Immunologia: sistema immunitario, immunità innata e adattativa

IMMUNOLOGIA

SCHEMA GENERALE DEL SISTEMA IMMUNITARIO

IMMUNE SYSTEM

• INNATE
• ADAPTIVE

PHYSICAL

BARRIERS

NK CELLS

NEUTOPHILS AND

MACROPHAGES

DCS

HUMORAL

CELL-MEDIATED

B-LYMPHOCYTES

T-LYMPHOCYTES

IG (antibodies)

Innate

Adaptive

Characteristics

Specificity

For molecules shared by groups

of related microbes and

molecules produced by damaged

host cells

For microbial and

nonmicrobial antigens

Diversity

Limited; recognition molecules

encoded by inherited (germline)

genes

Very large; receptor genes are

formed by somatic

recombination of gene

segments in lymphocytes

Memory

None or limited

Yes

Nonreactivity

to self

Yes

Yes

Components

Cellular and

chemical

barriers

Skin, mucosal epithelia;

antimicrobial molecules

Lymphocytes in epithelia;

antibodies secreted at

epithelial surfaces

Blood

proteins

Complement, various lectins and

agglutinins

Antibodies

Cells

Phagocytes (macrophages,

neutrophils), dendritic cells,

natural killer cells, mast cells,

innate lymphoid cells

Lymphocytes

RISPOSTA IMMUNITARIA INNATA E ADATTATIVA

Protective immunity against microbes is mediated by the early reactions of innate immunity

and the later responses of adaptive immunity.

Innate immune responses are stimulated by molecular structures shared by groups of microbes and by

molecules expressed by damaged host cells.

Adaptive immunity is specific for different microbial and nonmicrobial antigens and is increased by

repeated exposures to antigen (immunologic memory).

Many features of adaptive immunity are of fundamental importance for its normal functions.

These include specificity for different antigens, a diverse repertoire capable of recognizing a wide variety of

antigens, memory of antigen exposure, and the ability to discriminate between foreign antigens and self

antigens.

Immunity may be acquired by a:

• response to antigen (active immunity) or
• transfer of antibodies or effector cells (passive immunity).

LYMPHOCYTES are the only cells capable of specifically recognizing antigens and are thus the principal cells

of adaptive immunity. The total population of lymphocytes consists of many clones, each with a unique

antigen receptor and specificity.

The 2 major subsets of lymphocytes are B cells and T cells, and they differ in their antigen receptors and

functions.

The adaptive immune response is initiated by the recognition of foreign antigens by specific lymphocytes.

Specialized Antigen Presenting Cells (see chapter 7) capture microbial antigens and display these antigens

for recognition by lymphocytes-> Lymphocytes respond by proliferating and by differentiating into:

• effector cells, whose function is to eliminate the antigen, and into
• memory cells, which show enhanced responses on subsequent encounters with the antigen. The

elimination of antigens often requires the participation of various effector cells.

Humoral immunity is mediated by antibodies secreted by B lymphocytes and is the mechanism of defense

against extracellular microbes. Antibodies neutralize the infectivity of microbes and promote the

elimination of microbes by phagocytes and by activation of the complement system.

Cell-mediated immunity is mediated by T lymphocytes and their products, such as cytokines, and is

important for defense against intracellular microbes. CD4+ helper T lymphocytes help macrophages to

eliminate ingested microbes and help B cells to produce antibodies. CD8+ CTLs kill cells harboring

intracellular pathogens, thus eliminating reservoirs of infection.

So, the cardinal features of the adaptive immunity are:

• SPECIFICITY AND DIVERSITY: immune responses are specific for distinct antigens, and often for different

portions of a single complex protein. The part of the complex that is recognized by the lymphocyte is called

epitope or determinants. This antigenic specificity is possible thanks to the lymphocytes repertoire. And

this ability of the lymphocyte repertoire to recognize a large number of antigen is called diversity.

• MEMORY: exposure to a foreign antigen, enhances its ability to respond again to that antigen. This is why

the second immune response is usually stronger.

• CLONAL SELECTION: clones of lymphocytes are present in unimmunized individuals, and are able to

respond to foreign antigens.

• SELF TOLERANCE: is the immunologic unresponsiveness, called tolerance, with respect to self antigens.

Abnormalities in self tolerance can lead to autoimmune diseases.

PANORAMICA DELLE CELLULE DEL SISTEMA IMMUNITARIO

The anatomic organization of the cells and tissues of the immune system allows the rapid delivery of innate

immune cells, including neutrophils and monocytes, to sites of infection and allows a small number of

lymphocytes, specific for any antigen, to locate and respond effectively regardless of where in the body the

antigen is introduced.

The cells that perform the majority of effector functions of innate and adaptive immunity are PHAGOCYTES

(neutrophils and macrophages), MAST CELLS, BASOPHILS, EOSINOPHILS, DCS, and LYMPHOCYTES.

Cell

% counted

Relative #

Absolute #

ABS

Neutrophil

55-70

2500-8000

Lymphocyte

20-40

1000-4000

Monocyte

2-8

100-700

Eosinophil

1-4

50-500

Basophil

0-2

25-100

NEUTROPHILS-> the most abundant blood leukocyte with a distinctive multilobed segmented nucleus and

abundant cytoplasmic lysosomal granules, are rapidly recruited to sites of infection and tissue injury, where

they perform phagocytic functions.

