutes).

Vascular response (vasodilation & increased vascular permeability).

Cellular response (if sufficient tissue damage or infection has occurred).

5.! Appearance of PMNs in the tissues (within a few hours) .

6.! Monocyte and lymphocytes appear later if damage is serious enough.

Resolution – restoration of normal tissue architecture (possible scarring).

What substances make the capillaries more permeable?

Many agents increase vascular permeability, including:

C3a C5a

Ba

C2 kinin

Histamine Leukotrienes

Serotonin

Most release occurs from the post capillary venules.

Complement agents (several produced by MØs)

Released from mast cells

What’s in the initial inflammatory fluid exudate?

The inflammatory fluid exudate contains all the componets

of plasma including:

Fibrinogen – important for any necessary clotting

Kinins (e.g. bradykinin – induces pain, vascular vasodilation & permeability)

Complement - (see lecture on complement’s functions)

Immunoglobulins – act as opsonins and make antibody-dependent

cell-mediated cytotoxicity (ADCC) possible.

The fluid exudate causes pressure and thus pain, but other inflammatory

factors also induce pain (e.g. acidic pH, K+ ions, bradykinin and serotonin).

But blood cells are far bigger than plasma proteins. How do they get

out of the capillaries?

Leukocyte extravasation

In inflamed regions white blood cells are caught

“like flies on fly-paper” and escape from the blood by squeezing between endothelial cells and

crawling through the basement membrane with

the aid of digestive enzymes.

What makes the moving leukocytes stick to the endothelial cells?

One of the first effects of inflammation is to increase P-

selectin expression on endothelial cells which binds Sialyl-

Lewisx on the PMNs causing rolling.

How do the leukocytes come to a halt?

Activated endothelial cells express:

Intercellular adhesion molecule (ICAM-1)

Endothelial leukocyte adhesion molecule (ELAM-1) Vascular cell adhesion molecule (VCAM-1)

Human leukocytes express

integrins as receptors which bind to these molecules:

Leukocyte function associated antigen 1 (LFA-1)

Very late antigen 4 (VLA-4)

Rolling gives way to tight binding and the subsequent migration

of the PMN into the infected tissue.

What determines the PMN movement after tight binding and spreading?

(PECAM-1)

and spreading

Leukocytes can detect a concentration gradient of

chemotactic factors (e.g. of C3a, C5a, leukotrienes or IL-8) and move towards it.

This movement of leukocytes (e.g. PMNs, monocytes

and lymphocytes) towards a site of inflammation is

called Chemotaxis.

Chemotaxis differs from chemokinesis (a random

increase in movement).

What are the main cell types involved in the inflammatory response?

PMN

T CELL Neutrophils, Monocyte and T cells in the

blood extravasate into the tissues to contribute to the inflammatory response.

Macrophages and mast cells resident in

the tissue are of central importance to the inflammatory response, releasing

inflammatory mediators when activated.

MAST

CELL MACRO-

PHAGE

Cells of most tissues can themselves

secrete inflammatory mediators (prostaglandins) when damaged

or challenged.

Endothelial cells lining local blood

vessels, respond to secretions from MØs, mast cells and tissue cells, by

allowing serum to leak between them and by trapping leukocytes and

promoting their migration into the tissues.

Some of the most important cells of the inflammatory response

Monocyte

Complement

C5a, C3a, C4a C3b MAC (C5-C9)

Recruitment of Opsonisation Direct killing

Inflammatory of pathogens Cells

Most important for host defence against infection

Neutrophils (polymorphonuclear leukocytes - PMNs)

Bone marrow makes 1011 PMNs / day (1012 in acute Inflammation).

4-10hr !-life in circulation; 1-2 days survival in tissue.

Each day about 3 x 109 neutrophils enter tissues of the oral cavity (‘the most contaminated site of the body’).

At infected sites activated macrophages release

cytokines that attract neutrophils which soon become the

dominant phagocytic cell type.

PMNs are specialised for working under anaerobic

conditions which prevail in damaged tissues.

Neutrophil arrival - 1st event of inflammatory response.

Macrophages instigate an inflammatory response having

phagocytosed bacteria.

(IL-1, TNFa)

Do macrophage cytokines have any inflammatory functions other than

increasing vascular permeability?

Macrophage ingests and degrades bacteria and is activated

to secrete monokines

Activates vascular endothelium

Activates lymphocytes Local tissue destruction

increased access of effector cells

Chemotactic factor for leukocytes

increases access of effector cells

Activates binding by !2 integrins

Activates vascular endothelium and increases vascular permeability which leads to increased entry of IgG complement and cells and increased fluid drainage to lymph nodes

Lymphocyte activation increased

antibody production Activates NK cells

induces the differentiation of CD4 T cells into

TH1 cells

Fever Production of IL-6

Local effects

Systemic effects

Fver Mobilisation of metabolites

Shock

Fever Induces acute phase

protein production

IL-1 IL-8 TNF-" IL-6 IL-12

Macrophage Pro-inflammatory Mediators

Effects of cytokines produced by activated macrophages

IL-1 IL-8 TNF" IL-6 IL-12

Activates

vascular endothelium

Increases

vascular

permeability

Activates lymphocytes

Local tissue destruction

Increases

vascular permeability

Chemotactic

factor for

leukocytes

Activation of PMNs

(with TNF")

