LECT Diseases of the Immune System II (Singh) Flashcards
What is allorecognition?
The ability of an individual organism to distinguish its own tissues from those of another
What is the direct pathway for Allorecognition?
Donor organ carries an APC cell
Donor APC cell makes contact with host immune system
This initiates a targeted attack toward graft
What is the indirect pathway for Allorecognition?
Recipient’s APCs investigate the contents of the graft cells
Recipient’s APCs recognize graft as non self and elicit a targeted response against graft
This is a B and T cell response against the graft
Which of the following is B-cell mediated?
Hyperacute rejection
Acute rejection
Acute antibody-mediated rejection
Chronic rejection
Chronic antibody-mediated rejection
Hyperacute rejection
Acute antibody-mediated rejection
Chronic antibody-mediated rejection
*Anything with antibody in it is gonna be B cell mediated
What is the mechanism of a hyperacute rejection reaction?
Mediated by pre-formed antibodies
Accounts for the extremly quick response! Antibodies already exhist in host to act on graft!
In particular…Blood antibodies (ABO)
What type of antibody mediated rejection is this?
Acute Antibody-mediated rejection
*Note: Also do a Complement C4d stain to confirm this is acute antibody-mediated rejection
What type of antibody mediated rejection is this?
Chronic antibody-mediated rejection
What is this histologic image revealing?
Acute cellular rejection (T-cell mediated)
Tubulitis
Why do we care about the mechanism behind these different types of graft rejection?
Treatment is very different!!!
The way you treat a T-lymphocyte mediated cellular rejection is very different from an Antibody-mediated (humoral) rejection
What do we have to remember when we treat a patient with graft rejection?
There is no more rejection…
BUT!!!!
There are going to be issues because you induced Immunosuppression
Your patient is more prone to:
- Infections
- Tumors
What specific viral infection are immunosuppressed from transplant patients suseptible to?
VIRAL = Polyomavirus
What is the major occurance with a hematopoietic stem cell transplant?
Brand new immune system!!!
What is graft vs. host disease?
T-lymphocyte mediated response of the GRAFT against the host!
Common with bone marrow transplant.
Can occur when graft contains immune cells from donor
What are some common manifestations of graft vs. host disease?
Reactions in:
Skin - (rash –> desquamation)
Liver - (jaundice –> cholestasis)
Intestines - (bloody diarrhea –> strictures)
Chediak Higashi Syndrome
Inheritance pattern?
Mechanism?
AR
Failure of phagolysosomal function
Is the mechanism of Chediak Higashi syndrome microscopically visualized?
YES!
The failure of phagolysosomal fusion can be seen on a peripheral blood smear
*You can see GIANT granules in neutrophils.
What is the major clinical presentation of chediak higashi syndrome?
Albanism!!!
Defects in melanocytes lead to albanism or grey hair streaks in Chediak Higashi syndrome pts
Chronic granulomatous disease
How is it aquired?
Mechanism?
Genetically
Failure of superoxide production within phagocytes. Accumulation of macrophages“walls off” the infection because the innate immune system is compromised and cannot handle the infection!
Membrane attack complex deficiency
What is affected?
What happens without MAC?
What infections are common?
Terminal components C5, 6, 7, 8, 9
Without the final MAC, the lysis of the microbial membrane can’t occur
Neisseria infections, Meningitis
Hereditary angioedema
Genetic inheritance pattern?
Mechanism?
AD
Deficiency of C1 inhibitor
What are the symptoms of hereditary angioedema?
Facial swelling
Airway constriction
Intestinal swelling
TONS OF SWELLING OVERALL
*Remember, this is NOT an autoimmunity deficiency. It’s randomly here. meh.
Severe Combined Immunodeficiency (SCID)
What are two major facets of this disease?
“Bubble” “Boy”
“Bubble” –> Such a severe immunodeficiency, knocking out T and B cell response. Need to be isolated from pathogens
“Boy” –> X-linked, FAR more common in boys
What is the treatment for severe combined imunodeficiency (SCID)?
