Hunter: Innate Immunity Flashcards
This is the FIRST line of defense. Contains these components:
Epithelial Barriers
Anti-Microbial Enzymes and Peptides
The Complement System
Macrophages, Dendritic Cells, and Neutrophils (myeloid cells)
Pattern Recognition Receptors (germline encoded)
Inflammation (rubor, calor, tumor, and dolor)
Cytokines, Chemokines, Adhesion Molecules, and Acute Phase Proteins
Interferons and NK Cells
innate immunity
About how long does it take for innate immunity to take action?
0-4 hours
What are some ways in which pathogens enter mucosal surfaces?
airway
GI tract
reproductive tract
What are some ways in which pathogens enter external epithelia?
physical contact
wounds and abrasions
insect bites
List three sources of pathogens
the environment
humans
animals
These reside ON or IN your body but cause disease only when the host is immunosuppressed.
opportunistic pathogens
What are some MECHANICAL barriers to adhesion, colonization, and infection by pathogens?
epithelial cells with tight junctions
longitudinal flow of air or fluid
movement of mucus by cilia
tears, nasal cilia
What are some CHEMICAL barriers to adhesion, colonization, and infection by pathogens?
fatty acids low pH enzymes like pepsin pulmonary surfactant enzymes in tears
What is one MICROBIOLOGICAL barrier to adhesion, colonization, and infection by pathogens?
microbiota
What are some DIRECT mechanisms of tissue damage by pathogens?
exotoxin production *toxins penetrate tissues to get nutrients they need to survive
endotoxin production
direct cytopathic effect *take over the cell to accomplish their mission
What are some INDIRECT mechanisms of tissue damage by pathogens?
formation of immune complexes
anti-host antibodies
cell-mediated immunity
Microbes produce enzymes that can destroy our tissues. As defense, we produce enzymes that can fight back. List a few.
lysozyme
pepsin
secretory phospholipase A2
What are these examples of?
Defensins
Cathelicidins
Histatins
anti-microbial peptides
When anti-microbial peptides are activated via proteolysis, what do they release?
amphipathic peptides
**made in almost all tissues of the body
In what time period does the early induced innate response occur?
early: 4-96 hours
Discuss what happens to a pathogen when it gets past an epithelial barrier and encounters a macrophage.
Macrophages will recognize pathogens via TLRs.
Release cytokines which cause vasodilation and increased vascular permeability, as well as upregulation of adhesion molecules.
Kinin and coagulation systems upregulated.
Chemokines attract neutrophils and monocytes as a second line of defense.
Phagocytic cells and complement rid of the pathogen
What is one PAMP found on gram-positive bacteria, such as streptococcus pyogenes?
peptidoglycan
What is one PAMP found on gram-negative bacteria, such as escherichia coli?
lipoprotein
Macrophages have different receptors which recognize different PAMPs. What does TLR-4 recognize?
LPS endotoxin (gram-negative bacteria)
These are PAMP receptors. There are 10 genes that code for them. Some are on cell surface, while others are intracellular.
TLRs
When TLRs are activated, what transcription factor is produced to induce the production of inflammatory mediators?
NF-kB
These are similar in structure to TLRs, they detect cytoplasmic bacteria, and signal inflammation.
NOD-like proteins
These are similiar to TLRs, but detect viral RNA in the cytoplasm and induce inflammation
RIG-like proteins *retinoic acid inducible gene-I-like proteins
Explain what happens when TLRs bind a pathogen to ultimately lead to increased gene expression.
PAMP binds to TLR, TLRs dimerize, induce intracellular signaling, increased gene expression for trx factors like NF-kB, inflammation
Rare autosomal recessive defect which involves poor response of monocytes to TLR agonists, thus causing a defect in the NF-kB pathway and the response to pyogenic bacterial infections.
IRAK4 deficiency
What are the two most important phagocytic cells?
neutrophils
macrophages
Where are most microbes killed and digested?
in the phagolysome
This forms in the phagolysosomal membrane during phagocytosis of microbes. It generates ROS to cause a hostile environment, with a low pH, which causes death of the microbes.
NADPH oxidase
What makes the phagolysosome so toxic to microbes?
low pH reactive oxygen species NO antimicrobial peptides enzymes like lysoszyme
This disease results from a failure of the assembly of NADPH oxidase in phagolysosomes.
