Innate Immunity

By: Prof. Salma AboElNazar Professor of Immunology Medical Research Institute

Innate Immunity
Anatomical barriers epidermis, dermis, cilia, cough, sneeze, outward flow of urine Chemical barriers psoriasin on skin, acid pH of stomach, lysozyme in tears

But some organisms can evade these barriers, e.g., by attaching firmly to epithelial cells by fimbriae or pili

Vertebrates - Two Systems of Immunity 1. Innate immunity (early in infection) physical, chemical, cellular barriers 2. Adaptive immunity (or acquired immunity) specific response by B and T lymphocytes memory; future exposures quicker and more vigorous sensors = specific antibodies (Abs) and T cell receptors (TCRs)

p. 53

Connections Between Innate and Adaptive Immunity

Invaders must be sensed and destroyed

Invaders are recognized by soluble or membrane-bound molecules These molecules recognize broad structural motifs that are in germs, but not in self

PRRs and PAMPs PRRs = Pattern Recognition Receptors PAMPs = Pathogen-Associated Molecular Patterns - combinations of sugars, certain proteins, some lipid-bearing molecules, and some nucleic acid motifs - found only on microbes, never on self

In contrast, Abs and TCRs of adaptive immunity recognize finer details of molecular structure Summary: PRRs recognize broad, essential motifs, present on many groups of microbes;

Abs and T-cells recognize fine differences among different microbes

Examples of soluble mediators of innate immunity

1. Mannose-binding lectin (MBL)

2. C-reactive protein (CRP) When these bind to microbes with PAMPs they recognize, the complement system may be activated to opsonize microbes or lyse them

p. 58

Dendritic cell and macrophages have Toll-like receptors (TLRs) which detect microbial products

11 discovered in humans, 12 in mice

When TLR combines with microbe, macrophage: -has increased phagocytic activity -makes toxic chemicals -makes cytokines, like IL-1, IL-6, TNF-alpha -thus inflammatory response is induced

Immature dendritic cells internalize antigen, process it, mature, migrate to lymph node, and present processed Ag to T cells for adaptive immune response.

Dendritic cells also secrete a variety of cytokines that promote inflammation.

Defensive mechanisms include :

1) Innate immunity
(Natural or Non specific)

2) Acquired immunity (Adaptive or Specific)

Cell-mediated immunity immunity

Humoral

Component of Innate Immunity

Innate Immune system First line Second line
1) Mechanical barriers 2) Chemical & biochemical inhibitors killer 3) Normal flora Phagocytes A- cells 1- Natural 2B- Soluble

First line
1) Mechanical barriers - Intact skin - Mucous coat - Mucous secretion - Blinking reflex and tears - The hair at the nares - Coughing and sneezing reflex

First line
2) Chemical & biochemical inhibitors
- Sweet and sebaceous secretion - Hydrolytic enzymes in saliva - HCl of the stomach - Proteolytic enzyme in small intestine

- Lysozyme in tears
- Acidic pH in the adult vagina

First line
3) Normal bacterial flora - Competition for essential nutrients - Production of inhibitory substances

Second line
A) cells
1- Natural killer (NK) Definition: Large granular lymphocytes
Innate cytotoxic lymphocytes

Source

Bon marrow precursors 10% or 15% of lymphocytes in peripheral blood 1% or 2% of lymphocytes in spleen Tumor cells Viral infected cells Bacterial, fungal, parasitic infection

Location :

Function : Cytotoxic for

Responsible for antibodydependent cell mediated cytotoxicity (ADCC)

Second line
2- Phagocytes
Specialized cells for capture, Ingestion and destruction of invading microorganisms * Polymorphoniclear leucocytes, mainly neutrophils:
granulocytes circulate in blood

