Exam 4 Flashcards
(51 cards)
Primary immune deficiencies occur in several cell types, a deficiency in what cell type is the
most damaging and why?
T cell defects are more severe than B cells since T cells have multiple effects on target cells and are
essential for helping activate other immune.
main causes of SCID (severe combined
immunodeficiency)
1) Defective cytokine signaling. 2) Defects in purine metabolism (toxicity
death). 3) Rearrangement defects. 4) Signaling defects.
effects of SCID
The most extreme forms of combined immunodeficiencies
Stem from genetic defects leading to a lack of functional T cells
normally due to mutations in early T-cell development steps or upstream stem cells.
Infants with it have increased likelihood of viral and fungi infections and shortened lifespan
four main immunodeficiency mice described in the chapter
Nude mice, SCID mice, RAG knockout, RAG-g c knockout
Nude mice
have a vestigial thymus and no T cells. Can be used to study effects of transplantation
and cancers, drug testing, hybridoma implantation and antibody harvest.
SCID mice
are devoid of mature functional T and B cells. Can be “humanized” to study human immune system in mice. Over 30 immunodeficient SCID mouse models for disease research.
RAG knockout
have impairment of RAG1 or RAG 2 gene and are defective in VDJ recombination which results in no mature T or B cells. Often coupled with TCR or BCR transgene
RAG-gamma c knockout
mice have impairment of RAG1/2 gene and IL2 receptor g chain which results in
no mature T cells, B cells, and NK cells. Most common model for humanized mice.
What are the main causes of secondary immunodeficiencies?
The single most common cause of acquired immunodefiency is severe malnutrition. Other causes
include drug treatments, metabolic disease, age, and infectious agents such as HIV.
What is the structure of the HIV retrovirus?
HIV has two RNA genomes and reverse transcriptase (RT) enzyme that uses the RNA genome to form a cDNA copy that integrates into host cell chromosome, directing the rest of the viral replication cycle. HIV-1 is found in the U.S. and its close relative HIV-2 is found in Africa.
What is unique about the replication of HIV?
HIV retrovirus replicates through an RNA intermediate by making a DNA copy of its RNA genome (reverse transcription). Retrovirus particles contain a reverse transcription enzyme (RNA-dependent DNA polymerase) that catalyzes reverse transcription.
Outline the three main stages in the typical course of an HIV infection.
The precise course of HIV-1 infection and disease onset varies considerably in patents, but a general scheme with three phases can be outlined: 1) Acute phase. Spike in HIV levels in blood. Brought mostly under control by production of anti-HIV antibodies. 2) Asymptomatic phase. Lengthy, possibly years. Gradual decrease in CD4+ T cells and increase in viral load. 3) AIDS. Crash in CD4+ T cell numbers. High levels of HIV in blood. Fungal/opportunistic infections.
long-term non-progressors
individuals who are infected with HIV, but maintain a high CD4 count. Many of these patients have been HIV positive for 30 years without progressing to the point of needing to take medication in order not to develop AIDS. They have been the subject of a great deal of research, since an understanding of their ability to control HIV infection may lead to the development of immune therapies or a vaccine.
What stages in HIV replication cycle provide targets for therapeutic antiretroviral drugs?
HIV life cycle targets include chemokine receptor antagonists, fusion inhibition, reverse transcription inhibition, integrase inhibition, and protease inhibitors. High mutation rates make individual drugs less useful. Highly active antiretroviral therapy (HAART) is a multidrug cocktail that combines three or more drugs with different mechanisms. Unlikely mutations will sidestep all ndrugs. HAART can reduce viral loads below limits of detection, but not a cure.
How are countries working to prevent mother-to-child transmission of HIV?
The prescription of antiretroviral therapy for pregnant women and their babies has decreased transmission by more than 90% in the United States. The treatment is more difficult in sub-Saharan Africa and other less developed areas where many obstacles remain (higher rates of HIV infection, mothers not knowing of infection, poor access to health care, drug cost and availability). In these resource limited countries, a single dose of nevirapine at the onset of labor dramatically improves
the chances the baby will be born HIV free.
