Medical Archive

Definitions

Introduction

The innate immune system

Pattern recognition

Pattern Recognition Receptors (PRRs) and Their Ligands

Recognize pathogen-associated molecular patterns(PAMPs) -> activation of NK-kB
Examples of PAMPs: LPS (gram – bacteria), flagellin (bacteria), nucleic acids (viruses)

PRRs	Location	Class	Ligands	Effects
Toll-like receptors (TLR)	Extracellular	TLR-1, 2, 6	Bacterial lipopeptides	Activation of transcrip- tion factors (including NF-κB) which results in the transcription of cytokines, adhesion molecules, and enzymes that are antimi- crobial
		TLR-2	Bacterial peptidoglycan
		TLR-4	Lipopolysaccharide (LPS)
		TLR-5	Flagellin
	Intracellular (endo- somal)	TLR-3	DS RNA
		TLR-7,8	SS RNA
		TLR-9	Unmethylated CpG oligonucleotides
NOD-like receptors (NLR)	Intracellular (cytosolic)	NOD1, NOD2	Components of bacte- rial PG	Signals via NF-κB result in macrophage activation
		NLRP-3	Microbial products and molecules from damaged or dying cells (ATP, uric acid crystals, reactive oxygen species)	Inflammasome NLRP-3 (sensor) + adaptor protein links procaspase 1 and activates it to caspase 1; it is the caspase that cleaves the pro-IL-1β to generate IL-1β
RIG-like receptors (RLR)	Cytoplasmic	RIG-1, MDA-5	Viral RNA	Interferon production

Effector cells of innate immunity

Monocytes-Macrophages

CD14 (for PAMP), CD40, CCR5, MHC II, B7 (CD80/86), Fc and C3b receptors (enhanced phagocytosis)

Oxygen-independent lysosomal mechanisms: not enough to control rampant infection
Respiratory burst: activation of the phagocyte NADPH oxidase complex (e.g., in neutrophils, monocytes)

# CGD: bacteria? ??? ? H2O2? ???? MPO system? ??. Catalase+ bacteria? ???? (e.g., S.aureus, Aspergillus)
Pyocyanin: (by P.aeruginosa) generates ROS to kill competing pathogens.
Lactoferrin: (in secretory fluids and neutrophils) inhibits microbial growth via iron chelation.

Dendritic Cells

Large Granular Lymphocytes/Natural Killer Cells

CD16, CD56 (suggestive marker for NK)
Lymphocyte member of innate immune system.

• Perforin and granzymes
  • Induced by nonspecific activation signal and/or an absence of MHC I 
  • Enhanced by IL-2, IL-12, INF-?, INF-?
• ADCC
  • Activation: CD16 binds Fc of Ig

Neutrophils, Eosinophils, and Basophils

The complement system

Hepatically synthesized plasma proteins. MAC defends against gram (-) bacteria.

Classic: IgG or IgM mediated
Alternative: microbe surface molecules, especially encapsulated bacteria
Lectin: mannose or other sugars on microbe surface

Opsonins: C3b and IgG are the two 1° opsonins. C3b also helps clear immune complexes

Inhibitors: decay-accelerating factor (DAF aka CD55) and C1 esterase inh. Prevent complement activation on self cells e.g., RBCs.

C3a and C5a: histamine release; hypotension and edema

Cytokines

By Macrophages
IL-1	Causes fever & Naïve Th0 to differentiate into Th1, Th2	Hot T Bone stEAK.
IL-6	Causes fever and ?APR
IL-8	Major chemotactic factor for neutrophils ? persistent acute inflammation
IL-12	Induces differentiation of Th0?Th1 Activates NK cells.	?? ?? (T->Th1), Th1, NK?? ? ???..!
TNF-?	WBC recruitment, vascular leak. Cachexia in malignancy, granulomas in Tb	IL-1, IL-6, TNF-?: mediate fever and sepsis.
TGF-?	Anti-inflammatory roles in sepsis, including suppressing the release of IL-1 and TNF-?, and inhibiting lymphocyte proliferation.
Dendritic cells
IL-12	Induces differentiation of Th0?Th1
IL-23	Induces differentiation of Th0?Th17
By all T cells
IL-2	? growth of Th, Tc, Treg, NK cells.
IL-3	? growth and differentiation of BM stem cells (like GM-CSF)
From Th1
INF?	From NK, T cells in response to Ag or IL-12 from macrophages. Stimulate macrophages to kill phagocytosed pathogens Inhibits differentiation of Th2 Activates NK cells. ?MHC expression and Ag presentation by all cells.	Mø? ??.  Th2? ? ???(inhibit another), Th1, NK???? ????? (self induction) ?? ??? ??? ?? ??.
From Th2
IL-4	Induces differentiation of T?Th2 with IL-13 ?growth of B cells. ?class switching to IgE, IgG	Self induction, ??? ??? ??.
IL-5	?growth and differentiation of B cells & eosinophils ?class switching to IgA	Eosinophil ??? ??
IL-10	Attenuates inflammatory response. ?MHC II and Th1 cytokines. Inhibits activated macrophages, dendritic cells. Also by Treg.	Inhibit another.
From Th17
IL-17A IL-22

