Week 2 - Innate Immunity

What are the two principal types of reactions in the innate immune response?

Inflammation and antiviral defense.

Pattern recognition receptors (PRRs) sense which two kinds of molecular patterns?

Pathogen-associated molecular patterns (PAMPs) and damaged-associated molecular patterns (DAMPs).

Name four examples of pathogen-associated molecular patterns (PAMPs).

Lipopolysaccharide (LPS); mannose-containing glycans; double-stranded RNA (dsRNA); unmethylated CpG DNA.

How do innate and adaptive immunity differ in terms of receptor diversity?

Innate recognizes about 1000 patterns, is germline-encoded with limited diversity, has >1000 types, and is nonclonally distributed; Adaptive recognizes over a billion antigens, is the result of gene recombination, has 2 types with millions of variations, with high diversity and clonal distribution.

What are epithelial barriers and what do they provide?

Skin, GI tract, respiratory tract, and genitourinary tract; physical and chemical barriers against infection; production of antimicrobial peptides.

What are intraepithelial T lymphocytes?

T cells with receptors of limited diversity that often recognize microbial lipids.

Name the primary circulating phagocytes and their roles.

Neutrophils: first responders that phagocytose microbes and express receptors for complement/antibodies; Monocytes/macrophages: phagocytose, differentiate in tissues, produce cytokines, initiate tissue repair.

What are M1 and M2 macrophage activations?

M1 is classical activation promoting inflammation and microbicidal functions; M2 is alternative activation promoting tissue repair and regulation.

What are dendritic cells and their key function?

Sentinels that produce cytokines that initiate inflammation and stimulate adaptive immune responses; bridge innate and adaptive immunity, capture antigens and present fragments to T cells.

What are the roles of mast cells?

Granule-containing cells in skin/mucosa; kill bacteria, inactivate toxins, promote inflammation; allergic symptoms largely due to histamine.

What are innate lymphoid cells (ILCs)?

Innate counterparts of T cells; tissue-resident; produce cytokines; do not express antigen receptors; respond to damaged cells at site of infection

What are natural killer (NK) cells?

Innate lymphocytes that kill infected/stressed cells via cytotoxic granules; activate macrophages to kill phagocytosed microbes by releasing IFN-γ; can mediate ADCC when antibodies are present.

How does NK cell activation and killing occur?

NK cell activation involves recognition of stressed or infected cells’ activating ligands through activating receptors on NK cells, leading to the secretion of cytotoxic granules and the release of cytokines like IFN-γ.

What are γδ T cells?

Lymphocytes with limited TCR diversity that reside in epithelia and respond to lipid antigens without classical antigen presentation.

What are MAIT cells and their specificity?

Mucosal-associated invariant T cells; abundant in liver; recognize bacterial vitamin B metabolite antigens.

What are B-1 cells and where are they found?

B-1 cells; found in peritoneal cavity and mucosal tissues; produce natural antibodies to bacterial carbohydrates and ABO antigens.

What are marginal-zone B cells?

B cells at the edges of lymphoid follicles; provide rapid antibody responses to blood-borne polysaccharide-rich microbes.

Why are most cytokines called interleukins?

Because they’re responsible for leukocyte-to-leukocyte communication.

Which cytokines recruit neutrophils and monocytes to sites of infection?

TNF, IL-1, and chemokines.

Which cytokine activates NK cells?

IL-12.

Which cytokine activates macrophages?

IFN-γ, which are also produced by T-cells, making it a cytokine of both innate and adaptive immunity.

Which cytokines inhibit viral replication and spread?

Type I interferons (IFN-α and IFN-β).

How do macrophages initiate the process of tissue repair?

Macrophages produce growth factors that stimulate proliferation of residual tissue cells and fibroblasts to replace tissue of form scarring.

Which cells are a major source of type I interferons?

Plasmacytoid dendritic cells which are secreted in response to recognition of viral pathogen PAMPs.

Which cytokine acts as an anti-inflammatory mediator in innate responses?

IL-10.

Which molecule blocks IL-1 actions?

IL-1 receptor antagonist (IL-1Ra).

What are the second signals in cell-mediated immune responses?

Co-stimulators and cytokines; mediated by T cells

What serves as the second signal for responses against extracellular, blood-borne microbes?

Complement is second signal; mediated by B cells

What are RIG-like receptors (RLRs) and what do they sense?

RLRs sense viral RNA and induce production of type I interferons.

What are cytosolic DNA sensors (CDS) and what do they trigger?

CDS recognize microbial dsDNA and trigger type I IFN production and autophagy.

What are the three pathways of the complement system?

Classical, Lectin, and Alternative pathways.

