IMMUNOLOGY

Basic Concept
Dr Ravi Rokaya
FCPS Resident
Contents
• Introduction • MHC
• Types of Immunity • Complements
• Cells of Immunology • Cytokines and Chemokines
• Innate Immunity • Vaccines
• Adaptive Immunity • Hypersensitivity
Definition
• Latin word ‘Immunis’ meaning exempt → Immunity

• Refers to all the mechanisms used by the body as protection against

environmental agents that are foreign to the body.

• Agents → Microorganisms or their products, foods, chemicals, drugs,

pollen, or animal hair.
• Immunology is the study of the immune system and is a very
important branch of the medical science.

• The immune system protects us from infection through various

lines of defense.

• If the immune system is not functioning as it should, it can result

in disease, such as autoimmunity, allergy and cancer
Immune organ system
1° organs:

Bone marrow—immune cell production,

B cell maturation 1°

Thymus—T cell maturation

2° organs:

Spleen, lymph nodes, tonsils, Peyer patches 1°

Allow immune cells to interact with antigen
Fig: Threats to the individual
Types of Immunity
Cells of Immune System
Innate Vs Adaptive Immunity
Innate Immunity Adaptive Immunity

- Fast acting system (mins to hrs) - Slow – acting (days)

- Non-specific reaction - Highly specific

Same cells, same reaction to many invaders Unique cells activated to respond to a single
. invader
- No memory - Memory
2nd infection same response as 1st 2nd infection, faster response
Fig: Immunologic memory
Antigen Presentation
• Innate system can be activated by “free” antigen
-Pathogenic molecules detected freely in blood, tissue

• Adaptive system requires “antigen presentation”

-Pathogen must be engulfed by cells and broken down
-Pieces of protein transported to surface
-Antigen presented to T-cells for activation
Innate Immune System
General Principles
• Recognition: as Self or Non-self

• “Pathogen-associated molecular patterns” (PAMPs)

-Present on many microbes
-Not present on human cells

• Pattern recognition receptors:

“Toll-like receptors” (TRLs)
-Macrophages, dendritic cells, mast cells
-Recognize PAMPs → Secrete cytokines
Innate Immune System
Pattern Recognition

• Endotoxin (LPS)
• Peptidoglycan cell wall
• Mannose (polysaccharide on
bacteria/yeast)
• Lipoteichoic acid on
Gram-positive bacteria

Nature Reviews Microbiology, 5, 491-504, copyright 2007

Innate Immune System
Key Components

• Phagocyte
-Macrophages (hallmark cells)
-Neutrophils
• Complement
• Natural Killer Cells
• Eosinophils
• Mast cells & Basophils
Monocytes & Macrophages
Three key functions:
• Phagocytosis
• Cytokine production
• Antigen presentation
Monocytes & Macrophages

Each type of macrophage,

determined by its location, has a specific name:

 Bone marrow/Blood Monocytes

 Liver  Kuffer cells Liver
 CNS  Microglia
 Cnnective tissue  Histiocytes
 Kidney  Intraglomerular mesangial cells Alveoli
 Bone  Osteoclast
 Lung  Alveolar macrophage
Macrophages
• Macrophages can exist in several "states"
• Resting: Debris removal
• Activated ("primed"): more effective
• Major activators (via surface TLRs):
-LPS from bacteria
-Peptidoglycan
-Bacterial DNA (no methylation)
• Also, IFN-y from T-cells, NKC
• Attracted by C5a (complement)
Phagocytosis

• Macrophages engulf pathogens into phagosome

• Phagosome merges with lysosome
• Lysosomes contain deadly enzymes
• Death of bacteria, viruses

Fig: Phagocytosis
Neutrophils
• Acute inflammatory response cells.
• Phagocytic.
• Multilobed nucleus.
• Specific granules contain LAP,
collagenase, lysozyme, and lactoferrin.
• Azurophilic granules (lysosomes)
contain proteinases, acid phosphatase,
myeloperoxidase, and β-glucuronidase.
LAP-leukocyte alkaline phosphatase
Natural Killer Cells
• Two key roles:
• Kill human cells infected by viruses
• Produce INF-gamma to activate Macrophages
• Lymphocytes (same lineage as T-cells and B-cells)
• Do not mature in thymus
• No memory
• Do not require antigen presentation by MHC
Complement
• System of hepatically synthesized plasma proteins that
play a role in innate immunity and inflammation.

• Membrane attack complex (MAC) defends against

gram ⊝ bacteria.
Complement Activation
Pathways:
1. 2. 3.