* Mononuclear cells (macrophages) - Monocytes in blood

- Histocytes in connective tissues

- Fixed

reticuloendothelial cells in liver spleen, lymph

nods, bon marrow

Second line
B- Soluble factors 1- Acute phase protein (Plasma protein, CRP=C reactive protein, Fibrin.) 2- Complement (proteins in serum, body fluids) 2- Interferons (Proteins against viral infections) 3- Properdin (Complement activation) 4- Beta lysine (Antibacterial protein from Platelets) 5- Lactoferrrin,Transferrin (Iron binding protein) 6- Lactoperoxidase (Saliva & Milk) 7- Lysozyme (Hydrolyze cell wall)

Interferons
Proteins usually produced by virally infected cells * Types of interferons: 1- Alpha interferon
Secreted by Macrophages Induced by Viruses or Polynucleotide Secreted by Fibroblasts, Viruses

2- Beta interferon

3- Gamma interferon T- lymphocytes, Specific antigens

Interferons
Protective action of interferons: 1) Activate T-cells 2) Activate macrophages 3) Activate NK

Characteristics of Innate and Adaptive Immunity

Innate Immunity
Antigen independent
No time lag Not antigen specific No Immunologic memory

Adaptive Immunity
Antigen dependent A lag period Antigen specific Development of memory

Phagocytes: Macrophages
phagocytosis,

intracellular and extracellular killing, tissue repair, antigen presentation for specific immune response
characteristic nucleus

and CD14 membrane marker.

Characteristics of Neutrophil Granules

primary granules
azurophilic; characteristic of young neutrophils;

secondary granules
specific for mature neutrophils

contain cationic proteins, lysozyme, defensins, proteases and myeloperoxidase

contain lysozyme, NADPH oxidase, lactoferrin and B12-binding protein

Initiation of Phagocytosis
Attachment via
ScavengerR IgG FcR CR Toll-like R

Respiratory Burst
Oxygen Dependent Myeloperoxidase Independent Reactions
Glucose +NADP+ G-6-P-dehydrogenase
NADPH + O2 Cytochrome b558 2O2 + 2H+ Superoxide dismutase
-

Pentose-P + NADPH
NADP++ O2
-

H2O2 + 1O2
-

2O2 + H2O2

.OH + OH + 1O2

Respiratory Burst
Oxygen Dependent Myeloperoxidase dependent reactions H2 O2 + Cl
-

myeloperoxidase
2OCL + H2O 2O2 + 2H+
-

OCl + H2O
1O -+ Cl-+ 2

H2O
-

H2O2 + O2 H2O + O2
-

Superoxide dismutase 2 H2 O2
catalase

Mediators of Oxygen Independent Killing in the Phago-lysosome

Effector Molecule
Cationic proteins (cathepsin)
Lysozyme Lactoferrin

Function
Damage to microbial membranes
Hydrolyses mucopeptides in the cell wall Deprives pathogens of iron

Hydrolytic enzymes (proteases) Digests killed organisms

Nitric Oxide Dependent Killing

TNF TNF

Nitric Oxide Nitric Oxide

Non-specific Killer Cells

NK and LAK cells

ADCC (K) cell

Activated

macrophages
Eosinophils

They all kill foreign and altered self targets

Natural Killer (NK) cells

also known as large granular

lymphocytes (LGL)
kill infected and malignant

cells
are identified by the presence

of CD56 & CD16 and

absence of CD3
activated by IL2 and IFN- to

become LAK cells

Lymphokine Activated Killer (LAK) cell

kills transformed malignant and malignant cells cells

kills

K Cells
morphologically undefined
have IgG Fc receptor recognize antibody coated

targets
could be NK cells (IgG),

macrophages (IgG),

eosinophils (IgE) or other

cells (IgG)

Cells of the Innate Immune Response

IL-8

ADCC
Antibody-Dependent, Cell Mediated Cytotoxicity: target cells

coated with antibody are destroyed by specialized killer cells (Type II hypersensitivity).
Cells that mediate ADCC are NK cells, macrophages,

monocytes, neutrophils, eosinophils. Killing cells express receptors for the Fc portion of antibody coated targets.

Recognition of antibody coated target leads to release of lytic enzymes.

ADCC does not involve complement fixation or phagocytosis.