Lecture 9 - Homing, Regulation, Memory

What are the 4 types of cell homing and extravasation methods?

1. rolling adhesion

2. tight binding

3. diapedesis

4. migration

What are the 5 paradigms of the immune system?

1. sensing

2. specialization

3. reaction

4. regulation

5. memory

What is innate immune regulation?

• process of controlling the magnitude and duration of a response so that it is effective while minimizing damage to the host

What is immune activation and its pros and cons?

• pattern and damage recognition

• effector responses

• Pros: clears perturbations like infection

• Con: immune cells damage tissues; accidental immunity against self/harmless antigens

What is immune suppression and its pros and cons?

• suppressive cytokines

• clearance of immune activators

• Pros: avoid tissue damage

• Cons: limiting immunity may inhibit timely clearance of pathogens

What are systemic involvements of localized immunity?

1. secretion of cytokines into circulation for recruitment

2. cytokines released into blood signal to hypothalamus and fat cells to increase temperature = fever

• increased T limits pathogen replication

1. tissue-resident macrophages activated to secrete TNF-a in tissue

2. increased release of plasma protein into tissue —> increased phagocyte and lymphocyte migration into tissue —> increased platelet adhesion to blood vessel wall

3. phagocytosis of bacteria —> local vessel occlusion —> plasma and cells drain to local lymph node

4. removal of infection —> adaptive immunity

Why can systemic immunity be dangerous?

• pathogens in blood = trigger immunity everywhere (bacteremia, viremia)

• results in positive feedback loop

• sense pathogen everywhere —> produce cytokines —> increased immune cell activation —> produce even more cytokines

• cytokine storm: tons of cytokine being produced but cells can’t keep up

  • system shuts down —> death

What if there is too much Immune Activation or insufficient Immune Regulation?

• immunopathology

  • Chronic inflammation that damages tissues.

  • e.g. Inflammatory Bowel Disease

• autoimmunity

  • initiates an adaptive immune response against self proteins

  • e.g. type 1 diabetes

• allergy

  • initiates an adaptive immune response against harmless antigens

  • e.g. food allergies

Systemic Inflammation and Cytokine Storm

Systemic inflammation occurs when macrophages activated in the liver and spleen secrete TNF-

Consequences of Immune Malregulation

• Insufficient immune regulation or excessive immune activation leads to immunopathology characterized by chronic tissue-damaging inflammation such as in inflammatory bowel disease

• autoimmunity involving adaptive immune responses against self proteins such as in type 1 diabetes

• allergy involving adaptive responses against harmless environmental antigens such as in food allergies

Innate Immune Regulation and Suppression Balance

• Immune regulation controls the response magnitude and duration to ensure pathogen clearance while minimizing host tissue damage

• relying on immune suppression mechanisms like suppressive cytokines and the clearance of immune activators, where the positive aspect prevents tissue damage

• negative aspect may risk inhibiting timely pathogen clearance

Mechanisms of Innate Immune Suppression

• The innate immune system suppresses ongoing inflammation through the clearance of immune activating signals by phagocytosing apoptotic cells

• cellular debris eliminate pro-inflammatory drivers

• through the production of suppressive cytokines by innate immune cells, act on activated cells to restrict their effector functions

Sources and Inducers of Suppressive Cytokines

• Macrophages and dendritic cells serve as the major innate immune cell producers of suppressive cytokines

• macrophages are specifically induced to produce these suppressive factors following efferocytosis of dead cells as well as after prolonged exposure to pro-inflammatory cytokine signaling

Comparison of Innate and Adaptive Immunity Properties

• Innate immunity is non-specific, acts quickly with short persistence, lacks traditional memory, recognizes conserved microbial molecules like LPS and glycans via germline-encoded receptors

• adaptive immunity is antigen-specific, acts slowly taking 2 to 6 days longer with long persistence, possesses memory, recognizes diverse proteins and peptides, and utilizes receptors generated by gene segment rearrangement

Innate Versus Adaptive Memory Kinetics

• Innate immune cells exhibit identical response magnitudes upon both first and second exposure to a pathogen

  • showing no enhanced recall response

• adaptive immune cells demonstrate a markedly faster, larger, and more robust magnitude response upon secondary exposure due to true adaptive immunological memory

Evolutionary Distribution of Immunity

• Innate immunity is present across bacteria, plants, and all animals representing 99 percent of living diversity without traditional immune memory

• adaptive immunity is restricted to vertebrates representing 1 percent of living diversity, featuring VLR-based systems in jawless fishes and immunoglobulin-based systems in jawed vertebrates

Invertebrate and Vertebrate Model Organisms

• The star ascidian is the closest invertebrate relative to humans and lacks an adaptive immune system

• the lamprey is the most distant vertebrate relative with a unique VLR-based adaptive immune system

• elephant shark is the most distant jawed vertebrate relative with a typical immunoglobulin-based adaptive immune system

Invertebrate and Plant Resistance to Re-Infection

• Plants and invertebrates demonstrate long-term resistance to secondary infections and enhanced protection without possessing a traditional adaptive immune system

• beginning with an initial infection and local immune response that confers systemic protection against subsequent challenges

Trained Innate Immunity and the BCG Vaccine

• The bacille Calmette-Guerin vaccine developed against tuberculosis induces a non-specific protective immune response in innate immune cells, providing heterologous protection against unrelated infections

Timeline of Trained Immunity Discoveries

• Mycobacterium bovis was isolated in 1908 and attenuated by Calmette and Guerin in 1921 to create BCG

• followed by Lloyd demonstrating its antitumor effects in 1959

• Bistoni showing T and B cell independence in 1988

• Garly showing reduced child mortality in 2003

• Netea coining the term trained immunity in 2011

• subsequent discoveries showing epigenetic reprogramming, metabolic shifts to aerobic glycolysis, and hematopoietic stem cell reprogramming

Monocyte Training and Functional Changes Following BCG

• Following BCG vaccination, circulating monocytes become trained and exhibit heightened activation status

• increased Toll-like receptor 4 expression

• enhanced production of inflammatory cytokines when challenged with heterologous secondary infections

Epigenetic Basis of Innate Training

• Trained innate immunity relies on epigenetic modifications that transition highly condensed, inaccessible chromatin into open chromatin accessible for active gene transcription

Epigenetic Signatures in Trained Macrophages and NK Cells

• Naive macrophages and NK cells feature closed chromatin and low gene expression

• stimulation drives active gene expression with H3K4me3 and H3K27Ac signatures

• trained resting cells maintain H3K4me1 latent enhancers for rapid activation

• restimulation yields high gene expression marked by H3K4me3 and H3K27Ac

Trained Innate Immunity in the Lung Model

• Administration of adenovirus in mice induces trained innate immunity in the lung

• …leading 16 weeks later to increased host survival, enhanced alveolar macrophage activation, and elevated production of neutrophil chemokines upon secondary bacterial challenge

Respiratory Mucosal Vaccination and SARS-CoV-2 Research

Research published by Dr Zhou Xing and colleagues in Cell demonstrated that respiratory mucosal delivery of next-generation COVID-19 vaccines provides robust cross-protection against both ancestral and variant strains of SARS-CoV-2