Overview of the Immune system

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Overview of the Immune system
Dr. Gamal Badr PhD in Immunology (Paris Sud
University, France) Associate Professor of
Immunology Assiut University, Egypt Tel 2
01110900710 Fax [phone] E-mails
badr73_at_yahoo.com or gamal.badr_at_aun.edu.eg
Websites http//www.aun.edu.eg/membercv.php?M_ID
393 https//www.researchgate.net/profil/Gamal_Bad
r/ http//scholar.google.com.eg/citations?hlenu
serdz13dkQAAAAJ
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Topics
Microbes why they are formidable foes. Gross
anatomy of the immune system Cells of the immune
system how the immune system protects Immune
recognition of pathogens innate versus adaptive
immunity Cytokines and the inflammatory response
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Immunity Body defense against exogenous(microbes)
and endogenous(tumor cells) agents.
Pathogen microbe that causes disease Antigen
(Ag) material (from a pathogen) that induces an
immune response Immunogen material that induces
an immune response Innate (natural) immunity
rapid, non specific immune response Adaptive
(acquired) immunity slower, specific immune
response Leukocytes WBCs Lymphocytes
specialized blood cells that mediate adaptive
immunity (e.g. T and B cells)
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Immune response
Reaction of the body against any foreign Ag.
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by B- cells
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Organs of the immune system
The cells of the immune system are developed in
the primary lymphoid organs (bone marrow
Thymus), and they interact with antigens in
secondary lymphoid organs (lymph nodes, spleen,
addendix, Peyers patch etc.). Lymph nodes
collect antigens from tissues Spleen collects
antigens from blood stream Lymphocytes arise in
the stem cells in the bone marrow and then
differentiate in the bone marrow (B cells) or
thymus (T cells).
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T and B lymphocytes migrate via the peripheral
blood to the peripheral/secondary lymphoid
organs lymph nodes, spleen, addendix, Peyers
patch etc. Naïve lymphocytes circulate between
the blood and these organs until they encounter
antigen. They become activated when they
recognized an Ag in the secondary lymphoid
organs. The afferent lymphatic vessels carry APC
cells from infected tissues to the lymph nodes
where they activate T cells Activated T cells
(after they have undergone proliferation and
differentiation) leave via the efferent lymphatic
vessels The cells of the immune system
circulate through the body via lymph and blood.
Pathogens and their antigens are transported from
tissues via lymphatic vessels to the lymph nodes
where they encounter immune cells.
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Cells of the immune system Blood cells lineages
Most blood cells act to fight infection.
Dentritic cell (DC)
Adaptive immunity
Innate immunity
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Dentritic cell (DC)
Antigen (Ag)
Antigen presenting cells (APC)
Lymphocytes of the adaptive immune system T
helper cells regulate other immune cells T
cytotoxic (killer) cells kill infected cells B
cells produce antibodies (immunoglobulin)
DC and macrophage (APC) directly kill microbes
by phagocytosis and other mechanisms. They also
help to activate T cells (connection between
innate and adaptive immunity)
NK cells are lymphocytes that have
characteristics of innate and adaptive immunity.
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Cells of the Immune system (WBCs)

• 1- Granulocytes
• Neutrophils
• Eosinophils
• Basophils
• 2- Agranulocytes
• Lymphocytes
• B cells
• T cells (many types)
• NK cells
• Monocytes/Macrophages
• Dendritic cells

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Divisions of leukocytes

• Granulocytes
• Neutrophils
• Band cells (immature neutrophils)
• Eosinophils
• Basophils

• AGranulocytes
• (Mononuclear cells)
• Lymphocytes (many types)
• Monocytes
• Dendritic cells

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Neutrophils

• Granulocyte
• Phagocytes
• Short life span (hours)
• Very important at clearing bacterial infections
• Cytoplasmic granules

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Eosinophils

• A granulocyte
• A cell-killing cells
• Orange granules contain toxic compounds
• Important in parasitic infections

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Basophils

• A granulocyte
• A cell-killing cells
• Blue granules contain toxic and inflammatory
  compounds
• Important in allergic reactions

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Lymphocytes

• Many types important in both humoral and
  cell-mediated immunity
• B-cells produce antibodies
• T- cells
• Cytotoxic T cells
• Helper T cells
• Memory cells
• NK cells