Activates

binding of b2 integrins

Activates

vascular endothelium

Increases

vascular

permeability

increased entry of IgG,

complement,

and cells and increased fluid

drainage to lymph nodes

Activates

lymphocytes

Increased

antibody

production

Activates NK

cells

Induces

differentiation

of CD4 T cells to TH1 cells

Fever,

Production

of IL-6

Fever

Mobilisation of metabolites

Shock

Fever

Induces acute phase protein

production

LOCAL

EFFECTS

SYSTEMIC EFFECTS

Cytokines from activated macrophages coordinate the

body’s response to infection.

FEVER

What are acute phase proteins?

The acute

phase

response increases

the

supply of

recognition

molecules of innate

immunity.

Acute-phase proteins (CRP and MBP) produced by the liver can each

bind structural features of bacterial cells.

Upon binding they act as opsonins and also activate complement

(lysis – dotted bacterial margin).

CRP MBP

(found as far back as invertebrates)

Encapsulated bacteria are more efficiently engulfed by phagocytosis

when the bacteria are coated with antibody, C3b, CRP or MBP.

Cytokines from activated macrophages coordinate the

body’s response to infection.

FEVER

Has fever any benefits?

FEVER

IL-1, IL-6 and TNF" (endogenous pyrogens) released by macrophages

act on the hypothalamus and on muscle and fat cells to raise body

temperature (induce fever).

Fever helps the immune system fight infection because:

1.! Most bacterial and viral pathogens grow better at temperatures

lower than human body temperature (37oC).

2. Human cells become more resistant to the deleterious effects of

TNF" at raised temperatures.

3. Adaptive immunity becomes more potent at higher temperatures

(antigen processing is enhanced).

How else do macrophages promote T lymphocytes in the inflamed region?

Macrophage cytokines influencing T cells:

IL-1 A general activator of all T cells

IL-6 T cell growth and differentiation

IL-12 Preferentially activates TH1 cells

TH1 cytokines released in response to macrophage (MØ) cytokines:

Interferon-# (IFN- #) expression of MHC on MØs and other local cells

MØ antigen processing

induces MØ maturation

NK cell activity

inhibits TH2 cells

causes antiviral effects

Tumour necrosis factor (TNF) several roles in inflammation but high local

levels can cause tissue destruction and has

potent systemic effect of causing weight loss.

Th1 cell cytokine effects on MØs

IN CONCLUSION, molecular control of inflammation is by :

•! Cytokines

•! Plasma enzyme systems: Complement

Clotting (kinin & fibrinolytic) pathways

•! Lipid mediators: Prostaglandins & leukotrienes

•! Vasoactive mediators (e.g. histamine) from mast cells, basophils & platelets

•! The antigen itself – when Ag cannot be cleared the inflammation is chronic

and different from sites where it is rapidly cleared.

Acute inflammation is the term used to describe early and often transient

episodes. What types of antigen cannot be cleared in chronic inflammation?

Chronic inflammation occurs when there is ineffective elimination of

foreign bodies such as:

•! microbes especially intracellular infections (tuberculosis, leprosy,

brucellosis, leishmaniasis, schistosomiasis, trichinosis and fungi

(e.g. Histoplasma).

•! autoantigen in autoimmune diseases (e.g. rheumatoid arthritis)

•! substances which are phagocytosed but cannot be degraded (asbestos,

silica, talc, cotton wool, some metals and streptococcal cell walls)

infezione L’infezione è rimossa

L’Infezione

non è rimossa

L’infezione permane

Tuberculosis

Hepatitis B Schistosomiasis

INFIAMMAZIONE ACUTA Risposta Innata (PMNs, complemento, IFN)

Risposta adattativa

INFIAMMAMMAZIONE CRONICA

formazione del Granuloma

INFIAMMAZIONE ACUTA E CRONICA

What is a granuloma?

I MEDIATORI DELL’INFIAMMAZIONE

ENDOGENI

•!ISTAMINA

•!SEROTONINA

•!PROSTAGLANDINE

•!BRADICHININA

•!LEUCOTRIENI

•!C5a,C3a,C4a,proteasi

•!Radicali liberi

•!Enzimi lisosomiali

•!Elementi della coagulazione

•!Elementi sistema fibrinolitico

ESOGENI

•!LPS

•!PEPTIDI FORMILATI

•!PRODOTTI BATTERICI

MAST

CELL

vasoactive amines

e.g. histamine & serotonina (5-hydr-triptamina)

(also produced by basophils and platelets)

Trauma

Heat

Light

C3a & C5a

Allergens (via

specific IgE)

Factors causing mast cell degranulation

prostaglandins

& leukotrienes

(released later)

Substances released by mast cells

Tissue proteases

& cationic proteins

Toxins &

venoms

Cytokines

(TNF", IL-4,

IL-5 & IL-6)

What other factors cause the degranulation of mast cells?