INF?
From monocytes, macrophages, B cells, and NK cells.
Antiviral functions (eg, viral replication inhibition within cells, protection of uninfected cells from viral infection, stimulation of cytotoxic T cell and NK cell antiviral activity)

INF?,?
From virus-infected cells to local cells
 “Priming them” for viral defense by downregulating protein synthesis.
?MHC I expression
Active only in the presence of dsRNA. 

GM-CSF
From macrophages, T cells, NK cells, mast cells, endothelial cells, and fibroblasts.

The adaptive immune system

T cell

• TCR, CD3, CD28
• Tc; CD8
  • Release cytotoxic granules containing preformed proteins (eg., perforin, granzyme B, Fas/FasL(?))
• Th1; CD4, CD40L, CXCR4/CCR5 (HIV)
  • Induced by IL-12 (by macrophage), INF? (by self)
  • Inhibited by IL4, IL-10
  • Secretes IL-2, INF?
  • Activates Mø and Tc to kill phagocytosed microbes (enhanced by T cell CD40L with on Mø)
  • Deficiency: Mendelian susceptibility to mycobacterial disease.
• Th2
  • CD4, CD40L, CXCR4/CCR5 (HIV)
  • Induced by IL-4 (by other APCs and by self)
  • Inhibited by INF? (from Th1)
  • For parasite defense.
• Th17
  • Induced by TGF-?, IL-1, IL-6
  • Inhibited by INF?, IL-4
  • Against extracellular microbes, through induction of neutrophilic inflammation.
  • Identified by expression of CD3, CD4, CD25, and FOXP3.
  • Deficiency: hyper-IgE syndrome
• Treg
  • CD4, CD25
  • Induced by TGF-? (by self), IL-2
  • Inhibited by IL-6
  • Deficiency: IPEX (immune dysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome
  • Genetic deficiency of FOXP3 -> autoimmunity. Associated with diabtes in male infants.

B cell

Ig, CD19, CD20, CD21(EBV), CD40, MHC II, B7 (CD8086)

T- and B-cell activation

Humoral Mediators of Adaptive Immunity: Immunoglobulins

Antibody diversity (Ag dependent)
Random recombination of VJ (light chain) or VDJ (heavy chain)
Random addition of nucleotides during recombination by TdT
Random combination of heavy chains with light chains.

Antibody specificity (Ag dependent)
Somatic hypermutation and affinity maturation (variable region)=
Isotype switching (constant region)

Ig Isotypes	Description
IgG	Fixes complement, opsonizes bacteria, neutralizes bacterial toxins and viruses. ???? ?? ???.
IgA	Does not fix complement.
IgM	Fixes complement (most effective). Monomer on B cell
IgD	Unclear function.
IgE	Binds mast cells and basophils. Contribute to parasites by activating eosinophils.

Activities of Ig

1. Opsonization by Fc
2. Complement activation
3. ADCC (Ab-dependent cell mediated cytotoxicity, NK>Eosinophil>Mø>Neutrophil)
4. Neutralization

Half-life: 3 weeks

Immune tolerance and autoimmunity

Central tolerance

Positive selection in thymic cortex (capable of binding self-MHC)
Negative selection in thymic medulla (high affinity for self antigens -> apoptosis or Treg)
Autoimmune regulator (AIRE) deficiency -> autoimmune polyendocrine syndrome-1

Peripheral tolerance

?? ??? ???? T cell? ???? ??? ???? ??? ????? ignorance, anergy, apoptosis, clonal exhaustion, regulation ?? ???? ?? ??? ???? ??.

Autoantibodies

The cellular and molecular control of programmed cell death

Clinical evaluation of immune function

Infections in immunodeficiency <Harrison> C115 Approach to the Patient with an Infectious Disease

Immunotherapy