Immune Response Overview

Innate vs Adaptive Immune Response

• The innate immune system provides a rapid but non-specific response to pathogens, controlling replication while activating adaptive immunity.
• Adaptive immunity is slower, but highly specific to individual pathogens.
• Memory cells are produced by the adaptive immune system after the first infection, allowing for a faster and more potent response during reinfection.

Components of Immune Response

• Recognition of pathogens via receptors.
• Immune cell activation in response to infection.
• Effector mechanisms for killing pathogens:
  • Direct cytotoxicity: Killing through enzymes, etc.
  • Indirect communication: Signaling to other immune cells.
• Resolution of inflammation and return to homeostasis.
• Basement membrane transmigration for leukocyte migration.

Pattern Recognition Receptors (PRRs)

• PRRs are critical for detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs).
• They initiate an immune response to clear infection or repair damage.
• Types of PRRs:
  • Toll-like receptors (TLRs):
    • Located on the cell surface or within endosomal membranes.
    • Recognize diverse components from bacteria, viruses, and fungi.
    • Signal through MyD88 or TRIF pathways, leading to pro-inflammatory or antiviral responses.
  • Other PRRs:
    • A wide range of PRRs exist with distinct functions.

Reactive Oxygen Species (ROS)

• NADPH oxidase: Produces superoxide radicals by transferring electrons from NADPH to oxygen.
• Superoxide dismutase (SOD): Converts superoxide into hydrogen peroxide.
• Myeloperoxidase (MPO): Catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride ions.
• ROS functions:
  • Damage microbial proteins, lipids, and nucleic acids.
  • Contribute to pathogen killing via oxidative burst.

Macrophages

• Versatile immune cells involved in defense, tissue homeostasis, and inflammation.
• Development: Derived from yolk sac or monocytes.
• Lifespan: Long, months to years.
• Plasticity: Adopt different phenotypes based on signals.
• Polarization:
  • M1 (classically activated): Pro-inflammatory, induced by IFN-γ, LPS, and TNF-α.
  • M2 (alternatively activated): Anti-inflammatory, induced by IL-4, IL-13, IL-10.

Antigen Presentation

• MHC Class I:
  • Presents intracellular antigens (viral or tumor-derived proteins) to CD8+ cytotoxic T cells.
  • Involves proteasomal degradation of proteins and peptide transport via TAP complex.
• MHC Class II:
  • Presents extracellular antigens (bacteria, fungi, etc.) to CD4+ helper T cells.
  • Involves antigen uptake via phagocytosis, endocytosis, and proteolysis.

T Cell Development in the Thymus

• Double-negative (DN) stages: T cell progenitors lack CD4 and CD8 expression.
• Double-positive (DP) stage: T cells express both CD4 and CD8.
• Positive selection: Survival of T cells that weakly recognize self-MHC molecules.
• Negative selection: Elimination of T cells that bind too strongly to self-antigens, preventing autoimmunity.
• Regulatory T cells (Tregs): Develop from T cells that recognize self-antigens with intermediate affinity and suppress immune responses to self.

AIRE (Autoimmune Regulator)

• Transcription factor expressed by medullary thymic epithelial cells (mTECs).
• Enables the expression of tissue-specific antigens, allowing negative selection against a broad range of self-antigens.
• Plays a critical role in preventing autoimmunity.

T Cell Lineage Commitment and Exit

• After positive and negative selection, mature naive T cells exit the thymus:
  • CD4+ T cells: Help other immune cells fight infections.
  • CD8+ T cells: Directly kill infected cells.
• These T cells remain in a resting state until encountering their specific antigen.

Classical Pathway

• A major effector mechanism of humoral adaptive immunity.
• Detects antibodies (IgM, IgG) bound to microbes and binds to their Fc region.
• C1r and C1s become active, initiating a proteolytic cascade.
• Antibodies are produced first, followed by complement molecule binding to C1.
• Activates C4/C2, resulting in C4b/C2b.
• Further activates C3, generating C3a and C3b.

Alternative Pathway

• C3 undergoes spontaneous hydrolysis.
• Recognizes LPS, triggering a continuous activation process.
• Distinguishes self from foreign microbes based on regulatory proteins.
• Pathogens lack inhibitory proteins, leading to activation.
• C3 generates C3b, which binds to the pathogen.
• Bf activates Bb, which further binds to C3b on the pathogen.
• This creates an amplification loop with pathogen activation.

Tissue-Specific Cues

• ILC2 are primed to respond to allergens and helminths in the lungs.
• ILC3 are more responsive to bacterial signals in the gut.

Metabolic and Microbiota Signals

• Short-chain fatty acids (SCFAs) produced by commensal microbes modulate ILC activation.
• SCFAs influence cytokine production and barrier function.

Neuro-Immune Interactions

• Neuronal signals (VIP, neuromedin U) directly activate ILCs.
• These signals influence allergic reactions and tissue repair processes.

ILC Plasticity

• ILCs can switch from one type to another under certain conditions.
• ILC3 can transform into ILC1 in response to IL-12, associated with intestinal inflammation.
• This allows for functional flexibility in response to environmental changes and diseases.

