Immunology: Innate Immunity pt 2

Exam 1

cytokines are

signaling proteins that mediate and regulate immunity, inflammation, and hematopoiesis; they include interleukins, interferons, TNFs, colony-stimulating factors, and TGF-B

cytokine actions are

context dependent and characterized by pleiotropy (one cytokine, many effects), redundancy, syngergy and antagonism

chemokines are specialized

cytokines that direct the migration of immune cells (chemotaxis) via interaction with specific G protein coupled receptors (GPCRs)

cytokine receptors are grouped

into structural familes (type I and II< TNF, TGF-B, IL-1) and signal via pathways like JAK/STAT, NF-kB and MAPKs

chemokine receptors (eg. CCR5, CXCR4) are crucial for

immune cell trafficking and are also implicated in disease processes like HIV Infection and cancer metasis

JAK/STAT pathway is a

primary signaling route for many cytokines and target for immunomodulatory therapies

complement system

cascade of plasma proteins activated via 3 pathways

1. classical

2. lectin

3. alternative

leading to opsonization, inflammation, and cell lysis

complement is part of the

innate immune system and helps the membrane attack complex (MEC)

classical complement pathway is

initiated by immune complexes (Ag-Ab) activating C1q

lectin complement pathway

activated by microbial carbohydrates on cell surfaces

alternative complement pathway

occurs SPONTANEOUSLY at microbial cell walls

3 main outcomes of complement are

opsonization

phagocyte/leukocyte recruitment

MAC formation

cytokines

immune modulating agents made up of proteins

initiate immune responses from other cells

cell signals, cell mail

chemokines

superfamily of cytokines that mediate chemotaxis

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

how do cells interact with their environment

receptors

can be called cell ligand

introduce intracellular signaling events in cells

leads to altering gene transcription and protein expression

ligand vs receptor

receptor receive

ligand send out

remember central dogma

DNA is transcribed to RNA
RNA is translated to Protein

effector molecules

directly kill or target infectious agents

PRRs

recognize infection agents

interact with PAMPS and DAMPs (CONSERVED)

antigen receptors on adaptive immune cells interact with pathogenic epitopes

cytokines

enable cell signaling and migration

IFN

IL

CC or CXC

cytokines are small

secreted proteins that act upon a cell that released it (autocrine)

nearby cells (paracrine) or distant cells (endocrine)

*highly specific viral adaptations

chemokines are chemotactic cytokines that

are small secreted proteins that orchestrate spatial and temporal movement of leukocytes

CC chemokine

attract monocytes, T cells, eosinophils

CXC chemokines

attract neutrophils or lymphocytes (B/T cells)

selectins

passive; weak binding

integrins

strong binding, firm attachment

type I cytokine receptors

key for lymphocyte proliferation

IL-2,4,7

type II cytokine receptors

important in antiviral responses and immune regulation

TNF receptor superfamily

involved in inflammation, apoptosis, cell survival

TGF-B receptor family

regulates immune suppression, tissue repair, and fibrosis

IL-1 receptor family

key innate immune activation and pro-inflammatory signaling

CCR primary function

trafficking of T cells, dendritic cells, monocytes; lymph node homing (CCR7)

CXCR

B cell follicular homing (CXCR5), neutrophil recruitment, Th1 cell migration

XCR

involved in cross-presentation and CD8+ T cell recruitment

CX3CR

mediates leukocyte adhesion and migration; roles in microglia, monocytes

chemokine receptors are all

G-protein coupled receptors (GPCRs)

many chemokines bind multiple receptors and vice versa—creates a highly adaptable signaling network

JAK/STAT pathway (cytokines)

janus kinases (JAKs) associate with receptor cytoplasmic domains

ligand binding→receptor dimerization—>JAKS phosphorylate each other and the receptor

recruits STATS (sginal transducers and activators of transcription)—>phosphorylated—> dimerize—>translocate to the nucleus to drive gene transcription

NF-kB pathway

activation leads to nuclear translocation of NF-kB, a major transcription factor for inflammatory genes

key to initiating and sustaining innate and adaptive immunity

MAPK pathways

activated by multiple receptor families

involve ERK, JNK< and p38 kinases

lead to cell proliferation, cytokine production, and apoptosis depending on the context

SOCS (suppressor of cytokine signaling) proteins inhibit JAK/STAT signaling

soluble cytokine receptors can act as decoys (sTNFR)

receptor internalization and desensitization (common with chemokine CPCRs)

regulatory cytokines (IL-10, TGF-B) antagonize pro-inflammatory pathways

what is complement

complement proteins are part of a cascade within the INNATE immune system

account for 5-10% of protein in blood

complement proteins (C1-9) are made at several site

C2-macrophages

C1q- mast cells

C6 and 7—neutrophils

others are made in the liver hepatocytes

what’s the point of complement

to make membrane attack complex (MAC)!

3 complement pathways

classical

lectin

alternative

classical pathway

initiated by immune complexes (Ag-Ab) that activate C1q

can be activated by

1. conformational change of Ab in Ab-Ag

2. damaged cell components, C-reactive protein

3. some viruses, LPS, nucleic acids

Classical pathway

C1q to Ab in Ab-Ag—>C4b—>C2a—→C3b—>C5b

lectin pathway

activated by microbial carbohydrates=lectin

1. mannose binding lectin (MBL) is a serum lectin that binds to mannose in cell walls—>C4b—>C3b—→C5b

end result is the same as the other pathway (MAC)

alternative pathway

happens ONLY at cell surfaces usually microbial cell walls

SPONTANEOUSLY HYDROLYZES INTO C3b

C3b then binds to microbial surface

C3b joints [C3b(cell wall bound)+Bb] to make the C5 convertase

end result:MAC

outcomes of the pathways

classical and lectin pathways make a C3b+C4b=C3 convertase

ONLY the alternative pathway SPONTANEOULSY makes a C3b+Bb=C3 convertase

extra C3b (more likely to be ingested by phagocytes) can also bind to microbes, which causes a conformational change recognizable by a phagocyte—> OPSONIZATION

release of C3a and C5a during classical and lectin cascades can bind to and activate leukocytes