INFLAMMATION.

Definition:-

It is physiological protective response intended to

eliminate the initial cause of cell injury as well as the necrotic cells & tissues resulting from the original insult.
Inflammation does occurs in vascularized tissues. Inflammation is not a disease but it is manifestation of a

disease.
Inflammation accomplishes its protective effect by diluting,

destroying, or by neutralizing harmful agents.

INFLAMMATION
Tissue damage, microbial infections, or toxic agents are

classical inducers of inflammation.

These stimuli activate:

i. the complement system ii. mast cell degranulation iii. the blood coagulation contact system, leading indirectly to production of bradykinin. iv. macrophages

 The integrated effect of these processes produce biological

changes culminating in the diapedesis of leukocytes at the site

of infection .
These biological changes include:

i. secretion of chemokines and cytokines ii. generation of inflammatory mediators iii. altered expression and/or enhanced affinity of adhesion molecules iv. increased vascular permeability

v. localized degradation of the basement membrane

vi. Extravasation of neutrophils,monocytes and lymphocytes from the circulation.

 Inflammation is not always protective.

Some of the harmful effects of inflammation are:

-Life threatening anaphylactic reactions. -Formation of fibrous bands & scars. -Formation of abscess.

 Inflammatory response has many players:

>Circulating cells.

>Plasma proteins.
>Vascular wall cells.

>Cells & extracellular matrix of the surrounding connective tissues.

VASODILATATION,INCREASED VASCULARPERMEABILITY AND EDEMA

Classical inducers of inflammation give rise to an increase

in blood flow at the site of inflammation. Increased blood flow is caused by vasodilatation, due to histamine bradykinin and leukotriene 4.

 CIRCULATING CELLS:

-Bone marrow derived PMNL (neutrophils). -Eosinophils. -Basophils. -Lymphocytes & monocytes.

-Platelets.

 CIRCULATING PROTEINS:

-Clotting factors.

-Kinninogens.
-Complement components synthesized by the liver.

 VASCULAR WALL CELLS:

-Endothelial cells which are in direct contact with the blood. -Underlying smooth muscle cells that impart tone to vessels.

 Inflammation is divided according to its time course

into two categories: 1.ACUTE INFLAMMATION. 2.CHRONIC INFLAMMATION.

1.ACUTE INFLAMMATION.
agents.
It may last from afew hours to afew days.
It envolves several process:

It is the initial tissue reaction to a wide range of injurious

-Vscular component:- resulting in hyperemia. -Exudative component:- resulting in vascular leakage of aprotein-rich fluid.

-Cellular component:- resulting in the recruitment of leukocytes mainly neutrophil polymorphs.

-Proliferative component:- resulting in tissue regeneration, granulation tissue & healing.

Events in Acute Inflammation

Increased blood flow due to dilation of blood vessels

(arterioles) supplying the region.

Increased permeability of the capillaries, allowing fluid and

blood proteins to move into the interstitial spaces.

Migration of neutrophils (and perhaps a few macrophages)

out of the venules and into interstitial spaces .

The classic signs and symptoms of acute inflammation:

English Latin
Redness Rubor Heat Calor Swelling Tumor Pain Dolor Loss of function Functio laesa

Causes of acute inflammation.

The principal causes of acute inflammation are:

-microbial infections.
-hypersensitivity reactions.
-physical agents. -chemical agents. -tissue necrosis.

1.MICROBIAL INFECTIONS: -Are the commonest causes of inflammation. -Viruses lead to death of individual cells by intracellular multiplication. -Bacterial exotoxins & endotoxins bring inflammation -Parasitic infections & tuberculous inflammations cause immunologically-mediated inflammation through hypersencitivity reactions.

 2.HYPERSENSITIVITY REACTIONS.

-It occurs when an altered state of immunological responsiveness causes an inappropriate or excessive immune reaction which damage the tissue.

-HSR have both cellular or chemical mediators similar to those involved in inflammation.

3.PHYSICAL AGENTS. -Tissue damage leading to inflammation could occur through: >Physical trauma. >Ultraviolet radiation. >Ionizing radiation. >Burns. >Excessive cooling (frost bite).