What are the outcomes of complement activation?

Opsonization, inflammation, and membrane attack complex (MAC) formation.

What initiates the classical pathway of complement activation?

Antigen-antibody complexes (IgG or IgM) bound to pathogen; C1 complex binds antibody to form C3 convertase (C4b2a).

What initiates the lectin pathway of complement activation?

Mannose-binding lectin (MBL) or ficolins binding to microbial carbohydrates on pathogens, activating C4 and C2 to form C3 convertase (C4b2a).

What initiates the alternative pathway of complement activation?

Spontaneous hydrolysis of C3 or direct contact with pathogen surfaces, leading to the binding of factor B and factor D to form C3 convertase (C3bBb - stabilized by properdin).

What is opsonization?

The process of coating a microbe with molecules that are recognized by receptors on phagocytes; C3b coats microbes and promotes binding to phagocytes via C3b receptors expressed on phagocytes; microbes coated with complement proteins are rapidly ingested and destroyed by phagocytes.

What is inflammation?

A tissue reaction that delivers mediators of host defense to sites of infection and tissue damage.

What does the process of inflammation consist of?

Recruitment of cells, leakage of plasma proteins through blood vessels, and activation in extravascular tissue.

What causes the redness, warmth, swelling, and pain associated with inflammation?

The initial release of histamine, TNF, prostaglandins, and other mediators by mast cells and macrophages which causes increase in local blood flow (vascular permeability).

Which proteolytic fragments of complement proteins enhance inflammation?

C3a and C5a; they promote movement of leukocytes to sites of complement activation (tissues).

What are the three steps of phagocyte recruitment to sites of infection and tissue damage?

Rolling of leukocytes, firm adhesion, and leukocyte migration.

Describe the rolling of leukocytes.

Cytokines (TNF, IL-1) from macrophages activate endothelial cells to express E-selectin; P-selectin rapidly translocate to the endothelial surface; Neutrophils/monocytes bind via selectin-specific carbohydrates; Binding is transient — blood flow disrupts and reforms bonds, causing rolling along the endothelium.

Describe firm adhesion.

Leukocyte integrins (LFA-1, VLA-4) start in a low-affinity state (think lose clamp); Endothelial chemokines bind leukocyte receptors, triggering high-affinity integrin activation; TNF and IL-1 upregulate endothelial ligands (ICAM-1, VCAM-1); High-affinity integrins mediate firm adhesion (clamp), halting leukocyte rolling; Leukocyte cytoskeleton reorganizes, enabling cell spreading on endothelium.

Describe leukocyte migration.

Adherent leukocytes crawl to endothelial junctions and exit vessels; Neutrophils transmigrate first, followed by monocytes (become macrophages); Movement guided by chemokine gradients.

What is phagocytosis?

The process by which certain immune cells, such as macrophages and neutrophils, engulf and digest pathogens and cellular debris. It involves recognition, adherence, and internalization of the target, followed by degradation within phagolysosomes.

What enzymes are activated by phagocytes to destroy microbes?

Phagocytes activate enzymes, including reactive oxygen species (ROS), toxic nitric oxide (NO), and lysosomal proteases, to destroy microbes during the process of phagocytosis.

What is the function of toll-like receptors (TLRs)?

Stimulates expression of cytokines and other proteins involved in the inflammatory response and in the antimicrobial functions of activated phagocytes and other cells; signals are generated when TLRs engage with microbial molecules (i.e. PAMPs)

What is the function of NOD-like receptors (NLR)?

NLRs sense DAMPs and PAMPs in the cytosol and promote inflammation; recognizar peptides derived from bacterial glycans.

Where are NLRs highly expressed?

Intestinal cells in the small bowels; stimulate expression of antimicrobials in response to pathogens.

How are polymorphisms in some NLRs associated with inflammatory bowel disease?

Variants have reduced function, allowing luminal microbes to penetrate the intestinal wall and induce inflammation.

What is an inflammasome?

A multiprotein complex that assembles in the cytosol in response to microbes or changes associated w/ cell injury/damage; proteolytically generate active forms of the inflammatory cytokines IL-1β and IL-18.

What stimuli induce formation of the NLRP3 inflammasome?

Crystalline substances such as uric acid and cholesterol crystals, extracellular ATP (cell destruction), reduced intracellular potassium ion (K+) concentration, and reactive oxidative species (ROS).

What is the function of the NLRP3 inflammasome?

Mediates the production of IL-1β, which induces acute inflammation; stimulation of NLRP3 results in it complexing w/ adapter molecules and inactive caspase-1; active caspase-1 enzyme then cleaves pro-IL-1β creating the active cytokine which is then secreted.