Stem cell transplantation
Gene therapy
DiGeorge Syndrome
What are the primary causes?
Primary deficiency of T lymphocytes: due to failure of pharyngeal pouches 3/4, thymus, parathyroids, heart, great vessels are affected
Genetic: 22q11 deletions
What are the clinical manifestations of DiGeorge syndrome?
- Facial and palatal abnormalities
- Cardiac abnormalities
- Tetany
- Immune deficiency
X-Linked Agammaglobulinemia
Aka?
Mechanism?
“Bruton’s agammaglobulinemia”
Inability of pre-B cells to mature
Generally, what is the presentation of agammaglobulinemia?
Encapsulated bacteria
Hyper-IgM syndrome
What kind of mutation?
What does this cause?
How do you treat?
CD40/CD40L mutations
Interference w/ T cells helping B cells to class switch. Increased IgM levels, but lower leverls of other classes.
Treat with IVIg, stem cell transplantation
Common Variable Immunodeficiency (CVID)
A collection of disorders resulting in…
Hypogammaglobulinemia
What are some manifestations of Common Variable Immunodeficiency (CVID)?
Recurrent infections
Granulomas
Chronic diarrhea (Giardia)
Autoimmune disease
IgA Deficiency (isolated)
Describe:
W/out IgA, you have less defense against inhaled and ingested pathogens
Frequent:
Sinus/respiratory infections
Urinary bladder infections
GI infections
Also get:
Autoimmune disease and allergies
***Anaphylactic reaction against red cell transfusion
What is potentially a first indication a patient has an IgA deficiency?
Transfusion-related anaphylaxis
Wiskott Aldrich syndrome
Gene mutation?
WASP gene mutation
Wiskott Aldrich syndrome
Symptoms?
Triad of:
- Thrombocytopenia
- Eczema
- Recurrent infections
Wiskott Aldrich Syndrome
Treatment?
Stem cell transplant
Ataxia Telangiectasia
What kind of disease?
What is a common sign?
Major problems that arise?
Inheritance pattern?
Neurodegenerative disease
Vascular malformation (can see in sclera of eyes)
Immune deficiency causes, respiratory infections, autoimmune disease, cancer
AR
What can cause secondary immunodeficiency?
Cancer
Malnutrition
Metabolic disease
Chronic illness
Treatment-related (chemotherapy, radiation, immunosuppression)
Acquired immunodeficiency syndrome (AIDS)
Define:
Aquired Immunodeficiency syndrome (AIDS)
AIDS is the manifestation that occurs when the HIV affects the body to a degree where immune dysfunction results in:
- Opportunistic infections
- Secondary neoplasms
- Neurologic manifestations
How does HIV spread?
Sex w/out a condom
Passed from mother to baby
Sharing injecting equipment
Contaminated blood transfusions and organ transplants
Who is at risk for aquiring HIV?
- Homosexual/bisexual men
- IV drug users
- Hemophiliacs
- Other recipients of blood/blood components
- Heterosexual contacts of the above groups
- Newborns in areas with high female prevalence
HIV Transmission via transfusions
What are some important things to note with this mode of transmission?
Health care professionals do test blood products before administering…BUT
No test is perfect
There is a window of time from exposure to a positive test that gives the opportunity for a “false negative” test
HIV transmission from mother to child
What are the ways this can occur?
In utero through placental –> fetal transfer of virus
During delivery w/ contact of secretions in the birth canal
After birth with ingestion of breast milk
What is the likelihood that you will get infected with….
HIV
Hepatitis C
following a needle stick accident
HIV = 0.3%
Hepatitis C = 30%
What is the classification of HIV?
Retrovirus
Lentivirus family
HIV structure and Content
What is an important capsid protein?
Why do we care?
p24
We can test for p24 antigen
HIV structure and Content
What are important glycoproteins?