Why is it so difficult to make an HIV vaccine?
An HIV vaccine is hard because the virus mutates rapidly making it a moving target for the immune system and production of Ab is not good. There are many variants of the virus at any time. Good animal models are limited and there are dangers of testing attenuated vaccines.
characteristics of broadly neutralizing antibodies
appears to be the route for success with HIV. There are six sites in the HIV envelop that are “vulnerable”, meaning they are essential for membrane function
and are not mutated. To bind to these sites, broadly neutralizing antibodies must overcome the high levels of envelope glycosylation
Vaccine strategies are currently being examined that focus on finding the initial B cells that recognize these HIV epitopes and then designing a series of envelope protein boosts that could encourage the development of broadly neutralizing antibodies.
two main strategies broadly neutralizing antibodies use to penetrate the glycan barrier
1) 2/3 of the broadly neutralizing antibodies have extra-long heavy-chain CDR3 regions (15-
20 amino acids longer than standard antibodies).
2) Some broadly neutralizing antibodies have undergone extensive somatic hypermutation (up
to 30% of the nucleotides in the CDR3 regions are mutated)
How does an infant’s microbiome differ if it was born cesarean section?
The organisms associated with babies delivered vaginally look like those of the mother’s vagina, but babies born by cesarean section are originally colonized by organisms from the mother’s and the delivery nurses’ skins.
Describe the difference between animals
raised in standard versus “germ-free” environments.
Animals raised in the absence of
any sort of microbe are viable, but they develop abnormally. The heart, lungs, and livers are smaller, and the most noticeable
changes occur in the digestive tract. The cecum is dramatically enlarged, and the intestinal lining is altered. Germ-free animals require ~30% more calories to maintain their weight.
Why is our microbiome important for human nutrition?
Gut microbes enable us to use more nutrients by fermenting large molecules into smaller molecules that can be absorbed and used for energy by human cells. Gut microbes also produce nutrients that we couldn’t get otherwise, like vitamin B12 and vitamin
K.
How do commensal microbes help form a barrier between us and the outside world and aid in immunity?
Microbes form a barrier between us and the outside world by colonizing our skin and mucous membranes and preventing
disease-causing organisms from gaining a foothold by competing for nutrients and attachment sites. They also secrete
compounds that inhibit pathogens by altering the local environment or directly antagonizing pathogens. Germ-free animals are more susceptible to infectious diseases in part because the immune system is dependent on the normal microbiota for its
development. Microbes normally found in the gut educate the immune system to attack microbial invaders that may cause disease, while tolerating beneficial microbes.
What did Marshall and Warren discover about the role of H. pylori infection?
Marshall and Warren were awarded the Nobel Prize in 2005 for their discovery that H. pylori infection was a major cause of
chronic gastritis, peptic ulcers, and some types of stomach cancer. They overturned the conventional wisdom that ulcers were
caused by stress and no microbes could live in the stomach due to acid levels. This increased our understanding of chronic
infection, inflammation, and cancer. Treatment of H. pylori infection with antibiotics became the treatment for ulcers, and the incidence of stomach cancer fell.
What did René Dubos and Joshua Lederberg do to contribute to our understanding of the microbiome? What is the as “The Great Plate Count Anomaly” and how was it resolved?
Dubos initiated a shift in the microbiological paradigm to consider microorganism interactions with their environment and each
other. In contrast to the warlike germ theory model where microorganisms are the enemy, Dubos promoted viewing the human digestive tract an ecosystem, changing the conversation from “Us Against Them” to “We’re All in This Together”
. Joshua Lederberg later coined the term “microbiome”. The Great Plate Count Anomaly is where the number of bacteria in a sample counted directly under the microscope did not match the number of colonies that grew on agar plates. This was partially addressed by devising better methods to cultivate microbes. Finally, environmental microbiologists got past this issue by applying sensitive DNA-based technologies like sequencing to look directly at the genes. It was a culture-independent way to study complex
bacterial communities.
