Innate immunity: components and fxns pt 1

main idea sentinel cells

continuously monitor issues for infection and damage serving as the first line of immune detection

ex. macrophages

epithelial cells

dendritic cells

mast cells

pattern recognition receptors (PRRs) main idea

germline-encoded receptors that recognize conserved microbial structures (PAMPs) and endogenous danger signalsn (DAMPs)

PAMPs main idea

conserved aspects of microbial molecules such as LPS, flagellin, dsRNA, and unmethylate CpG DNA

DAMPs main idea

host derived molecules that signal sterile cellular damage (apoptosis > necrosis)

PRRs are categorized into

families based on their structure and localization: primarily TLRs, RLRs, and NLRs

PRR engagement initiates

intracellular signaling cascades involving adaptor proteins like MyD88, TRIF, and MAVS leading to transcriptional activation

Key transcription factors activated by

PRR signaling include NF-kB, IRF3/7, and AP-1 which regualte expression of inflammatory cytokines, interferons, and antimicrobial peptides

JAK/STAT signaling is a major downstream pathway of

many cytokine receptors activated during PRR signaling, and is targeted therapeutically in chronic inflammatory diseases

sentinel cell activation results in

cytokine and chemokine release (ex. TNF-a, IL-6, IL-1B)

***upregulation of costimulatory molecules used in adaptive immunity and recruitment of leukocytes and antigen presentation cells

dysregualted PRR signaling

contributes to disease states such as autoimmunity, autoinflammatory syndromes, sepsis, and chronic inflammatory conditions

therapeutic exploitation of PRR pathways includes

vx adjuvants (TLR agonists)

immunotherapies (STING agonists in cancer)

anti-inflammatory agents (NLRP3 inhibitors, JAK inhibitors)

cytokines

immune modulating agents made up of proteins

“cellular proteins’ that initiate immune responses from other cells

cell signals, “cell mail”

chemokines

super family of CYTOKINES that mediate chemotaxis

chemotaxis

movement towards or against cellular gradient

help direct cells in immune system to the site of infection/damage

interferons

type of cytokine that alerts the immune system

type I, II, III

help with antiviral defenses, inflammation, modulating immune responses, slowing down growth of cells

interleukin

class of glycoprotein made by leukocytes (WBCs) for regulating immune responses

innate immunity

first line of defense against pathogens

recruit other cells and stimulate inflammation

cellular receptors are

NON specific : self vs nonself

PATTERN RECOGNITION RECEPTORS (PRRs)

-recognize large patterns of molecules conserved across large classes of pathogens; Pathogen associated molecular patterns (PAMPs)

can also recognize cellular damage (DAMPs)

innate cells

**myeloid progenitors

mast cells

granulocytes

phagocytes

natural killer cells (overlap)

granulocytes

eosinophils, basophils, neutrophils

phagocytes

monocytes, dendritic cells, macrophages

sentinel cells THE FRONTLINE

innate immune cells embedded in tissues

recognizes PAMPs and DAMPs via specialized PRRs

macrophages and dendritic cells

kupffer cells (liver)

Langerhans cells (skin and mucosa)

alveolar macrophages (lung)

microglia (brain)

macrophages

engulfs and digests pathogens, damaged cells, debris, and foreign materials (PACMAN)

dendritic cells (DC)

processes antigen and presents it to circulating T/B cells (antigen-presenting cell or APC)

engulf with tentacles

mast cells

resident cell of connective tissues with histamine and heparin granules; roles in allergy

ex. mast cell tumor give antihistamine then send to onco.

epithelial cells

physical barriers with PRRs (pattern)

tissue-resident lymphoid cells

tissue resident natural killer cells

monocyte vs macrophage

circulating vs tissue-resident monocyte

get special name based on their tissue tropism

dendritic cell residing or circulating?

tissue resident

granulocytes reside or circulate?