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Benign WBCs Disorders
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Leukopenia (Leukocytopenia) -

• Leukopenia is a decrease in the number of WBCs
• Neutropenia is most common cause
• Absolute neutrophil count (ANC) lt 1.5 x 109
  cells/L
• Many causes
• Benign racial neutropenia common
• African Americans and Yemenite Jews may have ANC
  as low as 1.0
• Viral infections
• Epstein-Barr, Hepatitis B, HIV
• Drugs
• Careful review of medications be suspicious of
  any medication recently started in patient with
  acute onset neutropenia
• Splenomegaly
• Autoimmune disorders
• SLE (lupus), Rheumatoid Arthritis, etc.
• Bone marrow disorders

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Leukocytosis

• Leukocytosis is an increase in the number of
  WBCs
• WBC count gt 11,000
• Determine which type of WBC is leading to the
  leukocytosis
• Neutrophilia most common
• Causes
• Infection
• Connective tissue disorders
• Medications (especially steroids, growth factors)
• Cancer Myeloproliferative disorders
• Cigarette smoking
• Stress (physiologic)
• Pain, trauma
• Idiopathic (unknown cause)

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Leukocytosis

• Patients with acute bacterial infection often
  present with neutrophilia and band formation
• Bands young neutrophils
• Viral infections are usually associated with low
  WBCs leukocytosis may suggest complications
• Ex bacterial pneumonia with underlying influenza
  infection

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Leukocytosis

• Lymphocytosis is an increase in the number or
  proportion of lymphocytes in the blood
• Causes
• Viral infections HBV, HCV, EBV, CMV
• Tuberculosis
• Pertussis
• Drug Reaction
• Stress (physiologic) Trauma, cardiac arrest, etc
• Malignancy ALL, CLL, lymphoma

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Malignant WBCs Disorders
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• Myeloid vs. Lymphoid
• Myeloid malignancies
• Acute myeloid leukemia
• Chronic myeloproliferative disorders
• Lymphoid malignancies
• B-cell malignancies
• Acute lymphoblastic leukemia, B-cell type
• Non-Hodgkins lymphoma, B-cell types
• Myeloma
• T-cell malignancies
• Acute lymphoblastic leukemia, T-cell type
• Non-Hodgkins lymphoma, T-cell types
• Hodgkins disease

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Leukemia

• Leukemia is a type of cancer of the blood or bone
  marrow characterized by an abnormal increase of
  immature WBCs called blasts".
• Leukemia is a broad term covering a spectrum of
  diseases. In turn, it is part of the even broader
  group of diseases affecting the blood, bone
  marrow, and lymphoid system.

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Chronic Leukemia

• Chronic myelogenous leukemia (CML)
• Translocation between long arms of chromosomes 9
  and 22 Philadelphia Chromosome bcr/abl
  protein
• Chronic lymphocytic leukemia (CLL)
• Clonal malignancy of B-lymphocytes
• Course is usually indolent affects older
  patients, average age at diagnosis is 70 years

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Acute Leukemia

• Acute Myelogenous Leukemia (AML)
• Most common in adults
• Usually no apparent cause
• Exposure to radiation, benzene, and certain
  chemotherapy drugs (alkylators) associated with
  leukemia
• Underlying myelodysplastic syndrome (MDS) is risk
  factor
• Symptoms and signs
• Related to replacement of marrow space by
  malignant WBCs
• Patients often very ill for period of just days
  or weeks
• Skeletal pain
• Bleeding
• Gingival hyperplasia
• Infection
• Pancytopenia with circulating blasts is hallmark
  bone marrow biopsy required
• Auer rods on peripheral smear are pathognomonic

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Lymphoma

• Hodgkins disease
• Malignancy of B-lymphocytes
• Reed-Sternberg cells
• Various subtypes nodular sclerosing is most
  common
• Non-Hodgkins Lymphoma (NHL)
• Heterogeneous group of cancers affecting
  lymphocytes

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Myeloma

• Malignancy of plasma cells
• Abnormal paraproteins are created leading to
  systemic problems
• IgG 60
• IgM 20
• Primarily disease of elderly (median age 65
  years)
• Most common hematologic malignancy among African
  Americans 2 among Caucasians