4.CHEMICALS. -Corrosive chemicals & chemical irritants

provoke inflammation through gross

tissue damage. -Corrosive chemicals could be: >Acids. >Alkalis. >Oxidizing agents. -Some pathogenic organisms release chemical irritants.

5.TISSUE NECROSES. -Infarction due to lack of oxygen or

nutrient is a potent inflammatory stimulus. -The edge of a recent infarct often shows an acute inflammatory response.

 Early stage of acute inflammation involves

1.Change in vessel calibere.

2.Increased vascular permeability. 3.Formation of cellular component.

.The cellular component. -Neutrophil polymorph accumulation at site of inflammation is diagnostic of acute inflammation. -The steps where leukocytes reach a tissue are: 1.Margination of neutrophils. 2.Adhesion of neutrophils. 3.Neutrophil emigration. 4. Diapedesis.

Chemical mediators of acute inflammation.

The chemical mediators of inflammation cause:

-Vasodilatation.

-Emigration of neutrophils.
-Chemotaxis.

-Increased vascular permeability.

-Itching and pain.

 Chemical mediators released from cells:

A. HISTAMINE. B.LYSOSOMAL COMPOUNDS. C.PROSTAGLANDINS. D.LEUKOTRIENES.

E.SEROTONIN.
D.CHEMOKINES.

 Plasma factors for the chemical mediation

of inflammation consists of the following

enzymatic cascades:
-The complement system. -The kinin system. -The coagulation system. -The fibrinolytic system.

 Role of tissue macrophages in acute inflammation:

-They secrete numerous chemical mediators

when stimulated by an insult.

-Most important mediators are:

>Cytokines IL-1 & tumor necrotic factor alpha. >E-selectins. >Chemokines IL-8 & epithelial-derived neutrophil attractant.

 Role of lymphatics in acute inflammation.

-They drain away the oedema fluid of the inflammatory exudate. -They carry large molecules & some particulate matter which are important in the immune response to infecting agent. -They carry antigens to the regional lymph nodes for recognition by lymphocytes.

 Role of neutrophil polymorph in acute inflammation.

A. Adhesion to micro-organisms. B. Phagocytosis. C. Intracellular killing of microorganisms. D. Release of lysosomal products.

 Sequele of acute inflammation.

-RESOLUTION. -SUPPURATION. -ORGANIZATION. -PROGRESSION TO CHRONIC INFLAMMATION.

 Systemic effects of inflammation.

-PYREXIA. -CONSTITUTIONAL SYMPTOMS. -WEIGHT LOSS. -ENLARGEMENT OF LOCAL LYMPHNODES. -HAEMATOLOGIC CHANGES LIKE LEUKOCYTOSIS & ANEMIA. -AMYLOIDOSIS.

Chronic inflammation.
It is defined as an inflammatory process in which lympho

cytes, plasma cells & macrophages predominate.

It is the subsequent & often prolonged tissue reaction following the initial response.

Granulation tissue & scar formation is usually abundant. It could occur primarily or as a consequence of acute

inflammation.

Primary chronic inflammation.

Is the usual type of chronic inflammation.

The inflammatory response has all futures of chronic

inflammation with out acute phase of inflammation.

Some examples of primary chronic inflammation.

1. Resistance of infective agents to phagocytosis & intracellular killing. e.g >Tuberculoses,leprosy,brucellosis & viral infections. 2. Endogenous materials. e.g >Necrotic adipose tissue,bone & uric acid crystals. 3. Exogenous materials. e.g >Silica, asbestose fibres, suture materials, implanted prostheses. 4. Some autoimmune diseases. e.g >Hashimotos thyroiditis,chronic gastritis of pernicious anemia, rheumatoid artheritis.

 The commonest apearance of chronic inflammation are:

-Chronic ulcers.
-Chronic abscess cavity.

-Thickening of the wall of a hollow viscus.

-Granulomatous inflammation.

-Fibroses.

- The lymphocytic tissue infiltrate contains two main types of lymphocytes: >B-lymphocytes:- on contact with antigens become progressively transformed plasma cells which produce antibodies. >T-lymphocytes:-produce range of soluble factors called cytokines.

