4. Innate immunity I: The first lines of defense (barriers to infection)

What are the components of intrinsic innate immunity?

• Humoral: complement system, cytokines/chemokines, antimicrobial peptides

• Cellular: epithelial cells, neutrophils, eosinophils, monocytes/macrophages, dendritic cells (DCs), NK/NKT cells, γδ-T cells (Vδ1, Vδ2, Vδ3), innate lymphoid cells (ILC1, ILC2, ILC3)

  • Vδ1, Vδ2, Vδ3: Cutting edge of cancer immunotherapy                 

• Microbial: bacteria (microbiota), viruses (virome)

What are the properties of innate immunity?

• Specificity: non-specific

• Action time: quick

• Persistence: short

• Memory: none

• Antigen: diverse (conserved, microbe-specific molecules etc)

• Receptor: germ-line encoded

• Graph takeaway:

  • Normal humans: infection controlled at low level

  • No adaptive immunity: higher infection load than normal

  • No innate immunity: even higher infection load → innate is essential first

What are the key functions of the innate immune system?

• Prevent pathogen attachment/entry while allowing beneficial microbes

• Recognize, control, eliminate danger

• Induce inflammation, bring help to infection site

• Orchestrate adaptive immune response

• Regulate disease resistance and tolerance

How does the body respond to potential pathogens?

• Innate Immunity: No infection → No tissue damage

• Innate Immunity (immediate: 0-4 hours): Very minor tissue damage → Immediate repair

• Early induced innate response (early: 4-96 hours): Minor damage → Soon repaired

• Adaptive immune response (late: >96 hours): Major damage → Gradual repair, may leave consequences

• Important to have both innate and adaptive immunity

What is the role of intrinsic barriers in innate immunity?

• Prevent pathogen attachment and colonization

• Result: No infection, no tissue damage

• Types of intrinsic barriers: Mechanical, Chemical, Microbiological

  • Chemical: Sebaceous glands (fatty acids) in skin, low pH in stomach, skin and vaginal tissue

What epithelial surfaces provide the first line of defense?

• Dry surfaces: skin

• Wet surfaces: mucosa

• Epithelial cells are immune cells

Why is skin important in immunity?

• Skin is the largest immune organ

• Makes up 12–15% of body weight

• 3 Important Factors for Healthy Skin

  • Thick cretinoid layer

  • Lots of microbiota at the top of skin

  • Thin emulsion (oil) layer

Why is healthy skin resistant to infection?

1. No viable virus receptors

   • Virus needs receptors → receptors are only on live cells → skin is dead cells → no virus receptors

2. Lowest water activity in body

3. High fatty acid + salt levels

4. Harbors ~200 bacterial genera

Can normal skin microbiota help treat skin diseases?

• Potential treatments for:

  • Acne

  • Atopic dermatitis

  • Psoriasis

• Example: Facial microbiota transplantation

What is another key epithelial barrier besides skin?

• Mucosal surfaces

  • Covered with mucus + water, supporting microbiota growth

  • Contain mucin (traps microbes)

  • Rich in antibacterial + antimicrobial peptides

  • Have enzymes that break down pathogens

How does frequent renewal of mucosal epithelial cells aid defense?

• Renew every 24–48 hrs

• Rapid shedding removes attached pathogens

• Constantly provides fresh, healthy barrier

How do microbiological barriers (normal bacterial and viral flora) prevent infection?

• Microbiota: Important player of innate immunity and more

• GI tract: ~400 bacterial species (~2.8 kg in gut mucosa!)

• UG tract: high Lactobacillus concentration

• Upper respiratory: Gram+ (Strep/Staph)

Normal Flora (Microbiota) Mechanisms:

1. Occupy all available space (block bad bugs)

2. Produce antibacterial/viral components (bacteriocins, defensins, cationic proteins) to directly kill bad bags

Could we survive without normal flora? (Lessons from germ-free animals)

• Underdeveloped immune system

• Highly susceptible to infection

• Need ~30% more food than controls to get same nutrients/energy

How can first-line defenses treat GI diseases?

Examples:

• Clostridium difficile (C. defficile): Causes diarrhea and colon inflammation

  • Treatment: Fecal Microbiota Transplant to transfer healthy gut bacteria from a donor to the patient

• Inflammatory bowel disease (IBD)

• Other gut-related conditions (obesity)

How does natural immunity vary in the female reproductive tract (pH + Lactobacillus)?

• Pre-puberty: higher pH (less acidic), little/no LB

• Reproductive age: lower pH (acidic), +++++ LB

  • Normal pH = below 3.5

  • LB peak at ovulation because that’s the only time animals mate (exception: humans)

• Menopause: higher pH again, reduced LB

What dominates the vaginal microbiota in reproductive-age females?

• Healthy: high LB (80%)

• Sub-clinical BV: reduced LB

• BV: very low/no LB

What trends are seen in BV (bacterial vaginosis) and STIs?

• STI rate ↑ 2–5× among over-55s (2005–2015, still rising)

• BV ↑ in adolescents + elders

• Drug-resistant BV ↑

• Best treatment/prevention? → Support healthy vaginal microbiota

  • Transplantation of vaginal microbes or lactobacilli

What role does vaginal microbiota play for newborns?

• C-section babies lack full exposure to maternal microbiota

• Vaginal microbial transfer → partially restores infant microbiota

  • Take clean cloth, absorb vaginal secretion and rub it on newborn

What is the human virome?

• The collection of viruses that naturally exist in/on the human body

• Part of innate microbial environment

In GI tract there is more viruses than bacteria!

• GI tract has lots of phage virus

What antimicrobial substances do epithelial cells produce?

• Cryptidins & α-defensins (produced at base of small intestine crypts)

• β-defensins (produced within skin, respiratory tract)

• Surfactant proteins A & D (present in lung, vaginal tract) → act as opsonins (enhance efficiency of phagocytosis)

How do tears and saliva defend against bacteria?

• Contain lysozyme (natural disinfectant/potent antimicrobial agent)

• Effective against Gram+ and Gram– bacteria

• Composition of tears varies per condition: Foreign object in eye (high in lysosomes), sadness (cortisol)

What are the complement pathways and their effects?

• Main idea: Complement system are proteins normally produced in the liver, and increased production during injury → liver sends to blood so entire body soaked with complement protein

  • Part of humoral innate immunity

• Once activated, 2 main jobs:

  • Remove pathogen

  • Induce inflammation

• Alternative pathway: triggered by pathogen surface (first)

• Lectin pathway: mannose-binding lectin binds pathogen (second)

• Classical pathway: antibody or C-reactive protein binds antigen (third)

• All → C3 cleavage → C3a, C3b

• Results:

  1. Recruit inflammatory cells

  2. Opsonization → phagocytosis

  3. Pathogen membrane perforation

• Outcome: pathogen death

What are the take home messages about innate immunity?

• Intrinsic barriers prevent infection

• Epithelial cells = crucial defense

• Normal flora (microbiota) of skin and mucosal surfaces = first-line defense

• Strengthening natural immunity may treat/cure infectious diseases