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Production of antibodies
Pathogen is internalized and degraded
Plasma cells
B cell binds pathogen
TH1
B cells differentiate into antibody-secreting
plasma cells Produce antibodies against pathogen
Peptides from the pathogen are presented (MHC II)
to the T cell resulting in the activation of the
B cell
B cell proliferation
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Antigen recognition by T-cells
TH2 cells recognize antigen presented by MHC II
and activates B cells
TH1 cells recognize antigen presented by MHC II
and activates macrophages
Cytotoxic T cells recognize antigen presented by
MHC I and kills the cell
Kills
Activates
MHC I
MHC II
Cytotoxic T cell
Virus-infected cell
TH1
Macrophage
Dead intracellular bacteria
Anti-toxin antibodies
Apoptotic cell
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Th1 and Th2 response
To
Th1
Th2
IFN-?
IL-4 IL-10 IL-5 IL-6 IL-13
IL-2 TNF-?
NK
MØ
IL-8
B cell
Tc
PMN
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Monocytes/Macrophage

• Monocyte is a young macrophage
• There are tissue-specific macrophages
• MØ process antigen, are phagocytes and produce
  cytokines (esp., IL1 IL6)

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Dendritic cells

• Found mainly in lymphoid tissue
• Function as antigen presenting cells (APC)
• Most potent stimulator of T-cell response

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Mechanism of the Immune response
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• Physiological barriers at the portal of entry
  (The Skin Mucous Membranes)

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Mechanisms of Innate Immunity

• A. Epithelial Surfaces
• 1. Skin mucous membrane - protect against
  invasion by microbes.
• Healthy skin - high salt conc. in sweat
• - sebaceous secretions
• - long chain fatty acids
  soaps
• Respiratory tract - nose architecture
• - cough reflex
• - mucosal secretions
• - phagocytes in alveoli
• Intestinal mucosa - mucus , peristalsis

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• Epithelial Surfaces
• 2. Saliva - inhibits many micro-organisms.
• 3. Gastric acidity - destroys many microbes.
• 4. Conjunctiva - flushing action of lachrymal
  secretions.
• antibacterial substance
• - present in tissue fluid all secretions
• except cerebrospinal fluid (CSF), urine
  sweat
• - also present in phagocytes

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Epithelial Surfaces5. Flushing action of
urine6. Acidic pH of adult vagina7. Spermine
zinc in semen is antibacterial.B. Antibacterial
substances in blood tissues1. Complement
system - Alternative pathway of
complement leads to opsonization of microbes2.
Basic polypeptides like leukins derived from
leucocytes
platelets 3. Lactic acid in muscle
inflammatory zone 4. Lactoperoxidase in milk.
5. Interferons - antiviral
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C. Microbial antagonism - resident flora on
skin mucosa prevent colonization by
pathogens. - altered flora following oral
antibiotics may lead to enterocolitis
(inflammation of the digestive tract).
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D. Cellular factors1. Phagocytic cells are 2
types - polymorphonuclear (PMN) leukocytes
- mononuclear phagocytes in blood tissues
monocytes
macrophages Imp. link between innate
acquired immunity Chemotaxis - phagocytes are
attracted to the site of infection by
chemotactic factors.
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Phagocytosis

• This process involves - recognition binding
• - ingestion
• - digestion
• Requires opsonins - molecules on the surface of
  certain bacteria which bind to the receptor on
  phagocytes - Opsonization.

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Killing by granulocytes through phagocytosis

• Macrophages and neutrophils recognize pathogen by
  means of cell-surface receptors
• Example mannose receptor, CD14 receptor,
  scavenger receptors, glucan receptor etc.
• Binding of macrophage (MØ) or neutrophils with
  pathogen leads to phagocytosis
• Bound pathogen is surrounded by phagocyte
  membrane
• Internalized (phagosome)
• Killing of pathogen (Phagolysosome)
• Oxidative burst (synthesis of hydrogen peroxide
  (H2O2)or free oxygen radicals)
• Acidification
• Antimicrobial peptides (e.g. defensins)
• Phagolysosome lysosome phagosome

