Topic 0 basic concept of immunology

I. The Sentinels & First Responders (Innate Immune Cells)¶

These cells act as the body's rapid response team. They do not require prior sensitization and rely on Pattern Recognition Receptors (PRRs) to detect general danger signals.

1. Macrophages & Monocytes¶

The Logic: They function as both waste management (phagocytosis) and alarm systems (cytokine release). They dictate the local environment's "tone" (inflammatory vs. healing).
Key Features:
- Origin: Monocytes circulate in blood and differentiate into macrophages in tissues (e.g., Kupffer cells in liver, microglia in brain).
- Polarization (The Decision Makers): They can switch phenotypes based on signals:
  - M1 (Classically Activated): Pro-inflammatory; kill pathogens and tumor cells.
  - M2 (Alternatively Activated): Anti-inflammatory; promote tissue repair and healing.
Connection Mechanism: They act as Antigen-Presenting Cells (APCs), processing pathogens and presenting them to T cells via MHC II molecules to initiate the adaptive response.

2. Dendritic Cells (DCs) — The Master Bridge¶

The Logic: DCs are the central information hub connecting innate and adaptive immunity. They are the only cells capable of activating naive T cells, effectively "teaching" the adaptive system what to attack.
Key Features:
- Subtypes:
  - Myeloid DCs (mDCs): Focus on antigen processing and presentation.
  - Plasmacytoid DCs (pDCs): Specialized in producing massive amounts of Type I Interferons (antiviral).
    - Type I IFN $\alpha$ and $\beta$: induce an antiviral state
      - Normally, cells produce IFN only when detecting non-self nucleic acids, which means viral DNA/RNA
        
        DNA sensing: ==cGAS-STING== pathway
        
        RNA sensing: receptor like ==TLR3/7/8, RIG-I and MDA5== detect viral RNA
Connection Mechanism (The 3-Signal Hypothesis): DCs activate T cells through three distinct signals:
1. Recognition: Presenting antigen (pMHC) to the T Cell Receptor (TCR).
2. Costimulation: Surface molecules (CD80/86) binding to CD28 on T cells (prevents anergy).
3. Differentiation: Releasing cytokines (e.g., IL-12) to determine if the T cell becomes Th1, Th2, etc.

3. Granulocytes (The Heavy Infantry)¶

Neutrophils: The most abundant early responders. They engulf bacteria and release "nets" (NETs) to trap pathogens. They bridge mechanisms by performing Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) when antibodies are present.
Eosinophils: Specialized for killing parasites (too large to eat) by releasing toxic granules. They also act as APCs to modulate responses.
Basophils & Mast Cells: Crucial for allergic responses and defense against parasites. They express IgE receptors; when IgE binds, they degranulate (release histamine).

4. Natural Killer (NK) Cells¶

The Logic: They provide surveillance against "internal" threats (viruses, cancer) that try to hide. Unlike T cells, they kill cells missing "self" markers (MHC I).
Connection Mechanism:
- ADCC: They bind to antibodies (IgG) coating a target cell via CD16 receptors and destroy it.
- Crosstalk: They secrete IFN-$\gamma$ to activate macrophages and promote Th1 differentiation, pushing the adaptive system toward a cellular response.

II. The "Blur" (Innate-like Lymphocytes)¶

These cells share characteristics of both systems, acting as a rapid bridge with limited memory but semi-specific recognition. - NKT Cells: T cells that express NK markers. They recognize lipids (not proteins) presented by CD1 molecules and rapidly secrete cytokines (Th1/Th2) to tune the immune response. - $\gamma\delta$ T Cells: Found in mucosal tissues (skin, gut). They recognize stress signals directly without MHC presentation, acting as a barrier defense. - Innate Lymphoid Cells (ILCs): Mirror the functions of T helper cells but lack T cell receptors. - ILC1 $\approx$ Th1 (Viruses/Bacteria). - ILC2 $\approx$ Th2 (Parasites/Allergy). - ILC3 $\approx$ Th17 (Fungi/Extracellular bacteria).

III. The Specialized Effectors (Adaptive Immune Cells)¶

These cells provide specific, high-affinity recognition and long-term memory. They are activated only after receiving "permission" and instructions from the Innate system.

1. T Lymphocytes — The Coordinators & Assassins¶

CD4+ Helper T Cells (The Generals): They do not kill; they direct the war.
- Th1: Induced by IL-12 (from innate cells); activates Macrophages and CD8+ T cells (Cellular Immunity).
- Th2: Induced by IL-4; helps B cells produce antibodies (Humoral Immunity).
- Th17: Induced by IL-6/TGF-$\beta$; recruits Neutrophils for bacterial/fungal defense.
- Tregs: Suppress the immune response to prevent autoimmune damage and maintain tolerance.
CD8+ Cytotoxic T Cells (The Assassins): Recognize specific antigens on infected/tumor cells via MHC I and induce apoptosis (cell death) via perforin/granzymes.
Connection Mechanism: T cells rely on the Cancer-Immunity Cycle logic: release of antigen $\to$ presentation by DCs $\to$ priming T cells $\to$ trafficking to tumor $\to$ killing target.

2. B Lymphocytes — The Factories¶

The Logic: B cells recognize soluble antigens directly. Once activated (usually with T cell help), they transform into factories (Plasma Cells).
Subtypes:
- B1 Cells (Innate-like): Found in body cavities; produce "natural antibodies" (IgM) without T cell help; no memory.
- B2 Cells (Classic Adaptive): Require T cell help; undergo class switching (IgM $\to$ IgG/IgA/IgE) and high-affinity maturation in Germinal Centers.
- Plasma Cells: The effector form that pumps out thousands of antibody molecules per second.
- Memory B Cells: Long-lived sentinels that respond rapidly upon reinfection.

IV. The Logic of Interaction (Crosstalk)¶

The article emphasizes that these systems are not separate; they form a single integrated network.

Innate $\to$ Adaptive (Initiation):
- Innate cells (DCs/Macrophages) detect pathogens via PRRs (TLRs, NLRs).
- They present antigens and secrete specific cytokines (e.g., IL-12 vs IL-4) which dictate whether the Adaptive system launches a Th1 (cellular) or Th2 (humoral) response.
Adaptive $\to$ Innate (Enhancement):
- Antibodies (Adaptive) coat pathogens (Opsonization), making them "tasty" for Macrophages (Innate) to eat.
- Th1 Cells (Adaptive) release IFN-$\gamma$, which "supercharges" Macrophages (Innate) to kill bacteria they have ingested.
Trained Immunity (The New Paradigm):
- Unlike traditional views, innate cells (Monocytes/NKs) can have a form of memory. Through epigenetic and metabolic reprogramming ("Trained Immunity"), they react more strongly to secondary infections, bridging the gap between non-specific and specific immunity.