Innate Immunity Condensed

Question 1

a-Defensins

Answer 1

29-35 amino acids long, highly concentrated in the granules of PMNs and Paneth cells of the small intestine.  Production is regulated by pro-inflammatory cytokines.  There are 6 types of human α-defensins.
Human neutrophil peptide (HNP) 1-4 are primarily expressed in PMNs, monocytes, and lymphocytes.  
Human defensin (HD) 5-6 are mainly expressed in Paneth cells.

Question 2

b-Defensins

Answer 2

38-42 amino acids long, secreted by mucosal surface epithelia, including cells of the eye, skin, oral mucosa, urogenital and respiratory systems. There are 4 types of human β-defensins.
Human beta defensin (HBD) 1-4 are mainly expressed by various epithelial tissues (HBD4 is more limited to the testes and epididymis) but can also be expressed by monocytes, macrophages, and dendritic cells.

Question 3

TLR activation

Answer 3

TLRs bind to, and are activated by, pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs) – sometimes called damage-associated molecular patterns.

Stimulation of TLRs by PAMPs and DAMPs initiates signaling cascades that lead to the activation of AP-1, NF-κB, and interferon regulatory factors (IRFs).

Question 4

NF-κB

Answer 4

“the Mother of all immune system transcription factors”

Signaling results in the production of interferons (IFNs), pro-inflammatory cytokines, and effector cytokines that direct the adaptive immune response.

Activation of NF-κB which causes:
Expression of pro-inflammatory genes
Production of prostaglandins and other leukotrienes
Production of interleukins and other cytokines

Increased phagocytosis and synthesis of reactive oxygen and nitrogen molecules in macrophages and neutrophils

Increased efficiency of antigen presentation

Question 5

Classical pathway (adaptive immunity)

Answer 5

C1q binds to antigen:antibody complex. Cleaves and activates downstream complement components.
C5b binds to the membrane associated with the antigen:antibody complex which leads to the formation of the membrane attack complex.

Question 6

Lectin pathway (innate immunity)

Answer 6

Mannose binding protein bound to bacterial carbohydrates mimics C1q. Leads to the cleavage and activation of downstream complement components.
C5b binds to the membrane which leads to the formation of the membrane attack complex.

Question 7

Alternative pathway (innate immunity)

Answer 7

C3 is spontaneously cleaved or cleaved by C3b by serum proteases activated by bacteria.
C3b binds to bacterial and yeast cell walls and viral envelopes.
Bound C3b leads to the downstream activation of the complement components.

Question 8

C3a, C4a, and C5a

Answer 8

Chemotactic factors that increase directional migration of PMNs and macrophages
Activate PMN and macrophage degranulation
Release digestive enzymes and adhesion factors
Cause mast cells and basophils to degranulate releasing large quantities of histamine
Potency: C5a&raquo_space;> C3a&raquo_space;> C4a

Question 9

C3b and C4b

Answer 9

Deposited on any surface with an exposed amine or hydroxyl, such as a bacteria cell
Act as opsonins
Further cleave C3
When bound to host cells they are inactivated by decay-accelerating factor (DAF)

Question 10

C5b

Answer 10

Binds to microorganisms or host body cells
Acts as a focal point for the deposition of the membrane attack complex.
Body cells have protectin (CD59) and homologous restriction factor (HRF) to prevent the formation of the membrane attack complex.

Question 11

Histamine

Answer 11

Complement C5a stimulation of basophil and mast cell degranulation and activation

increased vascular permeability

Question 12

Prostaglandin E2

Answer 12

Complement C5a stimulation of basophil and mast cell degranulation and activation

vasodilation, increased vascular permeability

Question 13

Leukotriene D2

Answer 13

Complement C5a stimulation of basophil and mast cell degranulation and activation

neutrophil chemotaxis, increased vascular permeability

Question 14

Leukotriene D4

Answer 14

Complement C5a stimulation of basophil and mast cell degranulation and activation

increased vascular permeability

Question 15

TNF

Answer 15

Macrophages

can cause fever, stimulates the expression of E-selectin

Question 16

IL-1

Answer 16

Macrophages

endogenous pyrogen; stimulates the expression of E-selectin

Question 17

IL-8

Answer 17

Macrophages

chemotaxis

Question 18

IFNγ gamma

Answer 18

NK cells

activation of phagocytic cells and NK cells

Question 19

sites of acute inflammation tend to have…

sites of chronic inflammation have…

Answer 19

• sites of acute inflammation tend to have higher numbers of neutrophils and activated helper T cells.
• sites of chronic inflammation have a higher proportion of macrophages, cytotoxic T cells, and B cells

Question 20

particularly important inflammatory cytokines

Answer 20

TNFα (alpha), IL-1, and IFNγ (gamma)

Question 21

Tumor necrosis factor-α (alpha)

Answer 21

Produced primarily by macrophages and other mononuclear phagocytes

Question 22

Tissue Cells

Answer 22

Represent the physical barrier to infection.
When infected and/or damaged they can send signals to the immune system to call for help.
Interferons / cytokines
They can also make defensins and cathelicidins – direct antimicrobial molecules.