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Phagocytosis
Bacteria
Mannose receptor
Lysosome
Phagosome
Scavenger receptor
LPS receptor (CD14)
Bacteria binding to macrophage receptors initiate
the release of cytokines and small lipid
mediators of inflammation
Phagolysosome
The macrophage expresses receptors for many
bacterial constituents
Macrophages engulf and digest bacteria to which
they bind
CD Structurally defined leukocyte surface
molecule that is expressed on cells of a
particular lineage (differentiation) and
recognized by a group (cluster) of
cell-specific antibodies is called a member of a
cluster of differentiation (CD)
B cell CD19 T helper cell CD3, CD4 CD8- T
cytotoxic cell CD3, CD8 Macrophages/ monocyte
CD14 NK cell CD3neg, CD16 CD56
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Cytokines

• Cytokines are soluble proteins that are produced
  in response to an antigen and function as
  chemical messengers for regulating the innate and
  adaptive immunity
• Innate immune system
• Macrophages and Dendritic cells produce
• Tumor necrosis factor-alpha (TNF-?)
• Interleukin-1 (IL-1)
• Interleukin-12 (IL-12)
• Adaptive immune system
• T-lymphocytes produce
• Interleukin-2 (IL-2)
• Interleukin-4 (IL-4)

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release of lysosomal contents
phagolysosome
Invagination
fusion with lysosome
phagosome formation
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Process of Phagocytosis
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D. Cellular factors2. Natural killer cells

• Class of lymphocytes important in non- specific
  defense against viral infections tumor cells.
• Activated by interferons selectively kills
  viral infected cells tumor cells.

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Cell killing NK cells

• NK cells do not require prior immunization or
  activation
• They attach to target cells
• Produce cytotoxic proteins (perforin Granzymes
  ) onto the surface of tumor or viral infected
  cells.
• Effector proteins penetrate cell membrane and
  induce programmed cell death (Apoptosis)

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Apoptosis Cellular Suicide
Remnants undergo phagocytosis

• Nuclear fragmentation
• Proteolysis
• Blebbing
• Death

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D. Cellular factors2. Eosinophils

• Number increases during parasitic infections
  allergic conditions.
• Not efficient phagocytes but their granules
  contain molecules that are toxic to parasites.
• E. Temperature
• - Many micro- organisms are temperature
  dependent e.g. tubercle bacilli, pathogenic to
  mammals, do not infect cold-blooded animals.
• - destroys infecting pathogen e.g. fever
  induction used to destroy Treponema pallidum
  before penicillin became available for treatment.
  

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F. Inflammation

• Inflame to set fire.
• Inflammation is A dynamic response of
  vascularised tissue to injury.
• It is a protective response.
• It serves to bring defense healing mechanisms
  to the site of injury.
• A type of non specific defense mechanism.
• Tissue injury or irritation caused by the entry
  of pathogens or other irritants lead to
  inflammation.
• Events that occur are vasoconstriction
  followed by vasodilatation
• - Increased vascular
  permeability, stasis, hyperemia, accumulation of
  
• leukocytes, exudation of
  fluid, and deposition of fibrin.
• Changes are brought about by chemical mediators
  like histamine.
• Signs redness, heat, swelling, pain and lose of
  function.

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Cardinal Signs of Inflammation

• Redness Hyperaemia (increase of blood flow to
  different tissues).
• Warm Hyperaemia
• Pain Nerve, Chemical mediators.
• Swelling Exudation (escape of fluid, cells, and
  cellular debris from blood vessels and their
  deposition in tissues)
• Loss of Function

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Process of Inflammation
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Innate vs. adaptive immunity

• Innate immunity
• First line of defense (present in all individuals
  at all times)
• Immediate (0 4 hours)
• Non-specific
• Does not generate lasting protective immunity
• Adaptive immune response (late gt 96 hours)
• Is initiated if innate immune response is not
  adequate (gt 4 days)
• Antigen-specific immunity
• Generates lasting protective immunity (e.g.
  Antibodies, memory T-cells)

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Adaptive, Acquired, Specific immunity
Acquired Immunity
Passive
Active
Cell mediated immunity
Humoral Immunity
By B cell activation production of Abs
By T cell activation
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Adaptive immune system

• Initiated by ingestion of pathogen by an immature
  dentritic cell
• Antigen-presenting cell (APC)
• Dendritic cells, macrophages, and B cells
• Migrate through lymph to the regional lymph nodes
• Interact with naive T lymphocytes (present
  antigen to activate T cells)
• Proliferation
• Differentiation

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Active and passive immunity
Active immunity long-lasting protection
(memory), multiple effector mechanisms
activated, lag time Passive immunity rapid
protection, short duration
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Active Immunity

• Resistance developed by an individual as a result
  of an antigenic stimulus.
• Also called Adaptive immunity.
• Involves active functioning of the hosts immune
  system leading to the synthesis of antibodies and
  / or the production of immunologically active
  cells.

