Innate Immunity: (I) Molecules & (II) Cells · 2018-04-03 · Advanced Course in Basic & Clinical...

Advanced Course in Basic & Clinical Immunology

Februay 19, 2018

1

Innate Immunity:

(I) Molecules & (II) Cells

Stephanie Eisenbarth, M.D., Ph.D.

FOCIS Advanced Immunology Course

2/19/18

Department of

Immunobiology

Yale School of Medicine

Department of Laboratory Medicine

Yale School of Medicine

Part II: Cells (aka the Sentinels)

• Granulocytes

– Neutrophil, Eosinophil, Basophil, Mast cell

• Monocytes/macrophages

• Dendritic cells

• Innate lymphoid cells


Februay 19, 2018

2

Myeloid Cells• Recognize microbes

– PRRs

– Complement

– Antibody

• Ingest & destroy microbes

• Kill infected/injured cells

• Regulate tissue homeostasis

• Antigen presentation– Help T cells

Two pathways for macrophage development

During inflammatory reactions

Tissue-resident macrophages

Further reading: Epelman et al Immunity 2014)


Februay 19, 2018

3

First responders recruit

(Macrophages organize)

First responders clear pathogens and dead cells


Februay 19, 2018

4

Chronic Granulomatous Disease (CGD)

• Recurrent bacterial infection (catalase positive organisms)

• Granulomas of skin, liver, lungs, lymph nodes observed

• Gene defect: – gp91 phox (X‐Linked)

– p22 phox (Autosomal Recessive)



• Phagocytic cells ingest but do not kill

bacteria due to failure to form

oxygen radicals

Normal

CGD

IFN and macrophage activation

• Mendelian susceptibility to mycobacterial disease (MSMD) – Ifn‐mediated protection (IL‐12, Ifn, Stat1 defects)– Failure of CD4+ T cells to activate macrophage killing of intracellular bacteria

TIFN

Bustamante et al Semin. Immuno. 2014

TNF blockers might interfere

with this process…


Februay 19, 2018

5

Endothelium activated by cytokines Leukocytes activated

by chemokines

TNFaIL‐1

Integrins seal the deal Chemokines

direct

Leukocyte migrationduring inflammation

Neutrophil NETs

• Neutrophil extracellular traps

• NETosis with cell death traps microbes – Extrusion of chromatin decorated with antimicrobial molecules (e.g., elastase, MPO)

• Role in driving autoimmunity?

Kaplan et al, JI 2012

DNA


Februay 19, 2018

6

DCs = translators between innate & adaptive immunity

DCs & the next phase of immunityDCs survey for pathogens or host damage (via PRRs) and respond by

processing antigens and providing “second signals”T cell priming requires 2 signals to avoid anergy: antigen (constant) +

co‐stimulation (activated DC)

The innate immune system provides second signals required for lymphocyte activation

2nd signals for T cells: CD28: B7 family members

(CD80/B7.1, CD86/B7.2)[opposite for PDL1,2]

ICOS: ICOSLOX40: OX40LCD137: 4‐1BBL

2nd signals for B cells:CR3: Activated complement componentsTLRs: PAMPs

Abbas, Lichtman and Pillai. Cellular and Molecular Immunology, 7th edition, 2011 c Elsevier


Februay 19, 2018

7

Dendritic Cell Subsets (Spleen)

MDP

….

HSC Embryonic Precursor

FLT3L MCSF

Macrophages

Plasmacytoid

Conventional

Monocyte‐derived

Dendritic Cell Subsets (Spleen)

MDP

….

HSC Embryonic Precursor

FLT3L MCSF

Macrophages

Type I IFN

T cell priming

Inflammation


Februay 19, 2018

8

DC Migration is a Critical

Stepin T Cell Priming

PRR activation• Ag processing/presentation

• MHC/HLA• Co‐stimulatory molecule

expression• CCR7 expression follow a

gradient of CCL19/CCL21

…CCL19/21…

Innate instruction of adaptive immunity: implications

− Autoimmunity

− Allergy

+ Resistance to re‐infection

+ Vaccination

Once this principle was understood,

the role of adjuvants could be explained

• HBV vaccine : subunit and adjuvant

• Adjuvare = to help

• Hundreds of different adjuvants– CFA, Aluminum hydroxide, MF‐59 (Squalene), TLR agonists, AS04

(Alum+MPL)

Alum

2) Adjuvant

1) Antigen

Medzhitov, 2001


Februay 19, 2018

9

Questions?

• Thanks

– A. Abbas

– K. Rock

• Further reading

– Janeway’s Immunobiology, 8th edition

– Abbas, Lichtman & Pillai Cellular & Molecular Immunology, 8th edition

• Different from NKT cells

• Germline encoded receptors

• Kill cells that are missing “stop” signals

– Inhibitory receptors

• KIRs

• Kill cells that express foreign or stress signals

– Activating receptors

• CLRs

• NKG2D

• FcgRIII (CD16)

• Infections

• Tumors

NK Cells (ILC1)


Februay 19, 2018

10

A. Abbas

Innate lymphoid cells

ILCs make many of the same cytokines as T cells but lack TCRs

May contribute to early cytokine

responses in host defense and

inflammatory diseases


Februay 19, 2018

11

Principles of 11+ TLRs

Akira et al, Nat. Rev. Imm. 2004

Immune effector mechanisms

B T

PMN

Mac+ Complement

T cell help

Cytotoxicity

Intracellularkilling

Antibodyproduction

R. Fuleihan

DC


Februay 19, 2018

12

Timepoint: minutes‐hours

1. Block microbial invasion

2. Remove targeted microbes, dead cells & foreign bodies

3. Tissue homeostasis

Plasma proteins target & kill

– Complement

– Pentraxins (CRP, SAA, etc.)

– Collectins & Ficolins

Phagocytes eat & recruit

– Pattern recognition receptors

Innate lymphoid cells kill & coordinate

– NK cells kill things that are non‐self

K. Rock

Increased hydrostatic pressure/permeabilityLeak of protein‐rich fluid into site = EDEMA

Structure of TLRs

• A transmembrane domain

• A cytosolic domain with a conserved TIR (Toll‐interleukin 1 Receptor) domain– Shared with IL‐1R family

Choe et al, Science 2005Akira et al, Nat. Rev. Imm. 2004

• An extracellular domain with LRRs (Leucine Rich Repeats)

Innate Immunity: (I) Molecules & (II) Cells · 2018-04-03 · Advanced Course in Basic & Clinical...

Documents

Transcript of Innate Immunity: (I) Molecules & (II) Cells · 2018-04-03 · Advanced Course in Basic & Clinical...