NK Cells

• Type of ILC critical for defense against virally infected cells and tumors.
• Do not require prior sensitization or antigen-specific receptors.
• Rapidly respond to stressed cells showing changes through direct killing and cytokine secretion.
• Exhibit different killing mechanisms, with granzymes being the fastest.
• CD56 level distinguishes two subtypes:
  • Bright CD56: Killing NK cells.
  • Dim CD56: Cytokine producing NK cells.
• Can become memory cells.
• Found in blood, with mature cells expressing dim CD56, exhibiting pro-inflammatory functions.

NK Cell Functions

• Produce IFN-γ, leading to cytotoxic cytokine overproduction.

NK Cell Development

• Originate from CLPs in the bone marrow, sharing a lineage with T cells and other ILCs.
• Development driven by:
  • IL-15: Essential for development, proliferation, and survival.
  • IL-2 and IL-12: Maturation and activation.
  • Transcription factors: Eomes and T-bet regulate lineage commitment and specialization.
• Mature NK cells circulate in the blood and are present in peripheral tissues.
• Development stages:
  • Pro-NK cells (stage 1) -> pre-NK cells (stage 2) -> immature NK cells (stage 3) -> CD56 bright (stage 4) -> CD56 dim (stage 5).

NK Cell Activation

• Activated through a balance of activating and inhibitory receptors.
• Recognize stress signals and changes on target cell surfaces.
• Redundant system, making it difficult to determine activation/inhibition with receptor removal.

Inhibitory Receptors

• Prevent NK cells from attacking healthy cells by recognizing self-molecules (MHC class I).
• MHC I interaction with inhibitory receptors identifies cells as "self" and protects them from killing.
• Includes:
  • KIRs: Bind specific MHC class I molecules (HLA-A, HLA-B, HLA-C).
  • CD94/NKG2A: Recognizes the non-classical MHC class I molecule (HLA-E).
• Send inhibitory signals through ITIMs in their cytoplasmic domains, recruiting phosphates (SHP-1, SHP-2) to suppress activation signals.

Follicular DCs

• Not derived from bone marrow precursors.
• Do not present protein antigens to T cells.
• Involved in B cell activation in germinal centers of secondary lymphoid organs.
• Express TLRs and NLRs.
• Important for T-cell activation.
• Constantly express MHC-I (self-antigen expressed in healthy conditions).

Dendritic Cells

• Diverse population with distinct functions.
• Major players in immune responses.
• Can be classified based on surface markers, TLR expression, transcription factors, cytokine production, and function.

Dendritic Cell Subtypes

• cDC2s: Express CD11c, BCDA-1 (CD1c) and produce various cytokines. Source of inflammatory cytokines, involved in antigen presentation to CD4+ T cells.
• cDC1s: Express CD11c, BDCA-3 (CD141), CLEC9A, XCR1+, and produce IL-12. Capture antigens and cross-present them to CD8+ T cells, inducing Th1 responses.
• pDCs: Express BDCA-2 (CD303), BDCA-4 (CD304), CD123, and produce type I IFN. Play a role in antiviral immunity, early innate response, and priming antiviral T cells.
• Langerhans Cells: Express CD11b, Langerin (CD207), EPCAM, BDCA1, and CD1a. Capture and present antigens to CD4+ T cells.
• moDCs: Express CD11b, CCR2, CD14, and produce various cytokines. Involved in inflammatory cytokine production and other functions.

Dendritic Cell Development

• Originate from hematopoietic stem cells in the bone marrow.
• Develop from CMPs and CLPs.
  • Conventional DCs: From myeloid precursors, specialize in antigen presentation and T cell activation.
  • Plasmacytoid DCs: From lymphoid precursors, key producers of type I interferons during viral infections.

Immature Dendritic Cells

• Located in peripheral tissues, specialized for antigen capture.
• Express PRRs to detect pathogens.
• Highly phagocytic, capturing pathogens, dead cells, and foreign particles.
• Low expression of costimulatory molecules (CD80, CD86) necessary for T cell activation.

Antigen Uptake

• Immature DCs efficiently capture various antigens, including pathogens, dead cells, and soluble molecules.

Antigen Presentation Pathways

• Process whereby cells display antigenic peptides on MHC molecules for recognition by T cells.
• Two types of antigen presentation based on antigen origin:
  • Endogenous pathway: MHC class I
  • Exogenous pathway: MHC class II

Endogenous Pathway (MHC class I)

• Presents intracellular antigens (viral or tumor-derived proteins) on MHC class I.
• Active on all nucleated cells.
• Process:
  1. Protein synthesis and ubiquitination - tagging for degradation.
  2. Proteasomal degradation - breakdown into peptides by proteasomes.
  3. Peptide transport into the endoplasmic reticulum - by TAP complex.
  4. Peptide loading onto MHC-I - in the ER with chaperone proteins.
  5. Transport to the cell surface - via the Golgi apparatus, displayed for recognition by CD8+ cytotoxic T cells.

Exogenous Pathway (MHC class II)

• Presents extracellular antigens (bacteria, fungi, debris from dead cells) on MHC class II.
• Occurs in professional APCs like dendritic cells, macrophages, and B cells.
• Process:
  1. Antigen uptake - through phagocytosis, pinocytosis, or receptor-mediated endocytosis.
  2. Proteolytic processing - degradation in a lysosome after fusion with an endosome or phagosome.
  3. [Process continues - check back for final steps]

Explore the key aspects of innate and adaptive immune responses in this quiz. Understand the differences in speed and specificity, as well as the important roles of memory cells and pattern recognition receptors. Test your knowledge on how the immune system detects, responds to, and resolves infections.