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Passive Immunity

• Resistance transmitted to a recipient in a
  readymade form.
• Preformed antibodies are administered.
• No antigenic stimulus.
• Hosts immune system is not actively involved.

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Comparison of Active Passive Immunity

• Passive immunity
• Received passively, no active host participation
• Readymade antibody transferred
• Transient, less effective
• Immediate immunity
• No memory
• Not effective
• Applicable in the immunodeficient

• Active immunity
• Produced actively by hosts immune system
• Induced by infection or by immunogen
• Durable effective protection
• Immunity effective only after long period
• Immunological memory present
• Booster effective
• Not applicable in the immunodeficient

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Active immunity

• Natural active immunity results from an
  infection by a parasite e.g. an attack of measles
  give lifelong immunity.
• Artificial active immunity resistance induced
  by vaccines.
• Vaccines are preparations of live or killed
  micro- organisms or their products.

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Passive immunity

• Natural passive immunity resistance passively
  transferred from mother to baby
• Artificial passive immunity resistance
  passively transferred by the administration of
  readymade antibodies. e.g. tetanus immunoglobulin
  

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Lymphocytes (effector cells of the adaptive
immune system)

• Antigen receptors with single specificity (T and
  B cells)
• Gene re-arrangement
• T and B cells have 2 distinct recognition systems
  for detecting pathogens
• T cells - recognize intracellular pathogens (T
  cell receptors, TCR)
• B cells recognize extracellular pathogens
  (immunoglobins, BCR)
• Clonal selection
• Interaction of antigen and lymphocyte receptor
• Activation of lymphocyte
• Differentiation (progeny with identical
  specificity)

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Cell mediated immunity Antigen recognition by
T-cells

• T cells detect presence of intracellular
  pathogens
• T cells receptors
• Peptide fragments
• Major histocompatibility complex (MHC)
• MHC I (cytotoxic T cells /CD8)
• MHC II (T helper (1 and 2)/ CD4)
• Cell death

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Cell mediated immunity Antigen recognition by
T-cells
TH2 cells recognize antigen presented by MHC II
and activates B cells
TH1 cells recognize antigen presented by MHC II
and activates macrophages
Cytotoxic T cells recognize antigen presented by
MHC I and kills the cell
Kills
Activates
MHC I
MHC II
Cytotoxic T cell
Virus-infected cell
TH1
Macrophage
Dead intracellular bacteria
Anti-toxin antibodies
Apoptotic cell
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Antigen presenting cells (APC)
B cell
Dendritic cell
Macrophages
Lymph node
Lymph node
Lymph node
Antigen-presenting cells are distributed
differentially in the lymph node
An antigen-presenting cell (APC) or accessory
cell is a cell that displays foreign Ag complexe
with major histocompatibility complexes (MHC) on
their surfaces. T cells may recognize these
complexes using their T cell receptor (TCR).
These APC engulf and process antigens and present
them on their surface to T-cells.
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Where does antigen processing take place?
T CELLS BIND
Incubate with CHLOROQUINE
NO T CELLS BIND
Chloroquine inhibits lysosomal function (a
lysosomotrophic drug) Antigen processing involves
the lysosomal system
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Ag presentation to T cells
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The T cell antigen receptor (TCR)
Antigen combining site
Resembles an Ig Fab fragment
Va
Vb
Domain structure Ig gene superfamily
Carbohydrates
Monovalent
No alternative constant regions
Ca
Cb
Never secreted
Hinge
Heterodimeric, chains are disuphide-bonded



Very short intracytoplasmic tail
Positively charged amino acids in the TM region
Antigen combining site made of juxtaposed Va and
Vb regions
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T cell co-receptor (TCR) molecules
Ag
CD4 and CD8 can increase the sensitivity of T
cells to peptide antigen MHC complexes by 100
fold
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Th1 and Th2 response
To
Th1
Th2
IFN-?
IL-4 IL-10 IL-5 IL-6 IL-13
IL-2 TNF-?
NK
MØ
IL-8
B cell
Tc
PMN
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TCR and BCR (B cell Receptor)
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Humoral Immunity

• It is the production of proteins called
  immunoglobulin's or antibodies.
• .

