Immunology

- Immunology: the study of defense mechanisms of the body

- Immune system: the primary defense mechanism against:
 Microbes: only 3% of microbes are pathogenic
 Foreign bodies
 Cancer cells

- Infectious disease: Infectious Dose (MO) x Virulence (V) / Host defenses

 Infectious dose: number of MOs that enter the host body
 Virulence: the ability of MO to cause disease
 Host defenses : immune system

- Example on virulent microbes is the influenza virus

 It is a ss-RNA virus that causes respiratory infections
 Keeps changing its genetic makeup to evade the immune system
 Changes its genetic makeup by antigenic shift & drift to produce new strains
 Most respiratory viruses spread by droplets
 Particles are >5μm in diameter
 Transmitted by coughing and sneezing

- The first year of life is the most dangerous

 Most deaths are caused by infections
 Over the next 5 years there is 1 in 8 chance of dying from infection
 The largest threat is from water-borne bacteria causing diarrhea
 Diarrheal diseases are the number one killer of babies worldwide
 Measles infects the upper respiratory tract and kills 1 in 20 children in
developing countries

- The most common protozoa to cause death worldwide is Plasmodium

 Plasmodium causes malaria
 1/3 of population is at risk
 200 million dies every year
 Transmitted by the bite of female anopheles mosquito
Terms

- Immunocompetent: intact immune system

- Immunosuppressed: poor immunity, induced by medications (corticosteroids)
- Immunocompromised: poor immunity, caused by congenital or acquired defects

- Antigen: any substance that can bind to Ag-recognition molecule

- Immunogen: antigen that binds to and stimulates the immune response

- Epitope:
 Antigenic determinant that is recognized by immune system
 The active part of the antigen that binds the immune receptors
 An antigen can contain many different epitopes
 An epitope can be made of a continuous stretch of amino acids (linear)
 An epitope can be made of discontinuous stretch of AAs (conformational)
 A given epitope can be found on different antigens (cross-reactivity)
 Idiotope: epitope of the antibody because sometimes the antibody might be
attacked by another antibody

- Antibody
 Circulating, structurally-related glycoproteins
 Four chains: two identical heavy and two identical
light chains
 Fab region: Ag binding site
 Fc region: Bind cells & plasma proteins
 Classes (isotypes): IgA, IgD, IgE, IgG, & IgM
Failures of the immune system

1- Autoimmunity
 Immune system is unable to discriminate self from non-self
 The immune system attacks the self-antigens
 Examples:
 Rheumatoid arthritis: immune system attacks the joints
 Type one diabetes mellitus: immune system attacks pancreas
 Hashimoto thyroiditis: immune system attacks thyroid gland
 Addison’s disease: immune system attacks the adrenal glands

2- Immunodeficiency
 Congenital: caused by a genetic defect
 Acquired: like AIDS (HIV infection)

3- Hypersensitivity (allergic reactions)

 Excessive uncontrolled immune response
 Against normal environmental (harmless) antigen (dust)
 Divided into four types according to their mechanism
 Example: bronchial asthma and eczema

- Successes of the immunology

1- Vaccinations:
 Edward Jenner is the father of vaccination
 Cow maids who were exposed to cowpox were not infected by smallpox
 He developed a vaccine from cowpox against smallpox
 Vaccination term came from the Latin Vacca that means cows

2- Organ transplantation: kidney is the most successful transplant (40y)

3- Monoclonal antibodies:
 Antibodies against specific antigen
 Produced in the lab
o fusion of plasma cell and cancer cell (multiple myeloma cell)
o by a process called hybridoma
 Used to treat many infectious diseases & cancers
 In 1983 Nobel prize was awarded for Niels K. Jerne, Georges J.F.
Köhler and César Milstein for development of monoclonal Abs
 4- Treatment of hereditary defects in immune system: by
 Gene therapy
 BM transplant
5- Drugs that controls allergies: antihistamines
6- Hypo-sensitization: to treat allergies that don't respond to antihistamines
7- Treatment of Cancer
 By injecting the bladder with BCG vaccines by cystoscopy
 BCG is a live attenuated vaccine against tuberculosis
 It is used to treat urinary bladder cancer
 BCG vaccines stimulates macrophages to engulf tumor cells
8- Treatment of autoimmune diseases