Why do we care?
gp120 and gp41
Important for attachment
GOOD DRUG/VACCINE TARGETS
HIV structure and Content
What are the important viral enzymes?
Protease
Reverse transcriptase
Integrase
There are 4 high yield regions Dr. Singh wants us to know about in the HIV-1 genome. What are they?
LTR
gag
env
pol
What is the function of each region listed below in HIV-1?
LTR
gag
env
pol
LTR = initiates transcription, binds transcription factors
gag = encodes for the proteins inside the virus
env = encodes for the surface glycoproteins
pol: encodes the viral enzymes
HIV utilizes a _______ molecule for a receptor and co-receptors may include _________, _________
CD4
Chemokine receptors –> CCR5, CXCR4
Summarize the process of how HIV injects it’s HIV viral DNA into the host
HIV uses a CD4 molecule for a receptor to attach to the membrane, utilizes chemokine receptors to facilitate attachment.
Conformational change occurs
Gp41 acts as a “drill” and penetrates the membrane to facilitate membrane fusion to inject the HIV RNA genome into the host
Describe what occurs once the HIV RNA genome is inside the host cell
Reverse transcriptase synthesizes proviral double stranded DNA from the original RNA genome
Integrase inserts the proviral DNA sequence into the host genome
Host cell activation occurs, triggering LTR to initiate transcription of HIV viral RNA
NF-kB and HIV infection
Antigenic stimulation causes release of NF-kB
What is NF-kB supposed to do?
What does it actually do?
Supposed to: upregulate the T cell response
Actually does: Initiates viral transcription through the LTR
What is responsible for host cell death in HIV infection?
The viral replication within the cell
(Direct cytopathic effect)
What is pyroptosis?
Inflammasome-mediated programmed death pathway
It is responsible for cell death in non-replicating viral infections
Although HIV LOVES CD4+ cells, it can also infect…
Macrophages
Dendritic Cells
Microglia
B Lymphocytes in HIV infection
What is the general response?
Proliferative –> potentially due to secondary infection
Or may become clonal -lymphoma
Describe the pathogenesis of HIV infection
What are the major hallmarks in the timeline of HIV infection?
Day 7-14 = Viremia (viral load spikes)
Following day 16 = Seroconversion, (going from antibody (-) to antibody (+). 70% of people get symptoms
Testing for HIV
What is the first detectable substance?
What test do you use for this?
Viral RNA
Nucleic Acid Test (NAT)
Testing for HIV
What is the second detectable substance?
Protein antigen p24
Testing for HIV
What is the third detectable substance?
Antibody to HIV
What constitutes the diagnosis of AIDS?
Declining CD4+ counts and/or the onset of opportunistic infection or neoplasms
What lab value constitues AIDS?
CD4+ T cell count that is
LESS THAN 200
What diagnosis is likely with these findings?
CNS Toxoplasmosis
AIDS
What is this an example of?
Opportunistic fungal infection that is an AIDS defining illness
(Pneumocystisi jiroveci)
What is the major diarrhea inducing protozoa that Dr. Signh focused on?
Cryptosporidium
What are these?
Kaposi Sarcomas
Vascular tumors that are a manifestation of AIDS
AIDS related lymphomas
What is the primary mechanism to induce lymphomas?
HIV alters B-cell proliferation
OR
Reactivation of viruses (eg Epstein Barr Virus)
Name a concerning AIDS defining illness
CANCER
(cervical/anal cancer)
What co-infection is important in the development of Cancer driven by AIDS?
HPV
Describe Amyloidosis
Protein synthesis and secretion is normally tightly regulated
However
In the cases of mutations, misfolding occurs resulting in insoluble beta-pleated sheets
(if it isn’t broken down, it can accumulate)
(Amyloid)
What is AL?
Light chain diseases
(Amyloid)
What is AA?
Amyloid associated
Where does amyloid tend to manifest?
Kidney
Liver
Brain
Heart
What is the special stain performed to identify amyloid?
Congo red stain