• Memory (long-lived cells)
• .

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Humoral ImmunityB Cell Receptors for Antigens

• B cell receptors
• Bind to specific, intact antigens
• Are often called membrane antibodies or membrane
  immunoglobulin's (Ig)

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WHAT ARE ANTIBODIES?

• Antigen specific proteins produced by plasma
  cells
• Belong to immunoglobulin (Ig) superfamily
• Located in blood and extravascular tissues,
  secretions and excretions
• Bind pathogenic microorganism and their toxins in
  extracellular compartments

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Structural configuration of Antibody
Chains Light (L) Heavy (H)
Domains Variable (V) Single V domain in H and L
chains Constant (C) Single C domain in L
chains Three to four (C) domains in H chains
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CLASSES (ISOTYPES) OF IMMUNOGLOBULINS

• Classes based on constant region of heavy chains
• Immunoglobulin A (IgA) alpha  heavy chains
• Immunoglobulin D (IgD) Delta  heavy chains
• Immunoglobulin E (IgE) Epsilon  heavy chains
• Immunoglobulin G (IgG) Gamma  heavy chains
• Immunoglobulin M (IgM) Mu heavy chains
• Differentiation of heavy chains
• Length of C region,
• location of disulfide bonds, hinge region,
  distribution of carbohydrate
• Classes have different effector functions

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Different classes of Antibodies
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• Immunoglobulin Classes
• IgG
• Structure Monomer
• Percentage serum antibodies 80
• Location Blood, lymph, intestine
• Half-life in serum 23 days
• Complement Fixation Yes
• Placental Transfer Yes (the only Ig)
• Known Functions Enhances phagocytosis,
  neutralizes toxins and viruses, protects fetus
  and newborn.

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• Immunoglobulin Classes
• IgM
• Structure Pentamer
• Percentage serum antibodies 5-10
• Location Blood, lymph, B cell surface (monomer)
• Half-life in serum 5 days
• Complement Fixation Yes
• Placental Transfer No
• Known Functions First antibodies produced during
  an infection. Effective against microbes and
  agglutinating antigens.

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• Immunoglobulin Classes
• IgA
• Structure Dimer
• Percentage serum antibodies 10-15
• Location Secretions (tears, saliva, intestine,
  milk), blood and lymph.
• Half-life in serum 6 days
• Complement Fixation No
• Placental Transfer No
• Known Functions Localized protection of mucosal
  surfaces. Provides immunity to infant digestive
  tract.

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• Immunoglobulin Classes
• IgD
• Structure Monomer
• Percentage serum antibodies 0.2
• Location B-cell surface, blood, and lymph
• Half-life in serum 3 days
• Complement Fixation No
• Placental Transfer No
• Known Functions In serum function is unknown.
• On B cell surface, initiate immune response,
  discriminate between naïve (IgD), memory (IgD
  neg) and plasma cells (IgD neg)

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• Immunoglobulin Classes
• IgE
• Structure Monomer
• Percentage serum antibodies 0.002
• Location Bound to mast cells and basophils
  throughout body. Blood.
• Half-life in serum 2 days
• Complement Fixation No
• Placental Transfer No
• Known Functions Allergic reactions. Possibly
  lysis of worms.

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B cells act as APC
1. Capture by antigen specific Ig
maximises uptake of a single antigen
2. Binding and internalisation via Ig induces
expression of CD40
3. Antigen enters exogenous antigen processing
pathway
4. Peptide fragments of antigen are loaded onto
MHC molecules intracellularly. MHC/peptide
complexes are expressed at the cell surface
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T cell help to B cells
1. T cell antigen receptor
Signal 1antigen antigen receptor
2. Co-receptor (CD4)
3.CD40 Ligand
MHC class II
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Clonal Selection
Only one type of antibodyand one type of B
cellresponds to the antigenic determinant
That cell type then produces a large number of
clones
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Benefits of Immunological Memory
Primary
Latent period Gradual rise in Ab production
taking days to weeks
Secondary
Second exposure to same Ag. Memory cells are a
beautiful thing. Recognition of Ag is
immediate. Results in immediate production of
protective antibody, mainly IgG but may see some
IgM