Question 23

Polymorphonuclear Neutrophils

Answer 23

Contain granules that do not stain with either acidic or basic stains.
Short-lived cells.
Primary phagocytic cells in the blood.
First cells to migrate to a site of inflammation or infection.
Effector cells of acute inflammation or infection.
Phagocytize bacteria and viruses.
Phagosome fuses with granules to create a phagolysosome.
Contain enzymes that digest bacteria.
Have Fc receptors to bind antibodies which makes them able to kill by antibody-dependent cellular cytotoxicity

Question 24

Eosinophils

Answer 24

2-5% of blood leukocytes in healthy, non-allergic individuals.
Bilobed nucleus with many cytoplasmic granules which stain with acid dyes such as eosin.
Capable of phagocytosing and killing ingested microorganisms.
Granules in mature eosinophils contain the major basic protein (MBP) which:
Is a potent toxin for helminth worms
Induces histamine release from mast cells
Activates neutrophils and platelets
Can provoke bronchospasm
Activated by complement C5a and C3a to degranulate

Question 25

Basophils

Answer 25

<0.2% of blood leukocytes.
Multilobed nucleus.
Express FcεR1 receptors for IgE and therefore have IgE on their surface.
Contain an abundance of basophilic granules.
Mediators of the delayed reaction of the allergic response.
Release preformed histamine when IgE on the surface is cross-linked by antigen.
Activated by complement C5a and C3a to degranulate

Question 26

Basophils vs. Mast Cells

Answer 26

It is indistinguishable from the basophil in many characteristics.
Some differences:
The mast cell:
Mononuclear cells.
Present in tissues and not in the circulation.
Mediators of the immediate allergic response.

Some similarities:
Both release proinflammatory cytokines
Both release preformed histamine when surface IgE is cross-linked
Synthesize and release prostaglandins and leukocidins
Both activated by complement C5a and C3a to degranulate

Question 27

Monocytes

Answer 27

Differentiate to form macrophages in the peripheral tissues where they are the first line of defense against microbial invasion.
Kupfer cells in liver
Microglial cells in brain
Bronchial alveolar macrophages in lung
Horseshoe shaped nucleus with cytoplasmic granules
Long-lived cells

Question 28

Macrophages

Answer 28

Late migrators to sites of inflammation (effector cells of chronic inflammation)
Major producers of cytokines and lymphokines
IFNα (antiviral)
IL-1β, IL-6, and TNF-α: mediators of fever
CXCL8 (IL-8): chemotactic factor for PMNs, basophils, and T cells
IL-12: activation of NK cells and CD4+ Th1 T cells
Professional phagocytes, highly activated by IFNs
Also present antigen to the adaptive immune system.

Question 29

Dendritic Cells

Answer 29

Derived from several different lineages.
Classical dendritic cells (DCs) – process and present foreign protein antigens to T cells.
Follicular dendritic cells (FDCs) – passively present foreign antigen in the form of immune complexes to B cells in lymphoid follicles.

Most DCs derive from one of two precursors:
a myeloid progenitor (DC1) that gives rise to myeloid DCs, otherwise called bone-marrow derived or bm-DCs
a lymphoid progenitor (DC2) that develops into plasmacytoid DCs (pDCs).

Myeloid DCs can also be divided into at least three types: Langerhans’ cells (LCs), dermal or interstitial DCs (DDC-IDCs) and blood monocyte-derived DCs (moDCs).

BM-DCs express various receptors that are involved in antigen uptake:
C-type lectin receptors – for glycosyl groups, e.g. macrophage mannose receptor (MMR) family
Fc receptors for IgG, IgE
receptors for heat shock protein–peptide complexes
receptors for apoptotic corpses
‘scavenger’ receptors – for sugars, lipid etc
toll-like receptors (TLRs).

DCs are found primarily in the skin, lymph nodes, and spleen, and within or underneath most mucosal epithelia. They are also present in the thymus, where they present self antigens to developing T cells.

Question 30

NK Cells

Answer 30

Lymphocytes that participate in innate immunity.
Also known as large granular lymphocytes
Account for up to 15% of blood lymphocytes.
CD16 (FcγRIII) and CD56 (NCAM) are important markers of NK cells.
Recognize damaged cells by a deficiency in MHC antigens.
Exposure to IFNs highly activates NK cell killing
IL-12 and TNFα activate NK cells to secrete cytokines, primarily INFγ.

Question 31

Congenital neutropenia

Answer 31

Lack of GM-CSF

Frequent bacterial infections

Question 32

Chronic granulomatous disease

Answer 32

Inability to produce hydrogen peroxide and hypochlorous acid

Inability to kill phagocytosed bacteria

Question 33

Leukocyte adhesion deficiency (LAD)

Answer 33

Lack of integrin subunit, the common β chain
Inability to recruit innate immune cells to site of inflammation
Increased susceptibility to bacterial, fungal, and viral infections.

Question 34

Complement defects (various)

Answer 34

Increased susceptibility to bacterial infections

Reduced ability to remove immunocomplexes

Question 35

Chediak-Higashi Syndrome

Answer 35

Defect in gene LYST (CHS1), a lysosomal trafficking gene that affects lysosomes and melanosomes
Increased susceptibility to bacterial infections