- The lymphocytic tissue infilterate contains two main types of lymphocytes: >B-lymphocytes:- on contact with antigenes become progressively transformed plasma cells which produce antibodies. >T-lymphocytes:-produce range of soluble factors called cytokines.

CYTOKINES have the following activities: 1.Recruitment of macrophages into the area. 2.Production of inflammatory mediators. 3.Recruitment of other lymphocytes. 4.Destruction of targete cells. 5.Interferone production

Immunity to Microbes
The function of the immune system is to protect the host against microbial infections. The development of an infectious disease in an individual involves complex interactions between the microbe and the host The key events during infection include entry of the microbe, invasion and colonization of host tissues, evasion from host immunity, and tissue injury or functional impairment

 Defense against microbes is mediated by the effector

mechanisms of innate and adaptive immunity. Innate immunity provides early defense, and adaptive immunity is the later reaction Many pathogenic microbes have evolved to resist innate defense

mechanisms to sites of infection

Adaptive immune responses to microbes induce effector cells that eliminate the microbes and memory cells that protect the individual from subsequent infections, so-called protective immunity

 The immune system responds in distinct and specialized ways to different types of microbes to most effectively combat these infectious agents The survival and pathogenecity of microbes in a host are

critically influenced by the ability of the microbes to evade or

resist the effector mechanisms of immunity

Immuntiy to Extracellular Bacteria

Extracellular bacteria are capable of replicating outside host

cells, for example ,in the circulation, in connective tissues, and in tissue spaces such as the airways and intestinal lumens.

Innate Immunity
The principal mechanisms of innate immunity to extracellular

bacteria are complement activation, phagocytosis, and

inflammatory response

Adaptive Immune Responses Humoral immunity is the principal protective immune response against extracellular bacteria, and it functions to eliminate the

microbes and neutralize their toxins.

Antibody responses against extracellular bacteria are directed against cell wall antigens and secreted and cell associated toxins which may be polysacherides or proteins The Effector mechanisms used by antibodies to combat these

infections include neutralization, opsonization and phagocytosis,

and activation of complement by the classical pathway

Immune Evasion Mechanism

Immunity to Intracellular Bacteria

A characteristic of facultative intracellular bacteria is their ability to survive and even replicate within phagocytes.

- inaccessible to circulating antibodies

- requires the mechanisms of cellular immunity Innate Immunity The innate immune response to intracellular bacteria consists mainly of phagocytes and natural killer (NK) cells.

Phagocytes, initially neutrophils and later macrophages, ingest

and attempt to destroy these microbes but pathogenic intracellular bacteria are resistant to degradation within phagocytes

 Intracellular bacteria activate NK cells either directly or by

stimulating macrophage production of IL 12, a powerful NK cell-activating cytokine. The NK cells produce IFN gamma,

which inturn activates macrophages and promotes killing of

phagocytosed bacteria Adaptive Immune Responses

The major protective immune response against intracellular

bacteria is cell mediated immunity Cell mediated immunity consists of two types of reactions- Macrophage activation by the T cell derived signals CD 40 ligand and IFN gamma, which results in killing of phagocytosed microbes, and lysis of infected cells by cytolytic T lymphocytes (CTLs)

Innate Immuity to Viruses

The principal mechanisms of innate immunity against

viruses are inhibition of infection by type I IFNs and NK cellmediated killing of infected cells.

- Viral infection directly stimulates the production of type I

IFN by infected cells. Type I IFNs function to inhibit viral replication in both infected and uninfected cells by inducing an antiviral state early in the course of infection, before adaptive immune responses have developed

- NK cells lyse target cells infected with a variety of viruses

Adaptive Immune Responses to Viruses Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into host cells, and by CTLs, which eliminate the infection by killing infected cells - Antibodies - Effective during extracellular stage - Neutralizing antibodies to prevent virus attachement and entry into host cells - Opsonize viral particles and promote their clearance by phagocytes - Complement activation - Elimination of viruses that reside within cells is mediated by CTLs, which kill the infected cells. - The principal function of CTLs is surveillance against viral infection.