1. Classic—IgG or IgM
mediated.

2. Lectin—mannose or other
sugars on microbe surface.

3. Alternative—microbe
surface molecules.

Function:
C3b—opsonization.
C3a, C4a, C5a—anaphylaxis.
C5a—neutrophil chemotaxis.
C5b-9 (MAC)—cytolysis

MAC- Membrane attack complex

 Cytokines and Chemokines
• Cytokines are immune • Chemokines are superfamily of
modulating agents made up of cytokines which mediates
proteins chemotaxis
• Involves in both cellular and • Involves in directing cells at site of
antibody mediated immunity infection
• Eg: Interleukins, TNF, TGF • Eg: CC chemokines, CXC, CX3C

TNF-Tumor necrosis factor

TGF- Trasforming growth factor
Major histocompatibility complex (MHC)
• MHC encoded by HLA genes.
• Present antigen fragments to T cells and bind T-cell receptors (TCRs).
• Two classes:
• MHC I MHC I MHC II
• MHC II
MHC I
HLA-A, HLA-B, HLA-C
Binds TCR & CD8
1 long chain, 1 short chain
Expressed in all nucleated cells,
APCs, platelets (except RBCs)
Present endogenous antigens
(eg, viral or cytosolic proteins)
to CD8+ cytotoxic T cells
MHC II
HLA-DP, HLA-DQ, HLA-DR
Binds with TCR & CD4
2 equal length chains (2 alpha, 2 beta)
Expressed in APC
Present exogenous antigens
(eg, bacterial proteins) to
CD4+ helper T cells
Adaptive Immunity
• T cells
• B cells
• Circulating Antibodies
T cells
• T cells are born from hematopoietic stem cells, found in the
bone marrow.

• Developing T cells then migrate to the thymus gland to

develop (or mature).

• T cells derive their name from the thymus.

• After migration to the thymus, the precursor cells mature into

several distinct types of T cells.
Differentiation of T cell

CD8+

CD4+
T Cells Two key subsets:

CD4+ T-cells CD8+ T-cells

• Also known as helper T-cell
• Helps B cells make antibodies
• Produce cytokines
• Activate other cells
• Direct immune response
• Also known as cytotoxic T-cells
• Kill virus-infected cells (also tumor
cells)
 T cells activation
Dendritic cell
CD4+ T cell

3
 T cells activation
Signals: Once they have 3 signals like this,
1
T cell would re-enter the cell cycle and
2
3 proliferate rapidly k/a clonal expansion

Clonal expansion
Cell cycle
After proliferating rapidly, they could be differentiated into several sub lineages
based on the cytokines they encounter. They could become Th1, Th2, Th17 cells.
Th1 and Th2 cells
• Two subpopulations CD4 T-cells
• Th1 cells
• "Cell-mediated" immune response
• Activate CD8 T-cells, macrophages
• IL-12 (macrophages) drives Th1 production
• Promotes specific IgG subclasses (opsonizing/complement)
• Th2 cells
• "Humoral" immunity
• Activate B-cells to produce antibodies (IgE, IgA)
CD8 T-cells
• Many similarities to CD4 cells
• React to unique antigens
• Require antigen presentation
• TCR associated with CD3 for signal transmission
• Antigen presented by MHC Class I
• Found on all nucleated cells (not RBCs)
• Most human cells are antigen presenters for CD8
• Main role is to detect and kill virus-infected cells
 CD8 T-cell Functions
Killing of infected cells

Insert perforins
• Forms channels in cell membrane
→ cell death

Insert granzymes:
Proteases → degrade cell contents
Activate caspases to initiate apoptosis
B cells
• Part of adaptive immune system
• Each recognizes a unique antigen
• Once recognizes antigen: synthesizes antibodies
• Antibodies attach to pathogens → elimination
B cell Activation
• Two types of activation
• T-cell dependent (proteins)
• T-cell independent (non-proteins)

• For T-cell dependent, two signals required:

• 1: Crosslinking of receptors bound to antigen
• 2: T cell binding (T-cell dependent activation)
Antibody
• Antibodies are proteins produced and secreted by B cells.

• They bind to foreign substances that invade the body, such as

pathogens.

• Another name for this protein molecule is immunoglobulin

(abbreviated Ig).
 Antibody structure

Antibodies are Y-shaped molecules,

consisting of:
1. two heavy chains (H chains) and
2. two light chains (L chains)
arranged as shown in the diagram.

An antigen binds to the antigen-binding site.

Each antibody recognizes a

specific antigen called "antibody specificity".
 Antibody Functions
1: Opsonization
• Mark pathogens for phagocytosis

2: Neutralization
• Block adherence to structures

3: Activate complement
• "Classical" pathway activated
by antibodies
Vaccines
• B cell and T cell response without overt infection
• Protection via immune memory
• Various types:
• Live attenuated
• Killed
• Oral/intramuscular
Vaccines
• Live attenuated
• Pathogens modified to be less virulent
• Can induce a strong, cell-mediated response
• MMR, BCG, Polio(Sabin), Rotavirus
• Killed
• Pathogen killed but antigens remain intact
• Strong humoral response (antibodies)
• HepA, Rabies, Polio(Salk)
Vaccines
• Subunit, Recombinant, Polysachheride & Conjugate
• HBV, HPV, Streptococcus pneumoniae, Hib
• Toxoid
• Tetanus
 Hypersensitivity

Anaphylaxis or Atopic type

Immune complex mediated

Anaphylaxis to food, drug or AIHA SLE Type 1 DM

Bee sting allergies ITP PSGN GVHD
References
• Textbook of Microbiology & Immunology (SCP)
• Lippincott’s Illustrated Reviews: Immunology
• Immunology A Short Course
• UpToDate