- Immune system is subdivided into

a- Innate immune response:
 The first and second lines of immunity
 Often sufficient to destroy invading microbes
 If it fails to clear infection rapidly, it activates the adaptive system
b- Adaptive immune response: the third line of immunity

Immune system

Innate Adaptive

- Cytokines:
 Messenger molecules
 Mediate the connection between the two systems
 Example: interferon (mediates an early response to viral infection)
- Innate system:
 Inborn, nonspecific and with No memory
 Attack foreign cells nonspecifically
 Components
a- Physical barriers: skin and mucous membranes
 Skin
 The largest and most important immune organ
 Mainly the stratum corneum layer
 The best defense we are born with
 Dead keratinocytes prevent penetration of MOs
 Damaged keratinocytes produce IL-8 & TNF
 IL-8 & TNF stimulate inflammation
 Contains Langerhans cells
 Contains sweat and sebaceous glands
 Sebum:
 Composed of fatty acids
 Acidic in nature (low pH)
 Prevents growth of some MOs
 If flow is blocked acne
 If breached by wound or burn, MOs gain access to body
 Mucous membranes
 Produce mucus to trap invader
 Prevent MOs from affecting hollow organs
 Respiratory tract
 Upper tract is protected by mucociliary escalator
 Mucus is secreted from goblet cells to trap MOs
 Cilia waft the mucus toward mouth and nose to be expelled
 Mucus secretion is abnormal in cystic fibrosis (CF)
 Cilia are defective in primary ciliary dyskinesia (PCD)
 CF and PCD patients have recurrent respiratory infections
 Lower respiratory tract is protected by surfactant
 Respiratory epithelium is stimulated by IL-17 from TH17
 IL-4 from T helper 2 causes
 Hyperplasia of goblet cells
 Increased mucus secretion
 Hypertrophy of airway smooth muscles
 Airway obstruction and asthma
  Gastrointestinal tract
 Low pH of the stomach is the main defense
 Patients who are unable to secrete gastric acid have a high
risk for salmonella infection

b- Complement system
 Composed mainly of nine complement proteins (C1-9)
 Plays a role in
 Inflammation
 Phagocytosis
 Destruction of microbes
 Activated by three main pathways
 Classical pathway
 Alternative pathway
 Lectin pathway

c- Interferons
 Three types: alpha, beta and gamma
 Gamma is produced by T helper cells (TH1)
 Others are produced by any tissue
 Produced by virally infected cells
 Provide protection to other cells
 Species-specific not viral-specific
 Can activate macrophages

d- Collectins
 Proteins with globular heads and collagen-like tails
 Have a pattern recognition role
 Globular lectin heads bind sugars on microorganisms
 Collagen-like tails bind receptors on phagocytes
 Stimulates phagocytosis
 Examples:
 Mannan-binding lectin (MBL): bind & trigger complement
 Surfactant: prevents lung collapse and entrap invaders
e- Phagocytic WBC:
 Macrophages
 Adhere and phagocytize foreign agents
 Antigen presenting cells for T helper cells
 Don’t die after the immune reaction
 Phagocytic & APC (Antigen presenting cell)
 Activated by IFN gamma in response to IC MO (MTB)
 Macrophage: recruited to site of infection by IL-8
 Frustrated macrophage
 Fail to engulf the invader
 Causes extensive tissue damage
 Named according to the tissue of residence
 Monocytes: blood
 Langerhans cells: skin
 Kupffer cells: liver
 Histiocytes: normal tissues
 Osteoclasts: bones
 Mesenchymal cells: kidneys
 Glial cells: brain
 Giant and epithelioid cells: chronic inflammation
 Alveolar macrophage: lungs