Immune Evasion by Viruses

Innate lmmunity to Parasites The principal innate immune response to protozoa is phagocytosis, but many of these parasites are resistant to

phagocytic killing and may even replicate within macrophages.

Phagocytes also attack helminthic parasites and secrete microbicidal substances to kill organisms that are too large to be phagocytosed. Many helminths have thick teguments that make them

resistant to the cytocidal mechanisms of neutrophils and

macrophages.

Adaptive lmmune Responsest o Parasites

Different parasites elicit quite distinct adaptive immune responses Pathogenic protozoa have evolved to survive within host cells, so protective immunity against these organisms is mediated by mechanisms similar to those that eliminate intracellular bacteria and viruses. In contrast, metazoa such as helminths survive in extracellular tissues, and their elimination is often dependent on special types of antibody responses. The principal defense mechanism against protozoa that survive

within macrophages is cell-mediated immunity, particularly

macrophage activation by TH 1 cell -derived cytokines.

Defense against many helminthic infections is mediated by the activation of TH 2 cells, which results in production of IgE antibodies and activation of eosinophils

IgE antibodies bind to the surface of the helminth, eosinophils

then attach via FC receptors, and the eosinophils are activated

to secret granule enzymes that destroy the parasites

Adaptive immunity to parasites

Parasite Immune response Effector mechanism

Helminths

TH2 cells --> IL-4, IL-5 Eosinophils kill IgE-coated --> IgE, eosinophils parasites (form of ADCC)

Leishmania

T cells produce IFN-g --> Phagocytes kill parasites activation of phagocytes living in endosomes IFN-g, TNF activate macrophages, neutrophils to kill parasites

Malaria

CD8+ T cells --> secretion of cytokines Role of antibody?

Immune Evasion by Parasites

Specialization of immune responses to microbes

Type of microbe Adaptive immune response

Effector mechanism

Extracellular microbe Endocytosed antigen stimulates (bacteria, viruses) CD4+ helper T cells (TH1, TH17) --> antibody, inflammation

Neutralization, phagocytosis

Intracellular microbe Antigen in vesicles or cytosol IFN-g activates in phagocytes --> CD4+, CD8+ T cells phagocytes; killing of infected cells Intracellular microbe Antigen in cytosol --> in non-phagocytic CD8+ CTLs cell (virus) Helminthic parasites TH2 response --> IgE, eosinophils Killing of infected cells Eosinophil-mediated killing of IgE-coated parasites

Tolerance
Tolerance is a specific immunologic unresponsiveness to

antigens that are present during embryonic life are considered self and do not stimulate an immunologic response When the immune system recognizes a self antigen and mounts a strong response against it, autoimmune disease develops. the immune system has to recognize self-MHC to mount a response against a foreign antigen. the immune system is constantly challenged to discriminate self vs non-self and mediate the right response.
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When specific lymphocytes encounter antigen - Lymphocytes activated, leading to immune responses - Lymphocytes are inactivated or eliminated leading to tolerance - The antigen is ignored

 Normal individuals are tolerant of their own antigens (self antigens). - Failure of self tolerance results in immune reactions against self or autologous antigensAutoimmunity.

Central tolerance occurs because during maturation in the generative lymphoid organ lymphocytes pass through a stage in which encounter with antigen leads to tolerance than activation.

The most tolerance-sensitive stages of lymphocyte maturation are anatomically confined to the generative (also called central lymphoid organs, namely the thymus for T cells and the bone marrow for B lymphocytes.
Therefore, in the generative lymphoid organs, immature lymphocytes normally encounter only self antigens at high concentrations, and clones of lymphocytes whose receptors recognize these self antigens with affinity are killed (deleted). This process is called negative selection.

 Peripheral tolerance is induced by

- recognition of antigens without adequate levels of the costimulators that are required for lymphocyte activation, or - by persistent and repeated stimulation by

self antigens in peripheral tissues

 The principal mechanisms of lymphocyte tolerance

are

- Apoptotic cell death, called clonal deletion;

- Functional inactivation without cell death,

called clonal anergy;

- Suppression of lymphocyte activation and effector functions by regulatory lymphocytes

 Central tolerance is mainly due to clonal deletion, whereas

all three mechanisms contribute to peripheral tolerance.