MACROPHAGES-> include tissue resident sentinel cells, as well as cells derived from circulating monocytes

recruited in response to infection. All macrophages are phagocytic cells that ingest and kill microbes and

dead host cells and secrete cytokines and chemokines that promote the recruitment of leukocytes from the

blood and initiate the repair of damaged tissues (BETTER EXPLAINED CHAPTER 8.2)

DENDRITIC CELLS-> are cells with multiple extended cytoplasmic process, which are present in most tissues

of the body and function as innate sentinel cells and as APCs uniquely capable of activating naive T

lymphocytes (BETTER EXPLAINED CHPATER 8.1)

B AND T LYMPHOCYTES-> express highly diverse and specific antigen receptors and are the cells

responsible for the specificity and memory of adaptive immune responses (BETTER EXPLAINED CHAPTER 2,

3, 4, 5, 6)

INNATE LYMPHOID CELLS (ILCs)-> are cytokine-producing cells of the innate immune system with a

lymphocyte-like morphology. They perform similar functions to CD4+ or CD8+ effector T cells. ILCs, which

include NK cells, do not express highly diverse, clonally distributed antigen receptors.

Both B and T lymphocytes arise from a common precursor in the bone marrow. B cell development

proceeds in the bone marrow, whereas T cell precursors migrate to and mature in the thymus. After

maturing, B and T cells leave the bone marrow or thymus (respectively B-> bone marrow, T->thymus),

enter the circulation, and populate peripheral lymphoid organs.

Naive B and T cells are mature lymphocytes that have not been previously stimulated by antigen.

When they encounter antigen, they proliferate and differentiate into effector lymphocytes that have

functions in protective immune responses. Effector B lymphocytes are antibody-secreting plasma cells.

Effector T cells include cytokine-secreting CD4+ helper T cells and CD8+ Cytotoxic T-Lymphocytes.

Some of the progeny of antigen-activated B and T lymphocytes differentiate into memory cells that survive

for long periods in a quiescent state. These memory cells are responsible for the rapid and enhanced

responses to subsequent exposures to antigen.

TESSUTI DEL SISTEMA IMMUNITARIO

The organs of the immune system may be divided into the primary

lymphoid organs (bone marrow and thymus), where lymphocytes

mature, and the peripheral, or secondary, organs (lymph nodes,

spleen, and parts of the mucosal immune systems), where naive

lymphocytes are activated by antigens.

Bone marrow contains the stem cells for all blood cells, including

lymphocytes, and is the site of maturation of all of these cell types

except T cells, which mature in the thymus.

Extracellular fluid (lymph) is constantly drained from tissues

through lymphatics into lymph nodes and eventually into the blood.

Microbial antigens are carried in soluble form and within DCs in the

lymph to lymph nodes, where they are recognized by lymphocytes.

Immune System

Mucous

Membranes

Tonsils

Lymphatic

Vessels

Thymus

Lymph

Nodes

Skin

Spleen

Bone

Marrow

Lymphatic

Vessels

LYMPH NODES are encapsulated secondary lymphoid organs located throughout the body along

lymphatics, where naive B and T cells respond to antigens that are collected by the lymph from peripheral

tissues. The spleen is an encapsulated organ in the abdominal cavity where senescent or opsonized blood

cells are removed from the circulation, and in which lymphocytes respond to blood-borne antigens.

Lymph nodes and the white pulp

of the spleen are organized into

B cell zones (the follicles) and I

cell zones. The T cell areas are

also the sites of residence of

mature Dendritic Cells, which

are Antigen Presenting Cells

specialized for the activation of

naive T cells.

A lymph node

secondary

primary

lymphoid follicle

(mostly B cells)

lymphoid follicle

(with germinal center)

medullary cords

(macrophages

and plasma cells)

afferent

lymphatic vessel

medullary sinus

artery

vein

paracortical area

(mostly T cells)

efferent

lymphatic vessel

senescent

germinal center

germinal center

marginal sinus

MIGRAZIONE DEI LEUCOCITI NEI TESSUTI

Leukocyte migration from blood into tissues occurs through postcapillary venules and depends on

adhesion molecules expressed on the leukocytes and vascular endothelial cells as well as chemokines:

• SELECTINS are carbohydrate-binding adhesion molecules that mediate interaction of leukocytes with

endothelial cells (of the vessel), the first step in leukocyte migration from blood into tissues.

. E-selectin and P-selectin are expressed on activated endothelial cells and bind to selectin ligands on

leukocytes

. L-selectin is expressed on leukocytes and binds ligands on endothelial cells.

• INTEGRINS are a large family of adhesion molecules, some of which mediate tight adhesion of leukocytes

with activated endothelium, a critical step in leukocyte migration from blood into tissues. The important

leukocyte integrins include:

· LFA-1 which bind to ICAM-1

· VLA-4 which bind to VCAM-1, on endothelial cells.

• CHEMOKINES and other signals at sites of infection increase the affinity of integrins on leukocytes, and

various cytokines (TNF, IL-1) increase the expression of integrin ligands on endothelium. Chemokines are a

large family of cytokines that stimulate leukocytes movement and regulate migration. There are many

types:

o

CC CHEMOKINES-> made of 2 cysteine residues and induce the migration of monocytes, NK cells

and DCs.

o CXC CHEMOKINES-> 2 cysteine residues separated by an aminoacid. Only the CXC that contains the

ELR functional motifs, are able to control the neutrophils migration. The others act on monocytes

and other cells.

o C CHEMOKINES-> single cysteine residue.

o CX3C CHEMOKINE-> 2 cysteine separated by 3 amino acids.