 Neutrophils
 Polymorphonuclear leukocytes PMN
 Short lifespan (1-2 days)
 Die after performing their function
 Higher in number than macrophage
 Neutrophilia: increase in PMN count
 Neutrophilia is seen in bacterial infections
 Increase in number = pyogenic infection
 After death neutrophils become pus cells
 PMN: recruited to site of infection by IL-17 from TH17
 Contain enzymes to kill pathogens
 NADPH oxidase
 Myeloperoxidase
 Chronic granulomatous disease
 X-linked genetic defect
 Lack of NADPH oxidase
  Normal neutrophil count
 Abnormal PMN function
 Recurrent infections
 Diagnosed by nitroblue tetrazolium test (NBT)

f- Other WBC
 Natural killer (NK) cells
 Look like lymphocytes
 Called large granular lymphocytes
 Doesn’t have CD4 or CD8
 CD16+ and CD56+
 Non-specific & Non-phagocytic
 Able to kill
 Virally infected cells
 Tumor cells
 MHC-deficient cells
 dsRNA stimulates IFN alpha and beta that activate NK cell
 Mechanism of action:
 ADCC (antibody dependent cellular cytotoxicity)
 have a receptor for Fc component of IgG (CD16)
 Ab on surface of infected cell binds to Fc-R on NK
 NK cell make pores in the infected cell's membrane
 Tumor cell dies by apoptosis

 Eosinophils:
 Play a role in parasitic and protozoal infections
 Play a role in allergic reactions (type 1 hypersensitivity)
 Eosinophilia: increase in eosinophils count
 Eosinophilia is seen allergy and parasitic infections
  Mast cells
 Found in tissues
 Play a role in allergic reactions (type 1 hypersensitivity)
 Have Fc receptor for IgE (FcεRI)
 At first exposure to allergen, IgE produced by plasma cell
 IgE binds to its Fc receptor on the surface of mast cell
 After the second exposure the allergen binds to the IgE on
the surface of mast cells and degranulation occurs
 Granule of mast cell contains
 Vasoactive amines
 Histamine
 Leukotriene
 Heparin
 Slow reacting substance of Anaphylaxis
 Basophils
 Very low concentration in blood
 Same function of mast cells

 Pattern recognition molecules

 Bind patterns on surface of
 Pathogens: pathogen-associated molecular pattern PAMP
 Damaged cell:damage-associated molecular pattern DAMP
 PAMP and DAMP are not found on normal cell surface
 Pattern recognition molecules include

1- Toll-like receptors (TLR)

 Family of 10 different membrane receptors
 Found on macrophages and dendritic cells
TLR 2 Binds sugars and lipoproteins on bacterial surface
TLR 3 Binds dsRNA of viruses
TLR 4 Binds lipopolysaccharides (LPS) of gram negative
bacteria
TLR 5 Binds flagella on motile bacteria
TLR 7 Binds ssRNA of viruses
TLR 9 Binds unmethylated cytosine and guanine sequences
(CpG) of bacteria
 2- C-lectin receptors
 Sugar-binding proteins
 Recognize glycolipids and glycoproteins on pathogen surface
 Activate macrophage
 Required for pathogen capture and delivery to endocytic pathway
 Required for degradation of pathogens
3- Complement receptors
4- Immunoglobulin receptors

- Adaptive system:
 Specific & develops over time
 Acquired
 Activated if the innate system fails to clear the invading microbes
 Function: discriminate between self and non-self
 Slow response:
 Takes 7-10 days in first exposure
 Because it has three phases:
 Cognitive phase: recognition of antigen
 Activation phase: proliferation of specific lymphocytes
 Effector phase: cells differentiation & antigen elimination
 Characterized by
 Memory: faster response in the re-exposure
 Specificity
 Diversity
 Components
a- B cells (humoral immunity)
 Produced in the BM
 Has specific receptor on its surface (BCR) = monomeric IgM or IgD
 Differentiate into plasma cells after recognition of Ag
 Plasma cells produce antibodies
 Clonal selection: B cell recognizes the Ag by its BCR and the cells
that have this specific receptor will undergo clonal expansion
 Clonal expansion: proliferation of the cells that possess the
specific receptor of the Ag
 b- T cells (cell-mediated immunity)
 T helper (CD4)
 T helper 1: secretes cytokines that regulate the immune
response and kills virally infected cells
 T helper 2: secretes cytokines that activate B cells and
induce their differentiation into plasma cells
 T cytotoxic (CD8):
 Kills virally infected cells and tumor cells
 Herpesviruses are able to evade CD8 cells and the main
defense against them is NK cells