On recognition of self antigens, some immature lymphocytes

undergo a second round of antigen receptor gene rearrangements, producing receptors with a different (i.e.,

nonself) specificity

 Repeated stimulation of T lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis

T-Cell Tolerance
T lymphocytes acquire the ability to distinguish self from

nonself occurs in the fetal thymus , Clonal deletion

It involves the killing of T cells (negative selection) that

react against antigens (primarily self MHC proteins) present in the fetus at that time.
The self-reactive cells die by a process of programmed cell

death called apoptosis.

Tolerance to self acquired within the thymus is called central

tolerance,
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T-Cell Tolerance
tolerance acquired outside the thymus is called peripheral tolerance
Peripheral tolerance is necessary because some self reactive T cells are not killed in the thymus,
there are several mechanisms involved: some self-reactive T cells are killed some are inhibited Others suppressed by regulatory T cells producing inhibitory cytokines.
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Clonal anergy
Clonal anergy is the terms used to describe self-reactive T

cells that are not activated because proper co stimulation does not occur . Both T-cell and B-cell clonal deletion fail to eliminate all autoreactive cells The mechanism of clonal anergy involves the inappropriate presentation of antigen, leading to a failure of interleukin2(IL-2) production. Inappropriate presentation is due to a failure of Costimulatory signal, eg. Sufficient amounts of IL-1 might not be made, or cell surface proteins, such as CD28 on the T cell and B7 on the B cell, might not interact properly, leading to failure of signal transduction by ras proteins.
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Clonal ignorance
clonal ignorance refers to self-reactive T cells that are ignorant

by physical separation from the target antigens,

eg, the blood-brain barrier,
T cells reactive to self-antigen not represented in the thymus

will mature and migrate to the periphery but they may never encounter the appropriate antigen because it is sequestered in

inaccessible tissues.
Such cells may die out for lack of stimulus.
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B cell Tolerance
B cells also become tolerant to self by two mechanisms.
Clonal deletion, probably while the B-cell precursors are in the bone marrow clonal anergy of B cells in the periphery. Tolerance in B cells is less complete than in T cells, an observation supported by the finding that most autoimmune disease are mediated by antibodies.

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Immune Regulation
Regulation

of

immune

responses,

which

prevents

overproduction of antibody or excessive proliferation of T cells and/or B cells, occurs at several levels.
Antigen concentration: As antigen levels decrease

during an immune response that successfully eliminates

them, there is less of a stimulus for continued proliferation and differentiation of lymphocytes, so

immune responses decline.

Antibody levels: Free IgG antibody at high concentrations

can suppress immune responses

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Immune Regulation
Antigen-antibody complexes:

-When antigen is free, it can bind to B cells and act as a stimulatory signal -when most of the antigen is bound in complexes with IgG, it deliver an inhibitory signal to B cells Anti-idiotype antibodies the concentration of the particular idiotype of antibody produced by that clone will increase enormously that it can be recognized as an antigen, and an antibody response against it will be triggered. This anti-idiotype will usually turn off the immune response of the initial B (or T) cell.
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Helper T-cell subset cytokine regulation

Helper T-cell subset cytokine regulation is one of the most

important regulatory mechanisms.

Antigen-stimulated helper T cells exist in two distinct subsets,

Th 1 and Th2.
Each helper subset stimulates one arm of the immune system,

and inhibits the other, mainly through secretion of different cytokines.

The interferon-y secreted by the Th1 cell inhibits Th2 cytokine

production.
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Helper T-cell subset cytokine regulation

Th2 cells, on the other hand, stimulate antibody production

from B cells and direct it against extracellular pathogens or soluble foreign antigens (e.g., exotoxins) through the production of IL-4, IL-5, IL-6, and IL-1O.
IL-4 is a potent inhibitor of macrophage function IL-1O inhibits Th1-cell function.

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