Innate Immunity

First step

sistemul imun innascut

Component of Innate Immunity

Innate Immune system

First line
1) Mechanical barriers

Second line
A- cells 1- Natural killer 2- Phagocytes B- Soluble factors C- Inflammatory barriers

2) Chemical & biochemical inhibitors 3) Normal flora

Figure 2-2 part 2 of 2

Figure 2-2 part 1 of 2

 Anatomic Barriers Skin, Mucous membranes, Cilia, Normal flora Physiological Barriers

Innate Immunity (Nonspecific Immunity)

Temperature, Low pH, Chemical Mediators Lysozyme, Interferon, Complement, Collectin, TLR

Phagocytic/endocytic Barriers Phagocytosis (tissue macrophages, neutrophils) Endocytosis

Inflammatory Barriers
redness, swelling, heat, pain

Physical barriers

First line
1) Physic-Mechanical barriers:
A. Physical barriers:
Intact skin Mucous coat Mucous secretion

B. Mechanical
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
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) Biological Barriers: Normal bacterial flora Production of inhibitory substances Competition for essential nutrients

Component of Innate Immunity

Innate Immune system

First line
1) Mechanical barriers

Second line
A- cells 1- Natural killer 2- Phagocytes B- Soluble factors C- Inflammatory barriers

2) Chemical & biochemical inhibitors 3) Normal flora

 Anatomic Barriers Skin, Mucous membranes, Cilia, Normal flora Physiological Barriers

Innate Immunity (Nonspecific Immunity)

Temperature, Low pH, Chemical Mediators Lysozyme, Interferon, Complement, Collectin, TLR

Phagocytic/endocytic Barriers Phagocytosis (tissue macrophages, neutrophils) Endocytosis

Inflammatory Barriers
redness, swelling, heat, pain

I. Cells
Hematopoiesis

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

Source : Bon marrow precursors Location : 10% or 15% of lymphocytes in peripheral blood
1% or 2% of lymphocytes in spleen

Function : A. Cytotoxic for:

Tumor cells Viral infected cells Bacterial, fungal, parasitic infection

B. Responsible for (ADCC) :

antibodydependent mediated cytotoxicity cell

I. Cells
Hematopoiesis

Second line
2- Phagocytes
Specialized cells for capture, Ingestion and destruction of invading microorganisms

Polymorphoniclear leucocytes (neutrophils) granulocytes circulate in blood Mononuclear cells (macrophages)

a. b. c. - Monocytes in blood - Histocytes in connective tissues - Fixed reticuloendothelial cells in liver spleen, lymph nods, bon marrow

Second line: Phagocytes

Role of Neutrophil

MACROFAGEs are MONOCITES which left the circulation & established in tissues

Second line: Phagocytes

Macrophage
Monocytes in blood & Macrophages in the tissues

Enlarge & increase lysosomes ; lysozyme, hydrolytic enzymes

Second line: Phagocytes

Role of Macrophage

Toll-like receptors & Host-Pathogen Interaction

ONeill, Luke A.J. Immunitys Early-Warning System. Scientific American, Jan (2005), 38-45.

Cells of Innate Immunity recognize

Pathogen-associated molecular patterns known as (PAMPs) Damage-associated molecular patterns known as (DAMPs) Stressed induced proteins: HSP Crystals: monosodium urate Nuclear proteins: high mobility group box-1 protein

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)

Pattern Recognition Receptors (PRRs)

Toll-like receptors Soluble receptors: Mannose binding lectin (MBL) C-reactive protein Serum amyloid P

Pattern Recognition Receptors (PRRs)

Functions of PRRs:
Opsonization, Activation of complement and Activation of coagulation cascades, Phagocytosis, Activation of pro-inflammatory signaling pathways

Nuesslein-Volhard: Drosophila Toll

Identified a protein she called Toll meaning weird
Helps the Drosophila embryo to differentiate its top from its bottom (Neural tube development)
1985 1988 1989 1991

http://www.nature.com/genomics/papers/drosophila.html

1996 1997 1998 1999 2000 2001

Gay: Toll and Inner Part of Human IL-1R is Similar

Searching for proteins similar to Toll Shows cytoplasmic domain of Toll related to that of hIL-1R Identity extends for 135 aa Didnt make sense Why does a protein involved in human inflammation look like one involved in fly neural tube development?

1985

1988 1989

1991

1996 1997 1998 1999 2000 2001

Toll Molecular Structure

IL-1R
Ig-like domain

Toll (will become TLRs)

LRRs

Toll receptor has an extracellular region which contains leucine rich repeats motifs (LRRs) Toll receptor has a cytoplasmic tail which contains a Toll interleukin-1 (IL-1) receptor (TIR) domain

Box 1 Box 2 Box 3 TIR Domain

TLR
Recognize 1. PAMPs 1. Chemical structure 2. Localization 3. Origine 2. DAMPs 1. HSP 2. HMGB1

TLR Cell Type Distribution

Receptor TLR1 TLR2 TLR3* TLR4 TLR5 Cell Type Ubiquitous DCs, PMLs, and monocytes DC and NK cells, upregulated on epithelial and endothelial cells Macrophages, PMLs, DCs, ECs, but not on lymphocytes Monocytes, immature DCs, epithelial, NK, and T cells High expression in B cells, lower on monocytes and NK cells B cells, plasmacytoid percursor DCs

TLR6
TLR7

TLR8 TLR9
TLR10 TLR11

Monocytes, low in NK cells and T cells Plasmacytoid percursor DCs, B cells, macrophages, PMLs, NK cells, and microglial cells B cells, plasmacytoid precursor DCs
Not Determined

Converging Pathways

Beutler, Nature 2004

Effects of signaling are cell specific NF-B activation is the end result of TLR-signaling

1. TLR dimers 2. adaptor proteins (MyD88)/ TRIF) 3. Activation of transcriptin factors (NfKB, IRFs) 4. +Genes CC, CK, CAMs/IFN Acute inflammation Antiviral state
Adptoris I: MyD88=Myeloid differentiation factor 88); TRIF (TIR domain containing adaptor inducing IFN ) IRF (interferon response factor)

The end