 T cells can’t interact with the Ag directly

 They need the Ag to be presented to them by other cells
 The cells that present the Ag to the T cells are called: Ag-
presenting cell (APC)
 APCs:
 Dendritic cells: the most professional
 Macrophages
 B cells

 Cytokines:
 Mediate the communication between the innate and adaptive
 Activate and modulate the immune response
 If produced by lymphocytes are called lymphokines
 The most important cytokine is interleukin 1 (IL-1)
 IL-1 is the general activator of T cells
 The most important downregulating cytokine is IL-10

 Macrophages secrete IL-1, TNF, GM-CSF to promote BM

 TNF and IL-1 increases leukocytes adherence to endothelium
 Macrophages produce IL-1 and IL-12 that activate TH1
 IL-12 activates TH1 and NK cells
 Macrophages produce IL-8, TNF & IL-1 to recruit neutrophils
 IL-27 is produced by APCs mainly macrophages

 Interferon γ
 Produced by TH1 and NK cells
 Increases expression of MHC
  Increases Ag processing in macrophages
 Induces macrophages maturation
 Increases NK cell activity
 Inhibits TH2 cells
 Mild antiviral effect

 Chemokines
 Cytokines that play a role in chemotaxis
 Chemotaxis: attraction of WBCs to site of infection
 The most important one is IL-8

 The antigen recognition molecules

a- B cell receptor: immunoglobulin molecule
b- T cell receptor: composed of highly variable alpha and beta chains
c- Antibodies (immunoglobulins)
d- Major histocompatibility complex (MHC):
 For antigen presentation
 On the short arm of chromosome 6
 Expressed in co-dominant fashion
 Highly diverse and variable
 Variability decreases with consanguinity

 MHC I:
 On all nucleated cells
 RBC lacks MHC
 HLA-A, HLA-B, HLA-C, HLA-E, HLA-F, HLA-G

 MHC II:
 Only on APC
 HLA-DP, HLA-DQ, HLA-DR, HLA-DM & HLA-DO

 B and T cell receptors are of limited number and genetically determined and
their diversity can be increased by non-relative marriages
  Clonal Distribution:
 Each clone of T or B cells has only one type of receptors
 The epitope of an antigen should bind to its specific receptor
 We are born with 1011-1017 specificities
 Variability of specificities declines with consanguinity

 You should deal with every patient as if he/she has hepatitis B virus or HIV so
you should always wear gloves

 The most common cause of getting influenza is by hand shaking

 The problem that affect they society from influenza is abstinence from work

- Types of response to Antigen by B cells :

1- Thymus-dependent:
 For protein antigens
 Requires T helper cell involvement and cytokines production
 Antigen presentation is necessary
 Produces memory cells and effective immune response
 Causes isotype switching

2- Thymus-independent:
 For non-protein antigens (lipids, nucleic acids and polysaccharides)
 T helper cell involvement and cytokines are not required
 Antigen presentation is not necessary
 B cell interacts directly with the antigen
 Produces weak immune response and no memory
 No isotype switching

Primary and secondary immune response

 Primary response
 First exposure to the antigen
 No previous memory cells
 Needs time to take place (slow)
 Low in magnitude
 Produces memory cells and antibodies
  Secondary response
 Subsequent exposure to the same antigen
 Previous memory cells and antibodies present
 No lag phase (rapid response)
 Higher in magnitude
 Produces greater number of memory cells
 Produces higher affinity antibodies

Hepatitis B virus (HBV)

- Transmission
 Sexually
 Vertically (pregnant mother to fetus)
 Needle-stick injury

- Infects the liver and causes jaundice

- Immune response against it is by T cells
- T cells in most patients can eliminate the virus

- If the virus persists, T cells causes liver damage

 Hepatitis
 Cirrhosis
 Hepatoma (liver cancer)
- Infection is preventable by vaccines
 Composed of HBsAg (hepatitis B surface Ag)
 Stimulates the immune system to produce antibodies against the virus
 Given in three doses, 1 month between each two doses

Active and passive immunity

Active Passive
Natural Infection  Trans-placental IgG
 Colostrum IgA
Artificial Vaccination  Antibodies extracted
from animals to treat
infections like rabies