Chronic granulomatous disease
How does chronic granulomatous disease present?
granulomatous lesions in the skin and various internal organs due to pyogenic bacteria and fungi
What test is used to determine if a patient has chronic granulomatous disease?
dihydrohodamine test using flow cytometry - this reveals a defective respiratory burst
How can you treat chronic granulomatous disease?
antibacterial and antifungal agents, or IFN-gamma, or bone barrow transplant
NADPH oxidase generates antimicrobial superoxide, hydrogen peroxide, and other reactive oxygen species. This is referred to as (blank).
respiratory burst
This is an autosomal recessive disease with a defect in microtubule polymerization which decreases phagolysosome formation and impairs killing of bacteria.
Chediak-Higashi Syndrome
How does Chediak-Higashi Syndrome usually present?
as recurrent pyogenic infections (i.e. staph and strep) in early childhood, particularly gingival infections
What clinical cues can help you make a diagnosis of Chediak-Higashi syndrome?
partial albinism
large lysosomal vesicles in neutrophils and eosinophils
How to treat Chediak-Higashi Syndrome?
prophylactic antibiotics
bone marrow transplants
What is the most common defect in granulocyte-mediated host defenses?
neutropenia
What is neutropenia?
decreased absolute neutrophil count *like less than 1500 cells/mm3
What are two forms of acquired (common) neutropenia?
drug-induced *cancer drugs
autoimmune *anti-neutrophil antibodies
What are these examples of?
Familial (benign, ethnic) neutropenia
Infantile genetic agranulocytosis (severe congenital neutropenia)*
Cyclic neutropenia
hereditary neutropenia *rare
What is one common way to induce neutropenia?
cytotoxic anti-cancer drugs
A variety of pyogenic bacteria and fungi can cause this to occur.
neutrogenic sepsis
How to treat neutropenia?
broad-spectrum antibiotics
hrG-CSF prior to chemotherapy
A genetically and phenotypically heterogeneous group of hereditary neutropenias seen in infants
severe congenital neutropenia
How do infants with severe congenital neutropenia usually present?
recurrent infections of skin, soft tissues, lungs, deep organs
ANC below 200/ul
At what stage are neutrophils typically “stuck” in patients with SCN?
stuck at premyelocyte of myelocyte stage
*can treat w bone marrow transplant
How are neutrophils called to sites of inflammation?
by macrophages
Rare autosomal recessive disorder presenting with recurrent bacterial infections due to defects in neutrophil adhesion
Leukocyte adhesion deficiency
What occurs as a result of adhesion molecule defects?
Neutrophils cannot undergo chemotaxis, so there will be large numbers of neutrophils in the plasma. Infants will suffer from infections like omphalitis, pneumonia, gingivitis, peritonitis, because they cannot get neutrophils to site of infection.
In leukocyte adhesion deficiency, what molecule is not working properly? How is this condition diagnosed?
CD18, which is a subunit of the leukocyte CAM;
diagnosed by finding low CD18 and via flow cytometry
*treat w bone marrow transplant
The acute phase response is mediated by acute phase proteins. List one opsonin which is used to identify patients with active inflammatory processes.
C-reactive protein
This binds to and sequesters iron to inhibit microbial growth.
ferritin
This is a coagulation factor, which is telling of the rate of RBC sedimentation
fibrinogen
What happens to albumin production during an acute phase response?
it is downregulated
Viral RNA induces the gene expression of what inflammatory agent?
Interferon alpha/beta
When viral RNA enters a host, it activates (blank), which degrades the viral mRNA and causes apoptosis. Then, interferon alpha/beta increases the expression of (blank) on nucleated cells.
RNAse L; MHC class 1 molecules
What lineage are NK cells derived from?
lymphoid progenitor cells
NK cells produce large amount of (blank)
interferon gamma
What do NK cells do?
kill virus-infected cells, cells containing pathogens, and tumors by using cytotoxic granules full of nasty stuff. They don’t kill normal cells that have MHC class 1 molecules on their surface, but if there is abnormal MHC class 1 expression or a cell expressing stress molecules, they will attack
If there is a deficiency in NK cells, what are you more susceptible to?
infection with HERPES viruses
If a pathogen is coated in antibody, these cells can bind to that pathogen and induce death.
NK cells
*antibody dependent cell-mediated cytotoxicity (ADCC)