circulate

mast cells are a non circulating granulocyte that lives in the tissue

WBC circulate or reside

circulate

role of skin cells

langerhans cells

specialized DCs that capture antigens and migrate to draining lymph nodes to prime T cells

macrophages clear debris and recuit monocytes as needed

role of respiratory sentinel cells

alveolar macrophages patrol airway lumen and phagocytose pathogens

mast cells near blood vessels and mucosa release histamine upon allergen detection

role of GI tract sentinel cells

peyer’s patches are specialized lymphoid tissue patches where immune cells reside and process luminal contents

once sentinel cells are activated they initiate

1. cytokine and chemokine production

2. upregulation of costimulatory molecules and adaptive immune cell molecules (T cells)

3. type I IFN response

   1. phagocytosis and ROS nitric oxide production

pattern recognition receptors (PRRs)

cellular protein receptor that recognizes molecules frequentyl found in pathogens or molecules released by damaged cells

pathogen-associated molecular patterns (PAMPs)

damage-associated molecular patterns (DAMPs)

can be on the cell surface or in the cytosol (usually in endosome)

types of PRRs

cellular localization of PRRs

cell surface: TLR2, TLR4, TLR5

endosomal: TLR3, TLR7,TLR8, TLR9—→ endosome addresses intercellular problems such as double stranded DNA = virus!

cytosolic PRRs= RIG-1, MDA5 (floating through cell)

PAMPs are conserved

molecular motifs found on or made by microorganisms but NOT host cells

do not readily mutate, highly conserved across broad microbe classes

should be absent in host cells

DAMPs are host

host-derived molecules released from stressed, injured or dying cells—signal sterile tissue damage (necrosis not apoptosis) and alert the immune system often in the absence of infection

act as **alarmins to promote inflammation, repair, and immune recruitment

originate from host cells, especially after **necrosis

PAMPs (infxn)

non self

DAMPs (injury)

altered self

clinical implications

most PRRs require

adapter proteins

key downstream transcription factors

1. NF-kB: master regulator of inflammation

   a. activated by MyD88 (TLRs), NOD1/2, MAVS, and CLRs

2. induces transcription of

   a. cytokines IL-1B, TNF-a, IL-6

   b. chemokines CCL2, CXCL8

   c. adhesion molecules ICAM-1, VCAM-1

3. NF-kB is held inactive in the cytoplasm until activation leads to nuclear translocation (MASTER REGULATOR)

JAK/STAT pathway

arguably the most targeted immunological pathway in clinical medicine

clinical disorders linked to PRR dysregulation

1. sepsis and systemic inflammatory syndrome (SIRS)—hard to control once this occurs

2. autoimmune and autoinflammatory diseases

3. viral infxns and immune invasion

therapeutic and diagnostic applications

1. PRRs as drug targets

   modulation of PRR pathways—autoimmune diseases (inhibition of inflammasomes);cancer immunotherapy; chronic infections

2. vaccine adjuvants—many adjuvants are PAMP mimics that activate PRRs to enhance immune responses and memory formation

3. biomarker discovery—circulating DAMPs serve as biomarkers for tissue injury, cancer, and autoimmune flares

   cytokine profiling helps monitor disease activity and therapeutic responses

actual drugs—JAK/STAT inhibitors

critical downstream signaling cascade for many cytokine receptors including those induced by PRR activation

**inib=inhibitor

sentinel cells include

macrophages, dendritic cells, mast cells, and epithelial cells are the body’s first responders continously surveilling tissues for signs of infection or damage

pattern recognition receptors (PRRs)

detect conserved microbial motifs (PAMPs) and host derived signals of damage (DAMPs) initiating innate immune responses

major PRR families include

TLRs, NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs) each recognizing specific molecular patterns in distinct cellular compartments

PRR engagement triggers intracellular signaling cascades that activate

key transcription factors such as NF-kB, IRFs, and AP-1 leading to cytokine and interferon production

sentinel cells integrate

multiple signals to mount tailored responses—recruiting leukocytes, initiating phagocytosis, presenting antigen, and directing adaptive immunity

failure to regulate PRR signaling can lead to

pathological inflammation as seen in sepsis, autoimmune diseases, and autoinflammatory syndromes

PRRs are being leveraged in

clinical applications including vx adjuvants, immune therapies, and biomarkers for inflammation and infection